U.S. patent application number 11/631821 was filed with the patent office on 2008-05-22 for cetp inhibitors.
Invention is credited to Amjad Ali, Yi-Heng Chen, Qiaolin Deng, Adrian A. Dowst, Julianne A. Hunt, Hong Li, Zhijian Lu, Joann M. Napolitano, Nazia Quraishi, Peter J. Sinclair, Cameron J. Smith, Gayle E. Taylor, Christopher F. Thompson.
Application Number | 20080119476 11/631821 |
Document ID | / |
Family ID | 35045145 |
Filed Date | 2008-05-22 |
United States Patent
Application |
20080119476 |
Kind Code |
A1 |
Ali; Amjad ; et al. |
May 22, 2008 |
Cetp Inhibitors
Abstract
Compounds having the structures of Formula I, including
pharmaceutically acceptable salts of the compounds, are CETP
inhibitors, and are useful for raising HDL-cholesterol, reducing
LDL-cholesterol, and for treating or preventing atherosclerosis:
##STR00001## In the compounds of Formula I, B or R.sup.2 is a
phenyl group which has an ortho aryl, heterocyclic,
benzoheterocyclic or benzocycloalkyl substituent, and one other
position on the 5-membered ring has an aromatic, heterocyclic,
cycloalkyl, benzoheterocyclic or benzocycloalkyl substituent
connected directly to the ring or attached to the ring through a
--CH.sub.2--.
Inventors: |
Ali; Amjad; (Freehold,
NJ) ; Napolitano; Joann M.; (Woodbridge, NJ) ;
Deng; Qiaolin; (Edison, NJ) ; Lu; Zhijian;
(Clinton, NJ) ; Sinclair; Peter J.; (Scotch
Plains, NJ) ; Taylor; Gayle E.; (Jersey City, NJ)
; Thompson; Christopher F.; (Clark, NJ) ;
Quraishi; Nazia; (Arlington, MA) ; Smith; Cameron
J.; (Lawrenceville, NJ) ; Hunt; Julianne A.;
(Scotch Palins, NJ) ; Dowst; Adrian A.; (Hoboken,
NJ) ; Chen; Yi-Heng; (Whippany, NJ) ; Li;
Hong; (Edison, NJ) |
Correspondence
Address: |
MERCK AND CO., INC
P O BOX 2000
RAHWAY
NJ
07065-0907
US
|
Family ID: |
35045145 |
Appl. No.: |
11/631821 |
Filed: |
July 1, 2005 |
PCT Filed: |
July 1, 2005 |
PCT NO: |
PCT/US05/23775 |
371 Date: |
January 3, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60585274 |
Jul 2, 2004 |
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60646103 |
Jan 21, 2005 |
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Current U.S.
Class: |
514/252.05 ;
514/255.05; 514/256; 514/340; 514/341; 514/362; 514/372; 514/376;
514/392; 514/424; 514/426; 544/238; 544/333; 544/405; 546/271.4;
546/274.1; 548/134; 548/200; 548/229; 548/323.5; 548/331.5;
548/551 |
Current CPC
Class: |
A61K 31/4168 20130101;
A61K 31/4015 20130101; A61P 9/14 20180101; C07D 263/20 20130101;
C07D 263/24 20130101; A61P 3/00 20180101; A61P 9/00 20180101; A61P
43/00 20180101; A61K 31/427 20130101; C07D 233/32 20130101; A61P
7/00 20180101; C07D 263/26 20130101; C07D 263/04 20130101; A61P
3/04 20180101; A61K 31/4439 20130101; C07D 285/06 20130101; A61K
31/422 20130101; C07D 417/10 20130101; A61P 39/02 20180101; C07D
207/27 20130101; C07D 413/10 20130101; A61K 31/433 20130101; A61K
31/421 20130101; A61P 9/10 20180101; C07D 233/38 20130101; C07D
413/06 20130101; A61K 31/506 20130101; A61K 31/497 20130101; C07F
7/10 20130101; C07D 233/50 20130101; C07D 233/52 20130101; A61K
31/501 20130101; C07D 263/22 20130101; A61P 9/08 20180101; C07D
417/04 20130101; A61K 31/4166 20130101; A61P 3/06 20180101; C07D
285/10 20130101; A61K 45/06 20130101; C07D 207/26 20130101; A61P
9/12 20180101; C07D 413/04 20130101; C07D 401/04 20130101; A61P
3/10 20180101 |
Class at
Publication: |
514/252.05 ;
514/255.05; 514/256; 514/340; 514/341; 514/362; 514/372; 514/376;
514/392; 514/424; 514/426; 544/238; 544/333; 544/405; 546/271.4;
546/274.1; 548/134; 548/200; 548/229; 548/323.5; 548/331.5;
548/551 |
International
Class: |
A61K 31/422 20060101
A61K031/422; A61K 31/40 20060101 A61K031/40; A61K 31/4166 20060101
A61K031/4166; A61K 31/427 20060101 A61K031/427; A61K 31/4439
20060101 A61K031/4439; A61K 31/501 20060101 A61K031/501; A61P 9/10
20060101 A61P009/10; C07D 233/32 20060101 C07D233/32; C07D 263/20
20060101 C07D263/20; C07D 417/10 20060101 C07D417/10; C07D 417/04
20060101 C07D417/04; C07D 413/10 20060101 C07D413/10; C07D 413/04
20060101 C07D413/04; C07D 401/04 20060101 C07D401/04; C07D 285/10
20060101 C07D285/10; C07D 233/44 20060101 C07D233/44; C07D 207/24
20060101 C07D207/24; A61K 31/506 20060101 A61K031/506; A61K 31/497
20060101 A61K031/497; A61K 31/433 20060101 A61K031/433; A61K
31/4168 20060101 A61K031/4168; A61K 31/421 20060101
A61K031/421 |
Claims
1. A compound having Formula I, or a pharmaceutically acceptable
salt thereof, wherein ##STR00479## Y is selected from the group
consisting of --C(.dbd.O)-- and --(CRR.sup.1)--; X is selected from
the group consisting of --O--, --NH--, --N(C.sub.1-C.sub.5alkyl)-,
and --(CRR.sup.6)--; Z is selected from the group consisting of
--C(.dbd.O)--, --S(O).sub.2--, and --C(.dbd.N--R.sup.9)--, wherein
R.sup.9 is selected from the group consisting of H, --CN, and
C.sub.1-C.sub.5alkyl optionally substituted with 1-11 halogens;
Each R is independently selected from the group consisting of H,
--C.sub.1-C.sub.5 alkyl, and halogen, wherein --C.sub.1-C.sub.5
alkyl is optionally substituted with 1-11 halogens; B is selected
from the group consisting of A.sup.1 and A.sup.2, wherein A.sup.1
has the structure: ##STR00480## R.sup.1 and R.sup.6 are each
selected from the group consisting of H, --C.sub.1-C.sub.5 alkyl,
halogen, and --(C(R).sub.2).sub.nA.sup.2, wherein --C.sub.1-C.sub.5
alkyl is optionally substituted with 1-11 halogens; R.sup.2 is
selected from the group consisting of H, --C.sub.1-C.sub.5 alkyl,
halogen, A.sup.1, and --(C(R).sub.2).sub.nA.sup.2, wherein
--C.sub.1-C.sub.5 alkyl is optionally substituted with 1-11
halogens; Wherein one of B and R.sup.2 is A.sup.1; and one of B,
R.sup.1, R.sup.2, and R.sup.6 is A.sup.2 or
--(C(R).sub.2).sub.nA.sup.2; so that the compound of Formula I
comprises one group A.sup.1 and one group A.sup.2; A.sup.3 is
selected from the group consisting of: (a) an aromatic ring
selected from phenyl and naphthyl; (b) a phenyl ring fused to a 5-7
membered non-aromatic cycloalkyl ring, which optionally comprises
1-2 double bonds; (c) a 5-6-membered heterocyclic ring having 14
heteroatoms independently selected from N, S, O, and --N(O)--, and
optionally also comprising 1-3 double bonds and a carbonyl group,
wherein the point of attachment of A.sup.3 to the phenyl ring to
which A.sup.3 is attached is a carbon atom; and (d) a
benzoheterocyclic ring comprising a phenyl ring fused to a
5-6-membered heterocyclic ring having 1-2 heteroatoms-independently
selected from O, N, and --S(O).sub.x-- and optionally 1-2 double
bonds, wherein the point of attachment of A.sup.3 to the phenyl
ring to which A.sup.3 is attached is a carbon atom; A.sup.2 is
selected from the group consisting of: (a) an aromatic ring
selected from phenyl and naphthyl; (b) a phenyl ring fused to a 5-7
membered non-aromatic cycloalkyl ring, which optionally comprises
1-2 double bonds; (c) a 5-6-membered heterocyclic ring having 14
heteroatoms independently selected from N, S, O, and --N(O)--, and
optionally also comprising 1-3 double bonds and a carbonyl group;
(d) a benzoheterocyclic ring comprising a phenyl ring fused to a
5-6-membered heterocyclic ring having 1-2 heteroatoms independently
selected from O, N, and S and optionally 1-2 double bonds; and (e)
a --C.sub.3-C.sub.8 cycloalkyl ring optionally having 1-3 double
bonds; wherein A.sup.3 and A.sup.2 are each optionally substituted
with 1-5 substituent groups independently selected from R.sup.a;
Each R.sup.a is independently selected from the group consisting of
--C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.3-C.sub.8 cycloalkyl optionally
having 1-3 double bonds, --OC.sub.1-C.sub.6alkyl,
--OC.sub.2-C.sub.6 alkenyl, --OC.sub.2-C.sub.6 alkynyl,
--OC.sub.3-C.sub.8 cycloalkyl optionally having 1-3 double bonds,
--C(.dbd.O)C.sub.1-C.sub.6alkyl, --C(.dbd.O)C.sub.3-C.sub.8
cycloalkyl, --C(.dbd.O)H, --CO.sub.2H,
--CO.sub.2C.sub.1-C.sub.6alkyl, --C(.dbd.O)SC.sub.1-C.sub.6alkyl,
--OH, --NR.sup.3R.sup.4, --C(.dbd.O)NR.sup.3R.sup.4,
--NR.sup.3C(.dbd.O)OC.sub.1-C.sub.6 alkyl,
--NR.sup.3C(.dbd.O)NR.sup.3R.sup.4, --S(O).sub.xC.sub.1-C.sub.6
alkyl, --S(O).sub.yNR.sup.3R.sup.4,
--NR.sup.3S(O).sub.yNR.sup.3R.sup.4, halogen, --CN, --NO.sub.2, and
a 5-6-membered heterocyclic ring having 14 heteroatoms
independently selected from N, S, and O, said heterocyclic ring
optionally also comprising a carbonyl group and optionally also
comprising 1-3 double bonds, wherein the point of attachment of
said heterocyclic ring to the ring to which R.sup.a is attached is
a carbon atom, wherein said heterocyclic ring is optionally
substituted with 1-5 substituent groups independently selected from
halogen, --C.sub.1-C.sub.3 alkyl, and --OC.sub.1-C.sub.3 alkyl,
wherein --C.sub.1-C.sub.3 alkyl and --OC.sub.1-C.sub.3 alkyl are
optionally substituted with 1-7 halogens; wherein for compounds in
which R.sup.a is selected from the group consisting of
--C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.3-C.sub.8 cycloalkyl optionally
having 1-3 double bonds, --OC.sub.1-C.sub.6alkyl,
--OC.sub.2-C.sub.6 alkenyl, --OC.sub.2-C.sub.6 alkynyl,
--OC.sub.3-C.sub.8 cycloalkyl optionally having 1-3 double bonds,
--C(.dbd.O)C.sub.1-C.sub.6alkyl, --C(.dbd.O)C.sub.3-C.sub.8
cycloalkyl, --CO.sub.2C.sub.1-C.sub.6alkyl,
--C(.dbd.O)SC.sub.1-C.sub.6alkyl,
--NR.sup.3C(.dbd.O)OC.sub.1-C.sub.6 alkyl, and
--S(O).sub.xC.sub.1-C.sub.6 alkyl, then R.sup.a is optionally
substituted with 1-15 halogens and is optionally also substituted
with 1-3 substituent groups independently selected from (a) --OH,
(b) --CN, (c) --NR.sup.3R.sup.4, (d) --C.sub.3-C.sub.8 cycloalkyl
optionally having 1-3 double bonds and optionally substituted with
1-15 halogens, (e) --OC.sub.1-C.sub.4alkyl optionally substituted
with 1-9 halogens and optionally also substituted with 1-2
substituent groups independently selected from --OC.sub.1-C.sub.2
alkyl and phenyl, (f) --OC.sub.3-C.sub.8 cycloalkyl optionally
having 1-3 double bonds and optionally substituted with 1-15
halogens, (g) --CO.sub.2H, (h) --C(.dbd.O)CH.sub.3, (i)
--CO.sub.2C.sub.1-C.sub.4alkyl which is optionally substituted with
1-9 halogens, and (j) phenyl which is optionally substituted with
1-3 groups independently selected from halogen, --CH.sub.3,
--CF.sub.3, --OCH.sub.3, and --OCF.sub.3; with the proviso that
when B is A.sup.1, and X and Y are --CH.sub.2--, and Z is
--C(.dbd.O)--, and R.sup.2 is phenyl which has a substituent
R.sup.a in the 4-position, wherein R.sup.a is
--OC.sub.1-C.sub.6alkyl which is optionally substituted as
described above, then there are no other R.sup.a substitutents on
R.sup.2 in which R.sup.a is selected from --OH,
--OC.sub.1-C.sub.6alkyl, --OC.sub.2-C.sub.6 alkenyl,
--OC.sub.2-C.sub.6alkynyl, and --OC.sub.3-C.sub.8 cycloalkyl
optionally having 1-3 double bonds, optionally substituted as
described above. n is 0 or 1; p is an integer from 0-4; x is 0, 1,
or 2; y is 1 or 2; R.sup.3 and R.sup.4 are each independently
selected from H, --C.sub.1-C.sub.5 alkyl,
--C(.dbd.O)C.sub.1-C.sub.5 alkyl and --S(O).sub.yC.sub.1-C.sub.5
alkyl, wherein --C.sub.1-C.sub.5 alkyl in all instances is
optionally substituted with 1-11 halogens; and R.sup.5 is selected
from the group consisting of H, --OH, --C.sub.1-C.sub.8 alkyl, and
halogen, wherein --C.sub.1-C.sub.5 alkyl is optionally substituted
with 1-11 halogens.
2. The compound of claim 1, which is selected from the group
consisting of compounds having Formula Ia, Ib, and Id, or a
pharmaceutically acceptable salt thereof: ##STR00481##
3. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein: Y is --(CRR.sup.1)--; R and R.sup.6 are each
independently selected from the group consisting of H and
--C.sub.1-C.sub.5 alkyl, wherein --C.sub.1-C.sub.5 alkyl is
optionally substituted with 1-11 halogens; R.sup.1 is selected from
the group consisting of H, --C.sub.1-C.sub.8 alkyl, and
--(C(R).sub.2).sub.nA.sup.2, wherein --C.sub.1-C.sub.5 alkyl is
optionally substituted with 1-11 halogens; Wherein one of B and
R.sup.2 is A.sup.1; and one of B, R.sup.1, and R.sup.2 is A.sup.2
or --(C(R).sub.2).sub.nA.sup.2; so that the compound of Formula I
comprises one group A.sup.1 and one group A.sup.2; A.sup.3 is
selected from the group consisting of: (a) an aromatic ring
selected from phenyl and naphthyl; (b) a 5-6-membered heterocyclic
ring having 14 heteroatoms independently selected from N, S, O, and
--N(O)--, and optionally also comprising 1-3 double bonds and a
carbonyl group, wherein the point of attachment of A.sup.3 to the
phenyl ring to which A.sup.3 is attached is a carbon atom; and (c)
a benzoheterocyclic ring comprising a phenyl ring fused to a
5-6-membered heterocyclic ring having 1-2 heteroatoms independently
selected from O, N, and --S(O).sub.x-- and optionally 1-2 double
bonds, wherein the point of attachment of A.sup.3 to the phenyl
ring to which A.sup.3 is attached is a carbon atom; A.sup.2 is
selected from the group consisting of: (a) an aromatic ring
selected from phenyl and naphthyl; (b) a 5-6-membered heterocyclic
ring having 14 heteroatoms independently selected from N, S, O, and
--N(O)--, and optionally also comprising 1-3 double bonds and a
carbonyl group; (c) a benzoheterocyclic ring comprising a phenyl
ring fused to a 5-6-membered heterocyclic ring having 1-2
heteroatoms independently selected from O, N, and S and optionally
1-2 double bonds; and (d) a --C.sub.3-C.sub.8 cycloalkyl ring
optionally having 1-3 double bonds; wherein A.sup.3 and A.sup.2 are
each optionally substituted with 1-4 substituent groups
independently selected from R.sup.a; Each R.sup.a is independently
selected from the group consisting of --C.sub.1-C.sub.6 alkyl,
--C.sub.2-C.sub.6 alkenyl, --C.sub.3-C.sub.8 cycloalkyl optionally
having 1-3 double bonds, --OC.sub.1-C.sub.6alkyl,
--C(.dbd.O)C.sub.1-C.sub.6alkyl, --C(.dbd.O)H, --CO.sub.2H,
--CO.sub.2C.sub.1-C.sub.6alkyl, --OH, --NR.sup.3R.sup.4,
--NR.sup.3C(.dbd.O)OC.sub.1-C.sub.6 alkyl,
--S(O).sub.xC.sub.1-C.sub.6 alkyl, halogen, --CN, --NO.sub.2, and a
5-6-membered heterocyclic ring having 1-4 heteroatoms independently
selected from N, S, and O, said heterocyclic ring optionally also
comprising a carbonyl group and optionally also comprising 1-3
double bonds, wherein the point of attachment of said heterocyclic
ring to the ring to which R.sup.a is attached is a carbon atom,
wherein said heterocyclic ring is optionally substituted with 1-5
substituent groups independently selected from halogen,
--C.sub.1-C.sub.3 alkyl, and --OC.sub.1-C.sub.3 alkyl, wherein
--C.sub.1-C.sub.3 alkyl and --OC.sub.1-C.sub.3 alkyl are optionally
substituted with 1-7 halogens; wherein for compounds in which
R.sup.a is selected from the group consisting of --C.sub.1-C.sub.6
alkyl, --C.sub.2-C.sub.6 alkenyl, --C.sub.3-C.sub.8 cycloalkyl
optionally having 1-3 double bonds, --OC.sub.1-C.sub.6alkyl,
--C(.dbd.O)C.sub.1-C.sub.6alkyl, --CO.sub.2C.sub.1-C.sub.6alkyl,
--NR.sub.3C(.dbd.O)OC.sub.1-C.sub.6 alkyl, and
--S(O).sub.xC.sub.1-C.sub.6 alkyl, R.sup.a is optionally
substituted with 1-15 halogens and is optionally also substituted
with one substituent group selected from (a) --OH, (b)
--NR.sup.3R.sup.4, (c) --OC.sub.1-C.sub.4alkyl optionally
substituted with 1-9 halogens and optionally also substituted with
1-2 substituent groups independently selected from
--OC.sub.1-C.sub.2 alkyl and phenyl, and (d) phenyl which is
optionally substituted with 1-3 groups independently selected from
halogen, --CH.sub.3, --CF.sub.3, --OCH.sub.3, and --OCF.sub.3; with
the proviso that when B is A.sup.1, and X and Y are --CH.sub.2--,
and Z is --C(.dbd.O)--, and R.sup.2 is phenyl which has a
substituent R.sup.a in the 4-position, wherein R.sup.a is
--OC.sub.1-C.sub.6alkyl which is optionally substituted as
described above, then there are no other R.sup.a substitutents on
R.sup.2 in which R.sup.a is --OH or --OC.sub.1-C.sub.6alkyl which
is optionally substituted as described above; p is an integer from
0-2; R.sup.3 and R.sup.4 are each independently selected from H and
--C.sub.1-C.sub.5 alkyl, wherein --C.sub.1-C.sub.5 alkyl in all
instances is optionally substituted with 1-11 halogens; and R.sup.5
is selected from the group consisting of H, --OH, and
--C.sub.1-C.sub.5 alkyl, wherein --C.sub.1-C.sub.5 alkyl is
optionally substituted with 1-11 halogens.
4. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein: Y is --(CRR.sup.1)--; Z is selected from the
group consisting of --C(.dbd.O)--, --S(O).sub.2--, and
--C(.dbd.N--R.sup.9)--, wherein R.sup.9 is selected from the group
consisting of H, --CN, and CH.sub.3; Each R is independently
selected from the group consisting of H and C.sub.1-C.sub.2 alkyl;
R.sup.6 is selected from the group consisting of H and
--C.sub.1-C.sub.3 alkyl, wherein C.sub.1-C.sub.3 alkyl is
optionally substituted with 1-5 halogens; R.sup.1 is selected from
the group consisting of H, --C.sub.1-C.sub.3 alkyl, and
--(C(R).sub.2).sub.nA.sup.2, wherein --C.sub.1-C.sub.3 alkyl is
optionally substituted with 1-5 halogens; R.sup.2 is selected from
the group consisting of H, --C.sub.1-C.sub.3 alkyl, A.sup.1, and
--(C(R).sub.2).sub.nA.sup.2, wherein --C.sub.1-C.sub.3 alkyl is
optionally substituted with 1-5 halogens; Wherein one of B and
R.sup.2 is A.sup.1; and one of B, R.sup.1, and R.sup.2 is A.sup.2
or --(C(R).sub.2).sub.nA.sup.2; so that the compound of Formula I
comprises one group A.sup.1 and one group A.sup.2; A.sup.3 is
selected from the group consisting of: (a) phenyl; (b) a
5-6-membered aromatic heterocyclic ring having 1-2 heteroatoms
independently selected from N, S, O, and --N(O)--, wherein the
point of attachment of A.sup.3 to the phenyl ring to which A.sup.3
is attached is a carbon atom; and (c) a benzoheterocyclic ring
comprising a phenyl ring fused to a 5-membered aromatic
heterocyclic ring having 1-2 heteroatoms independently selected
from O, N, and --S(O).sub.x, wherein the point of attachment of
A.sup.3 to the phenyl ring to which A.sup.3 is attached is a carbon
atom; A.sup.2 is selected from the group consisting of: (a) phenyl;
(b) a 5-6-membered heterocyclic ring having 1-4 heteroatoms
independently selected from N, S, O, and --N(O)--, and optionally
also comprising 1-3 double bonds; (c) a benzoheterocyclic ring
comprising a phenyl ring fused to a 5-membered heterocyclic ring
having 1-2 heteroatoms independently selected from O, N, and S; and
(d) a --C.sub.5-C.sub.6 cycloalkyl ring; wherein A.sup.3 and
A.sup.2 are each optionally substituted with 1-4 substituent groups
independently selected from R.sup.a; Each R.sup.a is independently
selected from the group consisting of --C.sub.1-C.sub.4 alkyl,
--C.sub.2-C.sub.4 alkenyl, cyclopropyl, --OC.sub.1-C.sub.2alkyl,
--C(.dbd.O)C.sub.1-C.sub.2alkyl, --C(.dbd.O)H,
--CO.sub.2C.sub.1-C.sub.4alkyl, --OH, --NR.sup.3R.sup.4,
--NR.sup.3C(.dbd.O)OC.sub.1-C.sub.4 alkyl,
--S(O).sub.xC.sub.1-C.sub.2 alkyl, halogen, --CN, --NO.sub.2, and a
5-6-membered heterocyclic ring having 1-2 heteroatoms independently
selected from N, S, and O, wherein the point of attachment of said
heterocyclic ring to the ring to which R.sup.a is attached ring is
a carbon atom, wherein said heterocyclic ring is optionally
substituted with 1-5 substituent groups independently selected from
halogen; wherein for compounds in which R.sup.a is selected from
the group consisting of --C.sub.1-C.sub.4 alkyl, --C.sub.2-C.sub.4
alkenyl, --OC.sub.1-C.sub.2alkyl, --C(.dbd.O)C.sub.1-C.sub.2alkyl,
--CO.sub.2C.sub.1-C.sub.4alkyl, --NR.sup.3C(.dbd.O)OC.sub.1-C.sub.4
alkyl, and --S(O).sub.xC.sub.1-C.sub.2 alkyl, the alkyl group of
R.sup.a is optionally substituted with 1-5 halogens and is
optionally also substituted with one substituent group selected
from (a) --OH, (b) --NR.sup.3R.sup.4, (c) --OCH.sub.3 optionally
substituted with 1-3 fluorine atoms and optionally also substituted
with one phenyl group, and (d) phenyl which is optionally
substituted with 1-3 groups independently selected from halogen,
--CH.sub.3, --CF.sub.3, --OCH.sub.3, and --OCF.sub.3; with the
proviso that when B is A.sup.1, and X and Y are --CH.sub.2--, and Z
is --C(.dbd.O)--, and R.sup.2 is phenyl which has a substituent
R.sup.a in the 4-position, wherein R.sup.a is
--OC.sub.1-C.sub.2alkyl which is optionally substituted as
described above, then there are no other R.sup.a substitutents on
R.sup.2 in which R.sup.a is selected from --OH or
--OC.sub.1-C.sub.2alkyl which is optionally substituted as
described above; p is an integer from 0-2; and R.sup.3, R.sup.4,
and R.sup.5 are each independently selected from H and
--C.sub.1-C.sub.3 alkyl.
5. The compound of claim 4, or a pharmaceutically acceptable salt
thereof, wherein A.sup.3 is selected from the group consisting of
phenyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, pyridyl,
N-oxido-pyridyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl,
benzothienyl, benzothienyl-5-oxide, and benzothienyl-5-dioxide; and
A.sup.2 is selected from the group consisting of phenyl, thienyl,
imidazolyl, thiazolyl, pyrrolyl, pyrazolyl, 1,2,4-triazolyl,
tetrazolyl, benzodioxolyl, pyridyl, N-oxido-pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, cyclopentyl, cyclohexyl, and
tetrahydropyranyl.
6. The compound of claim 5, or a pharmaceutically acceptable salt
thereof, wherein X is selected from the group consisting of --O--,
--NH--, and --N(C.sub.1-C.sub.3alkyl)-; and Z is --C(.dbd.O)--.
7. The compound of claim 4, or a pharmaceutically acceptable salt
thereof, wherein A.sup.2 and A.sup.3 are both phenyl; and R.sup.a
is selected from the group consisting of --C.sub.1-C.sub.4 alkyl
which is optionally substituted with 1-5 fluorine atoms and is
optionally also substituted with one group selected from --OH and
--OCH.sub.3; --OC.sub.1-C.sub.2alkyl, which is optionally
substituted with 1-3 fluorine atoms; --C.sub.2-C.sub.4 alkenyl;
--C.sub.1-C.sub.2 alkyl which is substituted with one group
--NR.sup.3R.sup.4; --C.sub.1-C.sub.2 alkyl-O--C.sub.1-C.sub.2
alkyl-phenyl; cyclopropyl; --C(.dbd.O)H; --OH; --NR.sup.3R.sup.4;
--S(O).sub.xC.sub.1-C.sub.2 alkyl; halogen; --CN; --NO.sub.2; and a
5-6-membered heterocyclic ring comprising 1-2 oxygen atoms which is
optionally substituted with C.sub.1-C.sub.2alkyl; subject to the
same proviso as in claim 4.
8. The compound of claim 7 having Formula Ii, or a pharmaceutically
acceptable salt thereof, wherein: ##STR00482## R.sup.7 is selected
from the group consisting of Cl and --CF.sub.3; Each R.sup.b is
independently selected from the group consisting of
--C.sub.1-C.sub.3 alkyl, --OCH.sub.3, and F; R.sup.1 is selected
from the group consisting of H and --C.sub.1-C.sub.2 alkyl; R.sup.c
is selected from the group consisting of halogen,
--CH.sub.3--CF.sub.3 and --CN; q is 2 or 3; and t is an integer
from 0-2.
9. The compound of claim 7 having Formula Ij, or a pharmaceutically
acceptable salt thereof, wherein: ##STR00483## R.sup.7 is selected
from the group consisting of Cl and --CF.sub.3; Each R.sup.b is
independently selected from the group consisting of
--C.sub.1-C.sub.3 alkyl, --OCH.sub.3, and F; R.sup.1 is selected
from the group consisting of H and --C.sub.1-C.sub.2 alkyl; R.sup.c
is selected from the group consisting of halogen,
--CH.sub.3--CF.sub.3 and --CN; q is 2 or 3; and t is an integer
from 0-2.
10. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein A.sup.3 is phenyl, which is optionally substituted
with 1-4 substituent groups R.sup.a, wherein R.sup.a is
independently selected from --C.sub.1-C.sub.5 alkyl,
--OC.sub.1-C.sub.3alkyl, --CO.sub.2C.sub.1-C.sub.3alkyl,
--CO.sub.2H, halogen, --NR.sup.3R.sup.4,
--C(.dbd.O)C.sub.1-C.sub.3alkyl, --C(.dbd.O)H,
--C(.dbd.O)NR.sup.3R.sup.4, --SC.sub.1-C.sub.3 alkyl,
--C.sub.2-C.sub.3 alkenyl, --CN, --NO.sub.2, and 1,2,4-oxadiazolyl,
wherein --C.sub.1-C.sub.3 alkyl and --C.sub.1-C.sub.5 alkyl in all
occurrences is optionally substituted with 1-6 substituents
independently selected from 1-5 halogens and one --OH group; and
--C.sub.2-C.sub.3 alkenyl is optionally substituted with 1-3
halogens; A.sup.2 is selected from the group consisting of phenyl,
cyclohexyl, and a heterocyclic 5-6 membered ring comprising 1-2
heteroatoms independently selected from O, N, S, and --N(O)-- and
optionally also comprising 1-3 double bonds, wherein A.sup.2 is
optionally substituted with 1-2 substituent groups independently
selected from --C.sub.1-C.sub.4 alkyl, --OC.sub.1-C.sub.3 alkyl,
--NO.sub.2, --CN, --S(O).sub.xC.sub.1-C.sub.3 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.3 alkyl, --NR.sup.3R.sup.4,
--NR.sup.3C(.dbd.O)R.sup.4, --C.sub.2-C.sub.3 alkenyl,
--C(.dbd.O)NR.sup.3R.sup.4, halogen, and pyridyl, wherein
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.4 alkyl, and
C.sub.2-C.sub.3alkenyl in all instances is optionally substituted
with 1-3 halogens, with the proviso that when B is A.sup.1, and X
and Y are --CH.sub.2--, and Z is --C(.dbd.O)--, and R.sup.2 is
phenyl which has a substituent R.sup.a in the 4-position in which
R.sup.a is --OC.sub.1-C.sub.3alkyl which is optionally substituted
as described above, then there are no other R.sup.a substitutents
on R.sup.2 in which R.sup.a is --OC.sub.1-C.sub.3alkyl optionally
substituted as described above; R.sup.3 and R.sup.4 are each
independently selected from H and --C.sub.1-C.sub.3 alkyl; and p is
0-2.
11. The compound of claim 10, or a pharmaceutically acceptable salt
thereof, wherein A.sup.1 is ##STR00484## R.sup.7 and R.sup.8 are
each independently selected from the group consisting of H,
halogen, --NR.sup.3R.sup.4, --C.sub.1-C.sub.3 alkyl,
--OC.sub.1-C.sub.3 alkyl, --CN, --NO.sub.2, and pyridyl, wherein
C.sub.1-C.sub.3 alkyl in all instances is optionally substituted
with 1-3 halogens; and A.sup.2 is selected from the group
consisting of phenyl, pyridyl, and cyclohexyl, wherein A.sup.2 is
optionally substituted with 1-2 substituents independently selected
from --C.sub.1-C.sub.4 alkyl, --OC.sub.1-C.sub.3 alkyl, --NO.sub.2,
--CN, and halogen, wherein C.sub.1-C.sub.4 alkyl and
C.sub.1-C.sub.3 alkyl in all uses is optionally substituted with
1-3 halogens, with the proviso that when B is A.sup.1, and X and Y
are --CH.sub.2--, and Z is --C(.dbd.O)--, and R.sup.2 is phenyl
which has a substituent R.sup.a in the 4-position, wherein R.sup.a
is --OC.sub.1-C.sub.3alkyl which is optionally substituted with 1-3
halogens, then there are no other R.sup.a substitutents on R.sup.2
in which R.sup.a is selected from --OC.sub.1-C.sub.3alkyl which is
optionally substituted with 1-3 halogens.
12. The compound of claim 11, or a pharmaceutically acceptable salt
thereof, wherein A.sup.1 is ##STR00485## R.sup.7 is selected from
the group consisting of H, halogen, --NR.sup.3R.sup.4,
--C.sub.1-C.sub.3 alkyl, --OC.sub.1-C.sub.3 alkyl, --CN,
--NO.sub.2, and pyridyl, wherein C.sub.1-C.sub.3 alkyl in all
instances is optionally substituted with 1-3 halogens; and R.sup.8
is selected from the group consisting of H, halogen, --CH.sub.3,
--CF.sub.3, --OCH.sub.3, and --OCF.sub.3.
13. A pharmaceutical composition comprising the compound of claim
1, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
14. The compound of claim 4, which is selected from the group
consisting of the following compounds, or a pharmaceutically
acceptable salt thereof: ##STR00486## ##STR00487## ##STR00488##
##STR00489## ##STR00490## ##STR00491## ##STR00492##
15. The compound of claim 4, which is selected from the group
consisting of compounds with the formula (a) to (c), or a
pharmaceutically acceptable salt thereof: ##STR00493## wherein R is
selected from the group consisting of ##STR00494## ##STR00495##
##STR00496## wherein R is selected from the group consisting of
##STR00497## wherein R is selected from the group consisting of
##STR00498##
16. The compound of claim 4, which is selected from the group
consisting of the following compounds, or a pharmaceutically
acceptable salt thereof: ##STR00499## ##STR00500## ##STR00501##
##STR00502## ##STR00503## ##STR00504## ##STR00505## ##STR00506##
##STR00507## ##STR00508## ##STR00509## ##STR00510## ##STR00511##
##STR00512## ##STR00513## ##STR00514## ##STR00515## ##STR00516##
##STR00517## ##STR00518## ##STR00519##
17. The compound of claim 4, selected from the group consisting of
compounds having the formula (a) to (k), or a pharmaceutically
acceptable salt thereof: ##STR00520## wherein A.sup.3, A.sup.2, and
Z for the compounds (1) to (6) are selected from the group
consisting of: TABLE-US-00021 A.sup.3 A.sup.2 Z (1) ##STR00521##
##STR00522## CO (2) ##STR00523## ##STR00524## CO (3) ##STR00525##
##STR00526## CO (4) ##STR00527## ##STR00528## CO (5) ##STR00529##
##STR00530## CO and (6) ##STR00531## ##STR00532## SO.sub.2; (b)
##STR00533##
wherein A.sup.3 is selected from the group consisting of:
##STR00534## ##STR00535## ##STR00536## wherein A3 and A2 for the
compounds (1) to (6) are selected from the group consisting of:
TABLE-US-00022 A.sup.3 A.sup.2 (1) ##STR00537## ##STR00538## (2)
##STR00539## ##STR00540## (3) ##STR00541## ##STR00542## (4)
##STR00543## ##STR00544## (5) ##STR00545## ##STR00546## (6)
##STR00547## ##STR00548## (d) ##STR00549##
wherein R is selected from the group consisting of ##STR00550##
##STR00551## ##STR00552## ##STR00553## ##STR00554## wherein R is Et
or n-Pr; ##STR00555## wherein R and A3 for the compounds (1) to (4)
are selected from the group consisting of TABLE-US-00023 R A.sup.3
(1) ##STR00556## ##STR00557## (2) ##STR00558## ##STR00559## (3)
##STR00560## ##STR00561## (4) ##STR00562## ##STR00563## (g)
##STR00564##
wherein R is selected from the group consisting of: ##STR00565##
wherein A.sup.2 is selected from the group consisting of
##STR00566## wherein R is selected from the group consisting of
##STR00567## wherein A.sup.3 is selected from the group consisting
of: ##STR00568## wherein A.sup.3, R.sub.2 and R.sub.3 for the
compounds (1) to (3) are selected from the group consisting of:
TABLE-US-00024 A.sup.3 R.sub.2 R.sub.3 (1) ##STR00569## Et
##STR00570## (2) ##STR00571## Et ##STR00572## (3) ##STR00573## Et
##STR00574##
18. A method of treating atherosclerosis in a patient in need of
treatment comprising the administration of a therapeutically
effective amount of the compound of claim 1 to said patient, or a
pharmaceutically acceptable salt thereof.
19. A method of raising HDL-C in a patient in need of treatment
comprising the administration of a therapeutically effective amount
of the compound of claim 1 to said patient, or a pharmaceutically
acceptable salt thereof.
20. (canceled)
21. A pharmaceutical composition comprising the compound of claim 1
or a pharmaceutically acceptable salt thereof, a pharmaceutically
acceptable carrier, and one or more active ingredients selected
from the group consisting of: (i) HMG-CoA reductase inhibitors;
(ii) bile acid sequestrants; (iii) niacin and related compounds;
(iv) PPAR.alpha. agonists; (v) cholesterol absorption inhibitors;
(vi) acyl CoA:cholesterol acyltransferase (ACAT) inhibitors; (vii)
phenolic anti-oxidants; (viii) microsomal triglyceride transfer
protein (MTP)/ApoB secretion inhibitors; (ix) anti-oxidant
vitamins; (x) thyromimetics; (xi) LDL (low density lipoprotein)
receptor inducers; (xii) platelet aggregation inhibitors; (xiii)
vitamin B12 (also known as cyanocobalamin); (xiv) folic acid or a
pharmaceutically acceptable salt or ester thereof; (xv) FXR and LXR
ligands; (xvi) agents that enhance ABCA1 gene expression; and
(xvii) ileal bile acid transporters.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a class of chemical compounds that
inhibit cholesterol ester transfer protein (CETP) and therefore may
have utility in the treatment and prevention of
atherosclerosis.
BACKGROUND OF THE INVENTION
[0002] Atherosclerosis and its clinical consequences, coronary
heart disease (CHD), stroke and peripheral vascular disease,
represent a truly enormous burden to the health care systems of the
industrialized world. In the United States alone, approximately 13
million patients have been diagnosed with CHD, and greater than one
half million deaths are attributed to CHD each year. Further, this
toll is expected to grow over the next quarter century as an
epidemic in obesity and diabetes continues to grow.
[0003] It has long been recognized that in mammals, variations in
circulating lipoprotein profiles correlate with the risk of
atherosclerosis and CHD. The clinical success of HMG-CoA Reductase
inhibitors, especially the statins, in reducing coronary events is
based on the reduction of circulating Low Density Lipoprotein
cholesterol (LDL-C), levels of which correlate directly with
increased risk for atherosclerosis. More recently, epidemiologic
studies have demonstrated an inverse relationship between High
Density Lipoprotein cholesterol (HDL-C) levels and atherosclerosis,
leading to the conclusion that low serum HDL-C levels are
associated with an increased risk for CHD.
[0004] Metabolic control of lipoprotein levels is a complex and
dynamic process involving many factors. One important metabolic
control in man is the cholesteryl ester transfer protein (CETP), a
plasma glycoprotein that catalyzes the movement of cholesteryl
esters from HDL to the apoB containing lipoproteins, especially
VLDL (see Hesler, C. B., et. al. (1987) Purification and
characterization of human plasma cholesteryl ester transfer
protein. J. Biol. Chem. 262(5), 2275-2282)). Under physiological
conditions, the net reaction is a heteroexchange in which CETP
carries triglyceride to HDL from the apoB lipoproteins and
transports cholesterol ester from HDL to the apoBliprotein.
[0005] In humans, CETP plays a role in reverse cholesterol
transport, the process whereby cholesterol is returned to the liver
from peripheral tissues. Intriguingly, many animals do not possess
CETP, including animals that have high HDL levels and are known to
be resistant to coronary heart disease, such as rodents (see
Guyard-Dangremont, V., et. al., (1998) Phospholipid and cholesteryl
ester transfer activities in plasma from 14 vertebrate species.
Relation to atherogenesis susceptibility, Comp. Biochem. Physiol. B
Biochem. Mol. Biol. 120(3), 517-525). Numerous epidemiologic
studies correlating the effects of natural variation in CETP
activity with respect to coronary heart disease risk have been
performed, including studies on a small number of known human null
mutations (see Hirano, K.-I., Yamashita, S, and Matsuzawa, Y.
(2000) Pros and cons of inhibiting cholesteryl ester transfer
protein, Curr. Opin. Lipidol. 11(6), 589-596). These studies have
clearly demonstrated an inverse correlation between plasma HDL-C
concentration and CETP activity (see Inazu, A., et. al. (2000)
Cholesteryl ester transfer protein and atherosclerosis, Curr. Opin.
Lipidol. 11(4), 389-396), leading to the hypothesis that
pharmacologic inhibition of CETP lipid transfer activity may be
beneficial to humans by increasing levels of HDL-C while lowering
those of LDL.
[0006] Despite the significant therapeutic advance that statins
such as simvastatin (ZOCOR.RTM.) represent, statins only achieve a
risk reduction of approximately one-third in the treatment and
prevention of atherosclerosis and ensuing atherosclerotic disease
events. Currently, few pharmacologic therapies are available that
favorably raise circulating levels of HDL-C. Certain statins and
some fibrates offer modest HDL-C gains. Niacin, which provides the
most effective therapy for raising HDL-C that has been clinically
documented, suffers from patient compliance issues, due in part to
side effects such as flushing. An agent that safely and effectively
raises HDL cholesterol levels can answer a significant, but as yet
unmet medical need by offering a means of pharmacologic therapy
that can significantly improve circulating lipid profiles through a
mechanism that is complementary to existing therapies.
[0007] New classes of chemical compounds that inhibit CETP are
being investigated at several pharmaceutical companies or are in
clinical trials. No CETP inhibitors are currently being marketed.
New compounds are needed so that one or more pharmaceutical
compounds can be found that are safe and effective. The novel
compounds described herein are very potent CETP inhibitors. Some
structurally similar compounds are found in WO2003/032981.
SUMMARY OF THE INVENTION
[0008] Compounds having Formula I, including pharmaceutically
acceptable salts of the compounds, are CETP inhibitors, having the
utilities described below:
##STR00002##
[0009] In the compounds of Formula I,
[0010] Y is selected from --C(.dbd.O)-- and --(CRR.sup.1)--;
[0011] X is selected from --O--, --NH--,
--N(C.sub.1-C.sub.5alkyl)-, and --(CRR.sup.6)--;
[0012] Z is selected from --C(.dbd.O)--, --S(O).sub.2--, and
--C(.dbd.N--R.sup.9)--, wherein R.sup.9 is selected from the group
consisting of H, --CN, and --C.sub.1-C.sub.5alkyl optionally
substituted with 1-11 halogens;
[0013] Each R is independently selected from the group consisting
of H, --C.sub.1-C.sub.5 alkyl, and halogen, wherein
--C.sub.1-C.sub.5 alkyl is optionally substituted with 1-11
halogens;
[0014] B is selected from the group consisting of A.sup.1 and
A.sup.2, wherein A.sup.1 has the structure:
##STR00003##
[0015] R.sup.1 and R.sup.6 are each independently selected from H,
--C.sub.1-C.sub.5 alkyl, halogen, and --(C(R).sub.2).sub.nA.sup.2,
wherein --C.sub.1-C.sub.5 alkyl is optionally substituted with 1-11
halogens;
[0016] R.sup.2 is selected from the group consisting of H,
--C.sub.1-C.sub.5 alkyl, halogen, A.sup.1, and
--(C(R).sub.2).sub.nA.sup.2, wherein --C.sub.1-C.sub.5 alkyl is
optionally substituted with 1-11 halogens;
[0017] Wherein one of B and R.sup.2 is A.sup.1; and one of B,
R.sup.1, R.sup.2, and R.sup.6 is A.sup.2 or
--(C(R).sub.2).sub.nA.sup.2; so that the compound of Formula I
comprises one group A.sup.1 and one group A.sup.2;
[0018] A.sup.3 is selected from the group consisting of: [0019] (a)
an aromatic ring selected from phenyl and naphthyl; [0020] (b) a
phenyl ring fused to a 5-7 membered non-aromatic cycloalkyl ring,
which optionally comprises 1-2 double bonds; [0021] (c) a
5-6-membered heterocyclic ring having 1-4 heteroatoms independently
selected from N, S, O, and --N(O)--, and optionally also comprising
1-3 double bonds and a carbonyl group, wherein the point of
attachment of A.sup.3 to the phenyl ring to which A.sup.3 is
attached is a carbon atom; and [0022] (d) a benzoheterocyclic ring
comprising a phenyl ring fused to a 5-6-membered heterocyclic ring
having 1-2 heteroatoms independently selected from O, N, and S, and
optionally also having 1-2 double bonds (in addition to the double
bond of the fused phenyl ring) wherein the point of attachment of
A.sup.3 to the phenyl ring to which A.sup.3 is attached is a carbon
atom;
[0023] A.sup.2 is selected from the group consisting of: [0024] (a)
an aromatic ring selected from phenyl and naphthyl; [0025] (b) a
phenyl ring fused to a 5-7 membered non-aromatic cycloalkyl ring,
which optionally comprises 1-2 double bonds; [0026] (c) a
5-6-membered heterocyclic ring having 1-4 heteroatoms independently
selected from N, S, O, and --N(O)--, and optionally also comprising
1-3 double bonds and a carbonyl group; [0027] (d) a
benzoheterocyclic ring comprising a phenyl ring fused to a
5-6-membered heterocyclic ring having 1-2 heteroatoms independently
selected from O, N, and S, and optionally also having 1-2 double
bonds (in addition to the double bond of the fused phenyl ring);
and [0028] (e) a --C.sub.3-C.sub.8 cycloalkyl ring optionally
having 1-3 double bonds;
[0029] wherein A.sup.3 and A.sup.2 are each optionally substituted
with 1-5 substituent groups independently selected from
R.sup.a;
[0030] Each R.sup.a is independently selected from the group
consisting of --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.3-C.sub.8 cycloalkyl optionally
having 1-3 double bonds, --OC.sub.1-C.sub.6alkyl,
--OC.sub.2-C.sub.6 alkenyl, --OC.sub.2-C.sub.6 alkynyl,
--OC.sub.3-C.sub.8 cycloalkyl optionally having 1-3 double bonds,
--C(.dbd.O)C.sub.1-C.sub.6alkyl, --C(.dbd.O)C.sub.3-C.sub.8
cycloalkyl, --C(.dbd.O)H, --CO.sub.2H,
--CO.sub.2C.sub.1-C.sub.6alkyl, --C(.dbd.O)SC.sub.1-C.sub.6alkyl,
--OH, --NR.sup.3R.sup.4, --C(.dbd.O)NR.sup.3R.sup.4,
--NR.sup.3C(.dbd.O)OC.sub.1-C.sub.6 alkyl,
--NR.sup.3C(.dbd.O)NR.sup.3R.sup.4, --S(O).sub.xC.sub.1-C.sub.6
alkyl, --S(O).sub.yNR.sup.3R.sup.4,
--NR.sup.3S(O).sub.yNR.sup.3R.sup.4, halogen, --CN, --NO.sub.2, and
a 5-6-membered heterocyclic ring having 1-4 heteroatoms
independently selected from N, S, and O, said heterocyclic ring
optionally also comprising a carbonyl group and optionally also
comprising 1-3 double bonds, wherein the point of attachment of
said heterocyclic ring to the ring to which R.sup.a is attached is
a carbon atom, wherein said heterocyclic ring is optionally
substituted with 1-5 substituent groups independently selected from
halogen, --C.sub.1-C.sub.3 alkyl, and --OC.sub.1-C.sub.3 alkyl,
wherein --C.sub.1-C.sub.3 alkyl and --OC.sub.1-C.sub.3 alkyl are
optionally substituted with 1-7 halogens;
[0031] wherein for compounds in which R.sup.a is selected from the
group consisting of --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6
alkenyl, --C.sub.2-C.sub.6 alkynyl, --C.sub.3-C.sub.8 cycloalkyl
optionally having 1-3 double bonds, --OC.sub.1-C.sub.6alkyl,
--OC.sub.2-C.sub.6 alkenyl, --OC.sub.2-C.sub.6 alkynyl,
--OC.sub.3-C.sub.8 cycloalkyl optionally having 1-3 double bonds,
--C(.dbd.O)C.sub.1-C.sub.6alkyl, --C(.dbd.O)C.sub.3-C.sub.8
cycloalkyl, --CO.sub.2C.sub.1-C.sub.6alkyl,
--C(.dbd.O)SC.sub.1-C.sub.6alkyl,
--NR.sup.3C(.dbd.O)OC.sub.1-C.sub.6 alkyl, and
--S(O).sub.xC.sub.1-C.sub.6 alkyl, R.sup.a is optionally
substituted with 1-15 halogens and is optionally also substituted
with 1-3 substituent groups independently selected from (a) --OH,
(b) --CN, (c) --NR.sup.3R.sup.4, (d) --C.sub.3-C.sub.8 cycloalkyl
optionally having 1-3 double bonds and optionally substituted with
1-15 halogens, (e) --OC.sub.1-C.sub.4alkyl optionally substituted
with 1-9 halogens and optionally also substituted with 1-2
substituent groups independently selected from --OC.sub.1-C.sub.2
alkyl and phenyl, (f) --OC.sub.3-C.sub.8 cycloalkyl optionally
having 1-3 double bonds and optionally substituted with 1-15
halogens, (g) --CO.sub.2H, (h) --C(.dbd.O)CH.sub.3, (i)
--CO.sub.2C.sub.1-C.sub.4alkyl which is optionally substituted with
1-9 halogens, and (j) phenyl which is optionally substituted with
1-3 groups independently selected from halogen, --CH.sub.3,
--CF.sub.3, --OCH.sub.3, and --OCF.sub.3;
[0032] with the proviso that when B is A.sup.1, and X and Y are
--CH.sub.2--, and Z is --C(.dbd.O)--, and R.sup.2 is phenyl which
has a substituent R.sup.a in the 4-position, wherein R.sup.a is
--OC.sub.1-C.sub.6alkyl which is optionally substituted as
described above, then there are no other R.sup.a substitutents on
R.sup.2 in which R.sup.a is selected from --OH,
--OC.sub.1-C.sub.6alkyl, --OC.sub.2-C.sub.6 alkenyl,
--OC.sub.2-C.sub.6 alkynyl, and --OC.sub.3-C.sub.8 cycloalkyl
optionally having 1-3 double bonds, all of which are optionally
substituted as described above.
[0033] n is 0 or 1;
[0034] p is an integer from 0-4;
[0035] x is 0, 1, or 2;
[0036] y is 1 or 2;
[0037] R.sup.3 and R.sup.4 are each independently selected from H,
--C.sub.1-C.sub.5 alkyl, --C(.dbd.O)C.sub.1-C.sub.5 alkyl and
--S(O).sub.yC.sub.1-C.sub.5 alkyl, wherein --C.sub.1-C.sub.5 alkyl
in all instances is optionally substituted with 1-11 halogens;
and
[0038] R.sup.5 is selected from the group consisting of H, --OH,
--C.sub.1-C.sub.5 alkyl, and halogen, wherein --C.sub.1-C.sub.5
alkyl is optionally substituted with 1-11 halogens.
[0039] In the compounds of Formula I and in subsequent compounds,
alkyl, alkenyl, and alkynyl groups can be either linear or
branched, unless otherwise stated.
DETAILED DESCRIPTION OF THE INVENTION
[0040] Many of compounds of this invention have a structure in
accordance with Formula Ia, written below, or a pharmaceutically
acceptable salt thereof:
##STR00004##
[0041] Many compounds of the invention have the structure of
Formula Ib, or a pharmaceutically acceptable salt thereof:
##STR00005##
[0042] Many other compounds have the structure of Formula Ic or a
pharmaceutically acceptable salt thereof:
##STR00006##
[0043] Still other compounds of the invention have a structure in
accordance with Formula Id, or a pharmaceutically acceptable salt
thereof:
##STR00007##
In a subset of the compounds of Formula I,
[0044] Each R.sup.a is independently selected from the group
consisting of --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.3-C.sub.8 cycloalkyl optionally
having 1-3 double bonds, --OC.sub.1-C.sub.6alkyl,
--OC.sub.2-C.sub.6 alkenyl, --OC.sub.2-C.sub.6 alkynyl,
--OC.sub.3-C.sub.8 cycloalkyl optionally having 1-3 double bonds,
--C(.dbd.O)C.sub.1-C.sub.6alkyl, --C(.dbd.O)C.sub.3-C.sub.8
cycloalkyl, --C(.dbd.O)H, --CO.sub.2H,
--CO.sub.2C.sub.1-C.sub.6alkyl, --C(.dbd.O)SC.sub.1-C.sub.6alkyl,
--NR.sup.3R.sup.4, --C(.dbd.O)NR.sup.3R.sup.4,
--NR.sup.3C(.dbd.O)OC.sub.1-C.sub.6 alkyl,
--NR.sup.3C(.dbd.O)NR.sup.3R.sup.4, --S(O).sub.xC.sub.1-C.sub.6
alkyl, --S(O).sub.yNR.sup.3R.sup.4,
--NR.sup.3S(O).sub.yNR.sup.3R.sup.4, halogen, --CN, --NO.sub.2, and
a 5-6-membered heterocyclic ring having 1-4 heteroatoms
independently selected from N, S, and O, said heterocyclic ring
optionally also comprising a carbonyl group and optionally also
comprising 1-3 double bonds, wherein the point of attachment of
said heterocyclic ring to the attached ring is a carbon atom,
wherein said heterocyclic ring is optionally substituted with 1-5
substituent groups independently selected from halogen,
--C.sub.1-C.sub.3 alkyl, and --OC.sub.1-C.sub.3 alkyl, wherein
--C.sub.1-C.sub.3 alkyl and --OC.sub.1-C.sub.3 alkyl are optionally
substituted with 1-7 halogens;
[0045] wherein for compounds in which R.sup.a is selected from the
group consisting of --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6
alkenyl, --C.sub.2-C.sub.6 alkynyl, --C.sub.3-C.sub.8 cycloalkyl
optionally having 1-3 double bonds, --OC.sub.1-C.sub.6alkyl,
--OC.sub.2-C.sub.6 alkenyl, --OC.sub.2-C.sub.6 alkynyl,
--OC.sub.3-C.sub.8 cycloalkyl optionally having 1-3 double bonds,
--C(.dbd.O)C.sub.1-C.sub.6alkyl, --C(.dbd.O)C.sub.3-C.sub.8
cycloalkyl, --CO.sub.2C.sub.1-C.sub.6alkyl,
--C(.dbd.O)SC.sub.1-C.sub.6alkyl,
--NR.sup.3C(.dbd.O)OC.sub.1-C.sub.6 alkyl, and
--S(O).sub.xC.sub.1-C.sub.6 alkyl, then R.sup.a is optionally
substituted with 1-15 halogens and is optionally also substituted
with 1-3 substituent groups independently selected from (a) --OH,
(b) --CN, (c) --NR.sup.3R.sup.4, (d) --C.sub.3-C.sub.8 cycloalkyl
optionally having 1-3 double bonds and optionally substituted with
1-15 halogens, (e) --OC.sub.1-C.sub.4alkyl optionally substituted
with 1-9 halogens and optionally also substituted with 1-2
substituent groups independently selected from --OC.sub.1-C.sub.2
alkyl, (f) --OC.sub.3-C.sub.8 cycloalkyl optionally having 1-3
double bonds and optionally substituted with 1-15 halogens, (g)
--CO.sub.2H, (h) --C(.dbd.O)CH.sub.3, and (i)
--CO.sub.2C.sub.1-C.sub.4alkyl which is optionally substituted with
1-9 halogens;
[0046] with the proviso that when B is A.sup.1, and X and Y are
--CH.sub.2--, and Z is --C(.dbd.O)--, and R.sup.2 is phenyl which
has a substituent R.sup.a in the 4-position, wherein R.sup.a is
--OC.sub.1-C.sub.6alkyl which is optionally substituted with 1-11
halogens, then there are no other R.sup.a substitutents on R.sup.2
in which R.sup.a is selected from --OC.sub.1-C.sub.6alkyl,
--OC.sub.2-C.sub.6 alkenyl, --OC.sub.2-C.sub.6 alkynyl, and
--OC.sub.3-C.sub.8 cycloalkyl optionally having 1-3 double bonds,
all of which are optionally substituted as described above.
[0047] In many of the compounds of Formula I, Ia, Ib, Ic and Id,
and pharmaceutically acceptable salts thereof,
[0048] A.sup.3 is phenyl, which is optionally substituted with 1-4
substituent groups R.sup.a, wherein R.sup.a is independently
selected from --C.sub.1-C.sub.5 alkyl, --OC.sub.1-C.sub.3alkyl,
--CO.sub.2C.sub.1-C.sub.3alkyl, --CO.sub.2H, halogen,
--NR.sup.3R.sup.4, --C(.dbd.O)C.sub.1-C.sub.3alkyl, --C(.dbd.O)H,
--C(.dbd.O)NR.sup.3R.sup.4, --SC.sub.1-C.sub.3 alkyl,
--C.sub.2-C.sub.3 alkenyl, --CN, --NO.sub.2, and 1,2,4-oxadiazolyl,
wherein --C.sub.1-C.sub.3 alkyl and --C.sub.1-C.sub.5 alkyl in all
occurrences is optionally substituted with 1-6 substituents
independently selected from 1-5 halogens and one --OH group; and
--C.sub.2-C.sub.3 alkenyl is optionally substituted with 1-3
halogens.
[0049] In many of the compounds of Formula I, Ia, Ib, Ic, and Id,
and pharmaceutically acceptable salts thereof,
[0050] A.sup.2 is selected from the group consisting of phenyl,
cyclohexyl, and a heterocyclic 5-6 membered ring comprising 1-2
heteroatoms independently selected from O, N, S, and --N(O)-- and
optionally also comprising 1-3 double bonds, wherein A.sup.2 is
optionally substituted with 1-2 substituent groups independently
selected from --C.sub.1-C.sub.4 alkyl, --OC.sub.1-C.sub.3 alkyl,
--NO.sub.2, --CN, --S(O).sub.xC.sub.1-C.sub.3 alkyl,
--NHS(O).sub.2C.sub.1-C.sub.3 alkyl, --NR.sup.3R.sup.4,
--NR.sup.3C(.dbd.O)R.sup.4, --C.sub.2-C.sub.3 alkenyl,
--C(.dbd.O)NR.sup.3R.sup.4, halogen, and pyridyl, wherein
C.sub.1-C.sub.3 alkyl, CIC.sub.4 alkyl, and C.sub.2-C.sub.3alkenyl
in all instances is optionally substituted with 1-3 halogens, with
the proviso that for compounds of formula Ia, when B is A.sup.1,
and X and Y are --CH.sub.2--, and Z is --C(.dbd.O)--, and R.sup.2
is phenyl, then the number of R.sup.a groups on R.sup.2 that are
selected from --OC.sub.1-C.sub.3alkyl which are optionally
substituted is 0 or 1.
[0051] In many of the compounds of Formula I, Ia, Ib, Ic, and Id,
and pharmaceutically acceptable salts thereof, R.sup.3 and R.sup.4
are each independently selected from H and --C.sub.1-C.sub.3
alkyl.
[0052] In many of the compounds of Formula I, Ia, Ib, Ic, and Id,
and pharmaceutically acceptable salts thereof, p is 0-2.
[0053] In subgroups of compounds of Formula I, including
pharmaceutically acceptable salts thereof, A.sup.1 is
##STR00008##
[0054] Wherein R.sup.7 and R.sup.8 are each independently selected
from the group consisting of H, halogen, --NR.sup.3R.sup.4,
--C.sub.1-C.sub.3 alkyl, --OC.sub.1-C.sub.3 alkyl, --CN,
--NO.sub.2, and pyridyl, wherein C.sub.1-C.sub.3 alkyl in all
instances is optionally substituted with 1-3 halogens.
[0055] In sub-groups of the compounds of formula I, A.sup.2 is
selected from the group consisting of phenyl, pyridyl, and
cyclohexyl, wherein A.sup.2 is optionally substituted with 1-2
substituents independently selected from --C.sub.1-C.sub.4 alkyl,
--OC.sub.1-C.sub.4 alkyl, --NO.sub.2, --CN, and halogen, wherein
C.sub.1-C.sub.4 alkyl in all uses is optionally substituted with
1-3 halogens, with the proviso that for compounds of formula I,
when B is A1, and X and Y are CH.sub.2, and Z is --(C.dbd.O)--, and
R.sup.2 is phenyl, then the number of R.sup.a groups on R.sup.2
that are selected from --OC.sub.1-C.sub.4alkyl optionally
substituted with 1-3 halogens is 0 or 1.
[0056] In other subgroups, A.sup.2 is optionally substituted with
1-2 substituent groups independently selected from halogen,
--C.sub.1-C.sub.4 alkyl, and --CN, wherein --C.sub.1-C.sub.4 alkyl
is optionally substituted with 1-3 halogens.
[0057] In many embodiments of the invention, as described above,
including pharmaceutically acceptable salts,
[0058] A.sup.1 is
##STR00009##
[0059] Wherein R.sup.7 is selected from H, halogen,
--NR.sup.3R.sup.4, --C.sub.1-C.sub.3 alkyl, --OC.sub.1-C.sub.3
alkyl, --CN, --NO.sub.2, and pyridyl, wherein C.sub.1-C.sub.3 alkyl
in all instances is optionally substituted with 1-3 halogens;
and
[0060] R.sup.8 is selected from the group consisting of H, halogen,
--CH.sub.3, --CF.sub.3, --OCH.sub.3, and --OCF.sub.3.
[0061] In many preferred embodiments of this invention, A.sup.3 is
phenyl, which is substituted with 1-3 substituents independently
selected from C.sub.1-C.sub.4alkyl, OC.sub.1-C.sub.4alkyl, --CN,
Cl, F, --C(.dbd.O)CH.sub.3, --CH.dbd.CH.sub.2, --CO.sub.2H,
--CO.sub.2CH.sub.3, --S--CH.sub.3, --S(O)CH.sub.3,
--S(O).sub.2CH.sub.3, and --C(.dbd.O)NR.sup.3R.sup.4, wherein
C.sub.1-C.sub.4alkyl and --OC.sub.1-C.sub.4alkyl are optionally
substituted with 1-5 F substituents and optionally also substituted
with one group --OH.
[0062] In other embodiments, A3 is phenyl which is optionally
substituted with 1-3 substituents independently selected from the
group consisting of Cl, F, --C.sub.1-C.sub.4 alkyl, and
--OC.sub.1-C.sub.4 alkyl, wherein --C.sub.1-C.sub.4 alkyl and
--OC.sub.1-C.sub.4 alkyl are optionally substituted with 1-5 F.
[0063] A preferred value of Y is --(CRR.sup.1)--.
[0064] In some embodiments, R and R.sup.6 are each independently
selected from the group consisting of H and --C.sub.1-C.sub.5
alkyl, wherein --C.sub.1-C.sub.5 alkyl is optionally substituted
with 1-11 halogens. In subsets, of these embodiments, R.sup.1 is
selected from the group consisting of H, --C.sub.1-C.sub.5 alkyl,
and --(C(R).sub.2).sub.nA.sup.2, wherein --C.sub.1-C.sub.5 alkyl is
optionally substituted with 1-11 halogens. In these, one of B and
R.sup.2 is A.sup.1; and one of B, R.sup.1, and R.sup.2 is A.sup.2
or --(C(R).sub.2).sub.nA.sup.2; so that the compound of Formula I
comprises one group A.sup.1 and one group A.sup.2.
[0065] In subgroups of compounds, A.sup.3 is selected from the
group consisting of: [0066] (a) an aromatic ring selected from
phenyl and naphthyl; [0067] (b) a 5-6-membered heterocyclic ring
having 1-4 heteroatoms independently selected from N, S, O, and
--N(O)--, and optionally also comprising 1-3 double bonds and a
carbonyl group, wherein the point of attachment of A.sup.3 to the
phenyl ring to which A.sup.3 is attached is a carbon atom; and
[0068] (c) a benzoheterocyclic ring comprising a phenyl ring fused
to a 5-6-membered heterocyclic ring having 1-2 heteroatoms
independently selected from O, N, and --S(O).sub.x-- and optionally
1-2 double bonds, wherein the point of attachment of A.sup.3 to the
phenyl ring to which A.sup.3 is attached is a carbon atom.
[0069] In subgroups of compounds, A.sup.2 is selected from the
group consisting of: [0070] (a) an aromatic ring selected from
phenyl and naphthyl; [0071] (b) a 5-6-membered heterocyclic ring
having 1-4 heteroatoms independently selected from N, S, O, and
--N(O)--, and optionally also comprising 1-3 double bonds and a
carbonyl group; [0072] (c) a benzoheterocyclic ring comprising a
phenyl ring fused to a 5-6-membered heterocyclic ring having 1-2
heteroatoms independently selected from O, N, and S and optionally
1-2 double bonds; and [0073] (d) a --C.sub.3-C.sub.8 cycloalkyl
ring optionally having 1-3 double bonds;
[0074] In the subgroups of A.sup.3 and A.sup.2 above, A.sup.3 and
A.sup.2 are each optionally substituted with 1-4 substituent groups
independently selected from R.sup.a.
[0075] A subgroup of R.sup.a comprises substituents that are
independently selected from the group consisting of
--C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6 alkenyl,
--C.sub.3-C.sub.8 cycloalkyl optionally having 1-3 double bonds,
--OC.sub.1-C.sub.6alkyl, --C(.dbd.O)C.sub.1-C.sub.6alkyl,
--C(.dbd.O)H, --CO.sub.2H, --CO.sub.2C.sub.1-C.sub.6alkyl, --OH,
--NR.sup.3R.sup.4, --NR.sup.3C(.dbd.O)OC.sub.1-C.sub.6 alkyl,
--S(O).sub.xC.sub.1-C.sub.6 alkyl, halogen, --CN, --NO.sub.2, and a
5-6-membered heterocyclic ring having 1-4 heteroatoms independently
selected from N, S, and O, said heterocyclic ring optionally also
comprising a carbonyl group and optionally also comprising 1-3
double bonds, wherein the point of attachment of said heterocyclic
ring to the ring to which R.sup.a is attached is a carbon atom,
wherein said heterocyclic ring is optionally substituted with 1-5
substituent groups independently selected from halogen,
--C.sub.1-C.sub.3 alkyl, and --OC.sub.1-C.sub.3 alkyl, wherein
--C.sub.1-C.sub.3 alkyl and --OC.sub.1-C.sub.3 alkyl are optionally
substituted with 1-7 halogens;
[0076] wherein for compounds in which R.sup.a is selected from the
group consisting of --C.sub.1-C.sub.6 alkyl, --C.sub.2-C.sub.6
alkenyl, --C.sub.3-C.sub.8 cycloalkyl optionally having 1-3 double
bonds, --OC.sub.1-C.sub.6alkyl, --C(.dbd.O)C.sub.1-C.sub.6alkyl,
--CO.sub.2C.sub.1-C.sub.6alkyl, --NR.sup.3C(.dbd.O)OC.sub.1-C.sub.6
alkyl, and --S(O).sub.xC.sub.1-C.sub.6 alkyl, R.sup.a is optionally
substituted with 1-15 halogens and is optionally also substituted
with one substituent group selected from (a) --OH, (b)
--NR.sup.3R.sup.4, (c) --OC.sub.1-C.sub.4alkyl optionally
substituted with 1-9 halogens and optionally also substituted with
1-2 substituent groups independently selected from
--OC.sub.1-C.sub.2 alkyl and phenyl, and (d) phenyl which is
optionally substituted with 1-3 groups independently selected from
halogen, --CH.sub.3, --CF.sub.3, --OCH.sub.3, and --OCF.sub.3;
[0077] with the proviso that when B is A.sup.1, and X and Y are
--CH.sub.2--, and Z is --C(.dbd.O)--, and R.sup.2 is phenyl which
has a substituent R.sup.a in the 4-position, wherein R.sup.a is
--OC.sub.1-C.sub.6alkyl which is optionally substituted as
described above, then there are no other R.sup.a substitutents on
R.sup.2 in which R.sup.a is --OH or --OC.sub.1-C.sub.6alkyl which
is optionally substituted as described above.
[0078] In subgroups of compounds, n is an integer from 0-2. In
other subgroups, n is 1 or 2.
[0079] In independent subgroups, R.sup.3 and R.sup.4 are each
independently selected from H and --C.sub.1-C.sub.5 alkyl, wherein
--C.sub.1-C.sub.8 alkyl in all instances is optionally substituted
with 1-11 halogens. In other independent subgroups, R.sup.3 and
R.sup.4 each independently selected from H and --C.sub.1-C.sub.3
alkyl, or from H and --C.sub.1-C.sub.2 alkyl.
[0080] In subgroups of Formula I, Z is selected from the group
consisting of --C(.dbd.O)--, --S(O).sub.2--, and
--C(.dbd.N--R.sup.9)--, where R.sup.9 is selected from the group
consisting of H, --CN, and CH.sub.3. A preferred value of Z is
--C(.dbd.O)--.
[0081] In independent subgroups, R.sup.5 is selected from the group
consisting of H, --OH, and --C.sub.1-C.sub.5 alkyl, wherein
--C.sub.1-C.sub.5 alkyl is optionally substituted with 1-11
halogens. In other subgroups, R.sup.5 is selected from H and
--C.sub.1-C.sub.3 alkyl, or from H and --C.sub.1-C.sub.2 alkyl.
[0082] In some subgroups, each R is independently selected from the
group consisting of H and C.sub.1-C.sub.3 alkyl. In other groups, R
is selected from H and C.sub.1-C.sub.2 alkyl. In other groups, R is
H or CH.sub.3 In some subgroups, R.sup.6 is selected from the group
consisting of H and --C.sub.1-C.sub.3 alkyl,
[0083] wherein C.sub.1-C.sub.3 alkyl is optionally substituted with
1-5 halogens. In other subgroups, R.sup.6 is selected from H and
C.sub.1-C.sub.2 alkyl. In other groups, R.sup.6 is H or
CH.sub.3,
[0084] In some subgroups, R.sup.1 is selected from the group
consisting of H, --C.sub.1-C.sub.3 alkyl, and
--(C(R).sub.2).sub.nA.sup.2, wherein --C.sub.1-C.sub.3 alkyl is
optionally substituted with 1-5 halogens; and R.sup.2 is selected
from the group consisting of H, --C.sub.1-C.sub.3 alkyl, A.sup.1,
and --(C(R).sub.2).sub.nA.sup.2, wherein --C.sub.1-C.sub.3 alkyl is
optionally substituted with 1-5 halogens, and R.sup.6 is H or
alkyl. In these subgroups, one of B and R.sup.2 is A.sup.1; and one
of B, R.sup.1, and R.sup.2 is A.sup.2 or
--(C(R).sub.2).sub.nA.sup.2; so that the compound of Formula I
comprises one group A.sup.1 and one group A.sup.2.
[0085] In subgroups of compounds, A.sup.3 is selected from the
group consisting of: [0086] (a) phenyl; [0087] (b) a 5-6-membered
aromatic heterocyclic ring having 1-2 heteroatoms independently
selected from N, S, O, and --N(O)--, wherein the point of
attachment of A.sup.3 to the phenyl ring to which A.sup.3 is
attached is a carbon atom; and [0088] (c) a benzoheterocyclic ring
comprising a phenyl ring fused to a 5-membered aromatic
heterocyclic ring having 1-2 heteroatoms independently selected
from O, N, and --S(O).sub.x, wherein the point of attachment of
A.sup.3 to the phenyl ring to which A.sup.3 is attached is a carbon
atom.
[0089] In subgroups, A.sup.2 is selected from: [0090] (a) phenyl;
[0091] (b) a 5-6-membered heterocyclic ring having 1-4 heteroatoms
independently selected from N, S, O, and --N(O)--, and optionally
also comprising 1-3 double bonds; [0092] (c) a benzoheterocyclic
ring comprising a phenyl ring fused to a 5-membered heterocyclic
ring having 1-2 heteroatoms independently selected from O, N, and
S; and [0093] (d) a --C.sub.5-C.sub.6 cycloalkyl ring.
[0094] In many compounds, A.sup.3 and A.sup.2 are each optionally
substituted with 1-4 substituent groups independently selected from
R.sup.a. In various subgroups, A.sup.3 is optionally substituted
with 1-3 substituents R.sup.a, or with 2-3 substituents R.sup.a. In
various subgroups, A.sup.2 is optionally substituted with 1-3
substituents R.sup.a, or with 1-2 substituents R.sup.a. Often
A.sup.2 is substituted with 2 substituents R.sup.a, or with 2-3
substituents R.sup.a.
[0095] In many compounds, A.sup.3 is selected from the group
consisting of phenyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl,
pyridyl, N-oxido-pyridyl, thiazolyl, pyridazinyl, pyrimidinyl,
pyrazinyl, benzothienyl, benzothienyl-S-oxide, and
benzothienyl-S-dioxide.
[0096] In many compounds, A.sup.2 is selected from the group
consisting of phenyl, thienyl, imidazolyl, thiazolyl, pyrrolyl,
pyrazolyl, 1,2,4-triazolyl, tetrazolyl, benzodioxolyl, pyridyl,
N-oxidopyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, cyclopentyl,
cyclohexyl, and tetrahydropyranyl.
[0097] In some subsets, R.sup.a is selected from the group
consisting of --C.sub.1-C.sub.4 alkyl, --C.sub.2-C.sub.4 alkenyl,
cyclopropyl, --OC.sub.1-C.sub.2alkyl,
--C(.dbd.O)C.sub.1-C.sub.2alkyl, --C(.dbd.O)H,
--CO.sub.2C.sub.1-C.sub.4alkyl, --OH, --NR.sup.3R.sup.4,
--NR.sup.3C(.dbd.O)OC.sub.1-C.sub.4 alkyl,
--S(O).sub.xC.sub.1-C.sub.2 alkyl, halogen, --CN, --NO.sub.2, and a
5-6-membered heterocyclic ring having 1-2 heteroatoms independently
selected from N, S, and O, wherein the point of attachment of said
heterocyclic ring to the ring to which R.sup.a is attached ring is
a carbon atom, wherein said heterocyclic ring is optionally
substituted with 1-5 substituent groups independently selected from
halogen;
[0098] wherein for compounds in which R.sup.a is selected from the
group consisting of --C.sub.1-C.sub.4 alkyl, --C.sub.2-C.sub.4
alkenyl, --OC.sub.1-C.sub.2alkyl, --C(.dbd.O)C.sub.1-C.sub.2alkyl,
--CO.sub.2C.sub.1-C.sub.4alkyl, --NR.sub.3C(.dbd.O)OC.sub.1-C.sub.4
alkyl, and --S(O).sub.xC.sub.1-C.sub.2 alkyl, the alkyl group of
R.sup.a is optionally substituted with 1-5 halogens and is
optionally also substituted with one substituent group selected
from (a) --OH, (b) --NR.sup.3R.sup.4, (c) --OCH.sub.3 optionally
substituted with 1-3 fluorine atoms and optionally also substituted
with one phenyl group, and
[0099] (d) phenyl which is optionally substituted with 1-3 groups
independently selected from halogen, --CH.sub.3, --CF.sub.3,
--OCH.sub.3, and --OCF.sub.3;
[0100] with the proviso that when B is A.sup.1, and X and Y are
--CH.sub.2--, and Z is --C(.dbd.O)--, and R.sup.2 is phenyl which
has a substituent R.sup.a in the 4-position, wherein R.sup.a is
--OC.sub.1-C.sub.2alkyl which is optionally substituted as
described above, then there are no other R.sup.a substitutents on
R.sup.2 in which R.sup.a is selected from --OH or
--OC.sub.1-C.sub.2alkyl which is optionally substituted as
described above.
[0101] In preferred subsets, X is selected from the group
consisting of --O--, --NH--, and --N(C.sub.1-C.sub.3alkyl)-. X may
also be selected from the group consisting of --O--, --NH--, and
--N(CH.sub.3). In highly preferred subsets, X is O.
[0102] In many subsets, Z is --C(.dbd.O)--.
[0103] A preferred subgroup of compounds has Formula Ie, including
pharmaceutically acceptable salts thereof
##STR00010##
[0104] In compounds of formula Ie, X is selected from the group
consisting of --O--, --NH--, --N(C.sub.1-C.sub.5alkyl)- and
--(CH.sub.2)--;
[0105] Z is selected from the group consisting of --C(.dbd.O)--,
--S(O).sub.2--, and --C(.dbd.N--R.sup.9)--, wherein
[0106] R.sup.9 is selected from the group consisting of H, --CN,
and C.sub.1-C.sub.5alkyl optionally substituted with 1-11
halogens;
[0107] Each R is independently selected from the group consisting
of H and --CH.sub.3;
[0108] B is selected from the group consisting of A.sup.1 and
A.sup.2, wherein A.sup.1 has the structure:
##STR00011##
[0109] R.sup.1 is selected from the group consisting of H,
--C.sub.1-C.sub.5 alkyl, and --(C(R).sub.2).sub.nA.sup.2, wherein
--C.sub.1-C.sub.5 alkyl is optionally substituted with 1-11
halogens;
[0110] R.sup.2 is selected from the group consisting of H,
--C.sub.1-C.sub.5 alkyl, A.sup.1, and --(C(R).sub.2).sub.nA.sup.2,
wherein --C.sub.1-C.sub.5alkyl is optionally substituted with 1-11
halogens;
[0111] Wherein one of B and R.sup.2 is A.sup.1; and one of B,
R.sup.1, and R.sup.2 is A.sup.2 or --(C(R).sub.2).sub.nA.sup.2; so
that the compound of Formula Ie comprises one group A.sup.1 and one
group A.sup.2;
[0112] A.sup.2 is selected from the group consisting of phenyl,
cyclohexyl, and pyridyl, wherein A.sup.2 is optionally substituted
with 1-2 substituent groups independently selected from halogen,
--C.sub.1-C.sub.4 alkyl, and --CN, wherein --C.sub.1-C.sub.4 alkyl
is optionally substituted with 1-3 halogens;
[0113] Each R.sup.a is independently selected from the group
consisting of --C.sub.1-C.sub.3 alkyl and halogen, wherein
--C.sub.1-C.sub.3 alkyl is optionally substituted with 1-3
halogens;
[0114] Each R.sup.b is independently selected from the group
consisting of Cl, F, --C.sub.1-C.sub.4 alkyl, and
--OC.sub.1-C.sub.4 alkyl, wherein --C.sub.1-C.sub.4 alkyl and
--OC.sub.1-C.sub.4 alkyl are optionally substituted with 1-5 F;
[0115] n is 0 or 1;
[0116] p is an integer from 0-2; and
[0117] q is an integer from 0-3.
[0118] Subsets of compounds having formula Ie include compounds of
formula If, Ig, and Ih, and pharmaceutically acceptable salts
thereof:
##STR00012##
[0119] In the compounds of formula If, Ig, and Ih, R.sup.1 and
R.sup.2 are each independently selected from H and
--C.sub.1-C.sub.5 alkyl, wherein --C.sub.1-C.sub.5 alkyl is
optionally substituted with 1-11 halogens. Other groups are as
defined previously.
[0120] In subsets of the compounds described above, A.sup.2 may be
selected from the group consisting of phenyl, cyclohexyl, and
pyridyl, wherein A.sup.2 is optionally substituted with 1-2
substituent groups independently selected from halogen,
--CH.sub.3--CF.sub.3, and --CN.
[0121] In subsets of the compounds described above, each R.sup.a
independently is selected from the group consisting of --CF.sub.3
and Cl.
[0122] In subsets of the compounds described above, each R.sup.b is
independently selected from the group consisting of
--C.sub.1-C.sub.3 alkyl, --OCH.sub.3, and F.
[0123] In subsets of the compounds described above, R.sup.1 and
R.sup.2 are each independently selected from the group consisting
of H and --C.sub.1-C.sub.2 alkyl.
[0124] In subsets of the compounds described above, X is selected
from --O--, --NH--, --N(CH.sub.3)--, and --CH.sub.2--.
[0125] In subsets of the compounds described above, Z is selected
from the group consisting of --C(--O)--, --S(O).sub.2--, and
--C(.dbd.N--CN)--.
[0126] In subsets of the compounds described above, p is 1.
[0127] In subsets of the compounds described above, q is 2 or
3.
[0128] A subset of compounds defined previously comprises compounds
having formula Ii, and pharmaceutically acceptable salts
thereof:
##STR00013##
[0129] In formula Ii, R.sup.7 is selected from the group consisting
of Cl and --CF.sub.3;
[0130] R.sup.c is selected from the group consisting of halogen,
--CH.sub.3--CF.sub.3, and --CN; and
[0131] t is an integer from 0-2. Other groups are as defined
previously.
[0132] A subset of compounds defined previously comprises compounds
having formula Ij, or a pharmaceutically acceptable acceptable salt
thereof:
##STR00014##
[0133] In formula Ii, R.sup.7 is selected from the group consisting
of Cl and --CF.sub.3
[0134] R.sup.c is selected from the group consisting of halogen,
--CH.sub.3--CF.sub.3, and --CN; and
[0135] t is an integer from 0-2. Other groups are as defined
previously.
DEFINITIONS
[0136] "Ac" is acetyl, which is CH.sub.3C(.dbd.O)--.
[0137] "Alkyl" means saturated carbon chains which may be linear or
branched or combinations thereof, unless the carbon chain is
defined otherwise. Other groups having the prefix "alk", such as
alkoxy and alkanoyl, also may be linear or branched or combinations
thereof, unless the carbon chain is defined otherwise. Examples of
alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-
and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the
like.
[0138] "Alkylene" groups are alkyl groups that are difunctional
rather than monofunctional. For example, methyl is an alkyl group
and methylene (--CH.sub.2--) is the corresponding alkylene
group.
[0139] "Alkenyl" means carbon chains which contain at least one
carbon-carbon double bond, and which may be linear or branched or
combinations thereof. Examples of alkenyl include vinyl, allyl,
isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,
2-methyl-2-butenyl, and the like.
[0140] "Alkynyl" means carbon chains which contain at least one
carbon-carbon triple bond, and which may be linear or branched or
combinations thereof. Examples of alkynyl include ethynyl,
propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.
[0141] "Cycloalkyl" means a saturated carbocyclic ring having from
3 to 8 carbon atoms, unless otherwise stated (e.g., cycloalkyl may
be defined as having one or more double bonds). The term also
includes a cycloalkyl ring fused to an aryl group. Examples of
cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl,
cycloheptyl, and the like. "Cycloalkenyl" means a non-aromatic
carbocyclic ring having one or more double binds.
[0142] "Aryl" (and "arylene") when used to describe a substituent
or group in a structure means a monocyclic or bicyclic compound in
which the rings are aromatic and which contains only carbon ring
atoms. The term "aryl" can also refer to an aryl group that is
fused to a cycloalkyl or heterocycle. Preferred "aryls" are phenyl
and naphthyl. Phenyl is generally the most preferred aryl
group.
[0143] "EDC" is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
[0144] "Heterocyclyl," "heterocycle," and "heterocyclic" means a
fully or partially saturated or aromatic 5-6 membered ring
containing 1-4 heteroatoms independently selected from N, S and O,
unless otherwise stated.
[0145] "Benzoheterocycle" represents a phenyl ring fused to a
5-6-membered heterocyclic ring having 1-2 heteroatoms, each of
which is O, N, or S, where the heterocyclic ring may be saturated
or unsaturated. Examples include indole, benzofuran,
2,3-dihydrobenzofuran and quinoline.
[0146] "DIPEA" is diisopropylethylamine.
[0147] "Halogen" includes fluorine, chlorine, bromine and
iodine.
[0148] "HOBT" is 1-Hydroxybenzotriazole.
[0149] "IPAC" is isopropyl acetate.
[0150] "Me" represents methyl.
[0151] "Weinreb amine" is N,O-dimethylhydroxylamine.
[0152] The term "composition," as in pharmaceutical composition, is
intended to encompass a product comprising the active
ingredient(s), and the inert ingredient(s) that make up the
carrier, as well as any product which results, directly or
indirectly, from combination, complexation or aggregation of any
two or more of the ingredients, or from dissociation of one or more
of the ingredients, or from other types of reactions or
interactions of one or more of the ingredients. Accordingly, the
pharmaceutical compositions of the present invention encompass any
composition made by admixing a compound of the present invention
and a pharmaceutically acceptable carrier.
[0153] The substituent "tetrazole" means a 2H-tetrazol-5-yl
substituent group and tautomers thereof.
Optical Isomers--Diastereomers--Geometric Isomers--Tautomers
[0154] Compounds of Formula I may contain one or more asymmetric
centers and can thus occur as racemates, racemic mixtures, single
enantiomers, diastereomeric mixtures and individual diastereomers.
The present invention is meant to include all such isomeric forms
of the compounds of Formula I and all mixtures of the compounds.
When structures are shown with a stereochemical representation,
other stereochemical structures are also included individually and
collectively, such as enantiomers, diastereoisomers (where
diastereomers are possible), and mixtures of the enantiomers and/or
diastereomers, including racemic mixtures.
[0155] Some of the compounds described herein may contain olefinic
double bonds, and unless specified otherwise, are meant to include
both E and Z geometric isomers.
[0156] Some of the compounds described herein may exist as
tautomers. An example is a ketone and its enol form, known as
keto-enol tautomers. The individual tautomers as well as mixtures
thereof are encompassed with compounds of Formula I.
[0157] Compounds of Formula I having one or more asymmetric centers
may be separated into diastereoisomers, enantiomers, and the like
by methods well known in the art.
[0158] Alternatively, enantiomers and other compounds with chiral
centers may be synthesized by stereospecific synthesis using
optically pure starting materials and/or reagents of known
configuration.
[0159] Some of the biphenyl and biaryl compounds herein are
observed as mixtures of atropisomers (rotamers) in the NMR spectra.
The individual atropisomers as well as mixtures thereof are
encompassed with the compounds of this invention.
Salts
[0160] The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases or acids
including inorganic or organic bases and inorganic or organic
acids. Salts derived from inorganic bases include aluminum,
ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,
manganic salts, manganous, potassium, sodium, zinc, and the like.
Particularly preferred are the ammonium, calcium, magnesium,
potassium, and sodium salts. Salts in the solid form may exist in
more than one crystal structure, and may also be in the form of
hydrates. Salts derived from pharmaceutically acceptable organic
non-toxic bases include salts of primary, secondary, and tertiary
amines, substituted amines including naturally occurring
substituted amines, cyclic amines, and basic ion exchange resins,
such as arginine, betaine, caffeine, choline,
N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,
2-dimethylaminoethanol, ethanolamine, ethylenediamine,
N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,
histidine, hydrabamine, isopropylamine, lysine, methylglucamine,
morpholine, piperazine, piperidine, polyamine resins, procaine,
purines, theobromine, triethylamine, trimethylamine,
tripropylamine, tromethamine, and the like.
[0161] When the compound of the present invention is basic, salts
may be prepared from pharmaceutically acceptable non-toxic acids,
including inorganic and organic acids. Such acids include acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid, and the like. Particularly preferred are
citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric,
and tartaric acids.
[0162] It will be understood that, as used herein, references to
the compounds of Formula I are meant to also include the
pharmaceutically acceptable salts.
Metabolites--Prodrugs
[0163] Therapeutically active metabolites, where the metabolites
themselves fall within the scope of the claimed invention, are also
compounds of the current invention. Prodrugs, which are compounds
that are converted to the claimed compounds as they are being
administered to a patient or after they have been administered to a
patient, are also compounds of this invention.
Utilities
[0164] Compounds of the current invention are potent inhibitors of
CETP. They are therefore useful in treating diseases and conditions
that are treated by inhibitors of CETP.
[0165] One aspect of the present invention provides a method for
treating or reducing the risk of developing a disease or condition
that may be treated or prevented by inhibition of CETP by
administering a therapeutically effective amount of a compound of
this invention to a patient in need of treatment. A patient is a
human or mammal, and is most often a human. A "therapeutically
effective amount" is the amount of compound that is effective in
obtaining a desired clinical outcome in the treatment of a specific
disease.
[0166] Diseases or conditions that may be treated with compounds of
this invention, or which the patient may have a reduced risk of
developing as a result of being treated with the compounds of this
invention, include: atherosclerosis, peripheral vascular disease,
dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia,
hypercholesterolemia, hypertriglyceridemia,
familial-hypercholesterolemia, cardiovascular disorders, angina,
ischemia, cardiac ischemia, stroke, myocardial infarction,
reperfusion injury, angioplastic restenosis, hypertension, vascular
complications of diabetes, obesity, endotoxemia, and metabolic
syndrome.
[0167] The compounds of this invention are expected to be
particularly effective in raising HDL-C and/or increasing the ratio
of HDL-C to LDL-C. These changes in HDL-C and LDL-C may be
beneficial in treating atherosclerosis, reducing or reversing the
development of atherosclerosis, reducing the risk of developing
atherosclerosis, or preventing atherosclerosis.
Administration and Dose Ranges
[0168] Any suitable route of administration may be employed for
providing a mammal, especially a human, with an effective dose of a
compound of the present invention. For example, oral, rectal,
topical, parenteral, ocular, pulmonary, nasal, and the like may be
employed. Dosage forms include tablets, troches, dispersions,
suspensions, solutions, capsules, creams, ointments, aerosols, and
the like. Preferably compounds of Formula I are administered
orally.
[0169] The effective dosage of active ingredient employed may vary
depending on the particular compound employed, the mode of
administration, the condition being treated and the severity of the
condition being treated. Such dosage may be ascertained readily by
a person skilled in the art.
[0170] When treating the diseases for which compounds of Formula I
are indicated, generally satisfactory results are obtained when the
compounds of the present invention are administered at a daily
dosage of from about 0.01 milligram to about 100 milligram per
kilogram of animal or human body weight, preferably given as a
single daily dose or in divided doses two to six times a day, or in
sustained release form. In the case of a 70 kg adult human, the
total daily dose will generally be from about 0.5 milligram to
about 500 milligrams. For a particularly potent compound, the
dosage for an adult human may be as low as 0.1 mg. The dosage
regimen may be adjusted within this range or even outside of this
range to provide the optimal therapeutic response.
[0171] Oral administration will usually be carried out using
tablets. Examples of doses in tablets are 0.5 mg, 1 mg, 2 mg, 5 mg,
10 mg, 25 mg, 50 mg, 100 mg, 250 mg, and 500 mg. Other oral forms
can also have the same dosages (e.g. capsules).
Pharmaceutical Compositions
[0172] Another aspect of the present invention provides
pharmaceutical compositions which comprise a compound of Formula I
and a pharmaceutically acceptable carrier. The pharmaceutical
compositions of the present invention comprise a compound of
Formula I or a pharmaceutically acceptable salt as an active
ingredient, as well as a pharmaceutically acceptable carrier and
optionally other therapeutic ingredients. The term
"pharmaceutically acceptable salts" refers to salts prepared from
pharmaceutically acceptable non-toxic bases or acids including
inorganic bases or acids and organic bases or acids. A
pharmaceutical composition may also comprise a prodrug, or a
pharmaceutically acceptable salt thereof, if a prodrug is
administered. Pharmaceutical compositions may also consist
essentially of a compound of Formula I and a pharmaceutically
acceptable carrier without other therapeutic ingredients.
[0173] The compositions include compositions suitable for oral,
rectal, topical, parenteral (including subcutaneous, intramuscular,
and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal
inhalation), or nasal administration, although the most suitable
route in any given case will depend on the nature and severity of
the conditions being treated and on the nature of the active
ingredient. They may be conveniently presented in unit dosage form
and prepared by any of the methods well-known in the art of
pharmacy.
[0174] In practical use, the compounds of Formula I can be combined
as the active ingredient in intimate admixture with a
pharmaceutical carrier according to conventional pharmaceutical
compounding techniques. The carrier may take a wide variety of
forms depending on the form of preparation desired for
administration, e.g., oral or parenteral (including intravenous).
In preparing the compositions for oral dosage form, any of the
usual pharmaceutical media may be employed, such as, for example,
water, glycols, oils, alcohols, flavoring agents, preservatives,
coloring agents and the like in the case of oral liquid
preparations, such as, for example, suspensions, elixirs and
solutions; or carriers such as starches, sugars, microcrystalline
cellulose, diluents, granulating agents, lubricants, binders,
disintegrating agents and the like in the case of oral solid
preparations such as, for example, powders, hard and soft capsules
and tablets, with the solid oral preparations being preferred over
the liquid preparations.
[0175] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit form in
which case solid pharmaceutical carriers are obviously employed. If
desired, tablets may be coated by standard aqueous or nonaqueous
techniques. Such compositions and preparations should contain at
least 0.1 percent of active compound. The percentage of active
compound in these compositions may, of course, be varied and may
conveniently be between about 2 percent to about 60 percent of the
weight of the unit. The amount of active compound in such
therapeutically useful compositions is such that an effective
dosage will be obtained. The active compounds can also be
administered intranasally as, for example, liquid drops or
spray.
[0176] The tablets, pills, capsules, and the like may also contain
a binder such as gum tragacanth, acacia, corn starch or gelatin;
excipients such as dicalcium phosphate; a disintegrating agent such
as corn starch, potato starch, alginic acid; a lubricant such as
magnesium stearate; and a sweetening agent such as sucrose, lactose
or saccharin. When a dosage unit form is a capsule, it may contain,
in addition to materials of the above type, a liquid carrier such
as a fatty oil.
[0177] Various other materials may be present as coatings or to
modify the physical form of the dosage unit. For instance, tablets
may be coated with shellac, sugar or both. A syrup or elixir may
contain, in addition to the active ingredient, sucrose as a
sweetening agent, methyl and propylparabens as preservatives, a dye
and a flavoring such as cherry or orange flavor.
[0178] Compounds of formula I may also be administered
parenterally. Solutions or suspensions of these active compounds
can be prepared in water suitably mixed with a surfactant such as
hydroxypropylcellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene glycols and mixtures thereof in oils.
Under ordinary conditions of storage and use, these preparations
contain a preservative to prevent the growth of microorganisms.
[0179] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringability exists. It must be
stable under the conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such
as bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (e.g.
glycerol, propylene glycol and liquid polyethylene glycol),
suitable mixtures thereof, and vegetable oils.
Combination Therapy
[0180] Compounds of the invention (e.g. Formula I and Ia-Ij) may be
used in combination with other drugs that may also be useful in the
treatment or amelioration of the diseases or conditions for which
compounds of Formula I are useful. Such other drugs may be
administered, by a route and in an amount commonly used therefor,
contemporaneously or sequentially with a compound of Formula I.
When a compound of Formula I is used contemporaneously with one or
more other drugs, a pharmaceutical composition in unit dosage form
containing such other drugs and the compound of Formula I is
preferred. However, the combination therapy also includes therapies
in which the compound of Formula I and one or more other drugs are
administered on different schedules.
[0181] When oral formulations are used, the drugs may be combined
into a single combination tablet or other oral dosage form, or the
drugs may be packaged together as separate tablets or other oral
dosage forms. It is also contemplated that when used in combination
with one or more other active ingredients, the compound of the
present invention and the other active ingredients may be used in
lower doses than when each is used singly. Accordingly, the
pharmaceutical compositions of the present invention include those
that contain one or more other active ingredients, in addition to a
compound of Formula I.
[0182] Examples of other active ingredients that may be
administered in combination with a compound of this invention (e.g.
Formula I), and either administered separately or in the same
pharmaceutical composition, include, but are not limited to, other
compounds which improve a patient's lipid profile, such as (i)
HMG-CoA reductase inhibitors, (which are generally statins,
including lovastatin, simvastatin, rosuvastatin, pravastatin,
fluvastatin, atorvastatin, rivastatin, itavastatin, pitavastatin,
and other statins), (ii) bile acid sequestrants (cholestyramine,
colestipol, dialkylaminoalkyl derivatives of a cross-linked
dextran, Colestid.RTM., LoCholest.RTM., (iii) niacin and related
compounds, such as nicotinyl alcohol, nicotinamide, and nicotinic
acid or a salt thereof, (iv) PPAR.alpha. agonists, such as
gemfibrozil and fenofibric acid derivatives (fibrates), including
clofibrate, fenofibrate, bezafibrate, ciprofibrate, and etofibrate,
(v) cholesterol absorption inhibitors, such as stanol esters,
beta-sitosterol, sterol glycosides such as tiqueside; and
azetidinones, such as ezetimibe, (vi) acyl CoA:cholesterol
acyltransferase (ACAT) inhibitors, such as avasimibe and
melinamide, and including selective ACAT-1 and ACAT-2 inhibitors
and dual inhibitors, (vii) phenolic anti-oxidants, such as
probucol, (viii) microsomal triglyceride transfer protein
(MTP)/ApoB secretion inhibitors, (ix) anti-oxidant vitamins, such
as vitamins C and E and beta carotene, (x) thyromimetics, (xi) LDL
(low density lipoprotein) receptor inducers, (xii) platelet
aggregation inhibitors, for example glycoprotein IIb/IIIa
fibrinogen receptor antagonists and aspirin, (xiii) vitamin B12
(also known as cyanocobalamin), (xiv) folic acid or a
pharmaceutically acceptable salt or ester thereof, such as the
sodium salt and the methylglucamine salt, (xv) FXR and LXR ligands,
including both inhibitors and agonists, (xvi) agents that enhance
ABCA1 gene expression, and (xvii) ileal bile acid transporters.
[0183] Preferred classes of therapeutic compounds that can be used
with the compounds of this invention for use in improving a
patient's lipid profile (i.e. raising HDL-C and lowering LDL-C)
include one or both of statins and cholesterol absorption
inhibitors. Particularly preferred are combinations of compounds of
this invention with simvastatin, ezetimibe, or both simvastatin and
ezetimibe. Also preferred are combinations of compounds of this
invention with statins other than simvastatin, such as lovastatin,
rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin,
itavastatin, and ZD-4522.
[0184] Finally compounds of this invention can be used with
compounds that are useful for treating other diseases, such as
diabetes, hypertension and obesity, as well as other
anti-atherosclerotic compounds. Such combinations may be used to
treat one or more of such diseases as diabetes, obesity,
atherosclerosis, and dyslipidemia, or more than one of the diseases
associated with metabolic syndrome. The combinations may exhibit
synergistic activity in treating these disease, allowing for the
possibility of administering reduced doses of active ingredients,
such as doses that otherwise might be sub-therapeutic.
[0185] Examples of other active ingredients that may be
administered in combination with a compound of this invention
include, but are not limited to, compounds that are primarily
anti-diabetic compounds, including:
[0186] (a) PPAR gamma agonists and partial agonists, including
glitazones and non-glitazones
[0187] (e.g. pioglitazone, englitazone, MCC-555, rosiglitazone,
balaglitazone, netoglitazone, T-131, LY-300512, and LY-818;
[0188] (b) biguanides such as metformin and phenformin;
[0189] (c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;
[0190] (d) dipeptidyl peptidase IV (DP-IV) inhibitors, including
vildagliptin, sitagliptin, and saxagliptin;
[0191] (e) insulin or insulin mimetics, such as for example insulin
lispro, insulin glargine, insulin zinc suspension, and inhaled
insulin formulations;
[0192] (f) sulfonylureas, such as tolbutamide, glipizide,
glimepiride, acetohexamide, chlorpropamide, glibenclamide, and
related materials;
[0193] (g) .alpha.-glucosidase inhibitors (such as acarbose,
adiposine; camiglibose; emiglitate; miglitol; voglibose;
pradimicin-Q; and salbostatin);
[0194] (h) PPAR.alpha./.gamma. dual agonists, such as muraglitazar,
tesaglitazar, farglitazar, and naveglitazar;
[0195] (i) PPAR.delta. agonists such as GW501516 and those
disclosed in WO97/28149;
[0196] (j) glucagon receptor antagonists;
[0197] (k) GLP-1; GLP-1 derivatives; GLP-1 analogs, such as
exendins, such as for example exenatide (Byetta); and non-peptidyl
GLP-1 receptor agonists;
[0198] (l) GIP-1; and
[0199] (m) Non-sulfonylurea insulin secretagogues, such as the
meglitinides (e.g. nateglinide and rapeglinide).
[0200] These other active ingredients that may be used in
combination with the current invention also include antiobesity
compounds, including 5-HT (serotonin) inhibitors, neuropeptide Y5
(NPY5) inhibitors, melanocortin 4 receptor (Mc4r) agonists,
cannabinoid receptor 1 (CB-1) antagonists/inverse agonists, and
.beta..sub.3 adrenergic receptor agonists. These are listed in more
detail later in this section.
[0201] These other active ingredients also include active
ingredients that are used to treat inflammatory conditions, such as
aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids,
azulfidine, and selective cyclooxygenase-2 (COX-2) inhibitors,
including etoricoxib, celecoxib, rofecoxib, and Bextra.
[0202] Antihypertensive compounds may also be used advantageously
in combination therapy with the compounds of this invention.
Examples of antihypertensive compounds that may be used with the
compounds of this invention include (1) angiotensin II antagonists,
such as losartan; (2) angiotensin converting enzyme inhibitors (ACE
inhibitors), such as enalapril and captopril; (3) calcium channel
blockers such as nifedipine and diltiazam; and (4) endothelian
antagonists.
[0203] Anti-obesity compounds may be administered in combination
with the compounds of this invention, including: (1) growth hormone
secretagogues and growth hormone secretagogue receptor
agonists/antagonists, such as NN.sub.7O.sub.3, hexarelin, and
MK-0677; (2) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;
(3) cannabinoid receptor ligands, such as cannabinoid CB.sub.1
receptor antagonists or inverse agonists, such as rimonabant
(Sanofi Synthelabo), AMT-251, and SR-14778 and SR 141716A (Sanofi
Synthelabo), SLV-319 (Solvay), BAY 65-2520 (Bayer); (4)
anti-obesity serotonergic agents, such as fenfluramine,
dexfenfluramine, phentermine, and sibutramine; (5)
.beta.3-adrenoreceptor agonists, such as AD9677/TAK677
(Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568,
BMS-196085, BRL-35135A, CGP12177A, BTA-243, Trecadrine, Zeneca
D7114, and SR 59119A; (6) pancreatic lipase inhibitors, such as
orlistat (Xenical.RTM.), Triton WR1339, RHC80267, lipstatin,
tetrahydrolipstatin, teasaponin, and diethylumbelliferyl phosphate;
(7) neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO
3304, LY-357897, CP-671906, and GI-264879A; (8) neuropeptide Y5
antagonists, such as GW-569180A, GW-594884A, GW-587081X,
GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A,
CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and
JCF-104; (9) melanin-concentrating hormone (MCH) receptor
antagonists; (10) melanin-concentrating hormone 1 receptor (MCH1R)
antagonists, such as T-226296 (Takeda); (11) melanin-concentrating
hormone 2 receptor (MCH2R) agonist/antagonists; (12) orexin-1
receptor antagonists, such as SB-334867-A; (13) melanocortin
agonists, such as Melanotan II; (14) other Mc4r (melanocortin 4
receptor) agonists, such as CHIR86036 (Chiron), ME-10142, and
ME-10145 (Melacure), CHR86036 (Chiron); PT-141, and PT-14
(Palatin); (15) 5HT-2 agonists; (16) 5HT2C (serotonin receptor 2C)
agonists, such as BVT933, DPCA37215, WAY161503, and R-1065; (17)
galanin antagonists; (18) CCK agonists; (19) CCK-A
(cholecystokinin-A) agonists, such as AR-R 15849, GI 181771,
JMV-180, A-71378, A-71623 and SR146131; (20) GLP-1 agonists; (21)
corticotropin-releasing hormone agonists; (22) histamine receptor-3
(H3) modulators; (23) histamine receptor-3 (H3) antagonists/inverse
agonists, such as hioperamide, 3-(1H-imidazol-4-yl)propyl
N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan,
and GT2394 (Gliatech); (24) .beta.-hydroxy steroid dehydrogenase-1
inhibitors (11.beta.-HSD-1 inhibitors), such as BVT 3498 and, BVT
2733, (25) PDE (phosphodiesterase) inhibitors, such as
theophylline, pentoxifylline, zaprinast, sildenafil, aminone,
milrinone, cilostamide, rolipram, and cilomilast; (26)
phosphodiesterase-3B (PDE3B) inhibitors; (27) NE (norepinephrine)
transport inhibitors, such as GW 320659, despiramine, talsupram,
and nomifensine; (28) ghrelin receptor antagonists; (29) leptin,
including recombinant human leptin (PEG-OB, Hoffman La Roche) and
recombinant methionyl human leptin (Amgen); (30) leptin
derivatives; (31) BRS3 (bombesin receptor subtype 3) agonists such
as [D-Phe6,beta-Alall,Phe13,Nle14]Bn(6-14) and
[D-Phe6,Phe13]Bn(6-13) propylamide; (32) CNTF (Ciliary neurotrophic
factors), such as GI-181771 (Glaxo-SmithKline), SR146131 (Sanofi
Synthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (33)
CNTF derivatives, such as axokine (Regeneron); (34) monoamine
reuptake inhibitors, such as sibutramine; (35) UCP-1 (uncoupling
protein-1, 2, or 3) activators, such as phytanic acid,
4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-p-
ropenyl]benzoic acid (TTNPB), and retinoic acid; (36) thyroid
hormone agonists, such as KB-2611 (KaroBioBMS); (37) FAS (fatty
acid synthase) inhibitors, such as Cerulenin and C75; (38) DGAT1
(diacylglycerol acyltransferase 1) inhibitors; (39) DGAT2
(diacylglycerol acyltransferase 2) inhibitors; (40) ACC2
(acetyl-CoA carboxylase-2) inhibitors; (41) glucocorticoid
antagonists; (42) acyl-estrogens, such as oleoyl-estrone; (43)
dicarboxylate transporter inhibitors; (44) peptide YY, PYY 3-36,
peptide YY analogs, derivatives, and fragments such as BIM-43073D,
BIM-43004C, (45) Neuropeptide Y2 (NPY2) receptor agonists such
NPY3-36, N acetyl [Leu(28,31)] NPY 24-36, TASP-V, and
cyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (46) Neuropeptide Y4
(NPY4) agonists such as pancreatic peptide (PP); (47) Neuropeptide
Y1 (NPY1) antagonists such as BIBP3226, J-115814, BIBO 3304,
LY-357897, CP-671906, and GI-264879A; (48) Opioid antagonists, such
as nalmefene (Revex.RTM.), 3-methoxynaltrexone, naloxone, and
naltrexone; (49) glucose transporter inhibitors; (50) phosphate
transporter inhibitors; (51) 5-HT (serotonin) inhibitors; (52)
beta-blockers; (53) Neurokinin-1 receptor antagonists (NK-1
antagonists); (54) clobenzorex; (55) cloforex; (56) clominorex;
(57) clortermine; (58) cyclexedrine; (59) dextroamphetamine; (60)
diphemethoxidine, (61) N-ethylamphetamine; (62) fenbutrazate; (63)
fenisorex; (64) fenproporex; (65) fludorex; (66) fluminorex; (67)
furfurylmethylamphetamine; (68) levamfetamine; (69)
levophacetoperane; (70) mefenorex; (71) metamfepramone; (72)
methamphetamine; (73) norpseudoephedrine; (74) pentorex; (75)
phendimetrazine; (76) phenmetrazine; (77) picilorex; (78)
phytopharm 57; (79) zonisamide, (80) a minorex; (81) amphechloral;
(82) amphetamine; (83) benzphetamine; and (84)
chlorphenternine.
[0204] The combination therapies described above which use the
compounds of this invention may also be useful in the treatment of
the metabolic syndrome. According to one widely used definition, a
patient having metabolic syndrome is characterized as having three
or more symptoms selected from the following group of five
symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low
high-density lipoprotein cholesterol (HDL); (4) high blood
pressure; and (5) elevated fasting glucose, which may be in the
range characteristic of Type 2 diabetes if the patient is also
diabetic. Each of these symptoms is defined clinically in the
recently released Third Report of the National Cholesterol
Education Program Expert Panel on Detection, Evaluation and
Treatment of High Blood Cholesterol in Adults (Adult Treatment
Panel III, or ATP III), National Institutes of Health, 2001, NIH
Publication No. 01-3670. Patients with metabolic syndrome have an
increased risk of developing the macrovascular and microvascular
complications that are listed above, including atherosclerosis and
coronary heart disease. The combinations described above may
ameliorate more than one symptom of metabolic syndrome concurrently
(e.g. two symptoms, three symptoms, four symptoms, or all five of
the symptoms).
CETP Assay
[0205] An in vitro continuous assay for determining IC.sub.50's to
identify compounds that are CETP inhibitors was performed based on
a modification of the method described by Epps et al. employing
BODIPY.RTM.-CE as the cholesteryl ester lipid donor. See Epps et
al. (1995) Method for measuring the activities of cholesteryl ester
transfer protein (lipid transfer protein), Chem. Phys. Lipids. 77,
51-63.
[0206] Particles used in the assay were created from the following
sources: Synthetic donor HDL particles containing DOPC (Dioleoyl
Phosphatidyl Choline), BODIPY.RTM.-CE (Molecular Probes C-3927),
triolein (a triglyceride), and apoHDL were essentially created by
probe sonication as described by Epps et al, but with the addition
of a non-diffusable quencher molecule, dabcyl dicetylamide, in
order to reduce background fluorescence. Dabcyl dicetylamide was
made by heating dabcyl n-succinimide with dicetylamine in DMF at
95.degree. C. overnight in the presence of diisopropylamine
catalyst. Native lipoproteins from human blood were used as
acceptor particles. Particles having a density less than 1.063 g/ml
were collected by ultracentrifugation. These particles include
VLDL, IDL, and LDL. Particle concentrations were expressed in terms
of protein concentration as determined by BCA assay (Pierce, USA).
Particles were stored at 4.degree. C. until use.
[0207] Assays were performed in Dynex Microfluor 2 U-bottom black
96-well plates (Cat #7205). An assay cocktail containing CETP,
1.times.CETP buffer (50 mM Tris, pH 7.4, 100 mM NaCl, 1 mM EDTA),
and half the final concentration of acceptor particles was
prepared, and 100 .mu.L of the assay cocktail was added to each
well of the plate. Test compounds in DMSO were added in a volume of
3 .mu.L. The plate was mixed on a plate shaker and then incubated
at 25.degree. C. for 1 hour. A second assay cocktail containing
donor particles, the remaining acceptor particles and 1.times. CETP
buffer was prepared. 47 .mu.L of the second assay cocktail was
added to the reaction wells to start the assay. Assays were
performed at 25.degree. C. in a final volume of 150 .mu.L. Final
concentrations of materials were: 5 ng/.mu.L donor particles, 30
ng/.mu.L acceptor particles (each expressed by protein content),
1.times.CETP buffer, 0.8 nM recombinant human CETP (expressed in
CHO cells and partially purified), and up to 2% DMSO when testing
compounds. The assay was followed in a fluorescence plate reader
(Molecular Devices Spectramax GeminiXS) set for a 45 minute kinetic
run at 25.degree. C. which read the samples every 45 sec at Ex=480
nm, Em=511 nm, with a cutoff filter at 495 nm, photomultiplier tube
setting of medium, calibration on, and 6 reads/well.
[0208] Data was evaluated by obtaining an initial rate, expressed
in relative fluorescence units per second, for the pseudolinear
portion of the curve, often 0-500 or 1000 sec. Comparison of the
rates of samples with inhibitors to an uninhibited (DMSO only)
positive control yielded a percent inhibition. A plot of percent
inhibition vs. log of inhibitor concentration, fit to a Sigmoidal 4
parameter equation was used to calculate IC.sub.50.
EXAMPLES
[0209] The following schemes and examples are provided so that the
invention will be more fully appreciated and understood. Starting
materials are made using known procedures or as shown below.
[0210] The examples should not be construed as limiting the
invention in any way. The scope of the invention is defined by the
appended claims. Compounds of this invention have an IC.sub.50
value as measured using the assay described above of less than or
equal to 50 .mu.M.
##STR00015##
[0211] Intermediates 1-2, 1-3, 1-4, 1-5 and 1-6 utilized in the
present invention can be purchased or prepared as shown in Scheme
1. An appropriately substituted 2-haloaniline 1-1 wherein R.sup.a
and p are as defined in the claims and where the halogen is
preferably iodo or bromo is treated with CuCN in DMF at elevated
temperature to afford the corresponding 2-cyanoaniline.
Alternatively, the nitrile can be prepared by treatment of 1-1 with
KCN and CuI in the presence of a palladium (11) salt or in the
presence of certain copper or nickel complexes (See: Smith, M. B.
and March, J. "March's Advanced Organic Chemistry", 5.sup.th Ed.,
John Wiley and Sons, New York, pp. 867 (2001) and references
therein). Iodides 1-3 are prepared by treatment of 1-2 with
isoamylnitrite, n-pentylnitrite, t-butyl nitrite or the like in the
presence of diiodomethane (see for example: Smith et al., J. Org.
Chem. 55, 2543, (1990) and references cited therein) either neat or
in a solvent such as THF or acetonitrile. Alternatively, the iodide
can be prepared first by diazonium formation using isoamylnitrite,
n-pentylnitrite, t-butyl nitrite, sodium nitrite, nitrous acid or
the like followed by heating in the presence of iodine or an iodide
salt such as copper iodide, sodium iodide, potassium iodide,
tetrabutylammonium iodide or the like. Reduction of 1-3 with DIBAL
in dichloromethane affords aldehyde 1-4. Reduction of aldehyde 1-4
with sodium borohydride or the like in methanol or ethanol or the
like gives alcohol 1-5. Treatment of 1-5 with carbon tetrabromide
and triphenylphosphine in solvents such as dichloromethane,
dichloroethane or the like gives benzyl bromide 1-6 (See: Smith, M.
B. and March, J. "March's Advanced Organic Chemistry", 5.sup.th
Ed., John Wiley and Sons, New York, pp. 518-519 (2001) and
references therein).
##STR00016##
[0212] Intermediates 2-2 and 2-3 of the present invention wherein
R.sup.a, p, and A.sup.3 are as defined in the claims can be
prepared as shown in Scheme 2. 2-Cyanoiodobenzenes 2-1 can be
purchased or prepared according to the procedures outlined in
Scheme 1. Compounds 2-2 are prepared via a Suzuki or Stille
reaction or variation thereof employing palladium catalyzed cross
coupling of iodide 2-1 with an appropriately substituted aryl- or
heteroaryl-boronic acid, -boronate ester or -trialkyl tin as
described in Miyaua et al., Chem. Rev. 95, 2457 (1995) and
references cited within and as described in Smith, M. B. and March,
J. "March's Advanced Organic Chemistry", 5.sup.th Ed., John Wiley
and Sons, New York, pp. 868-869 (2001) and references cited
therein. Reduction of nitrile 2-2 is accomplished with lithium
aluminum hydride in diethyl ether to afford 2-aminomethyl aniline
2-3. Alternatively, the nitrile can be reduced with palladium on
carbon or Raney nickel under hydrogen atmosphere in methanol,
ethanol or the like. Other methods for reduction of a nitrile to an
aminomethyl group can be found in Smith, M. B. and March, J.
"March's Advanced Organic Chemistry", 5.sup.th Ed., John Wiley and
Sons, New York, pp. 1204 (2001) and references therein.
##STR00017##
[0213] Compounds 3-4 of the present invention wherein R, R.sup.a,
p, A.sup.2, A.sup.3 and n are as defined in the claims can be
prepared according to the procedure outlined in Scheme 3. Benzyl
amines 3-1 can be purchased or prepared according to the procedure
outlined in Scheme 2. Reaction of 3-1 with an appropriately
substituted alkyl acetate bearing a leaving group at the 2-position
affords secondary amine 3-2. Alkyl acetates can be purchased or
prepared using known methods. The preferred leaving group is
bromide or iodide, but may also be mesylate, tosylate or the like
and the solvent may be dichloromethane, dichloroethane,
tetrahydrofuran, dimethoxyethane, or the like. The reaction may be
run with or without a base such as triethylamine,
diisopropylethylamine, N-methylmorpholine, or the like. Reduction
of the ester functionality of 3-2 affords amino alcohol 3-3. The
preferred reducing reagent is LiAlH.sub.4, in a solvent such as
ether, tetrahydrofuran, dimethoxyethane, dioxane, or the like.
Other methods for reduction of an ester can be found in "March's
Advanced Organic Chemistry" 5.sup.th Ed., John Wiley and Sons, New
York, pp 1551. Amino alcohol 3-3 can be cyclised to oxazolidinone
34 using phosgene (Y=Cl) or a phosgene equivalent such as
triphosgene, (Y.dbd.OCCl.sub.3) or carbonyl-diimidazole
(Y=imidazole) or the like in a solvent such as dichloromethane,
dichloroethane, tetrahydrofuran, dimethoxyethane, or the like and a
base such as triethylamine, diisopropylethylamine,
N-methylmorpholine, or the like. Enantiopure products may be
obtained via chiral chromotography.
##STR00018##
[0214] Compounds of the present invention 4-3 wherein R, R.sup.a,
p, A.sup.2, A.sup.3 and n are as defined in the claims can be
prepared as shown in Scheme 4. An appropriately substituted
benzylamine 4-1 can be reacted with an appropriately substituted
oxirane to give amino alcohol 4-2. The oxiranes may be purchased or
prepared from the corresponding aldehyde and a sulfur ylide as
described in "March's Advanced Organic Chemistry" 5.sup.th Ed.,
John Wiley and Sons, New York, pp 1247. Alternatively the epoxide
may be made from epoxidation of an olefin, cyclization of a
halohydrin or 1,2-diol, or other methods described in "March's
Advanced Organic Chemistry" 5.sup.th Ed., John Wiley and Sons, New
York, pp 1051. The preferred solvent for this reaction is
isopropanol. Alternatively, the epoxide opening may be carried out
in a solvent such as acetonitrile or the like with the aid of a
Lewis Acid catalyst such as Yb(OTf).sub.3 or the like. Amino
alcohol 4-2 can be cyclised to oxazolidinone 4-3 using phosgene
(Y=Cl) or a phosgene equivalent such as triphosgene
(Y.dbd.OCCl.sub.3) or carbonyl-diimidazole (Y=imidazole) or the
like in a solvent such as dichloromethane, dichloroethane,
tetrahydrofuran, dimethoxyethane, or the like and a base such as
triethylamine, diisopropylethylamine, N-methylinorpholine, or the
like. Alternatively, aminoalcohol 4-2 can be converted to an
appropriate carbamate by treatment with reagents such as dibenzyl
dicarbonate or benzyl chloroformate in the presence of bases such
as triethylamine, diisopropylethylamine or the like in solvents
such as dichloromethane, dichloroethane, tetrahydrofuran,
dimethoxyethane or the like. The carbamates can then be converted
into oxazolidinones 4-3 by treating with bases like lithium-,
sodium- or potassium hexamethyldisilazide in solvents like
tetrahydrofuran, dimethoxyethane or the like. Enantiopure products
may be obtained via chiral chromatography.
##STR00019##
[0215] Compounds of the present invention 5-5 wherein R, R.sup.a,
p, A.sup.2, A.sup.3 and n are as defined in the claims can be
prepared as shown in Scheme 5. Appropriately substituted
aminoalcohol 5-1 can be prepared as shown in Scheme 4 and
preferentially protected as a carbamate such as t-butyl carbamate
(BOC) or benzyl carbamate (Cbz). Other carbamate and alternative
protecting groups for nitrogen can be found in "Protective Groups
in Organic Synthesis", 3.sup.rd Ed. John Wiley and Sons, New York,
pp 494. Protection of the nitrogen with a BOC or Cbz group can be
carried out by reaction of 5-1 with di-t-butyldicarbonate or
dibenzyldicarbonate in an appropriate solvent such as
dichloromethane, dichloroethane, tetrahydrofuran, dimethoxyethane,
or the like. Alcohol 5-2 can be converted to azide 5-3 by reaction
with methanesulfonyl chloride in dichloromethane, dichloroethane,
tetrahydrofuran, dimethoxyethane, or the like in the presence of an
appropriate base such as triethylamine, diisopropylethylamine,
N-methylmorpholine, or the like. Alternatively, the alcohol may be
converted to an alternative leaving group, such as tosylate,
iodide, bromide, or the like. The mesylate is then displaced by an
azide source, such as NaN.sub.3, LiN.sub.3, Bu.sub.4NN.sub.3 or the
like in an appropriate solvent, such as DMF, DMPU, or the like.
Azide 5-3 can also be prepared by treatment of alcohol 5-2 with
diphenylphosphoryl azide, diethylazodicarboxylate and
triphenylphosphine in THF. Azide 5-3 can be reduced by
hydrogenation over a metal catalyst such as PtO.sub.2 or Pd/C or
the like in an appropriate solvent, such as EtOAc, THF, EtOH, or
the like. Following reduction and removal of the protecting group
diamine 5-4 is obtained. For the BOC protecting group,
TFA/CH.sub.2Cl.sub.2 is the preferred method of removal; for the
CBZ protecting group, hydrogenation over a metal catalyst, such as
PtO.sub.2 or Pd/C or the like in an appropriate solvent, such as
EtOAc, THF, EtOH, or the like is the preferred method of removal.
Diamines 5-4 are cyclized to imidazolidinones 5-5 using phosgene
(Y=Cl) or a phosgene equivalent such as triphosgene
(Y.dbd.OCCl.sub.3) or carbonyldiimidazole (Y-imidazole) or the like
in a solvent such as dichloromethane, dichloroethane,
tetrahydrofuran, dimethoxyethane, or the like and a base such as
triethylamine, diisopropylethylamine, N-methylmorpholine, or the
like. Enantiopure products may be obtained via chiral
chromatography.
##STR00020##
[0216] Compounds of the present invention 6-4 wherein R, R.sup.a,
p, A.sup.2, A.sup.3 and n are as defined in the claims can be
prepared as shown in Scheme 6. Treatment of 6-1 with an
appropriately substituted protected aminoaldehyde which can be
purchased or prepared by known methods in the presence of a
reducing agent such as sodium borohydride, sodium cyanoborohydride,
sodium triacetoxyborohydride or the like in methanol, ethanol,
dichloroethane, tetrahydrofuran or the like or according to methods
described in Smith, M. B. and March, J. "March's Advanced Organic
Chemistry", 5.sup.th Ed., John Wiley and Sons, New York, pp.
1187-1189 (2001) and references cited therein affords 6-2.
Preferred conditions for this transformation are sodium
cyanoborohydride in methanol with catalytic acetic acid.
Deprotection of 6-2 affords 6-3. For the BOC protecting group,
TFA/CH.sub.2Cl.sub.2 is the preferred method of deprotection.
Diamines 6-3 are then cyclized to imidazolidinones 6-4 using
phosgene (Y=Cl) or a phosgene equivalent such as triphosgene
(Y=OCCl.sub.3) or carbonyl-diimidazole (Y=imidazole) or the like in
a solvent such as dichloromethane, dichloroethane, tetrahydrofuran,
dimethoxyethane, or the like and a base such as triethylamine,
diisopropylethylamine, N-methylmorpholine, or the like. Enantiopure
products may be obtained using chiral chromatography.
##STR00021##
[0217] Compounds of the present invention 7-5 wherein R, R.sup.a,
p, A.sup.2, A.sup.3 and n are as defined in the claims can be
prepared as shown in Scheme 7. Treatment of amine 7-1, prepared as
described in Scheme 4 with an appropriate dicarbonate or
chloroformate affords 7-2. 7-2 can be converted to azide 7-3 by
reaction with methanesulfonyl chloride in dichloromethane,
dichloroethane, tetrahydrofuran, dimethoxyethane, or the like in
the presence of an appropriate base such as triethylamine,
diisopropylethylamine, N-methylmorpholine, or the like.
Alternatively, the alcohol may be converted to an alternative
leaving group, such as tosylate, iodide, bromide, or the like. The
mesylate is then displaced by an azide source, such as NaN.sub.3,
LiN.sub.3, Bu.sub.4NN.sub.3 or the like in an appropriate solvent,
such as DMF, DMPU, or the like. Azide 7-3 can also be prepared by
treatment of alcohol 5-2 with diphenylphosphoryl azide,
diethylazodicarboxylate and triphenylphosphine in THF. Azide 7-3
can be reduced to amine 7-4 with H.sub.2 over PtO.sub.2 with THF as
a solvent when R.sub.4 is benzyl. Cyclization of 7-4 to
imidazolidinones 7-5 is accomplished through the use of an
appropriate base, such as lithium diisopropylamide or lithium-,
sodium-, or potassium bis(trimethylsilyl)amide or the like in an
appropriate solvent, such as THF, dimethoxyethane, DMF, DMA, or the
like. Enantiopure products may be obtained via chiral
chromatography.
##STR00022##
[0218] Compound 8-1 (prepared as described in Schemes 5, 6, and 7)
wherein R, R.sup.a, A.sup.2, A.sup.3, p, and n are as defined in
the claims can be converted to 8-2 by treatment with an appropriate
alkylating agent such as an alkyl halide, alkyl tosylate, alkyl
mesylate, or the like (for example methyl iodide) in an appropriate
solvent such as THF, dimethoxyethane, DMF, DMA, or the like, in the
presence of an appropriate base, such as lithium diisopropylamide
or lithium-, sodium-, or potassium bis(trimethylsilyl)amide or the
like.
##STR00023##
[0219] Intermediates 9-3 and 9-4 wherein R.sup.a, p, and A.sup.3
are as defined in the claims utilized in the present invention can
be prepared as shown in Scheme 9. An appropriately substituted
benzyl nitrile 9-1 prepared as shown in Scheme 2 can be heated with
a base such as sodium hydroxide or potassium hydroxide or the like
in an appropriate aqueous alcohol such as ethanol, propanol or the
like to afford the appropriately substituted benzoic acid 9-2 (See:
Smith, M. B. and March, J. "March's Advanced Organic Chemistry",
5.sup.th Ed., John Wiley and Sons, New York, pp. 1179-1180 (2001)
and references therein). Benzoic acids 9-2 can be reduced to benzyl
alcohols 9-3 with reducing agents such as borane in solvents such
as tetrahydrofuran or the like (See: Smith, M. B. and March, J.
"March's Advanced Organic Chemistry", 5.sup.th Ed., John Wiley and
Sons, New York, pp. 1549 (2001) and references therein).
Alternatively, 9-2 can be esterified by known methods including
treatment with trimethylsilyldiazomethane and the resulting ester
reduced to alcohol 9-3 with LiAlH.sub.4 or the like. Intermediates
9-3 can be transformed into benzyl bromides 9-4 using reagents such
as triphenylphosphine and carbon tetrabromide in solvents such as
dichloromethane, dichloroethane or the like (See: Smith, M. B. and
March, J. "March's Advanced Organic Chemistry", 5.sup.th Ed., John
Wiley and Sons, New York, pp. 518-519 (2001) and references
therein).
##STR00024##
[0220] Intermediates 10-4 of the present invention wherein R,
R.sup.1, A.sup.2, p, and n are as defined in the claims can be
prepared as shown in Scheme 10 from an appropriately substituted
benzaldehyde 10-1 by condensation with a nitroalkane to afford the
substituted nitroalcohol 10-2. This reaction may be catalyzed by
aqueous bases such as sodium hydroxide or the like in solvents such
as ethanol, methanol or the like. Nitroalcohols 10-2 can be reduced
to aminoalcohols 10-3 with reductants such as Raney nickel,
palladium on activated carbon or platinum oxide in the presence of
hydrogen gas and aqueous acid in alcoholic solvents such as
methanol, ethanol or the like (See: Langer, O., et al., Bioorg.
Med. Chem., 2001, 9, 677-694). Aminoalcohols 10-3 can be cyclised
to oxazolidinones 10-4 using reagents such as phosgene (Y=Cl),
triphosgene (Y=OCCl.sub.3) or carbonyl diimidazole (Y=imidazole)
with bases such as triethylamine, diisopropylethylamine or the like
in solvents like dichloromethane, dichloroethane, tetrahydrofuran,
dimethoxyethane or the like.
##STR00025##
[0221] Intermediates 11-4 of the present invention wherein R,
R.sup.1, A.sup.2, p and n are as defined in the claims can be
prepared as shown in scheme 11. Treatment of an
N-carbamoyl-(N-methoxy-N-methyl)amide of an amino acid 11-1 which
can be purchased or prepared by known methods with a Grignard or
other organometallic reagent such as an organolithium affords the
corresponding ketone 11-2. Reduction of the ketone with sodium
borohydride or zinc borohydride in alcoholic solvents or THF or the
like or with other reducing agents such as phenyldimethyl silane in
THF affords alcohol 11-3 which can be cyclized to oxazolidinone
11-4 upon treatment with base such as KOH in solvents such as MeOH,
EtOH or the like and THF, dioxane, dimethoxyethane or the like.
##STR00026##
[0222] Compounds of the present invention 12-3 wherein R, R.sup.1,
R.sup.a, A.sup.2, A.sup.3, p and n are as defined in the claims can
be prepared as shown in Scheme 12. Oxazolidinones 12-2, prepared as
shown in Schemes 10 and 11 can be alkylated with benzyl bromides
12-1 which is prepared as shown in Scheme 9 using bases such as
sodium hexamethyldisilazide or sodium hydride in solvents like
tetrahydrofuran, dimethoxyethane, diethyl ether, dimethylformamide,
dimethylacetamide, or the like to afford products 12-3.
##STR00027##
[0223] Compounds of the present invention 13-4 wherein R, R.sup.1,
R.sup.a, A.sup.2, A.sup.3, p and n are as defined in the claims can
be prepared as shown in Scheme 13. Oxazolidinones 13-2, prepared as
shown in Schemes 10 and 11 can be alkylated with benzyl bromides
13-1 which can be prepared as shown in Scheme 1 using bases such as
sodium hexamethyldisiliazide or sodium hydride in solvents like
tetrahydrofuran, dimethoxyethane, diethyl ether or the like to
afford products 13-3. Compounds 13-4 are then prepared via a Suzuki
or Stille reaction or variation thereof employing palladium
catalyzed cross coupling of iodide 13-3 with an appropriately
substituted aryl- or heteroaryl-boronic acid, -boronate ester or
-trialkyl tin as described in Miyaua et al., Chem. Rev. 95, 2457
(1995) and references cited within and as described in Smith, M. B.
and March, J. "March's Advanced Organic Chemistry", 5.sup.th Ed.,
John Wiley and Sons, New York, pp. 868-869 (2001) and references
cited therein.
##STR00028##
[0224] Compounds 14-5 of the present invention wherein R, R.sup.a,
A.sup.2, A.sup.3, p and n are as defined in the claims can be
prepared as shown in Scheme 14. Benzyl alcohols 14-1 can be
purchased or prepared according to the procedure outline in Scheme
9. Reaction of 14-1 with the Dess-Martin periodinane affords the
corresponding benzylaldehydes 14-2. Other methods for oxidizing a
primary hydroxyl group to an aldehyde can also be used, for
example, Swern oxidation conditions, tetrapropylammonium
perruthenate, pyridinium chlorochromate, sulfur trioxide-pyridine,
or the like. 2-Amino-1-phenylethanols 14-3 can be prepared from
14-2 via the corresponding silylated cyanohydrin by treatment with
trimethylsilyl cyanide and catalytic zinc iodide followed by
reduction with lithium aluminum hydride or the like reducing agent.
Alternatively, 2-amino-1-phenylethanols 14-3 can be prepared from
14-2 via the corresponding cyanohydrin by treatment with potassium
cyanide followed by reduction. 2-Amino-1-phenylethanols 14-3 can be
cyclized to oxazolidinones 14-4 using reagents such as phosgene
(Y=Cl), triphosgene (Y=OCCl.sub.3) or carbonyl diimidazole
(Y=imidazole) with bases such as triethylamine,
diisopropylethylamine or the like in solvents like dichloromethane,
dichloroethane, tetrahydrofuran, dimethoxyethane or the like.
Oxazolidinones 14-4 can be alkylated with alkyl, heteroalkyl, aryl,
or heteroaryl bromides using bases such as sodium
hexamethyldisiliazide or sodium hydride in solvents like
tetrahydrofuran, dimethoxyethane, diethyl ether or the like to
afford products 14-5. Enantiopure products may be obtained via
chiral chromatography.
##STR00029##
[0225] Compounds 15-6 of the present invention wherein R, R.sup.1,
R.sup.a, A.sup.2, A.sup.3, p and n are as defined in the claims can
be prepared as shown in Scheme 15. Aldehydes 15-1 can be purchased
or prepared according to the procedure outline in Scheme 1.
Condensation of 15-1 with a nitroalkane affords the substituted
nitroalcohols 15-2. This reaction may be catalyzed by aqueous bases
such as sodium hydroxide or the like in solvents such as ethanol,
methanol, or the like. Nitroalcohols 15-2 can be reduced to
aminoalcohols 15-3 with reductants such as Raney nickel, palladium
on activated carbon, or platinum oxide in the presence of hydrogen
gas and aqueous acid in alcoholic solvents such as methanol,
ethanol or the like (See: Langer, O., et al., Bioorg. Med. Chem.,
2001, 9, 677-694). Aminoalcohols 15-3 can be cyclized to
oxazolidinones 15-4 using reagents such as phosgene (Y=Cl),
triphosgene (Y=OCCl.sub.3) or carbonyl diimidazole (Y=imidazole)
with bases such as triethylamine, diisopropylethylamine or the like
in solvents like dichloromethane, dichloroethane, tetrahydrofuran,
dimethoxyethane or the like. Oxazolidinones 15-5 are prepared via a
Suzuki or Stille reaction or variation thereof employing palladium
catalyzed cross coupling of iodides 15-4 with appropriately
substituted aryl- or heteroaryl-boronic acids, -boronate esters or
-trialkyl tin compounds, as described in Miyaura et al., Chem. Rev.
95, 2457 (1995) and references cited within, and as described in
Smith, M. B. and March, J. "March's Advanced Organic Chemistry",
5.sup.th Ed., John Wiley and Sons, New York, pp. 868-869 (2001) and
references cited therein. Oxazolidinones 15-5 can be alkylated with
alkyl, heteroalkyl, aryl, or heteroaryl bromides using bases such
as sodium hexamethyldisiliazide or sodium hydride in solvents like
tetrahydrofuran, dimethoxyethane, diethyl ether or the like to
afford products 15-6. Enantiopure products may be obtained via
chiral chromatography.
##STR00030##
[0226] Compounds 16-5 of the present invention wherein R, R.sup.1,
R.sup.a, A.sup.2, A.sup.3, p and n are as defined in the claims can
be prepared as shown in Scheme 16. Aldehydes 16-1 can be purchased
or prepared according to the procedure outline in Scheme 1.
Condensation of 16-1 with chiral N-acyloxazolidinones affords the
aldol adducts 16-2, as described in Evans, D. A. et al., J. Am.
Chem. Soc., 2002, 124, 392-3. The chiral N-acyloxazolidinones can
be purchased or prepared as described in Ager, D. J.; Allen, D. A.;
Schaad, D. R. Synthesis 1996, 1283-5. Compounds 16-2 can be
hydrolyzed to the corresponding acids and then treated with
diphenylphosphorazidate and a trialkylamine base to effect a
Curtius rearrangement, affording chiral oxazolidinones 16-3.
Oxazolidinones 16-4 are prepared via a Suzuki or Stille reaction or
variation thereof employing palladium catalyzed cross coupling of
iodides 16-3 with appropriately substituted aryl- or
heteroaryl-boronic acids, -boronate esters or -trialkyl tin
compounds, as described in Miyaura et al., Chem. Rev. 95, 2457
(1995) and references cited within, and as described in Smith, M.
B. and March, J. "March's Advanced Organic Chemistry", 5.sup.th
Ed., John Wiley and Sons, New York, pp. 868-869 (2001) and
references cited therein. Oxazolidinones 16-4 can be alkylated with
alkyl, heteroalkyl, aryl, or heteroaryl bromides using bases such
as sodium hexamethyldisiliazide or sodium hydride in solvents like
tetrahydrofuran, dimethoxyethane, diethyl ether or the like to
afford products 16-5. Alternatively, oxazolidinones 16-3 are
alkylated with the appropriate bromides to afford compounds 16-6,
which are subjected to a Suzuki or Stille reaction or variation
thereof with appropriately substituted aryl- or heteroaryl-boronic
acids, -boronate esters or -trialkyl tin compounds to afford
products 16-5.
Example 1
##STR00031##
[0227] 2-Amino-5-(trifluoromethyl)benzonitrile
[0228] A 2-liter flask was charged with 100 g (0.348 mol) of
4-amino-3-iodobenzotrifluoride, 40 g of CuCN and 750 mL of DMF. The
mixture was heated to and then maintained at reflux for 1 hour. The
reaction was cooled and poured into 3 L of water containing 300 mL
of concentrated ammonium hydroxide. To the mixture was added 1 L
CH.sub.2Cl.sub.2. The mixture was then filtered through celite. The
layers were separated and the aqueous layer was back extracted with
CH.sub.2Cl.sub.2. The organic extracts were combined and the
solvent removed under reduced pressure. The residue was dissolved
in 1.5 L of ether and the resulting solution was washed with 1N
ammonium hydroxide, aqueous sodium bisulfite, 1N aqueous HCl and
brine. The solution was dried over anhydrous MgSO.sub.4 and
filtered through a silica gel plug containing a layer of MgSO.sub.4
on top. The plug was washed with 0.5 L ether. The ether solutions
were combined and concentrated to 750 mL and let stand at room
temperature. After 2 days the resulting solids were collected,
washed with hexanes and dried under reduced pressure to afford
2-amino-5-(trifluoromethyl)benzonitrile .sup.1H NMR (CDCl.sub.3,
500 MHz) .delta. 7.68 (s, 1H), 7.58 (d, J=8.5 Hz, 1H), 6.81 (d,
J=8.5 Hz, 1H), 4.80 (br s, 2H).
Example 2
##STR00032##
[0229] 2-Iodo-5-(trifluoromethyl)benzonitrile
[0230] To a solution of 2-amino-5-(trifluoromethyl)benzonitrile
(15.1 g) and diiodomethane (24 mL) in acetonitrile (150 mL) at
35.degree. C. was added t-butyl nitrite (21 mL) dropwise. The
reaction was maintained at 30-35.degree. C. during the addition.
The reaction was aged for 30 min and then was heated to 60.degree.
C. for 30 minutes. The reaction mixture was cooled, diluted with
ether and washed 2.times. with water, 2.times. with aqueous sodium
bisulfite, water and then brine. The solution was dried over
anhydrous MgSO.sub.4, filtered through a silica gel plug and then
concentrated giving 100 g of a red oil. The product was purified by
silica gel chromatography eluting sequentially with hexanes, 3:1
hexanes/CH.sub.2Cl.sub.2 and 1:1 hexanes/CH.sub.2Cl.sub.2 to afford
2-iodo-5-(trifluoromethyl)benzonitrile. .sup.1H NMR (CDCl.sub.3,
500 MHz) .delta. 8.10 (d, J=8.5 Hz, 1H), 7.85 (d, J=1.8 Hz, 1H),
7.52 (dd, J=8.5, 1.8 Hz, 1H).
Example 3
##STR00033##
[0231]
5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile
[0232] To a solution of 2-iodo-5-(trifluoromethyl)benzonitrile (2.0
g, 6.7 mmol) and (5-isopropyl-2-methoxyphenyl)boronic acid (1.6 g,
8.4 mmol) in dimethyl ethylene glycol (30.4 mL) was added 2M
Na.sub.2CO.sub.3 (6.8 mL), ethanol (9.6 mL), and water (10 mL). The
solution was degassed with nitrogen for 2 minutes.
Pd(PPh.sub.3).sub.4 (774 mg, 0.67 mmol) was added and the solution
was degassed with nitrogen again for 2 minutes. The solution was
divided equally into two 40 mL microwave tubes. Each tube was
degassed with nitrogen for 1 minute, sealed, and placed in a
microwave reactor. The wattage was set for 200 W until the
temperature reached 150.degree. C. and then the temperature was
held at 150.degree. C. for ten minutes. The tubes were then cooled
to room temperature, combined, poured into H.sub.2O (50 mL), and
extracted with EtOAc (100 mL). The organic layer was washed with
brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification by flash chromatography with 15%
CH.sub.2Cl.sub.2/hexanes afforded
5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile
as a light yellow oil. R.sub.f=0.65 (25% EtOAc/hexanes). .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 7.97 (s, 1H), 7.85 (d, J=8.0 Hz,
1H), 7.63 (d, J=8.0 Hz, 1H), 7.31 (dd, J=8.5, 2.0 Hz, 1H), 7.12 (d,
J=2.0 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 3.82 (s, 3H), 2.93 (m, 1H),
1.27 (d, J=7.0 Hz, 6H).
Example 4
##STR00034##
[0233]
1-[5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methana-
mine
[0234]
5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile
(996.2 mg, 3.12 mmol) was dissolved in Et.sub.2O (33 mL) and cooled
to 0.degree. C. LAH (12.49 mL of a 1 M solution in Et.sub.2O, 12.49
mmol) was added dropwise by syringe. After stirring at 0.degree. C.
for 10 minutes, the reaction was warmed to room temperature and
stirred at room temperature for 6 hours. The reaction was then
quenched by slow dropwise addition of 1.5 mL of H.sub.2O (vigorous
evolution of gas), followed by 1.5 mL of 30% NaOH, followed by 3.0
mL of H.sub.2O. The resulting gelatinous precipitate was washed
with 5.times.20 mL of CH.sub.2Cl.sub.2; the organic washes were
dried over Na.sub.2SO.sub.4, filtered and concentrated.
Purification of the residue by flash chromatography with 2%
MeOH/CH.sub.2Cl.sub.2 containing 0.1% Et.sub.3N afforded
1-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanamine.
R.sub.f=0.30 (10% MeOH/CH.sub.2Cl.sub.2). LCMS=324.3 (M+1).sup.+.
.sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 7.77 (s, 1H), 7.55 (d,
J=6.8 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 7.25 (dd, J=8.3, 2.1 Hz,
1H), 7.00 (d, J=2.1 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 3.66-3.74 (m,
5H), 2.91 (m, 1H), 1.26 (d, J=6.9 Hz, 6H).
Example 5
##STR00035##
[0235]
4-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4-(t-
rifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one
Step A: methyl [3,5-bis(trifluoromethyl)phenyl](hydroxy)acetate
[0236] To solution of
[3,5-bis(trifluoromethyl)phenyl](hydroxy)acetic acid (510 mg, 1.77
mmol) in benzene (10 mL) was added MeOH (1.5 mL) followed by
(trimethylsilyl)diazomethane (1.06 mL of a 2M solution in hexanes,
2.12 mmol). After 10 minutes, the reaction was quenched with
several drops of HOAc (add until yellow color disappears). The
reaction was concentrated and purified by flash chromatography with
10 to 80% EtOAc/hexanes to afford methyl
[3,5-bis(trifluoromethyl)phenyl](hydroxy)acetate. .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 7.94 (s, 2H), 7.85 (s, 1H), 5.32 (s,
1H), 3.83 (s, 3H), 3.68 (bs, 1H).
Step B: methyl [3,5-bis(trifluoromethyl)phenyl](bromo)acetate
[0237] Methyl [3,5-bis(trifluoromethyl)phenyl](hydroxy)acetate (300
mg, 0.993 mmol) was dissolved in CH.sub.2Cl.sub.2 (10 mL). The
solution was cooled to 0.degree. C. and CBr.sub.4 (659 mg, 1.986
mmol) was added followed by PPh.sub.3 (521 mg, 1.986 mmol). After 1
hour, the reaction was warmed to room temperature and stirred at
room temperature for 1 hour. The reaction was filtered through a
short plug of silica gel with CH.sub.2Cl.sub.2. The filtrate was
concentrated and the residue was purified by flash chromatography
with 5% EtOAc/hexanes to afford methyl
[3,5-bis(trifluoromethyl)phenyl](bromo)acetate. R.sub.f=0.24 (5%
EtOAc/hexanes). .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 8.02 (s,
2H), 7.87 (s, 1H), 5.41 (s, 1H), 3.83 (s, 3H).
Step C:
methyl[3,5-bis(trifluoromethyl)phenyl]({[5'-isopropyl-2'-methoxy-4-
-(trifluoromethyl)biphenyl-2-yl]methyl}amino)acetate
[0238] To a flask containing methyl
[3,5-bis(trifluoromethyl)phenyl](bromo)acetate (237.7 mg, 0.651
mmol) was added
1-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methena-
mine (102.1 mg, 0.316 mmol) in CH.sub.2Cl.sub.2 (4 mL). The
reaction was stirred at room temperature for 5 hours and then
diluted with EtOAc (50 ml). The organic solution was washed with
water and brine (15 mL each). The organic extract was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography (5 to 15% EtOAc/hexanes) afforded
methyl[3,5-bis(trifluoromethyl)phenyl]
({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)-
acetate. R.sub.f=0.33 (15% EtOAc/hexanes). LCMS=608.4 (M+1).sup.+.
.sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 7.76-7.79 (m, 3H), 7.62
(s, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.23 (dd,
J=8.2, 1.9 Hz, 1H), 6.96 (m, 1H), 6.89 (d, J=8.5 Hz, 1H), 4.30 (m,
1H), 3.54-3.70 (m, 8H), 2.87 (m, 1H), 1.21-1.23 (m, 6H).
Step D:
2-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methoxy-4--
(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol
[0239] A solution of
methyl[3,5-bis(trifluoromethyl)phenyl]({[5'-isopropyl-2'-methoxy-4-(trifl-
uoromethyl)biphenyl-2-yl]methyl}amino)acetate (13.2 mg, 0.0217
mmol) was dissolved in Et.sub.2O (1.5 mL) and cooled to 0.degree.
C. LAH (108.5 .mu.L of a 1 M solution in LAH, 0.1085 mmol) was
added dropwise by syringe. The reaction was warmed to room
temperature and stirred at room temperature for 1 hour. The
reaction was then quenched by addition of H.sub.2O (100 .mu.L)
followed by 1 N NaOH (100 .mu.L), followed by H.sub.2O (300 .mu.L).
The gelatinous precipitate was washed several times with
CH.sub.2Cl.sub.2. The organic washes were filtered through a plug
of silica gel with 2% MeOH/CH.sub.2Cl.sub.2 and the filtrate was
concentrated. Purification of the residue by PTLC with 25%
EtOAc/hexanes afforded
2-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methoxy--
4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol. R.sub.f=0.27
(25% EtOAc/hexanes). LCMS=580.4 (M+1).sup.+. .sup.1H NMR
(CD.sub.2Cl.sub.2, 500 MHz) .delta. 7.79 (s, 1H), 7.75 (s, 2H),
7.63-7.68 (m, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H),
7.23 (m, 1H), 6.94 (m, 1H), 6.89 (m, 1H), 3.43-3.76 (m, 9H), 2.86
(m, 1H), 1.90 (bs, 1H), 1.20 (d, J=6.8 Hz, 6H).
Step E:
4-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4-(-
trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one
[0240] To a solution of phosgene (21 .mu.L of a 20% solution in
toluene, .about.0.0535 mmol) in CH.sub.2Cl.sub.2 (0.5 mL) was added
2-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methoxy-4-(triflu-
oromethyl)biphenyl-2-yl]methyl}amino)ethanol (3.1 mg, 0.00535 mmol)
in CH.sub.2Cl.sub.2 (0.5 mL), followed by DIPEA (19 .mu.L, 0.107
mmol). After stirring for 5 minutes, the reaction was poured into
water (1 mL) and the mixture was extracted with EtOAc (20 mL). The
organic extract was washed with H.sub.2O, saturated NaHCO.sub.3,
and brine (5 mL each). The organic layer was then dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by PTLC to afford
4-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4-(trifluo-
romethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one. R.sub.f=0.27
(25% EtOAc/hexanes). LCMS=606.3 (M+1).sup.+. .sup.1H NMR
(CD.sub.2Cl.sub.2, 500 MHz) (Doubling of some peaks observed;
atropisomers present in 1:1 ratio) .delta. 7.84 (s, 1M), 7.19-7.60
(m, 6H), 6.80-6.87 (m, 2H), 3.84-4.68 (m, 5H), 3.68 & 3.64 (2
singlets, 3H), 2.82 (m, 1H), 1.17-1.21 (m, 6H).
Example 6
##STR00036##
[0241]
5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4-(t-
rifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one
Step A: 2-[3,5-bis(trifluoromethyl)phenyl]oxirane
[0242] In a dry flask was placed NaH (1.09 g of 60% NaH, 27.27
mmol). DMSO (90 mL) was added followed by trimethylsulfoxonium
iodide (7.0 g, 31.82 mmol). The reaction was stirred for 5 minutes
and then 3,5-bis(trifluoromethyl)benzaldehyde (1.5 mL, 9.09 mmol)
was added as a solution in DMSO (15 mL). The reaction was stirred
at room temperature for 1 hour and then poured into ice/water (300
mL). The mixture was extracted with pentanes (3.times.150 mL). The
pentane extracts were combined and filtered through a short plug of
silica gel with 10% Et.sub.2O/pentanes. The filtrate was
concentrated and the residue was purified by flash chromatography
with 10% Et.sub.2O/pentanes to give
2-[3,5-bis(trifluoromethyl)phenyl]oxirane. R.sub.f=0.42 (10%
Et.sub.2O/pentanes). .sup.1H NMR (CDCl.sub.3, 500 MHz) 7.82 (s,
1H), 7.74 (s, 2H), 3.99 (dd, J=3.9, 2.5 Hz, 1H), 3.23 (dd, J=5.2,
4.1 Hz, 1H), 2.79 (dd, J=5.5, 2.5 Hz, 1H).
Step B:
1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methoxy-4--
(trifluoroethyl)biphenyl-2-yl]methyl}amino)ethanol
[0243] A solution of
1-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methenamine
(300 mg, 0.929 mmol) and 2-[3,5-bis(trifluoromethyl)phenyl]oxirane
(297 mg, 1.161 mmol) in 2-propanol (9 mL) was heated at reflux for
15 hours and then cooled to room temperature. The solution was
concentrated, and purification of the residue by flash
chromatography with 10 to 80% EtOAc/hexanes afforded
1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methoxy-4-(triflu-
oromethyl)biphenyl-2-yl]methyl}amino)ethanol. R.sub.f=0.24 (25%
EtOAc/hexanes). LCMS=580.3 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3,
500 MHz) .delta. 7.75-7.76 (m, 3H), 7.69 (s, 1H), 7.58 (d, J=7.8
Hz, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.25 (m, 1H), 6.98 (bs, 1H), 6.92
(d, J=8.5 Hz, 1H), 4.62 (m, 1H), 3.65-3.82 (m, 5H), 2.89 (m, 1H),
2.79 (dd, J=12.4, 3.0 Hz, 1H), 2.48 (m, 1H), 1.23 (d, J=6.8 Hz,
6H).
Step C:
5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4-(-
trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one
[0244] To a solution of
1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methoxy-4-(triflu-
oromethyl)biphenyl-2-yl]methyl}amino)ethanol (31.9 mg, 0.0551 mmol)
in CH.sub.2Cl.sub.2 (5 mL) at 0.degree. C. was added DIPEA (67
.mu.L, 0.386 mmol), followed by triphosgene (8.2 mg, 0.0276 mmol).
The reaction was stirred at 0.degree. C. for 30 minutes. The
reaction was then poured into saturated NaHCO.sub.3 (15 mL) and the
mixture was extracted with EtOAc (50 mL). The organic layer was
washed with brine (15 mL), dried over Na.sub.2SO.sub.4, filtered,
and concentrated. Purification of the residue by flash
chromatography (20% EtOAc/hexanes) afforded
5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4-(trifluo-
romethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one. R.sub.f=0.32
(25% EtOAc/hexanes). LCMS=606.3 (M+1).sup.+. .sup.1H NMR
(CD.sub.2Cl.sub.2, 500 MHz) (atropisomers present in 1:1 ratio,
doubling of some peaks) .delta. 7.90 (s, 1H), 7.77 (s, 2H),
7.57-7.62 (m, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.27 (m, 1H), 6.98 (s,
1H), 6.93 (dd, J=8.4, 3.2 Hz, 1H), 5.42-5.53 (m, 1H), 4.15-4.59 (m,
2H), 3.72 & 3.73 (2 singlets, 3H), 3.05-3.65 (m, 2H), 2.88 (m,
1H), 1.19-1.23 (m, 6H). The 2 enantiomers could be separated by
chiral HPLC using 15% IPA/heptanes and an AD chiral column.
Example 7
##STR00037##
[0245]
3-{[5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl-
}-5-pyridin-2-yl-1,3-oxazolidin-2-one
Step A:
2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]meth-
yl}amino)-1-pyridin-2-ylethanol
[0246] A solution of
1-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methenamine
(300 mg, 0.929 mmol) and 2-oxiran-2-ylpyridine (640 mg) [prepared
by reaction of 2-pyridine carboxaldehyde with NaH and
trimethylsulfoxonium iodide in DMSO] in 2-propanol (9 mL) was
heated at reflux for 5 hours and then cooled to room temperature.
The solution was concentrated, and the residue was purified by
flash chromatography with 50 to 100% EtOAc/hexanes containing 0.5%
Et.sub.3N to afford
2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amin-
o)-1-pyridin-2-ylethanol. Analysis by LCMS showed the desired
product contaminated with several minor impurities. This material
was used in the next reaction without further purification or
analysis.
Step B: Benzyl
(2-hydroxy-2-pyridin-2-ylethyl){[5'-isopropyl-2'-methoxy-4-(trifluorometh-
yl)biphenyl-2-yl]methyl}carbamate
[0247] A solution of (PhCH.sub.2OCO).sub.2-0 (103 mg, 0.360 mmol)
in dry CH.sub.2Cl.sub.2 (2 mL) was added by cannula to a stirred
solution of
2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amin-
o)-1-pyridin-2-ylethanol (160 mg, 0.360 mmol) in dry
CH.sub.2Cl.sub.2 (10 mL) at room temperature under N.sub.2. The
reaction was stirred for 2 h at room temperature and concentrated
in vacuo to give the crude product. This was purified by flash
chromatography (Si, 25.times.160 mm, 0-50% EtOAc in hexanes
gradient) to afford benzyl (2-hydroxy-2-pyridin-2-ylethyl)
{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbama-
te. R.sub.f=0.63 (50% EtOAc/hexanes). LCMS calc.=579.25;
found=579.2 (M+1).sup.+.
Step C:
3-{[5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methy-
l}-5-pyridin-2-yl-1,3-oxazolidin-2-one
[0248] A solution of potassium bis(trimethylsilyl)amide (464 .mu.L
of a 0.5M solution in toluene, 0.232 mmol) was added dropwise to a
stirred solution of benzyl
(2-hydroxy-2-pyridin-2-ylethyl){[5'-isopropyl-2'-methoxy-4-(trifluorometh-
yl)biphenyl-2-yl]methyl}carbamate (134.3 mg, 0.232 mmol) in dry THF
(10 mL) at room temperature under N.sub.2. After stirring at room
temperature for 1 h, the reaction was quenched with saturated
NH.sub.4Cl (10 mL) and extracted with EtOAc (3.times.20 mL). The
combined extracts were dried (Na.sub.2SO.sub.4) and concentrated in
vacuo to give the crude product. This was purified by flash
chromatography (Si, 25.times.160 mm, 0-70% EtOAc in hexanes
gradient) to afford
3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-py-
ridin-2-yl-1,3-oxazolidin-2-one. R.sub.f=0.58 (50% EtOAc/hexanes).
LCMS calc.=471.19; found=471.2 (M+1).sup.+.
Example 8
##STR00038##
[0249]
5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carboxylic
acid
[0250] A solution of
5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile
(727 mg, 2.28 mmol) and KOH (767 mg, 13.7 mmol) in H.sub.2O (7.70
mL) and i-PrOH (11.55 mL) was subjected to microwave irradiation
(300 W 130.degree. C., 4 h) in a sealed tube. The reaction mixture
was concentrated in vacuo to remove the i-PrOH. The aqueous slurry
obtained was diluted with water (50 mL) and extracted with EtOAc
(50 mL). The organic extract was dried (Na.sub.2SO.sub.4) and
concentrated in vacuo to afford
5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carboxamide.
The aqueous layer was acidified with concentrated HCl and extracted
with EtOAc (3.times.50 mL). The combined organic extracts were
dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give
5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carboxylic
acid as a colorless solid. .sup.1H NMR (CDCl.sub.3, 500 MHz)
.delta. 8.01 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.41 (d, J=7.8 Hz,
1H), 7.14 (d, J=8.1 Hz, 1H), 7.04 (s, 1H), 6.77 (d, J=8.1, 1H),
3.68 (s, 3H), 2.84 (septet, J=6.7 Hz, 1H), 1.19 (d, J=6.7 Hz,
6H).
Example 9
##STR00039##
[0251]
[5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol
[0252] A solution of borane in THF (1 M, 859 .mu.L, 0.859 mmol) was
added dropwise to a stirred solution of
5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carboxylic
acid and
5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carboxamide
(3:1, 96.8 mg, 0.286 mmol) in dry THF at room temperature under
N.sub.2. The reaction was stirred at room temperature for 3 h and
carefully quenched with water (10 mL). The mixture was extracted
with EtOAc (3.times.20 mL) and the combined extracts were washed
with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo to
give the crude product. This was purified by flash chromatography
(Si, 125.times.160 mm, 0-30% EtOAc in hexanes gradient) to afford
[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol
as a colorless oil. R.sub.f=0.27 (10% EtOAc/hexanes).
[0253] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 7.89 (br s, 1H),
7.62 (dd, J=8.0, 1.3 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.29 (dd,
J=8.5, 2.3 Hz, 1H), 7.03 (d, J=2.3 Hz, 1H), 6.96 (d, J=8.5, 1H),
4.51 (m, 2H), 3.74 (s, 3H), 2.93 (septet, J=7.0 Hz, 1H), 2.51 (s,
1H), 1.29 (d, J=7.0 Hz, 6H).
Example 10
##STR00040##
[0254]
2-(Bromomethyl)-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl
[0255] CBr.sub.4 (112 mg, 0.211 mmol) and Ph.sub.3P (55 mg, 0.211
mmol) were added successively to a stirred solution of
[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol
(57.1 mg, 0.176 mmol) in dry CH.sub.2Cl.sub.2 (1 mL) at 0.degree.
C. under N.sub.2. The solution was stirred at room temperature for
1 h and the reaction mixture was concentrated in vacuo to afford
the crude product. This was purified by flash chromatography (Si,
12.times.160 mm, 0-20% EtOAc in hexanes gradient) to give
2-(bromomethyl)-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl
as a colorless oil. R.sub.f=0.95 (20% EtOAc/hexanes). LCMS
calc.=387.05; found=387.0 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 7.83 (br s, 1H), 7.60 (dd, J=8.0, 1.3 Hz, 1H), 7.37
(d, J=8.0 Hz, 1H), 7.29 (dd, J=8.5, 2.3 Hz, 1H), 7.14 (d, J=2.3 Hz,
1H), 6.95 (d, J=8.5, 1H), 4.45 (d, J=10.6 Hz, 1H), 4.33 (d, J=10.6
Hz, 1H), 3.76 (s, 3H), 2.94 (septet, J=6.9 Hz, 1H), 1.29 (d, J=6.9
Hz, 6H).
Example 11
##STR00041##
[0256] 1-(4-Methylphenyl)-2-nitroethanol
[0257] A stirred solution of 4-methylbenzaldehyde (325 mg, 319
.mu.L, 2.71 mmol) and nitromethane (531 .mu.L, 9.89 mmol) in
absolute EtOH (20 mL) at 0.degree. C. was treated with 10% aq. NaOH
(m/v) (1.14 mL, 2.84 mmol), stirred for 1 h and treated with 2% aq.
acetic acid (n/v) (8.54 mL, 2.84 mmol). The reaction was stirred
for 1 h at room temperature then partitioned between water (50 mL)
and EtOAc (50 mL). The aqueous layer was extracted with EtOAc
(2.times.50 mL) and the combined organic extracts were washed with
saturated NaHCO.sub.3 (50 mL) and brine (50 mL), dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to afford
1-(4-methylphenyl)-2-nitroethanol as a colorless oil. .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 7.28 (d, J=8.1 Hz, 2H), 7.21 (d,
J=8.1 Hz, 2H), 5.42 (dt, J=9.6, 3.3 Hz, 1H), 4.60 (dd, J=13.3, 9.7
Hz, 1H), 4.49 (dd, J=13.3, 3.1 Hz, 1H), 2.79 (d, J=3.7, 1H), 2.36
(s, 3H).
Example 12
##STR00042##
[0258] 2-Amino-1-(4-methylphenyl)ethanol
[0259] A suspension of 10% Pd/C (24 mg) in a solution of
1-(4-methylphenyl)-2-nitroethanol (50 mg, 0.276 mmol) in absolute
EtOH (1 mL) was stirred overnight at room temperature under 15 psi
of H.sub.2. The reaction mixture was filtered through a pad of
Celite and the filtrate was concentrated in vacuo to afford
2-amino-1-(4-methylphenyl)ethanol as an oil. LCMS calc.=152.10;
found=152 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.
7.20 (d, J=8.0 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 4.57 (dd, J=7.9,
3.9 Hz, 1H), 2.86 (dd, J=12.7, 3.9 Hz, 1H), 2.76 (dd, J=12.7, 7.9
Hz, 1H), 2.33 (s, 3H).
Example 13
##STR00043##
[0260] 5-(4-Methylphenyl)-1,3-oxazolidin-2-one
[0261] Diisopropylethylamine (181 mg, 244 .mu.L, 1.40 mmol) and
triphosgene (138 mg, 0.466 mmol) were added successively to a
stirred solution of 2-amino-1-(4-methylphenyl)ethanol (35.2 mg,
0.233 mmol) in dry CH.sub.2Cl.sub.2 (22 mL) at 0.degree. C. under
N.sub.2. The reaction was stirred at 0.degree. C. for 1 h then
concentrated in vacuo to a volume of about 5 mL. The mixture was
diluted with water (50 mL) and extracted with EtOAc (3.times.50
mL). The combined organic extracts were dried (Na.sub.2SO.sub.4)
and concentrated in vacuo to give the crude product. This was
purified by flash chromatography (Si, 12.times.160 mm, 0-80% EtOAc
in hexanes gradient) to afford
5-(4-methylphenyl)-1,3-oxazolidin-2-one. R.sub.f=0.41 (50%
EtOAc/hexanes). LCMS calc.=178.08; found=178.1 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 7.25 (d, J=7.4 Hz, 2H), 7.19 (d,
J=7.4 Hz, 2H), 6.69 (br s, 1H), 5.55 (t, J=7.8 Hz, 1H), 3.93 (t,
J=8.6 Hz, 1H), 3.52 (t, J=8.1 Hz, 1H), 2.35 (s, 3H).
Example 14
##STR00044##
[0263]
3-{[5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl-
}-5-(4-methylphenyl)-1,3-oxazolidin-2-one
[0264] Sodium hydride (6.4 mg of a 60% dispersion in mineral oil,
0.161 mmol) was added to a stirred solution of
5-(4-methylphenyl)-1,3-oxazolidin-2-one (37.7 mg, 0.0973 mmol) in
dry THF (1 mL) at room temperature under N.sub.2. The reaction was
stirred for 30 min and a solution of
2-(bromomethyl)-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl
(19.0 mg, 0.107 mmol) in dry THF (2 mL) was added by cannula. The
reaction was stirred at room temperature for 3 days. The reaction
was quenched with saturated NH.sub.4Cl (10 mL) and extracted with
EtOAc (3.times.20 mL). The combined organic extracts were washed
with brine (10 mL), dried (Na.sub.2SO.sub.4) and concentrated in
vacuo to give the crude product. This was purified by flash
chromatography (Si, 12.times.160 mm, 0-80% EtOAc in hexanes
gradient) to afford
3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-(4-
-methylphenyl)-1,3-oxazolidin-2-one as a colorless oil.
R.sub.f=0.37 (20% EtOAc/hexanes). LCMS calc.=484.21; found=484.2
(M+1).sup.+. .sup.1H NMR (benzene-d.sub.6, 500 MHz, 1:1 mixture of
atropisomers) .delta. 7.76 (s, 0.5H), 7.65 (s, 0.5H), 7.31 (d,
J=7.7 Hz, 1H), 7.08 (dd, J=8.4, 2.4 Hz, 1H), 7.05 (br d, J=7.8 Hz,
1H), 6.95-6.86 (m, 5H), 6.58 (t, J=7.7 Hz, 1H), 4.74 (t, J=8.0 Hz,
0.5H), 4.70 (t, J=8.0 Hz, 0.5H), 4.50 (d, J=15.7 Hz, 0.5H), 4.42
(d, J=15.7 Hz, 0.5H), 4.25 (d, J=15.7 Hz, 0.5H), 4.11 (d, J=15.7
Hz, 0.5H), 3.26 (s, 1.5H), 3.21 (s, 1.5H), 2.81 (t, J=8.6 Hz,
0.5H), 2.76 (septet, J=7.0 Hz, 1H), 2.68 (t, J=8.6 Hz, 0.5H), 2.55
(t, J=8.6 Hz, 0.5H), 2.53 (t, J=8.6 Hz, 0.5H), 2.04 (s, 3H), 1.20
(t, J=7.0 Hz, 3H), 1.19 (t, J=7.0 Hz, 3H).
Example 15
##STR00045##
[0265] 1-[3,5-Bis(trifluoromethyl)phenyl]-2-nitropropan-1-ol
[0266] A stirred solution of 3,5-bis(trifluoromethyl)benzaldehyde
(1.00 g, 4.13 mmol) and nitroethane (1.13 g, 1.08 mL, 15.1 mmol) in
absolute EtOH (20 mL) at 0.degree. C. was treated with 10% aq. NaOH
(m/v) (1.73 mL, 4.34 mmol), stirred for 1 h and treated with 2% aq.
acetic acid (rn/v) (13.0 mL, 4.32 mmol). The reaction was stirred
for 1 h at room temperature then partitioned between water (50 mL)
and EtOAc (50 mL). The aqueous layer was extracted with EtOAc
(2.times.50 mL) and the combined organic extracts were washed with
saturated NaHCO.sub.3 (50 mL) and brine (50 mL), dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to afford a 1.5:1
mixture of threo- and
erythro-1-[3,5-bis(trifluoromethyl)phenyl]-2-nitropropan-1-ol as a
colorless oil. .sup.1H NMR (CDCl.sub.3, 500 MHz)
threo-diastereoisomer: .delta. 7.88 (br s, 1H), 7.86 (br s, 2H),
5.22 (d, J=8.4 Hz, 1H), 4.77 (dq, J=8.4, 6.9 Hz, 1H), 3.03 (br s
1H), 1.42 (d, J=6.9 Hz, 3H), erythro-diastereoisomer: .delta. 7.90
(br s, 1H), 7.86 (br s, 2H), 5.59 (d, J=3.2 Hz, 1H), 4.72 (dq,
J=3.2, 6.9 Hz, 1H), 3.03 (br s 1H), 1.50 (d, J=6.9 Hz, 3H).
Example 16
##STR00046##
[0267] 2-Amino-1-[3,5-bis(trifluoromethyl)phenyl]propan-1-ol
[0268] A suspension of Raney Nickel (50 mg) in a solution of a
1.5:1 mixture of threo- and
erythro-1-[3,5-bis(trifluoromethyl)phenyl]-2-nitropropan-1-ol (50
mg, 0.158 mmol) in 30% (v/v) aqueous HCO.sub.2H (0.75 mL) and MeOH
(10 mL) was stirred overnight at room temperature under 15 psi of
H.sub.2. The reaction mixture was filtered through a pad of Celite
and the filtrate was concentrated in vacuo to remove the MeOH. The
aqueous slurry was adjusted to pH 9-10 with 28% aq NH.sub.4OH,
diluted with water (20 mL) and extracted with EtOAc (3.times.20
mL). The combined extracts were washed with brine (10 mL), dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to afford a mixture of
threo- and
erythro-2-amino-1-[3,5-bis(trifluoromethyl)phenyl]propan-1-ol as
colorless solid. LCMS calc.=288.08; found=288.1 (M+1).sup.+.
.sup.1H NMR (CDCl.sub.3, 500 MHz) threo-diastereoisomer: .delta.
7.79 (br s, 3H), 4.35 (br s, 1H), 3.25 (br s, 1H), 2.59 (br s, 3H),
0.86 (d, J=6.1 Hz, 3H), erythro-diastereoisomer: .delta. 7.79 (br
s, 3H), 4.71 (br s, 1H), 3.00 (br s, 1H), 2.59 (br s, 3H), 1.06 (d,
J=5.0 Hz, 3H).
Example 17
##STR00047##
[0269]
5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
[0270] Diisopropylethylamine (106 mg, 142 .mu.L, 0.817 mmol) and
triphosgene (20.2 mg, 0.068 mmol) were added successively to a
stirred solution of
2-Amino-1-[3,5-bis(trifluoromethyl)phenyl]propan-1-ol (39.1 mg,
0.136 mmol) in dry CH.sub.2Cl.sub.2 (10 mL) at 0.degree. C. under
N.sub.2. The reaction was stirred at 0.degree. C. for 1 h then
concentrated in vacuo to a volume of about 5 mL. The mixture was
diluted with water (50 mL) and extracted with EtOAc (3.times.50
mL). The combined organic extracts were dried (Na.sub.2SO.sub.4)
and concentrated in vacuo to give the crude product. This was
purified by flash chromatography (Si, 12.times.160 mm, 0-70% EtOAc
in hexanes gradient) to afford
threo-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
(17.5 mg) and
erythro-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
(14.4 mg) as colorless solids. threo-diastereoisomer: R.sub.f=0.63
(50% EtOAc/hexanes). LCMS calc.=314.06; found=314.1 (M+1).sup.+.
.sup.1H NMR (CDCl.sub.3, 600 MHz) .delta. 7.90 (br s, 1H), 7.83 (br
s, 2H), 6.71 (br s, 1H), 5.17 (d, J=7.0 Hz, 1H), 3.86 (br pentet,
J=6.2 Hz, 1H), 1.48 (d, J=6.2 Hz, 1H). This compound was separated
into its enantiomers
(4R,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
and
(4S,5S)-5-[3,5-bistrifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-o-
ne using chiral HPLC (AS column, 20.times.250 mm, 20% i-PrOH in
heptane). erythro-diastereoisomer: R.sub.f=0.38 (50%
EtOAc/hexanes). LCMS calc.=314.06; found=314.1 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 600 MHz) .delta. 7.90 (br s, 1H), 7.79 (br s, 2H),
5.83 (d, J=8.0 Hz, 1H), 5.34 (br s, 1H), 4.31 (br pentet, J=7.0 Hz,
1H), 0.84 (d, J=6.6 Hz, 1H). This compound was separated into its
two enantiomers
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
and
(4R,5S)-5-[3,5-bistrifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-o-
ne using chiral HPLC (AS column, 20.times.250 mm, 15% i-PrOH in
heptane).
Chiral Synthesis of
(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
[0271] This intermediate can be made directly from the chiral
starting material CBZ-L-alanine by the 3-step route shown below.
The compound
(4R,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
can be made by an analogous route starting from CBZ-D-alanine.
##STR00048##
[0272] CBZ-L-Alanine (6.5 kg, 28.5 mol), HOBT-hydrate (4.8 kg, 34.8
mol), Weinreb amine-HCl salt (3.4 kg, 36.2 mol) and THF (32 L) are
charged to a clean flask under nitrogen. The mixture is cooled to
0-10.degree. C. and then DIPEA (12.4 L) is slowly added at a
temperature less than 25.degree. C. EDC-HCl (7 Kg, 36.2 mol) is
then added slowly with cooling at 15.degree.-25.degree. C. The
slurry is aged overnight at 20.degree.-25.degree. C. The mixture is
then cooled to 0-10.degree. C. and 3 N HCl (12 L) is added slowly.
Then IPAC (32 L) is added and the layers are separated. The organic
layer is washed once with HCl (13 L) and twice with 8% NaHCO.sub.3
(13 L) (CAUTION:FOAMING). The organic layer is then concentrated
under vacuum to about 15 L at 50.degree. C. The clear solution is
cooled slowly to room temperature, allowing the product to
crystallize. Heptane (.about.70 L) is then added slowly. The slurry
is filtered, washed with heptane (18 L), and dried at room
temperature on the filter pot. Product is obtained with >99.9%
ee measured by chiral HPLC.
##STR00049##
[0273] The Weinreb amide from Step 1 (6 kg, 22.5 mol) and
3,5-bis(trifluoromethyl)bromobenzene (4.85 L, 28.1 mol) are
dissolved in anhydrous THF (24 L). The solution is purged with
nitrogen to remove oxygen. The water content should be <500 ppm
at this point. Atmospheric distillation can be carried out to
azeotropically remove water if necessary. The solution is cooled to
-10.degree. C. and iso-PrMgCl in THF (56.4 mol) is slowly added (2
hours) to the reaction via addition funnel, maintaining a reaction
temperature <-5.degree. C. The solution is allowed to warn to
20.degree. C. and aged overnight at 20.degree. C., until the amide
is <0.5 LCAP. The reaction is then cooled to -10.degree. C.
under nitrogen and is quenched slowly over 2 hours into 5N HCl (14
L) that is maintained at 0-5.degree. C. MTBE (12 L) is added and
the biphasic mixture is agitated for 5 min. After warming to
20.degree.-25.degree. C., it is allowed to settle for 30 min, and
then the layers are separated. The organic layer is washed with
water twice (12 L).
[0274] The organic layer is vacuum transferred through a 1-micron
in-line PTFE filter into a distillation flask and is then
concentrated to .about.12 L under vacuum (internal temperature
<40.degree. C.) to a minimum agitated volume. The solution is
then azeotropically dried with toluene and taken to a minimum
agitated volume again. The solution is used directly in the next
step.
[0275] If a solid product is desired, heptane is added to the
organic layer after it has been concentrated to a minimum agitated
volume. The distillation is continued under vacuum at
40.degree.-55.degree. C. until the final volume is 40 L. The
solution is cooled to 35.degree.-37.degree. C., seeded
(.about.0.5%, 30 gms) and then aged for 30 min to allow for a full
seed bed to grow. The slurry is cooled to 10.degree. C. over 2-3
hrs. The slurry is then filtered, washed with 5.degree. C. heptane
(18 L), and allowed to dry fully on the filter pot using a
vacuum/nitrogen sweep overnight. The dried solid is obtained with
>99.9 ee %. The amide can be recrystallized from straight
heptane if the optical purity is not sufficient.
##STR00050##
[0276] TFA (9 L) is added to a 100 L Buchi reactor under an inert
atmosphere and is cooled to -5.degree. C. The ketone product from
Step 2 (5.50 kg, 13.1 mol) is added as a solid followed by a TFA
rinse (2 L). The solution is cooled to -5.degree. C. and is stirred
until all the solid dissolves. The silane (2.18 kg, 15.7 mol) is
added slowly over .about.1 h (in two portions) while keeping the
temperature at <0.degree. C. The reaction is aged at -2 to
-6.degree. C. for 15-20 h, at which time LC reveals <2% of the
ketone remains. A 50 w/w % KOH solution is prepared by adding 13.6
kg of KOH pellets (87 w %) slowly to 10 L water while keeping the
highly exothermic dissolution at <30.degree. C. The solution is
stored in a refrigerator.
[0277] The reaction is quenched with .about.2 L of the 50 w/w % KOH
solution with vigorous stirring and cooling, keeping temp at
.about.20.degree. C. Cold THF (16.5 L, previously stored in
freezer) is added, followed by slow addition of the remainder of
the KOH solution (.about.13.7 L), followed by a 2 L water rinse
while keeping temp <20.degree. C. After complete addition of
KOH, the reaction is aged at room temperature. The reaction is
quenched after 3 h with 27.5 L IPAC and 20 L 20% w/v aq NaCl.
[0278] The aqueous and organic layers are separated. The organic
layer is washed with 26 L of 20% w/v aq NaCl, then with 36 L water,
then with 31 L 0.5 NHCl, and finally with 32 L of water. The
organic layer is concentrated to .about.10 L. Heptane (20 L) is
added, yielding crystals. The organic layer is concentrated to
.about.10 L. Heptane (20 L) is added again, and the organic layer
is concentrated to .about.10 L. Heptane (22 L) is added and the
slurry is aged at rt. The solid is filtered and washed with 24 L
heptane. A solid product is obtained (98.8% purity, >99.95% ee,
by LC). The solid is then re-dissolved in 12.5 L MeOH
(endothermic). At rt, 3 L water is added, and the mixture is aged
to initiate crystallization. Water (9.5 L) is added over .about.60
min at rt. After aging for 60 min, the slurry is filtered and the
solid is washed with 5 L MeOH/water (1/1.5), 5 L MeOH/water (1/4)
and then 4 L water. The solid product is dried at 50.degree. C.
under vacuum (99.9% pure by LC, >99.95% ee).
[0279] The reaction in Step 3 can also be carried out using
Al(O-i-Pr).sub.3 as the reducing agent. For example, the ketone (6
kg) is heated at 50.degree. C. with 0.3 eq of Al(O-i-Pr).sub.3 (790
g) in 12 L IPA and 18 L of toluene for 15.5 hours. The solution is
cooled to ambient temperature, and solid KOH pellets (1.35 kg) are
added slowly with vigorous stirring, while keeping the temperature
at <25.degree. C. After about 2 hours, when HPLC shows >99.5%
cyclization, 33 L of 1N HCl solution is added to quench the
reaction, which is kept at <25.degree. C. If a rag layer of
solids forms, it should be filtered off to upgrade the enantiomeric
excess. The organic layer is then washed first with 36 L of 0.5N
HCl, then with 6 L IPA combined with 45 L water, and finally with 6
L IPA combined with 36 L water. The organic layer is transferred
via an inline filter. The solvent is switched to heptane (target
volume is .about.42 L) at .about.40.degree. C. until <2 v %
toluene is left. Aging at rt for 2 h gives the solid product.
HPLC Method for Assays Used in Step 3:
[0280] Ace-C8 column 250.times.4.6 mm A: MeCN; B: 0.1%
H.sub.3PO.sub.4 in H.sub.2O;
[0281] Gradient: 5A:95B at 0 min to 95A:5B at 9 min; hold 95A:5B
until 13 min; return to 5A:95B 13-15 min.
[0282] Conditions: 35.degree. C., 1.5 mL/min, 210 nm
Example 18
##STR00051##
[0283]
erythro-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-meth-
oxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
[0284] Sodium bis(trimethylsilyl)amide (172 .mu.L of a 1M solution
in THF, 0.172 mmol) was added to a stirred solution of
erythro-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
(50 mg, 0.129 mmol) in dry THF (1 mL) at room temperature under
N.sub.2. The reaction was stirred for 15 min and a solution of
2-(bromomethyl)-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl
(27.0 mg, 0.0861 mmol) in dry THF (2 mL) was added by cannula. The
reaction was stirred at room temperature for 3 days. The reaction
was quenched with saturated NH.sub.4Cl (10 mL) and extracted with
EtOAc (3.times.20 mL). The combined organic extracts were washed
with brine (10 mL), dried (Na.sub.2SO.sub.4) and concentrated in
vacuo to give the crude product. This was purified by flash
chromatography (Si, 12.times.160 mm, 0-40% EtOAc in hexanes
gradient) to afford
erythro-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4--
(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
as a colorless oil. R.sub.f=0.64 (20% EtOAc/hexanes). LCMS
calc.=620.18; found=620.2 (M+1).sup.+. .sup.1H NMR
(benzene-d.sub.6, 600 MHz, 1:1 mixture of atropisomers) .delta.
7.94 (s, 0.5H), 7.72 (s, 0.5H), 7.64 (s, 0.5H), 7.63 (s, 0.5H),
7.39-7.34 (m, 3H), 7.12-7.04 (m, 2H), 6.95 (d, J=2.1 Hz, 0.5H),
6.86 (d, J=1.7 Hz, 0.5H), 6.64 (d, J=8.5 Hz, 0.5H), 6.56 (d, J=8.5
Hz, 0.5H), 4.99 (d, J=15.9 Hz, 0.5H), 4.93 (d, J=15.9 Hz, 0.5H),
4.73 (d, J=7.9 Hz, 0.5H), 4.61 (d, J=7.9 Hz, 0.5H), 3.88 (d, J=15.9
Hz, 0.5H), 3.82 (d, J=15.9 Hz, 0.5H), 3.35 (s, 1.5H), 3.24 (s,
1.5H), 3.05 (septet, J=6.9 Hz, 0.5H), 3.01 (septet, J=6.9 Hz,
0.5H), 2.75 (m, 1H), 1.19 (dd, J=6.9, 2.7 Hz, 3H), 1.17 (dd,
J=10.9, 6.9 Hz, 3H), -0.18 (d, J=6.4 Hz, 1.5H), -0.33 (t, J=6.4 Hz,
1.5H). This compound was separated into its two enantiomers
(4R,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4--
(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
and
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4--
(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
using chiral HPLC (AD column, 20.times.250 mm, 3% i-PrOH in
heptane).
Example 19
##STR00052##
[0285]
4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5'-isopropyl-2'-methoxy-4-(t-
rifluoromethyl)biphenyl-2-yl]methyl}imidazolidin-2-one
Step A:
tert-butyl{2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethyl}{[5'--
isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate
[0286] To a solution of
1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methoxy-4-(triflu-
oromethyl)biphenyl-2-yl]methyl}amino)ethanol (Example 6 Step B,
325.0 mg, 0.561 mmol) in CH.sub.2Cl.sub.2 (15 mL) was added
BOC.sub.2O (122 mg, 0.561 mmol) and DIPEA (98 .mu.L, 0.561 mmol).
The reaction was stirred at room temperature. After 5 hours,
additional BOC.sub.2O (50 mg, 0.229 mmol) and DIPEA (50 .mu.L,
0.287 mmol) were added. The reaction was stirred at room
temperature for 48 hours. The reaction was then concentrated to
.about.2 mL, diluted with hexanes (8 mL) and purified by flash
chromatography with 10 to 20% EtOAc/hexanes to afford
tert-butyl{2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethyl}{[5'-isoprop-
yl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate.
R.sub.f=0.38 (25% EtOAc/hexanes). LCMS=580.3 (M+1-BOC).sup.+.
.sup.1H NMR (CD.sub.2Cl.sub.2, 500 MHz) .delta. 7.78 (s, 1H),
7.54-7.67 (m, 4H), 7.23-7.33 (m, 2H), 6.90-6.95 (m, 2H), 3.15-4.82
(m, 9H), 2.87 (m, 1H), 1.19-1.43 (m, 15 M).
Step B:
1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[5'-is-
opropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl
methanesulfonate
[0287] To a solution of
tert-butyl{2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethyl}{[5'-isoprop-
yl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate
(350.1 mg, 0.516 mmol) in CH.sub.2Cl.sub.2 (15 mL) was added DIPEA
(450 .mu.L, 2.58 mmol). The solution was cooled to 0.degree. C. and
MsCl (100 .mu.L, 1.29 mmol) was added. After 45 minutes of stirring
at 0.degree. C., the reaction was diluted with EtOAc (100 mL) and
washed with saturated NaHCO.sub.3 (25 mL), brine (25 mL), 1N HCl
(25 mL), and brine (2.times.25 mL). The organic layer was dried
over Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
put through a short plug of silica gel with 25% EtOAc/hexanes and
concentrated. The product,
1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[5'-isopropyl-
-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl
methanesulfonate, was used immediately in the next reaction without
further characterization. R.sub.f=0.33 (25% EtOAc/hexanes).
Step C:
tert-butyl{2-azido-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5'-is-
opropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate
[0288] The
1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[5'-
-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl
methanesulfonate from the previous reaction was dissolved in DMPU
(15 mL) and treated with NaN.sub.3 (140 mg, 2.15 mmol). The
reaction was stirred at room temperature for 15 hours and then
diluted with EtOAc (75 ml). The solution was washed with H.sub.2O
(5.times.40 mL) and brine (40 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified with 20% EtOAc/hexanes to afford
tert-butyl{2-azido-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5'-isopropyl-
-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate.
R.sub.f=0.52 (15% EtOAc/hexanes). LCMS=605.3 (M+1-BOC).sup.+.
.sup.1H NMR (C.sub.6D.sub.6, 500 MHz, 70.degree. C.) .delta. 7.80
(s, 1H), 7.67 (s, 1H), 7.48 (s, 2H), 7.36 (d, J=7.8 Hz, 1H),
7.01-7.11 (m, 2H), 6.89 (m, 1H), 6.64 (d, J=8.6 Hz, 1H), 4.22-4.69
(m, 3H), 3.28 (s, 3H), 2.61-3.16 (m, 3H), 1.34 (s, 9H), 1.13-1.18
(m, 6H).
Step D: mixture of tert-butyl
{2-amino-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5'-isopropyl-2'-methox-
y-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate and
tert-butyl[1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methox-
y-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethyl]carbamate
[0289] To a solution of
tert-butyl{2-azido-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5'-isopropyl-
-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (300
mg, 0.426 mmol) in EtOAc (15 mL) was added 10% Pd on C (100 mg).
The reaction was placed under H.sub.2 and stirred at room
temperature for 5 hours. At this time the reaction was complete to
give a mixture of two products, tert-butyl
{2-amino-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5'-isopropyl-2'-methox-
y-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate and tert-butyl
[1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methoxy-4-(trifl-
uoromethyl)biphenyl-2-yl]methyl}amino)ethyl]carbamate. The catalyst
was filtered off and the filtrate was concentrated to afford the
product mixture. LCMS=679.3 (M+1).sup.+. The products were used in
the next reaction without further purification or
characterization.
Step E:
1-[3,5-bis(trifluoromethyl)phenyl]-N.sup.2-{[5'-isopropyl-2'-metho-
xy-4-(trifluoromethyl)biphenyl-2-yl]methyl}ethane-1,2-diamine
[0290] To a solution of 283.5 mg (0.418 mmol) of the mixture of
tert-butyl
{2-amino-2-[3,5-bis(trifluoromethyl)phenyl]ethyl}{[5'-isopropyl-2'-methox-
y-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate and tert-butyl
[1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methoxy-4-(trifl-
uoromethyl)biphenyl-2-yl]methyl}amino)ethyl]carbamate in
CH.sub.2Cl.sub.2 (15 mL) was added TFA (1.5 mL). The reaction was
stirred at room temperature for 5 hours and then poured into 1 N
NaOH (50 mL). The mixture was extracted with CH.sub.2Cl.sub.2
(3.times.50 mL) and the organic extracts were combined, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography with 5 to 10% MeOH/CH.sub.2Cl.sub.2
gave
1-[3,5-bis(trifluoromethyl)phenyl]-N.sup.2-{[5'-isopropyl-2'-methoxy-4-(t-
rifluoromethyl)biphenyl-2-yl]methyl}ethane-1,2-diamine.
R.sub.f=0.46 (10% MeOH(CH.sub.2Cl.sub.2). LCMS=579.2 (M+1).sup.+.
.sup.1H NMR (CD.sub.2Cl.sub.2, 500 MHz) .delta. 7.83 (s, 2H), 7.77
(s, 2H), 7.55 (d, J=7.8 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.24 (dd,
J=8.4, 2.3 Hz, 1H), 6.99 (d, J=2.0 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H),
4.06 (m, 1H), 3.59-3.76 (m, 2H), 3.69 (s, 3H), 2.88 (m, 1H), 2.67
(dd, J=11.9, 4.3 Hz, 1H), 2.51 (m, 1H), 1.22 (d, J=6.9 Hz, 6H).
Step F:
4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5'-isopropyl-2'-methoxy-4-(-
trifluoromethyl)biphenyl-2 yl]methyl}imidazolidin-2-one
[0291] A solution of
1-[3,5-bis(trifluoromethyl)phenyl]-N.sup.2-{[5'-isopropyl-2'-methoxy-4-(t-
rifluoromethyl)biphenyl-2-yl]methyl}ethane-1,2-diamine (125.2 mg,
0.217 mmol) in CH.sub.2Cl.sub.2 (30 mL) was cooled to 0.degree. C.
and DIPEA (227 .mu.L, 1.30 mmol) was added. Next, triphosgene (32.2
mg, 0.109 mmol) was added. The reaction was stirred at 0.degree. C.
for 45 minutes and then poured into saturated NaHCO.sub.3 (20 mL).
The mixture was extracted with EtOAc (100 mL) and the organic layer
was washed with brine (25 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified by flash
chromatography with 40% EtOAc/hexanes to afford
4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5'-isopropyl-2'-methoxy-4-(trifluo-
romethyl)biphenyl-2-yl]methyl}imidazolidin-2-one. R.sub.f=0.22 (40%
EtOAc/hexane). LCMS=605.2 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500
MHz) (atropisomers present in 1:1 ratio; doubling of some peaks
observed) .delta. 7.83 (s, 1H), 7.78 (s, 2H), 7.55-7.62 (m, 2H),
7.32 (d, J=7.8 Hz, 1H), 7.22 (m, 1H), 6.94 (s, 1H), 6.88 (d, J=8.3
Hz, 1H), 5.33 & 5.24 (2 singlets, 1H), 4.80-4.88 (m, 1H),
4.00-4.61 (m, 2H), 3.72 & 3.70 (2 singlets, 3H), 3.55-3.59 (m,
1H), 2.83-2.93 (m, 2H), 1.17-1.23 (m, 6H).
[0292] The two enantiomers of this compound could be separated
using an AD chiral column with 5% IPA/heptanes.
Example 20
##STR00053##
[0293]
(4R)-1-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl-
]methyl}-4-phenylimidazolidin-2-one
Step A: tert-butyl [(1R)-2-hydroxy-1-phenylethyl]carbamate
[0294] To a solution of (2R)-2-amino-2-phenylethanol (400 mg, 2.91
mmol) in CH.sub.2Cl.sub.2 (15 mL) was added BOC.sub.2O (636 mg,
2.91 mmol) and DIPEA (507 .mu.L, 2.91 mmol). The reaction was
stirred at room temperature for 18 hours, diluted with EtOAc (75
mL) and washed with H.sub.2O, brine, 1N HCl, brine, saturated
NaHCO.sub.3, and brine (25 mL each). The organic layer was dried
over Na.sub.2SO.sub.4, filtered, and concentrated. Purification of
the residue by flash chromatography with 50% EtOAc/hexanes afforded
tert-butyl [(1R)-2-hydroxy-1-phenylethyl]carbamate. R.sub.f=0.23
(40% EtOAc/hexane). .sup.1H NMR (CDCl.sub.3, 600 MHz) .delta.
7.27-7.37 (m, 5H), 5.27 (bs, 1H), 4.78 (bs, 1H), 3.83 (bs, 2H),
2.46 (bs, 1H), 1.44 (bs, 9H).
P Step B: tert-butyl [(1R)-2-oxo-1-phenylethyl]carbamate
[0295] To a solution of tert-butyl
[(1R)-2-hydroxy-1-phenylethyl]carbamate (200 mg, 0.844 mmol) in
CH.sub.2Cl.sub.2 (20 mL) at 0.degree. C. was added Dess-Martin
periodinane (447 mg, 1.05 mmol). The reaction was stirred at
0.degree. C. for 15 minutes and then at room temperature for 30
minutes. The reaction was then diluted with EtOAc (75 mL) and
washed rapidly with 10% K.sub.2CO.sub.3 (2.times.30 mL). The
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification of the residue on a short column of
silica gel with 50% EtOAc/hexanes gave tert-butyl
[(1R)-2-oxo-1-phenylethyl]carbamate. .sup.1H NMR (CDCl.sub.3, 600
MHz) (a major and a minor conformer observed). Data for major
conformer given) .delta. 9.53 (s, 1H), 7.29-7.40 (m, 5H), 5.80 (bs,
1H), 5.31 (m, 1H), 1.42 (s, 9H). This material was used immediately
in the following reaction.
Step C:
tert-butyl[(1R)-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)bi-
phenyl-2-yl]methyl}amino)-1-phenylethyl]carbamate
[0296] To a solution of
tert-butyl[(1R)-2-oxo-1-phenylethyl]carbamate (113.8 mg, 0.484
mmol) in MeOH (7 mL) was added
1-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methenamine
(98 mg, 0.303 mmol), followed by NaCNBH.sub.3 (30 mg, 0.477 mmol)
and HOAc (2 drops). The reaction was stirred overnight at room
temperature, diluted with EtOAc (75 mL), and washed with 1 N NaOH
(25 mL) and brine (25 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography with 5 to 25% EtOAc/hexanes gave
tert-butyl[(1R)-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl--
2-yl]methyl}amino)-1-phenylethyl]carbamate. R.sub.f=0.30 (25%
EtOAc/hexane). LCMS=543.4 (M+1).sup.+.
Step D:
(1R)-N.sup.2-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]methyl}-1-phenylethane-1,2-diamine
[0297] To a solution of
tert-butyl[(1R)-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl--
2-yl]methyl}amino)-1-phenylethyl]carbamate (150 mg, 0.277 mmol)
containing minor impurities in CH.sub.2Cl.sub.2 (10 mL) was added
TFA (1 mL). The reaction was stirred at room temperature for 2
hours and then poured into 1 N NaOH (25 mL). The mixture was
extracted with CH.sub.2Cl.sub.2 (3.times.25 mL). The combined
organic extracts were dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification of the resulting residue by flash
chromatography with 0 to 10% MeOH/CH.sub.2Cl.sub.2 afforded
(1R)--N.sup.2-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-
methyl}-1-phenylethane-1,2-diamine. R.sub.f=0.27 (10%
MeOH/CH.sub.2Cl.sub.2). LCMS=443.4 (M+1).sup.+.
Step E:
(4R)-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-
methyl}-4-phenylimidazolidin-2-one
[0298] A solution of
(1R)-N.sup.2-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]m-
ethyl}-1-phenylethane-1,2-diamine (96.0 mg, 0.22 mmol) in
CH.sub.2Cl.sub.2 (15 mL) was cooled to 0.degree. C. and DIPEA (230
.mu.L, 1.32 mmol) was added followed by triphosgene (32.6 mg, 0.11
mmol). After 45 minutes, the reaction was poured into saturated
NaHCO.sub.3 (25 mL). The mixture was extracted with EtOAc (75 mL).
The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography with 10 to 60% EtOAc/hexanes
afforded
(4R)-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-
-4-phenylimidazolidin-2-one. The minor enantiomer was removed by
chiral HPLC using an AD chiral column and 15% IPA/heptanes to
afford enantiomerically pure product. R.sub.f=0.16 (40%
EtOAc/hexanes). LCMS=469.3 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3,
500 MHz) (atropisomers present in 1:1 ratio, doubling of some peaks
observed) .delta. 7.65 (m, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.21-7.36
(m, 7H), 6.87-6.94 (m, 2H), 4.65-4.77 (m, 2H), 4.10-4.49 (m, 2H),
3.71 & 3.72 (2 singlets, 3H), 3.49-3.53 (m, 1H), 2.94-2.97 (m,
1H), 2.87 (m, 1H), 1.19-1.24 (m, 6H).
Example 21
##STR00054##
[0299]
4-(4-chlorophenyl)-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)b-
iphenyl-2-yl]methyl}imidazolidin-2-one
Step A:
1-(4-chlorophenyl)-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl-
)biphenyl-2-yl]methyl}amino)ethanol
[0300] A solution of
1-[5'-isopropyl-2'-methoxy-5-(trifluoromethyl)biphenyl-2-yl]methanamine
(300 mg, 1.1 mmol) and 2-(4-chlorophenyl)oxirane (143 .mu.L, 1.2
mmol) in isopropyl alcohol (10.5 mL) was heated to reflux for 24
hours. The reaction was concentrated and purified by flash
chromatography with 5% to 80% EtOAc/hexanes to afford
1-(4-chlorophenyl)-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphen-
yl-2-yl]methyl}amino)ethanol. R.sub.f=0.37 (50% EtOAc/hexanes).
LCMS=478.1 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.
7.70 (s, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.33-7.19 (m, 6H), 6.97 (s,
1H), 6.90 (d, J=8.5 Hz, 1H), 4.52 (m, 1H), 3.77-3.62 (m, 5H), 2.89
(m, 1H), 2.71 (m, 1H), 2.51 (m, 1H), 1.24 (d, J=7.0 Hz, 6H).
Step B: benzyl
[2-(4-chlorophenyl)-2-hydroxyethyl]{[5'-isopropyl-2'-methoxy-4-(trifluoro-
methyl)biphenyl-2-yl]methyl}carbamate
[0301] To a solution of
1-(4-chlorophenyl)-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphen-
yl-2-yl]methyl}amino)ethanol (40 mg, 0.08 mmol) in CH.sub.2Cl.sub.2
(2 mL) was added dibenzyl dicarbonate (24 mg, 0.08 mmol). The
reaction was stirred at room temperature for 24 hours and then
poured into H.sub.2O (15 mL). The resultant mixture was extracted
with EtOAc (50 mL) and the organic layer was washed with brine (15
mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Purification of the residue by flash chromatography with 5% to 60%
EtOAc/hexanes afforded benzyl
[2-(4-chlorophenyl)-2-hydroxyethyl]{[5'-isopropyl-2'-methoxy-4-(trifluoro-
methyl)biphenyl-2-yl]methyl}carbamate. R.sub.f=0.20 (25%
EtOAc/hexanes). LCMS=612.2 (M+1).sup.+. .sup.1H NMR
(C.sub.6D.sub.6, 600 MHz, peaks broadened and/or doubled; rotamers
and/or atropisomers present) .delta. 7.98-6.45 (m, 15H), 5.00-3.46
(m, 6H), 3.20-2.96 (m, 5H), 2.72 (m, 1H), 1.20-1.15 (m, 6H).
Step C: benzyl
[2-azido-2-(4-chlorophenyl)ethyl]{[5'-isopropyl-2'-methoxy-4-(trifluorome-
thyl)biphenyl-2-yl]methyl}carbamate
[0302] A solution of benzyl
[2-(4-chlorophenyl)-2-hydroxyethyl]{[5'-isopropyl-2'-methoxy-4-(trifluoro-
methyl)biphenyl-2-yl]methyl}carbamate. (44 mg, 0.07 mmol) in
CH.sub.2Cl.sub.2 (6 mL) was cooled to 0.degree. C. and N,N
diisopropylethylamine (63 .mu.L, 0.36 mmol) was added followed by
methanesulfonyl chloride (14 .mu.L, 0.18 mmol). The reaction was
stirred at 0.degree. C. for 30 minutes and then poured into
saturated NaHCO.sub.3 (15 mL). The resultant mixture was extracted
with EtOAc (50 mL) and the organic layer was washed with brine (15
mL), dried over Na.sub.2SO.sub.4, filtered through a short plug of
silica gel, and concentrated. The residue was redissolved in DMPU
(6 mL) and sodium azide (12 mg, 0.18 mmol) was added. The reaction
was stirred at room temperature for 24 hours and then poured into
H.sub.2O (15 mL). The resultant mixture was extracted with EtOAc
(50 mL) and the organic layer was washed with H.sub.2O (2.times.15
mL) and brine (15 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification of the residue by flash chromatography
with 25% EtOAc/hexanes afforded benzyl
[2-azido-2-(4-chlorophenyl)ethyl]{[5'-isopropyl-2'-methoxy-4-(trifluorome-
thyl)biphenyl-2-yl]methyl}carbamate. R.sub.f=0.66 (25%
EtOAc/hexanes). LCMS=637.3 (M+1).sup.+. .sup.1H NMR
(C.sub.6D.sub.6, 600 MHz, peaks doubled; rotamers and/or
atropisomers present) .delta. 8.03-6.52 (m, 15 H), 5.00-5.08 (m,
2H), 4.76-4.12 (m, 3H), 3.28-2.86 (m, 5H), 2.77 (m, 1H), 1.23-1.18
(m, 6H).
Step D: benzyl
[2-amino-2-(4-chlorophenyl)ethyl]{[5'-isopropyl-2'-methoxy-4-(trifluorome-
thyl)biphenyl-2-yl]methyl}carbamate
[0303] To a solution of benzyl [2-azido-2-(4-chlorophenyl)ethyl]
{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbama-
te (30 mg, 0.05 mmol) in THF (1 mL) was added PtO.sub.2 (8 mg) and
the reaction was stirred at room temperature under hydrogen for 1
hour. The catalyst was removed by filtration through a plug of
Celite with 100% EtOAc and the filtrate was concentrated to afford
crude benzyl
[2-amino-2-(4-chlorophenyl)ethyl]{[5'-isopropyl-2'-methoxy-4-(trifluorome-
thyl)biphenyl-2-yl]methyl}carbamate. R.sub.f=0.66 (25%
EtOAc/hexanes). LCMS=611.3 (M+1).sup.+.
Step E:
4-(4-chlorophenyl)-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)-
biphenyl-2-yl]methyl}imidazolidin-2-one
[0304] To a solution of benzyl
[2-amino-2-(4-chlorophenyl)ethyl]{[5'-isopropyl-2'-methoxy-4-(trifluorome-
thyl)biphenyl-2-yl]methyl}carbamate (30 mg, 0.05 mmol) in THF (2
mL) was added potassium bis(trimethylsilyl)amide (295 .mu.L of a
0.5M solution in toluene, 0.147 mmol) The reaction was stirred at
room temperature for 30 minutes and then quenched with saturated
NH.sub.4Cl (15 mL). The resultant mixture was extracted with EtOAc
(25 mL) and the organic layer was washed with H.sub.2O (15 mL) and
brine (15 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification of the residue by flash chromatography
with 5% to 60% EtOAc/hexanes afforded
4-(4-chlorophenyl)-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)bipheny-
l-2-yl]methyl}imidazolidin-2-one. R.sub.f=0.46 (5%
MeOH/CH.sub.2Cl.sub.2). LCMS=503.1 (M+1).sup.+. .sup.1H NMR
(C.sub.6D.sub.6, 600 MHz, atropisomers observed; doubling of
peaks.) .delta. 7.90-7.03 (m, 6H), 6.89-6.20 (m, 4H), 4.69-3.88 (m,
3H), 3.16 (s, 3H), 2.88-2.30 (m, 3H), 1.18-1.13 (m, 6H).
Example 22
##STR00055##
[0305]
(4R)-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]m-
ethyl}-3-methyl-4-phenylimidazolidin-2-one
[0306] To a solution of
(4R)-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-
-4-phenylimidazolidin-2-one (12.6 mg, 0.0269 mmol) in THF (1.5 mL)
was added MeI (10 .mu.L, 0.162 mmol), followed by KHMDS (162 .mu.L
of a 0.5 M solution in toluene, 0.081 mmol). The reaction was
stirred at room temperature for 10 minutes, and then poured into
water (10 mL). The mixture was extracted with EtOAc (30 mL) and the
organic layer was washed with brine (10 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography with 50% EtOAc/hexanes afforded
(4R)-1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-
-3-methyl-4-phenylimidazolidin-2-one. R.sub.f=0.26 (40%
EtOAc/hexanes). LCMS=483.2 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3,
500 MHz, atropisomers observed; doubling of peaks.) .delta.
7.68-7.53 (m, 2H), 7.21-7.36 (m, 7H), 6.87-6.94 (m, 2H), 4.08-4.56
(m, 3H), 3.72 & 3.71 (2 singlets, 3H), 3.34-3.38 (m, 1H),
2.77-2.89 (m, 2H), 2.67 & 2.63 (2 singlets, 3H), 1.18-1.26 (m,
6H).
[0307] Following the procedures outlined in EXAMPLES 1-22 the
compounds listed in Table 1 were prepared:
TABLE-US-00001 TABLE 1 ##STR00056## LCMS Example R (M + 1).sup.+ 23
##STR00057## 618.1 24 ##STR00058## 470.2 25 ##STR00059## 470.4 26
##STR00060## 538.2 27 ##STR00061## 504.1 28 ##STR00062## 538.2 29
##STR00063## 471.2 30 ##STR00064## 538.2 31 ##STR00065## 504.2 32
##STR00066## 476.2 33 ##STR00067## 471.2 34 ##STR00068## 484.2 35
##STR00069## 484.2 36 ##STR00070## 620.2 37 ##STR00071## 620.2 38
##STR00072## 470.2 39 ##STR00073## 469.2 40 ##STR00074## 475.2 41
##STR00075## 503.1 42 ##STR00076## 503.1 43 ##STR00077## 537.2 44
##STR00078## 537.2 45 ##STR00079## 470.2 46 ##STR00080## 470.2 47
##STR00081## 619.2 48 ##STR00082## 634.1 49 ##STR00083## 634.1
##STR00084##
4-[3,5-bis(trifluoromethyl)phenyl]-2-{[5'-isopropyl-2'-methoxy-4-(trifluo-
romethyl)biphenyl-2-yl]methyl}-1,2,5-thiadiazolidine
1,1-dioxide
[0308] A solution of
1-[3,5-bis(trifluoromethyl)phenyl]-N.sup.2-{[5'-isopropyl-2'-methoxy-4-(t-
rifluoromethyl)biphenyl-2-yl]methyl}ethane-1,2-diamine (8.0 mg,
0.014 mmol) and sulfamide (2.0 mg, 0.021 mmol) in pyridine (300
.mu.L) was heated to 120.degree. C. in a sealed tube. After 3
hours, the reaction was cooled to room temperature and diluted with
25 mL of EtOAc. The organic solution was washed with 1 N HCl
(2.times.5 mL) and brine (1.times.5 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by PTLC with 25% EtOAc/hexanes afforded
4-[3,5-bis(trifluoromethyl)phenyl]-2-{[5'-isopropyl-2'-methoxy-4-(trifluo-
romethyl)biphenyl-2-yl]methyl}-1,2,5-thiadiazolidine 1,1-dioxide.
R.sub.f=0.29 (25% EtOAc/hexanes). LCMS=641.1 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz; atropisomers present) .delta. 7.58-7.85
(m, 5H), 7.35-6.86 (m, 4H), 4.82-4.94 (m, 2H), 3.54-4.42 (m, 6H),
2.71-2.91 (m, 2H), 1.11-1.26 (m, 6H).
Example 51
##STR00085##
[0309]
5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-ox-
azolidin-2-one
Step A:
[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol
[0310] To a solution of 1.08 g of
5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile
(EXAMPLE 3) in 25 mL of n-PrOH, was added 0.97 g of KOH. The
mixture was heated to reflux and stirred at this temperature for 36
h, then cooled and concentrated to a clear oil. This oil was
partitioned between 15 mL of water and 10 mL of Et.sub.2O. The
aqueous phase was extracted with 10 mL of Et.sub.2O. The combined
organics were washed with brine (15 mL), dried over
Na.sub.2SO.sub.4, and concentrated. The residue was purified by
flash chromatography on a Biotage Horizon 40S column, eluting with
1 CV of 95% hexanes-5% of a mixture of 5% formic acid in acetone,
followed by a linear gradient of the acetone mixture in hexanes
from 5 to 100% over 10 CV. The resulting white solid was dissolved
in 10 mL of 9:1 benzene-MeOH and excess TMSCH.sub.2N.sub.2 was
added. The mixture was stirred for 10 min at room temperature, then
quenched with trifluoroacetic acid and concentrated. The residue
was dissolved in 15 mL of Et.sub.2O and cooled to 0.degree. C. A
1-M solution of LiAlH.sub.4 in Et.sub.2O (5.4 mL) was added
dropwise via addition funnel. The cooling bath was removed once the
addition was complete, and the mixture was stirred 2 h at room
temperature, then recooled to 0.degree. C. and quenched by dropwise
addition of 0.2 mL of water, 0.2 mL of 15% aqueous NaOH, and 0.5 mL
of water. The cooling bath was removed once the addition was
complete, and the mixture was stirred 30 min at room temperature,
filtered (washing the solids liberally with Et.sub.2O), and
concentrated. Flash chromatography on a Biotage Horizon, 40S
column, eluting with 1 CV of 4% EtOAc in hexanes, followed by a
linear gradient of EtOAc in hexanes from 4 to 100% over 10 CV
provided the title compound. Mass spectrum (ESI) 307.2 (M-17).
.sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 7.85 (s, 1H), 7.60 (d,
J=8 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.25 (dd, J=2 Hz, 9 Hz, 1H),
6.99 (d, J=2.5 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 4.49 (m, 2H), 3.74
(s, 3H), 2.90 (septet, J=7 Hz, 1H), 1.25 (d, J=7 Hz, 6H).
Step B:
5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde
[0311] To a solution of 0.725 g of
[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol
in 10 mL of CH.sub.2Cl.sub.2 was added 1.14 g of Dess-Martin
periodinane. The mixture was stirred at room temperature for 30
min, then filtered and concentrated. The residue was purified by
flash chromatography on a Biotage Horizon, 40S column, eluting with
1 CV of 1% EtOAc in hexanes, followed by a linear gradient of EtOAc
in hexanes from 1 to 100% over 10 CV to provide the title compound.
Mass spectrum (ESI) 323.2 (M+1). .sup.1H NMR (500 MHz, CDCl.sub.3):
.delta. 9.81 (s, 1H), 8.28 (s, 1H), 7.88 (dd, J=1.5 Hz, 8 Hz, 1H),
7.54 (d, J=8 Hz, 1H), 7.33 (dd, J=2 Hz, 8 Hz, 1H), 7.16 (d, J=2.5
Hz, 1H), 6.95 (d, J=8.5 Hz, 1H), 3.74 (s, 3H), 2.95 (septet, J=7
Hz, 1H), 1.29 (d, J=7 Hz, 6H).
Step C:
2-amino-1-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-y-
l]ethanol
[0312] To a solution of 0.679 g of
5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde
in 1.5 mL of CH.sub.2Cl.sub.2 was added ca. 5 mg of ZnI.sub.2, then
0.23 g of trimethylsilyl cyanide. The mixture was stirred at room
temperature for 3 h, and then partitioned between 15 mL of water
and 10 mL of Et.sub.2O. The aqueous phase was extracted with
2.times.10 mL of Et.sub.2O. The combined organics were dried over
Na.sub.2SO.sub.4 and concentrated. The residue was dissolved in 15
mL of Et.sub.2O and cooled to 0.degree. C. A 1-M solution of
LiAlH.sub.4 in Et.sub.2O (4.2 mL) was added dropwise via addition
funnel. The cooling bath was removed once the addition was
complete, and the mixture was stirred overnight at room
temperature, then recooled to 0.degree. C. and quenched by dropwise
addition of 0.15 mL of water, 0.15 mL of 15% aqueous NaOH, and 0.4
mL of water. The cooling bath was removed once the addition was
complete, and the mixture was stirred 30 min at room temperature,
filtered (washing the solids liberally with Et.sub.2O), and
concentrated to provide the title compound, which was used without
further purification. Mass spectrum (ESI) 354.2 (M+1). Some .sup.1H
NMR signals are doubled because of atropoisomerism. .sup.1H NMR
(500 MHz, CDCl.sub.3): .delta. 7.88 (s, 1H), 7.55 (app t, J=7.5 Hz,
1H), 7.22-7.28 (m, 2H), 6.99, 6.95 (d, J=2.5 Hz, 1H), 6.92, 6.90
(sm 1H), 4.52 (m, 1H), 3.70 (s, 3H), 2.90 (septet, J=7 Hz, 1H),
2.81 (m, 1H), 2.60-2.70 (m, 2H), 1.23-1.28 (m, 6H).
Step D:
5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-o-
xazolidin-2-one
[0313] To a 0.degree. C. solution of 0.44 g of
2-amino-1-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]ethan-
ol in 15 mL of CH.sub.2Cl.sub.2 was added 0.241 g of
diisopropylethylamine, then 0.185 g of triphosgene. The mixture was
stirred at 0.degree. C. for 30 min, and then diluted with 30 mL of
EtOAc and 20 mL of saturated NaHCO.sub.3. The phases were separated
and the organic phase was washed with 20 mL of brine, dried
(Na.sub.2SO.sub.4), and concentrated. The residue was purified by
flash chromatography on a Biotage Horizon, 40S column, eluting with
1 CV of 5% EtOAc in hexanes, followed by a linear gradient of EtOAc
in hexanes from 5 to 100% over 10 CV to provide the title compound.
Mass spectrum (ESI) 380.2 (M+1). .sup.1H NMR signals are doubled
because of atropoisomerism .sup.1H NMR (500 MHz, CDCl.sub.3):
.delta. 7.90, 7.86 (s, 1H), 7.66 (d, J=8 Hz, 1H), 7.35 (d, J=8 Hz,
1H), 7.27 (dd, J=2.5 Hz, 8.5 Hz 1H), 7.03 (d, J=2.5 Hz, 0.5H),
6.87-6.93 (m, 1.5H), 5.65, 5.50 (t, J=8 Hz, 1H), 5.23, 5.09 (s,
1H), 3.75 (s, 1.5H), 3.69 (s, 1.5H), 3.68, 3.51 (t, J=9 Hz, 1H),
3.31, 3.19 (t, J=8.5 Hz, 0.5H), 2.90 (septet, J=7 Hz, 1H), 1.25,
1.24 (d, J=7 Hz, 6H).
[0314] Further purification by HPLC on Chiralpak AD 2.times.25 cm,
eluting with 10% isopropanol in heptane at 9 mL/min, provided two
enantiomers: enantiomer A, t.sub.R=15.1 min; enantiomer B,
t.sub.R=17.4 min.
Example 52
##STR00086##
[0315]
3-Benzyl-5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-y-
l]-1,3-oxazolidin-2-one
[0316] To a 0.degree. C. solution of 44 mg of
5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolid-
in-2-one in 1 mL of DMF was added 10 mg of sodium hydride. The
mixture was stirred 10 min at room temperature, and then 24 mg of
benzyl bromide was added. The mixture was stirred overnight at room
temperature, then diluted with 15 mL of EtOAc and 5 mL of water.
The phases were separated and the organic phase was washed with 5
mL each of water and brine, dried (Na.sub.2SO.sub.4), and
concentrated. The residue was purified by flash chromatography on a
Biotage Horizon, 25S column, eluting with 1 CV of hexanes, followed
by a linear gradient of EtOAc in hexanes from 0 to 50% over 10 CV
to provide the title compound. Mass spectrum (ESI) 470.1 (M+1).
.sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 7.86, 7.76 (s, 1H), 7.62
(d, J=8 Hz, 1H), 7.14-7.40 (m, 7H), 7.01, 6.77 (d, J=2.5 Hz, 1H),
6.87, 6.83 (d, J=8.5 Hz, 1H), 5.45, 5.53 (m, 1H), 4.30-4.53 (m,
2H), 3.73, 3.55 (s, 3H), 3.48, 3.30 (m, 1H), 3.10, 2.96 (t, J=8.5
Hz, 1H), 2.89, 2.82 (septet, J=7 Hz, 1H), 1.24, 1.16 (m, 6H).
Example 53
##STR00087##
[0317]
3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-isopropyl-2'-methoxy-4-(tr-
ifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one (racemic)
[0318] Following the procedure described in EXAMPLE 50, 43 mg of
5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolid-
in-2-one and 43 mg of 3,5-bis(trifluoromethyl)benzyl bromide gave
the title compound. Mass spectrum (ESI) 606.1 (M+1). .sup.1H NMR
signals are doubled because of atropoisomerism. .sup.1H NMR (500
MHz, CDCl.sub.3): .delta. 7.58-7.88 (m, 5H), 7.34 (d, J=8 Hz, 1H),
7.23 (m, 1H), 7.02, 6.79 (d, J=2 Hz, 1H), 6.88, 6.85 (d, J=8.5 Hz,
1H), 5.45, 5.42 (m, 1H), 4.52-4.64 (m, 1.5H), 4.36 (d, J=15.5 Hz,
0.5H), 3.74, 3.57 (s, 3H), 3.49, 3.34 (m, 1H), 3.09, 2.99 (t, J=8.5
Hz, 1H), 2.89, 2.81 (septet, J=7 Hz, 1H), 1.24, 1.12 (m, 6H).
Example 54
##STR00088##
[0319]
3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-isopropyl-2'-methoxy-4-(tr-
ifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one (enantiomer
A)
[0320] Following the procedure described in EXAMPLE 50, 43 mg of
5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolid-
in-2-one, enantiomer A, and 43 mg of 3,5-bis(trifluoromethyl)benzyl
bromide gave the title compound. Analytical HPLC on Chiralpak AS
4.6.times.250 mm, eluting with 5% isopropanol in heptane at 0.5
mL/min: t.sub.R=9.9 min
Example 55
##STR00089##
[0321]
3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-isopropyl-2'-methoxy-4-(tr-
ifluoromethyl)biphenyl-2-yl]-1,3-oxazolidin-2-one (enantiomer
B)
[0322] Following the procedure described in EXAMPLE 50, 44 mg of
5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolid-
in-2-one, enantiomer B, and 43 mg of 3,5-bis(trifluoromethyl)benzyl
bromide gave the title compound. Analytical HPLC on Chiralpak AS
4.6.times.250 mm, eluting with 5% isopropanol in heptane at 0.5
mL/min: t.sub.R=11.0 min
Example 56
##STR00090##
[0323] 1-(4-Fluorophenyl)-1-hydroxyacetone
[0324] A suspension of ground LaCl.sub.3 (26 mg, 0.104 mmol) in dry
THF (7.8 mL) under N.sub.2 was cooled to -78.degree. C. and stirred
for 15 min. A solution of n-BuLi (1.6 M in hexanes, 195 .mu.L,
0.312 mmol) was added and stirring was continued for 15 min. The
reaction was warmed to 0.degree. C. and stirred for 30 min.
Trimethylsilyl cyanide (31 mg, 42 .mu.L, 0.312 mmol) was added and
the reaction was stirred for 30 min at 0.degree. C. and warmed to
room temperature over 30 min. A solution of acetyltrimethylsilane
(Cunico, R. F., Kuan, C.-P., J. Org. Chem., 1985, 50, 5410-5413)
(121 mg, 1.04 mmol) and 4-fluorobenzaldehyde (142 mg, 1.14 mmol) in
dry THF (19 mL) was added by cannula and the reaction was stirred
at room temperature for 2 h. After this time 1N HCl (24 mL) was
added and the reaction was stirred for 1 h. Et.sub.2O (25 mL) was
added and the organic layer was separated and washed with H.sub.2O
(2.times.25 mL). The combined aqueous layers were extracted with
Et.sub.2O (3.times.50 mL). The combined organic extracts were dried
(MgSO.sub.4) and concentrated in vacuo to give the crude product.
This was purified by flash chromatography (Si, 25.times.160 mm,
0-50% EtOAc in hexanes gradient) to give
1-(4-fluorophenyl)-1-hydroxyacetone as a colorless solid.
R.sub.f=0.31 (20% EtOAc/hexanes). .sup.1H NMR (CDCl.sub.3, 500 MHz)
.delta. 7.29 (m, 2H), 7.08-7.04 (m, 2H), 5.06 (d, J=3.6 Hz, 1H),
4.35 (t, J=6.5 Hz, 1H), 2.05 (s, 3H).
Example 57
##STR00091##
[0325] erythro- and
threo-1-(4-Fluorophenyl)-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)-
biphenyl-2-yl]methyl}amino)propan-1-ol
[0326] NaCNBH.sub.3 (19 mg, 0.306 mmol) was added to a solution of
{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amine
(67 mg, 0.204 mmol) and 1-(3,5-dichlorophenyl)-1-hydroxyacetone (45
mg, 0.204 mmol) in MeOH at room temperature followed by acetic acid
(2 drops). The reaction was stirred for 5 h at room temperature.
The reaction mixture was diluted with EtOAc (20 mL), H.sub.2O (20
.mu.L and brine (5 mL). The aqueous layer was extracted with EtOAc
(2.times.20 mL). The combined organic extracts were dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to give the crude
product. This was purified by flash chromatography (Si,
12.times.160 mm, 0-50% EtOAc in hexanes gradient) to give the two
possible diastereoisomers,
erythro-1-(4-fluorophenyl)-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethy-
l)biphenyl-2-yl]methyl}amino)propan-1-ol (68.4 mg) and
threo-1-(4-fluorophenyl)-2-({[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)-
biphenyl-2-yl]methyl}amino)propan-1-ol (48.9 mg) as colorless oils.
erythro-diastereoisomer: R.sub.f=0.40 (20% EtOAc/hexanes). LCMS
calc.=476.22; found=476.2 (M+1).sup.+. .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.72 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.36 (m,
1H), 7.27 (dd, J=8.5, 2.3 Hz, 1H), 7.19 (m, 2H), 7.04-6.92 (m, 4H),
4.63-4.56 (m, 1H), 3.85-3.65 (m, 7H), 2.92 (m, 1H), 2.72 (m, 1H),
1.26 (t, J=8.0 Hz, 6H), 0.64 (t, J=5.4 Hz, 3H).
threo-diastereoisomer: R.sub.f=0.20 (20% EtOAc/hexanes). LCMS
calc.=476.22; found=476.2 (M+1).sup.+. .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.73 (d, J=9.0 Hz, 1H), 7.58 (d, J=7.9 Hz, 1H),
7.32 (m, 1H), 7.24 (m, 3H), 7.07-6.97 (m, 3H), 6.92 (d, J=8.5 Hz,
1H), 4.05 (d, J=7.9 Hz, 1H), 3.82-3.70 (m, 5H), 3.59 (d, J=13 Hz,
1H), 3.51 (d, J=13 Hz, 1H), 2.90 (m, 1H), 2.51 (m, 1H), 1.25 (m,
6H), 0.73 (d, J=6.4 Hz, 3H).
Example 58
##STR00092##
[0327]
erythro-5-(4-Fluorophenyl)-3-{[5'-isopropyl-2'-methoxy-4-(trifluoro-
methyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
[0328] As for EXAMPLE 7 Step 3. R.sub.f=0.38 (20% EtOAc/hexanes).
LCMS calc.=502.20; found=502.2 (M+1).sup.+. .sup.1H NMR (500 MHz,
benzene-d.sub.6, 1:1 mixture of atropisomers) .delta. 7.96 (s,
0.5H), 7.75 (s, 0.5H), 7.35 (d, J=7.7 Hz, 1H), 7.10-7.06 (m, 2H),
6.94 (d, J=2.1 Hz, 0.5H), 6.88 (d, J=2.1 Hz, 0.5H), 6.69-6.62 (m,
4.5H), 6.55 (d, J=8.4 Hz, 0.5H), 4.95 (d, J=15.9 Hz, 0.5H), 4.86
(d, J=15.8 Hz, 0.5H), 4.80 (d, J=7.9 Hz, 0.5H), 4.70 (d, J=7.8 Hz,
0.5H), 4.04 (d, J=15.8 Hz, 0.5H), 3.93 (d, J=15.9 Hz, 0.5H), 3.36
(s, 1.5H), 3.22 (s, 1.5H), 3.14 (m, 0.5H), 3.05 (m, 0.5H),
2.79-2.71 (m, 1H), 1.18 (m, 6H), 0.02 (d, J=6.5 Hz, 1.5H), -0.04
(d, J=6.5 Hz, 1.5H). This compound was separated into its two
enantiomers
(4R,5S)-5-(4-Fluorophenyl)-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl-
)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one and
(4S,5R)-5-(4-Fluorophenyl)-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl-
)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one using chiral
HPLC (AD column, 20.times.250 mm, 3% EtOH in heptane).
[0329] Following the procedures outlined in EXAMPLE 58 the
compounds listed in Table 2 were prepared:
TABLE-US-00002 TABLE 2 ##STR00093## LCMS Example R (M + 1).sup.+ 59
##STR00094## 502.2 60 ##STR00095## 502.2 61 ##STR00096## 552.2 62
##STR00097## 552.2 63 ##STR00098## 552.1
Example 64
##STR00099##
[0330]
1-{[5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl-
}-4-phenylpyrrolidin-2-one
[0331] Sodium bis(trimethylsilyl)amide (114 .mu.L of a 1M solution
in THF, 0.114 mmol) was added to a stirred solution of
4-phenylpyrrolidin-2-one (Winans, C. F., Adkins, H., J. Am. Chem.
Soc., 1933, 55, 4167-4176) (17 mg, 0.103 mmol) in dry THF (1 mL) at
room temperature under N.sub.2. The reaction was stirred for 5 min
and a solution of
2-(bromomethyl)-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl
(20 mg, 0.0516 mmol) in dry THF (2 mL) was added by cannula. The
reaction was stirred at room temperature for 3 days. The reaction
was quenched with saturated NH.sub.4Cl (10 mL) and extracted with
EtOAc (3.times.20 mL). The combined organic extracts were washed
with brine (10 mL), dried (Na.sub.2SO.sub.4) and concentrated in
vacuo to give the crude product. This was purified by flash
chromatography (Si, 12.times.160 mm, 0-90% EtOAc in hexanes
gradient) to afford
1-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-ph-
enylpyrrolidin-2-one as a colorless oil. R.sub.f=0.11 (20%
EtOAc/hexanes). LCMS calc.=468.22; found=468.2 (M+1).sup.+. .sup.1H
NMR (600 MHz, benzene-d.sub.6, 1:1 mixture of atropisomers) .delta.
7.79 (s, 0.5H), 7.73 (s, 0.5H), 7.33 (d, J=7.7 Hz, 1H), 7.08-7.04
(m, 4H), 6.99 (m, 1H), 6.92 (s, 0.5H), 6.88 (s, 0.55H), 6.76 (dd,
J=16.0, 7.4 Hz, 2H), 6.60 (dd, J=8.5, 3.1 Hz, 1H), 4.58 (d, J=15.4
Hz, 1H), 4.38 (t, J=13.9 Hz, 1H), 3.29 (s, 1.5H), 3.26 (s, 1.5H),
2.85-2.73 (m, 3H), 2.63-2.57 (m, 1H), 2.38-2.28 (m, 1H), 2.21-2.11
(m, 1H), 1.20-1.16 (m, 6H).
Example 65
##STR00100##
[0332]
4-(3,4-Difluorophenyl)-1-{[5'-isopropyl-2'-methyl-4-(trifluoromethy-
l)biphenyl-2-yl]methyl}pyrrolidin-2-one
[0333] Prepared by a similar method as EXAMPLE 64 starting with
4-(3,4-difluorophenyl)pyrrolidin-2-one (prepared by a similar
method as in Marivet, M. C., Bourguignon, J.-J.; Lugnier, C., Mann,
A., Stoclet, J.-C., Wermuth, C.-G. J. Med. Chem., 1989, 32,
1450-1457). LCMS calc.=504.20; found=504.2 (M+1).sup.+.
Example 66
##STR00101##
[0334]
5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)ben-
zyl]1,3-oxazolidin-2-one
[0335] A stirred suspension of sodium hydride (60% in oil, 167 mg,
4.18 mmol) in THF (5 mL) was treated at 0.degree. C. with
5-[3,5-bis(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one (500 mg,
1.67 mmol) dissolved in THF (1 mL), under an atmosphere of N.sub.2.
The reaction was stirred for 20 min and a solution of
2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (610 mg, 1.67
mmol) in THF (1 mL) was added dropwise. The reaction was stirred at
room temperature for 18 h. The reaction was quenched with H.sub.2O
(1 mL) and partitioned between EtOAc (80 mL) and H.sub.2O (25 mL).
The aqueous phase was re-extracted with EtOAc (2.times.20 mL) and
the combined organic extracts were washed with brine (30 mL), dried
(MgSO.sub.4) and concentrated in vacuo to give the crude product.
This was purified by flash silica-gel chromatography (0-30% EtOAc
in hexanes gradient) to afford
5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)be-
nzyl]1,3-oxazolidin-2-one. R.sub.f=0.55 (515% EtOAc/hexanes). LCMS
584 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 8.05 (d,
J=8.2 Hz, 1H), 7.95 (br s, 1H), 7.85 (br s, 2H), 7.51 (br s, 1H),
7.32 (m, 1H), 5.72 (t, J=8.0 Hz, 1H), 4.74 (d, J=15.5 Hz, 1H), 4.64
(d, J=15.3 Hz), 4.14 (t, J=7.1 Hz, 1H), 3.47 (dd, J=7.1, 1.6
Hz).
Example 67
##STR00102##
[0336]
(4S)-4-benzyl-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphen-
yl-2-yl]methyl}-1,3-oxazolidin-2-one
Step A:
(4S)-4-benzyl-3-[2-iodo-5-(trifluoromethyl)benzyl]1,3-oxazolidin-2-
-one
[0337] A stirred suspension of sodium hydride (60% in oil, 27 mg,
0.68 mmol) in THF (3 mL) was treated at 0.degree. C. with
(S)-4-benzyl-2-oxazolidinone (49 mg, 0.27 mmol) dissolved in THF (1
mL), under an atmosphere of N.sub.2. The reaction was stirred for
20 min and a solution of
2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (100 mg, 0.27
mmol) in THF (1 mL) was added dropwise. The reaction was stirred at
room temperature for 18 h. The reaction was quenched with H.sub.2O
(1 mL) and partitioned between EtOAc (80 mL) and H.sub.2O (25 mL).
The aqueous phase was re-extracted with EtOAc (2.times.20 mL) and
the combined organic extracts were washed with brine (30 mL), dried
(MgSO.sub.4) and concentrated in vacuo to give the crude product.
This was purified by flash silica-gel chromatography (0-30% EtOAc
in hexanes gradient) to afford
(4S)-4-benzyl-3-[2-iodo-5-(trifluoromethyl)benzyl]
1,3-oxazolidin-2-one. R.sub.f=0.45 (15% EtOAc/hexanes). LCMS 462
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 8.04 (d,
J=8.2 Hz, 1H), 7.54 (br s, 1H), 7.33-7.27 (m, 5H), 7.11-7.10 (m,
2H), 7.32 (m, 1H), 4.80 (d, J=16.0 Hz, 1H), 4.49 (d, J=16.1 Hz),
4.28 (t, J=8.7 Hz, 1H), 4.25 (t, J=9.1, 4.8 Hz, 1H), 3.94 (m, 1H),
3.16 (dd, J=13.5, 4.8 Hz, 1H), 2.73 (dd, J=9.1, 4.4 Hz, 1H).
Step B:
(4S)-4-benzyl-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphe-
nyl-2-yl]methyl}-1,3-oxazolidin-2-one
[0338] A stirred suspension of
(4S)-4-benzyl-3-[2-iodo-5-(trifluoromethyl)benzyl]1,3-oxazolidin-2-one
(63 mg, 0.137 mmol), 2-methoxy-5-isopropylphenyl boronic acid (52
mg, 0.274 mmol), K.sub.2CO.sub.3 (47 mg, 0.34 mmol) and
Pd(OAc).sub.2 (9.2 mg, 0.0137 mmol) in acetone:H.sub.2O (5:1) (6
mL) was heated at reflux for 1 h. The reaction mixture was
concentrated in vacuo, diluted with H.sub.2O (15 mL) and extracted
with EtOAC (3.times.30 mL). The combined organic extracts were
washed with brine (30 mL), dried (MgSO.sub.4), filtered and
concentrated. The crude product was purified by silica-gel flash
chromatography (0-20% EtOAc in hexanes gradient) to
(4S)-4-benzyl-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-y-
l]methyl}-1,3-oxazolidin-2-one. R.sub.f=0.35 (15% EtOAc/hexanes).
LCMS 484 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz)
(atropisomers present; doubling of some peaks observed in .sup.1H
NMR) .delta. 7.72 (br s 1H), 7.65 (br s, 1H), 7.42 (m, 1H),
7.32-7.22 (m, 3H), 7.08 (d, J=2.3 Hz, 1H), 6.90-6.84 (m, 3H), 4.80
(d, J=15.8 Hz, 1H), 4.35 (d, J=15.8 Hz), 4.28 (t, J=8.7 Hz, 1H),
3.96-3.92 (m, 3H), 3.78 (s, 3H), 3.62-3.52 (m, 1H), 2.94-2.86 (m,
1H), 2.82 (dd, J=9.4, 3.9 Hz, 1H), 2.42 (dd, J=9.6, 3.9 Hz), 1.26
(s, 3H), 1.10 (s, 3H).
Example 68
##STR00103##
[0339] 2-Iodo-5-(trifluoromethyl)benzoic acid
[0340] Potassium hydroxide (3.78 g; 0.0673 mol) was added to a
stirred solution of 2-iodo-5-(trifluoromethyl)benzonitrile (EXAMPLE
2; 4 g; 0.0135 mol) in a 1:1 isopropanol:H.sub.2O solution (60 mL).
The reaction was heated at reflux for 14 h and then partitioned
between H.sub.2O (50 mL) and EtOAc (50 mL). The aqueous layer was
extracted with EtOAc (50 mL) and acidified to pH 5 with 6N HCl. The
aqueous layer was further extracted with EtOAc (4.times.50 mL) and
the combined extracts were washed with brine (50 mL), dried over
MgSO.sub.4, filtered, and concentrated in vacuo to afford
2-iodo-5-(trifluoromethyl)benzoic acid as a yellow solid.
LCMS=317.0 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.
8.27 (d, J=1.6 Hz, 1H), 8.25 (d, J=8.2 Hz, 1H), 7.47 (dd, J=8.2,
1.8 Hz, 1H).
Example 69
##STR00104##
[0341] [2-Iodo-5-(trifluoromethyl)phenyl]methanol
[0342] Borane-THF (1.0M solution in THF; 94 .mu.L; 94 mmol) was
added to a stirred solution of 2-iodo-5-(trifluoromethyl)benzoic
acid (2.97 g; 9.4 mmol) in THF (300 mL) at 0.degree. C. under
N.sub.2. The reaction was heated at reflux for 90 min and then
carefully quenched with 6N HCl until no further gas evolution. The
reaction was diluted with H.sub.2O (250 mL) and extracted with
EtOAc (3.times.250 mL). The combined extracts were washed with
brine (300 mL), dried over MgSO.sub.4, filtered, and concentrated
in vacuo. The crude material was purified by flash chromatography
(0-25% EtOAc/hexanes gradient) to afford
[2-iodo-5-(trifluoromethyl)phenyl]methanol as a white solid.
LCMS=285.0 (M-17).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.
7.97 (d, J=8.3 Hz, 1H), 7.79 (s, 1H), 7.28 (d, J=8.4 Hz, 1H), 4.75
(s, 2H). An alternative procedure is as follows: To a solution of
2-Iodo-5-(trifluoromethyl)benzaldehyde (EXAMPLE 80, Step A, 9 g) in
THF (100 mL) and water (10 mL) at 0.degree. C. was added NaBH.sub.4
(0.5 g). The reaction was stirred 30 minutes. To the reaction
mixture was added dilute aqueous HCl (cautiously). The mixture was
extracted with ether and the ether layer was washed with water,
then brine. The ether layer was then dried over anhydrous
MgSO.sub.4, filtered and concentrated. The material is
chromatographed on SiO.sub.2 using a step gradient of 1:3
CH.sub.2Cl.sub.2/hexanes, then 1:1 CH.sub.2Cl.sub.2/hexanes, then
100% CH.sub.2Cl.sub.2 to afford
[2-iodo-5-(trifluoromethyl)phenyl]methanol as a white solid.
Example 70
##STR00105##
[0343] 2-(Bromoethyl)-1-iodo-4-(trifluoromethyl)benzene
[0344] Carbon tetrabromide (1.86 g; 5.6 mmol) and
triphenylphosphine (1.47 g; 5.6 mmol) were added successively to a
stirred solution of [2-iodo-5-(trifluoromethyl)phenyl]methanol
(1.13 g; 3.74 mmol) in CH.sub.2Cl.sub.2 (25 mL) at 0.degree. C.
under N.sub.2. The reaction was stirred at room temperature for 48
h. A second equivalent of carbon tetrabromide (1.2 g; 3.74 mmol)
and triphenylphosphine (0.98 g; 3.74 mmol) was added and the
reaction was stirred an additional 14 h. The solvent was removed in
vacuo and the residue was purified by flash chromatography (0-25%
EtOAc/hexanes gradient) to afford
2-(bromoethyl)-1-iodo-4-(trifluoromethyl)benzene as a clear oil.
.sup.1H NMR (CDCl.sub.3, 500 MHz): .delta. 8.02 (d, J=8.2 Hz, 1H),
7.73 (d, J=1.8 Hz, 1H), 7.26 (dd, J=8.3, 1.8 Hz, 1H), 4.64 (s,
2H).
Example 71
##STR00106##
[0345] 5-[3,5-bis(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one
[0346] Following the procedure described in EXAMPLE 13, 5.46 g of
2-amino-1-[3,5-bis(trifluoromethyl)phenyl]ethanol yielded
5-[3,5-bis(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one as an
off-white solid. LCMS=300.1 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3,
500 MHz): .delta. 7.94 (s, 1H), 7.89 (s, 2H), 5.81-5.77 (m, 1H),
5.29 (s, 1H), 4.17-4.12 (m, 1H), 3.59-3.55 (m, 1H).
Example 72
##STR00107##
[0347] 5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'
isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazoli-
din-2-one
[0348] A mixture of
5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-1-
,3-oxazolidin-2-one (60 mg; 0.103 mmol),
(4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (27 mg; 0.129
mmol), palladium acetate (7 mg; 0.0103 mmol), and potassium
carbonate (36 mg; 0.257 mmol) in 5:1 acetone/water (6 mL) was
heated at reflux for 1 h. Acetone was removed in vacuo and the
residue was diluted with H.sub.2O (10 mL) and extracted with
CH.sub.2Cl.sub.2 (3.times.10 mL). The combined extracts were washed
with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The residue was purified by flash
chromatography (0-25% EtOAc/hexanes gradient) to afford
5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'isopropyl-2'-methoxy-4-
-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one as a
clear glass. LCMS=624.2 (M+1).sup.+. .sup.1H NMR (benzene-d.sub.6,
500 MHz, 1:1 mixture of atropisomers): .delta. 7.60 (s, 1.5H), 7.45
(s, 0.5H), 7.31-7.25 (m, 3H), 6.98-6.94 (m, 1H), 6.87-6.82 (m, 1H),
6.43-6.37 (m, 1H), 4.54 (d, J=15.6 Hz, 0.5H), 4.40-4.36 (m, 1H),
4.47 (d, J=15.6 Hz, 0.5H), 3.96 (d, J=15.5 Hz, 0.5H), 3.80 (d,
J=15.8 Hz, 0.5H), 3.24-3.15 (m, 1H), 3.02 (s, 3H), 2.62-2.58 (m,
0.5H), 2.53-2.48 (m, 0.5H), 2.12-2.07 (m, 0.5H), 2.04-2.00 (m,
0.5H) 1.22-1.11 (m, 6H).
[0349] The racemic material was separated by chiral HPLC using 15%
IPA/heptane and an OD column into its two enantiomers.
[0350]
(5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropyl--
2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one:
LCMS=624.2 (M+1).sup.+. .sup.1H NMR (benzene-d.sub.6, 500 MHz, 1:1
mixture of atropisomers): .delta. 7.62 (s, 1.5H), 7.47 (s, 0.5H),
7.34-7.27 (m, 3H), 6.99-6.95 (m, 1H), 6.88-6.83 (m, 1H), 6.44-6.39
(m, 1H), 4.54 (d, J=15.5 Hz, 0.5H), 4.47-4.41 (m, 1H), 4.33 (d,
J=15.6 Hz, 0.5H), 3.98 (d, J=15.7 Hz, 0.5H), 3.82 (d, J=15.8 Hz,
0.5H), 3.24-3.15 (m, 1H), 3.05 (s, 3H), 2.67-2.62 (m, 0.5H),
2.57-2.52 (m, 0.5H), 2.16-2.11 (m, 0.5H), 2.09-2.04 (m, 0.5H)
1.22-1.11 (m, 6H).
[0351] (5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'
isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazoli-
din-2-one: LCMS=624.2 (M+1).sup.+. .sup.1H NMR (benzene-d.sub.6,
500 MHz, 1:1 mixture of atropisomers): .delta. 7.63 (s, 1.5H), 7.48
(s, 0.5H), 7.35-7.27 (m, 3H), 7.00-6.95 (m, 1H), 6.88-6.83 (m, 1H),
6.44-6.38 (m, 1H), 4.54 (d, J=15.8 Hz, 0.5H), 4.48-4.42 (m, 1H),
4.34 (d, J=15.8 Hz, 0.5H), 3.99 (d, J=15.8 Hz, 0.5H), 3.83 (d,
J=15.8 Hz, 0.5H), 3.25-3.15 (m, 1H), 3.05 (s, 3H), 2.68-2.63 (m,
0.5H), 2.58-2.53 (m, 0.5H), 2.18-2.12 (m, 0.5H), 2.10-2.05 (m,
0.5H) 1.23-1.11 (m, 6H).
Example 73
##STR00108##
[0352] Step 1:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)b-
enzyl]-4-methyl-1,3-oxazolidin-2-one
[0353] To a stirred suspension of sodium hydride (60% dispersion in
mineral oil; 1.3 g; 0.0325 mol) in THF (60 mL) at 0.degree. C.
under N.sub.2 was added dropwise a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
(Example 17) (4.077 g; 0.013 mol) in THF (50 .mu.L). Gas evolution
was observed. The resultant mixture stirred at 0.degree. C. for 30
min prior to addition of a solution of
2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (4.754 g; 0.013
mol) in THF (20 mL). The reaction was allowed to warm to room
temperature and stirred for 14 h. The reaction was carefully
quenched with H.sub.2O (15 mL) and partitioned between EtOAc (250
mL) and H.sub.2O (75 mL). The aqueous layer was extracted with
EtOAc (3.times.100 mL). Combined organic layers were washed with
brine (100 mL), dried (MgSO.sub.4), filtered and concentrated in
vacuo. The residue was purified by flash chromatography (0-20%
EtOAc/hexanes gradient) to afford 6.4 g (82.5%) of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)b-
enzyl]-4-methyl-1,3-oxazolidin-2-one as a white solid. LCMS=598.1
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta. 8.03 (d,
J=8.2 Hz, 1H), 7.90 (s, 1H), 7.79 (s, 2H), 7.58 (s, 1H), 7.30 (dd,
J=8.2 Hz, J=2.0 Hz, 1H), 5.76 (d, J=8 Hz, 1H), 4.88 (d, J=15.8 Hz,
1H), 4.37 (d, J=15.8 Hz, 1H), 4.09-4.02 (m, 1H), 0.8 (d, J=6.6 Hz,
3H).
Step 2:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'isoprop-
yl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazol-
idin-2-one
[0354] A stirred mixture of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)b-
enzyl]-4-methyl-1,3-oxazolidin-2-one (4.29 g; 7.19 mmol),
(4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Example 78)
(4.57 g; 21.57 mmol), tetrakis(triphenylphosphine)palladium (0)
(1.0 g; 0.86 mmol), and sodium carbonate (6.35 g) in
C.sub.6H.sub.6/EtOH/H.sub.2O (120 mL/17 mL/51 mL) was heated at
reflux (100.degree. C.) under N.sub.2 for 14 h. The reaction was
partitioned between EtOAc (200 mL) and H.sub.2O (100 mL). The
aqueous phase was extracted with EtOAc (3.times.200 mL). The
combined organic phases were washed with brine (100 mL), dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue was
purified by silica-gel flash chromatography (0-25% EtOAc/hexanes
gradient) to afford
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'isopropyl-2'-m-
ethoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2--
one as a yellow solid. To remove the yellow impurity, 2.7 g were
dissolved in 165 mL EtOH and 275 mg decolorizing charcoal was added
(activated carbon, Darco, G-60, 100 mesh powder, Aldrich). The
mixture was stirred at room temperature for 40 min, filtered, and
concentrated in vacuo. Trituration with ca. 25 mL hexanes afforded
2.46 g of the title compound as a white solid. .sup.1H NMR
indicated trace impurities which were removed by silica gel flash
chromatography (0-15% EtOAc/hexanes gradient). Residual solvent was
removed by lyophilization from acetonitrile. LCMS=638.3
(M+1).sup.+. .sup.1H NMR (benzene-d.sub.6, 500 MHz, 1:1 mixture of
atropisomers): .delta. 7.82 (s, 0.5H), 7.60 (s, 0.5H), 7.57 (s,
1H), 7.33 (d, J=8 Hz, 1H), 7.27 (d, J=9.9 Hz, 2H), 7.02-6.98 (m,
1H), 6.89 (d, J=8.5 Hz, 0.5H), 6.82 (d, J=8.5 Hz, 0.5H), 6.45 (d,
J=12.1 Hz, 0.5H), 6.35 (d, J=11.9 Hz, 0.5H), 4.94 (d, J=16.0 Hz,
0.5H), 4.87 (d, J=15.8 Hz, 0.5H), 4.54 (d, J=8.0 Hz, 0.5H), 4.50
(d, J=7.8 Hz, 0.5H), 3.74-3.66 (m, 1H), 3.23-3.15 (m, 1H), 3.12 (s,
1.5H), 2.99 (s, 1.5H), 2.97-2.92 (m, 0.5H), 2.89-2.84 (m, 0.5H),
1.21-1.09 (m, 6H), -0.27 (d, J=6.7 Hz, 1.5H), -0.40 (d, J=6.7 Hz,
1.5H).
[0355] Alternate procedure for making
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'isopropyl-2'-m-
ethoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2--
one:
[0356] A mixture of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)b-
enzyl]-4-methyl-1,3-oxazolidin-2-one (50 mg; 0.084 mmol),
(4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (EXAMPLE 78, 22
mg; 0.105 mmol), palladium acetate (6 mg; 0.0103 mmol), and
potassium carbonate (29 mg; 0.257 mmol) in 5:1 acetone/water (6 mL)
was heated at reflux for 1 h. Acetone was removed in vacuo and the
residue was diluted with H.sub.2O (10 mL) and extracted with
CH.sub.2Cl.sub.2 (3.times.10 mL). The combined extracts were washed
with brine (10 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The residue was purified by flash
chromatography (0-25% EtOAc/hexanes gradient) to afford
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'isopropyl-2'-m-
ethoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2--
one as a clear glass. This product can also be made by the method
provided in Example 372.
Example 74
##STR00109##
[0357]
(4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5'-isopropyl-2'-meth-
oxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methylimidazolidin-2-one
Step A:
(4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-met-
hoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1-methyl-1,3-oxazolidin-2-on-
e
[0358]
((4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-
-2-one) (46.2 mg, 0.148 mmol) was placed in a dry flask and DMA (3
mL) was added. NaHMDS (296 .mu.L of a 1M solution in THF, 0.296
mmol) was added and the reaction was stirred for 5 min. At this
time,
2'-(bromomethyl)-5-isopropyl-4'-(trifluoromethyl)biphenyl-2-yl
methyl ether (80.0 mg, 0.207 mmol) was added by cannula in DMA (2
mL). After 30 min, the reaction was quenched with saturated
NH.sub.4Cl (2 mL). The mixture was diluted with EtOAc (40 mL). The
organic layer was washed with water (15 mL), and brine (15 mL),
dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Purification of the residue by flash chromatography with 25%
EtOAc/hexanes afforded
(4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4--
(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.
R.sub.f=0.27 (25% EtOAc/hexanes). LCMS=620.2 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz; atropisomers present) .delta. 6.90-7.88
(m, 9H), 4.04-5.05 (m, 3H), 3.25-3.74 (m, 4H), 2.88 (m, 1H),
1.19-1.24 (m, 6H), 0.99-1.07 (m, 3H).
Step B:
(1S,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-me-
thoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propan-1-ol
[0359] To a solution of
(4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-isopropyl-2'-methoxy-4--
(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
(147.7 mg, 0.239 mmol) in EtOH (7.5 mL) was added H.sub.2O (1.5 mL)
and KOH (150 mg, 2.67 mmol). The solution was heated to 75.degree.
C. for 30 h and then cooled to room temperature. EtOAc (75 mL) was
added and the organic layer was washed with H.sub.2O (15 mL) and
brine (2.times.15 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by flash chromatography to afford
(1S,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methoxy-4-
-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propan-1-ol.
R.sub.f=0.44 (40% EtOAc/hexanes). LCMS=594.2 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 6.93-7.78 (m, 9H), 3.51-4.20 (m,
6H), 2.91 (m, 1H), 2.49 (m, 1H), 1.22-1.26 (m, 6H), 0.79-0.81 (m,
3H).
Step C:
tert-butyl{(1S,2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1--
methylethyl}{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]met-
hyl}carbamate
[0360] To a solution of
(1S,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5'-isopropyl-2'-methoxy-4-
-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propan-1-ol (135.5 mg,
0.228 mmol) in CH.sub.2Cl.sub.2 (5 mL) was added BOC.sub.2O (49.7
mg, 0.228 mmol). The reaction was stirred at room temperature for 2
days; during this time, 2 additional portions of BOC.sub.2O (25 mg
each) were added. After 2 days, the reaction was concentrated, and
the residue was purified by flash chromatography with 20%
EtOAc/hexanes to afford
tert-butyl{(1S,2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1-methyle-
thyl}{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}car-
bamate. R.sub.f=0.41 (40% EtOAc/hexanes). LCMS=594.2
(M+1-BOC).sup.+.
Step D:
tert-butyl{(1S,2R)-2-azido-2-[3,5-bis(trifluoromethyl)phenyl]-1-me-
thylethyl}{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methy-
l}carbamate
[0361] A dry flask was charged with THF (1 mL) diethyl
azodicarboxylate (DEAD) (11 .mu.L, 0.0698 mmol) and
diphenylphosphoryl azide (DPPA) (15 .mu.L, 0.0698 mmol).
tert-butyl{(1S,2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1-methyle-
thyl}{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}car-
bamate (20.7 mg, 0.0698 mmol) was added by cannula in THF (1 mL).
Next Ph.sub.3P (18.3 mg, 0.0698 mmol) was added. The reaction was
stirred at room temperature for 30 min, and then additional DEAD
(11 .mu.L, 0.0698 mmol), DPPA (15 .mu.L, 0.0698 mmol), and
Ph.sub.3P (18.3 mg, 0.0698 mmol) were added. After an additional 30
min, the reaction was diluted with EtOAc (40 mL) and washed with
water and brine (15 mL each). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography with 15% EtOAc/hexanes afforded
tert-butyl{(1S,2R)-2-azido-2-[3,5-bis(trifluoromethyl)phenyl]-1-methyleth-
yl}{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carba-
mate. R.sub.f=0.60 (25% EtOAc/hexanes). LCMS=619.3
(M+1-BOC).sup.+.
Step E:
(1R,2S)-1-azido-1-[3,5-bis(trifluoromethyl)phenyl]-N-{[5'-isopropy-
l-2'-methoxy-4-(trifluoromethyl)bi
phenyl-2-yl]methyl}propan-2-amine
[0362] To a solution of
tert-butyl{(1S,2R)-2-azido-2-[3,5-bis(trifluoromethyl)phenyl]-1-methyleth-
yl}{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carba-
mate (21.7 mg, 0.030 mmol) in CH.sub.2Cl.sub.2 (2 mL) was added TFA
(200 .mu.L). The reaction was stirred at room temperature for 1
hour and then diluted with CH.sub.2Cl.sub.2 (25 mL). The
CH.sub.2Cl.sub.2 solution was washed with 1 N NaOH (15 mL) and the
aqueous phase was re-extracted with CH.sub.2Cl.sub.2 (25 mL). The
organic extracts were combined, washed with brine (20 mL), dried
over Na.sub.2SO.sub.4, filtered, and concentrated. Purification of
the residue by flash chromatography with 15% EtOAc/hexanes afforded
(1R,2S)-1-azido-1-[3,5-bis(trifluoromethyl)phenyl]-N-{[5'-isopropyl-2'-me-
thoxy-4-(trifluoromethyl)bi phenyl-2-yl]methyl}propan-2-amine.
R.sub.f=0.45 (15% EtOAc/hexanes). LCMS=619.2 (M+1).sup.+.
Step F:
(1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N.sup.2-{[5'-isopropyl--
2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propane-1,2-diamine
[0363] To a solution of
(1R,2S)-1-azido-1-[3,5-bis(trifluoromethyl)phenyl]-N-{[5'-isopropyl-2'-me-
thoxy-4-(trifluoromethyl)bi phenyl-2-yl]methyl}propan-2-amine (17.8
mg, 0.0288 mmol) in THF (3 mL) was added PtO.sub.2 (12 mg, 0.053
mmol). The reaction was placed under hydrogen balloon atmosphere
and stirred at room temperature for 3 h. The catalyst was removed
by filtration and the filtrate was concentrated. The residue was
put through a short plug of silica gel with 0-10%
MeOH/CH.sub.2Cl.sub.2 to give
(1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N.sup.2-{[5'-isopropyl-2'-meth-
oxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propane-1,2-diamine.
LCMS=619.2 (M+1).sup.+.
Step G:
(4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5'-isopropyl-2'-met-
hoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methylimidazolidin-2-one
[0364] A solution of
(1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N.sup.2-{[5'-isopropyl-2'-meth-
oxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propane-1,2-diamine
(8.0 mg, 0.0135 mmol) in CH.sub.2Cl.sub.2 (2 mL) was cooled to
0.degree. C. and DIPEA (14 .mu.L, 0.081 mmol) was added followed by
triphosgene (2 mg, 0.00657 mmol). The reaction was stirred at
0.degree. C. for 30 min and then diluted with EtOAc (30 mL). The
reaction was washed with saturated NaHCO.sub.3 (10 mL) and brine
(10 mL). The organic layer was dried over Na.sub.2SO.sub.4,
filtered, and concentrated. Purification of the residue by flash
chromatography with 40% EtOAc/hexanes afforded
(4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5'-isopropyl-2'-methoxy-4--
(trifluoromethyl)biphenyl-2-yl]methyl}-5-methylimidazolidin-2-one.
R.sub.f=0.24 (40% EtOAc/hexanes). LCMS=619.2 (M+1).sup.+. .sup.1H
NMR (CD.sub.2Cl.sub.2, 600 MHz; atropisomers present) .delta.
6.91-7.84 (m, 9H), 3.84-4.94 (m, 4H), 3.64-3.80 (m, 4H), 2.88 (m,
1H), 1.18-1.26 (m, 6H), 0.27-0.42 (m, 3H).
Example 75
##STR00110##
[0365]
(3S,4R)-4-[3,5-bis(trifluoromethyl)phenyl]-2-{[5'-isopropyl-2'-meth-
oxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-3-methyl-1,2,5-thiadiazolidin-
e 1,1-dioxide
[0366] A glass reaction tube was charged with
(1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N.sup.2-{[5'-isopropyl-2'-meth-
oxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propane-1,2-diamine
(15.9 mg, 0.0269 mmol), sulfamide (4 mg, 0.0403 mmol), and pyridine
(600 .mu.L). The tube was flushed with N.sup.2, sealed, and heated
at 120.degree. C. for 2 h. The reaction was then cooled to room
temperature, diluted with EtOAc (40 mL) and washed with H.sub.2O,
1N HCl, and brine (10 mL each). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography with 25% EtOAc/hexanes afforded
(3S,4R)-4-[3,5-bis(trifluoromethyl)phenyl]-2-{[5'-isopropyl-2'-methoxy-4--
(trifluoromethyl)biphenyl-2-yl]methyl}-3-methyl-1,2,5-thiadiazolidine
1,1-dioxide. R.sub.f=0.27 (25% EtOAc/hexanes). LCMS=655.2
(M+1).sup.+. .sup.1H NMR (C.sub.6D.sub.6, 500 MHz; atropisomers
present) .delta. 6.51-8.19 (m, 9H), 3.64-4.53 (m, 4H), 3.00-3.18
(m, 4H), 2.73 (m, 1H), 1.13-1.20 (m, 6H), -0.03-0.09 (m, 3H).
Example 76
##STR00111##
[0367] 2-fluoro-1-isopropenyl-4-methoxybenzene
Step A: 2-(2-fluoro-4-methoxyphenyl)propan-2-ol
[0368] To a solution of 2'-fluoro-4'-methoxyacetophenone (4.45 g,
26.5 mmol) in THF (50 ml) at 0.degree. C., a solution of 2.4 M
MeMgBr (11.6 mmol, 27.8 mmol) was added. The mixture was stirred at
0.degree. C. and then room temperature for 4 h. The reaction was
quenched with saturated ammonium chloride solution. The organic was
extracted with ethyl acetate (3.times.50 ml). The combined ethyl
acetate layers were washed with brine and dried over sodium
sulfate. The resulting alcohol was obtained as an oil after flash
column using EtOAc:hexane=2:8 as the elute.
Step B: 2-fluoro-1-isopropenyl-4-methoxybenzene
[0369] To a solution of 2-(2-fluoro-4-methoxyphenyl)propan-2-ol
from Step A (3.89 g, 21.14 mmol) in methylene chloride (50 ml) at
0.degree. C., MsCl (1.95 ml, 25.4 mmol) and triethylamine (6.52 ml,
46.5 mmol) were added. The solution was stirred at 0.degree. C. and
then room temperature for 2 h. The solution was diluted with
methylene chloride (100 ml), washed with water, and dried over
sodium sulfate. The title compound was obtained as an oil after
flash column using EtOAc:hexane=1:9 as the elute. .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 7.25 (t, J=9.0 Hz, 1 H), 6.68 (dd,
J=8.5, 2.5 Hz, 1H), 6.63 (dd, J=13, 2.5 Hz, 1H), 5.20 (d, J=17.0
Hz, 2H), 3.82 (s, 3H), 2.18 (s, 3H).
Alternate Route to Make 2-fluoro-1-isopropenyl-4-methoxybenzene
[0370] A solution of sodium bis(trimethylsilyl)-amide, 1.0M in
tetrahydrofuran (714 ml, 0.714 m) was added to a suspension of
methyltriphenylphosphonium bromide (255 g, 0.714 m) in THF (2.50 L)
cooled with an ice bath. The resultant yellow colored suspension
was stirred for 30 minutes at ice bath temperature and then cooled
to -78.degree. C. A total of 2-fluoro-4-methoxyacetophenone (10 g,
0.595 m) in THF (200 ml) was added dropwise and stirred at
-78.degree. C. for 1.5 hours. Reaction mixture was allowed to warm
to room temperature for one hour, quenched with acetic acid
(.about.80 ml) where color change was observed from yellow to off
white and stirred for 30 minutes (pH.about.7)(slight exotherm
noted). The mixture was concentrated to a slush, diluted with 7:2
hexane:ethyl acetate, and was allowed to sit overnight. Solids were
removed by filtration and the filtrate was concentrated to yellow
oil. The title compound was obtained after flash column using 9:1
hexane:ethyl as the eluant.
Example 77
##STR00112##
[0371] 1-fluoro-4-iodo-2-isopropyl-5-methoxybenzene
[0372] A solution of the 2-fluoro-1-isopropenyl-4-methoxybenzene
(Example 76, 1.96 g, 11.81 mmol) in MeOH (30 ml) was charged with
hydrogen at 1 atm with catalytic amount of Pd/C. The mixture was
stirred at room temperature for 1 h. The mixture was filtered
through Celite. The filtrate was then added to a mixture of silver
sulfate (3.68 g, 11.81 mmol) and Iodine (3.00 g, 11.81 mmol) in
MeOH (10 ml). The mixture was stirred at room temperature for 3 h
until the color of solution became light yellow. The mixture was
filtered and the filtrate was concentrated. The title compound was
obtained after flash column using EtOAc:hexane 5:95 as the elute.
.sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 7.61 (d, J=8.0 Hz, 1H),
6.56 (d, J=12.5 Hz, 1H), 3.90 (s, 3H), 3.18 (m, 1H), 1.28 (m,
6H).
Example 78
##STR00113##
[0373] (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid
[0374] To a solution of
1-fluoro-4-iodo-2-isopropyl-5-methoxybenzene (Example 77, 2.61 g,
8.88 mmol) in THF at -78.degree. C., n-BuLi (4.26 ml, 10.65 mmol,
2.5 M) was added dropwise. The solution was stirred at -78.degree.
C. for 30 min. Trimethyl borate (2.98 ml, 26.6 mmol) was added. The
solution was then stirred at -78.degree. C. for 3 h. The reaction
was quenched at -78.degree. C. with saturated ammonium chloride and
the mixture was warmed to room temperature. The organic was
extracted with ethyl acetate (3.times.50 ml). The combined ethyl
acetate layers were washed with brine and dried over sodium
sulfate. The title compound was obtained as a solid pure enough for
next step. Further purification with silica gel caused
decomposition of product. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.
7.74 (d, J=10.0 Hz, 1H), 6.62 (d, J=12.5 Hz, 1H), 5.65 (br s, 2H),
3.92 (s, 3H), 3.20 (m, 1H), 1.22 (m, 6H).
[0375] The boronic acid intermediate can also be made by the
following 4-step process:
##STR00114##
Conversion of 1 to 2:
[0376] THF (24 L) was added to a 100 L cylindrical vessel at room
temperature. To this was added 2.75 kg of CeCl.sub.3. The resultant
slurry was aged at room temperature for 1.5 hours. A sample was
then examined under a microscope to confirm that the desired form
change had occurred. The slurry was cooled to 9.degree. C. and
MeMgCl was added. The rate of addition was adjusted to maintain
internal temperature below 19.degree. C. The mixture was cooled to
-11.degree. C., and a solution of acetophenone 1 (4.0 kg diluted to
10 L with THF) was added dropwise, maintaining the internal
temperature below 0.degree. C. The reaction mixture was then aged
at a temperature below 0.degree. C. for an hour. The reaction was
quenched with 5.7 L of 3N HCl in a dropwise fashion, maintaining
the internal temperature below 15.degree. C. The quenched reaction
mixture was then aged at 5-10.degree. C. for 1.5 hours and was
filtered through a plug of Solka Floc.
Hydrogenation of 2 to 3:
[0377] The THF solution of 2 was solvent switched into ethanol
(.about.18 L volume), and 1.9 L HCl was added, followed by 190 gm
of 10% Pd/C (50% water). The mixture was placed under 15 psi
hydrogen at 40.degree. C. until the reaction was complete based on
HPLC analysis. The mixture was cooled to room temperature. The
catalyst was removed by filtration using Solka-Flok as a filter
aid. The anisole product in ethanol was then solvent switched into
acetonitrile for the next step.
Bromination of 3 to 4:
[0378] Anisole 3 is diluted in acetonitrile (1.72 L, 4 mL MeCN/mMol
3). This mixture is warmed to 35.degree. C., and NBS (1.1 eq, 84 g)
is added in a single solid addition. The reaction is complete in
2-4 hours. The solution is concentrated to 400 mL total volume and
diluted with 1 L of toluene. The solution is then washed with
sodium thiosulfate and water to remove the succinimide by-product.
The organic layer is then concentrated and solvent switched to
toluene.
Conversion of Aryl Bromide 4 to Boronic Acid 5:
[0379] A 75 L glass reaction vessel was charged with 1.87 kg of
aryl bromide 4 (7.6 Mol), which was added as 6.4 kg of a 29.1 wt %
solution of 4 in toluene. This solution was diluted with 5.6 L of
THF. The vessel was flushed with nitrogen, and tri-isopropylborate
(1.35 eq, 2.35 L, 10.3 Mol) was added. The mixture was cooled to
<-70.degree. C. Then 5.9 L of 1.6 M n-BuLi in hexanes (9.5 Mol)
was added slowly over 4 hours, maintaining a temperature of
<-55.degree. C. Thirty minutes after completion of the n-BuLi
addition, the reaction was complete by LC analysis. The reaction
was warmed to -35.degree. C. and quenched into 3.0 M
H.sub.2SO.sub.4 solution (5.6 L). The aqueous phase after the
quench should be acidic (pH .about.2). MTBE (7.5 L) was added to
the mixture to dilute the organic layer. The mixture was stirred
(15 min) and the aqueous layer was cut away. The organic layer was
washed with another 5.6 L of a 3.0 M H.sub.2SO.sub.4 solution (15
min). After separating layers again, the organic MTBE/Toluene layer
was extracted twice with 1 M KOH (15.1 L first and then 7.6 L). The
two KOH extractions were combined, diluted with 2-propanol (6.4 L),
and cooled to 15.degree. C. Then the solution was slowly acidified
to pH .about.2 using 3.0 M sulphuric acid (.about.7.6 L) while
maintaining temperature at 15-20.degree. C. The resulting slurry
was stirred for 1 h and then filtered. The filter cake was washed
with water (2.times.6 L) and dried under an air flow for 1 day. The
filtered solid was placed in an oven under vacuum at 50.degree. C.
for 2-3 days to decompose a diaryl impurity and to dry the solid.
The off-white crystalline solid was isolated to yield 1.59 kg of
boronic acid 5.
Example 79
##STR00115##
[0380]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-chloro-4'-fluoro-5-
'-isopropyl-2'-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
Step A: 1-bromo-2-(bromomethyl)-4-chlorobenzene
[0381] A mixture of 2-bromo-5-chloro-toluene (2.00 g, 9.75 mmol),
NBS (2.08 g, 11.7 mmol) and catalytic amount of AIBN in carbon
tetrachloride (50 ml) was stirred under refluxing conditions for 4
h. TLC (EtOAc:hexane=5:95) showed no starting material. The mixture
was filtered and the filtrate was concentrated. The title compound
was obtained as a white solid after flash column using
EtOAc:hexane=5:95 as the elute. .sup.1H NMR (CDCl.sub.3, 500 MHz)
.delta. 7.53 (d, J=9.0 Hz, 1H), 7.47 (d, J=2.5 Hz, 1H), 7.18 (dd,
J=8.5, 2.5 Hz, 1H), 4.60 (s, 2H).
Step B.
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-chlorobenz-
yl)-4-methyl-1,3-oxazolidin-2-one
[0382] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
(0.050 g, 0.16 mmol) in THF (1 ml) at 0.degree. C., NaH (7.6 mg,
0.19 mmol, 60%) was added. The mixture was stirred at 0.degree. C.
for 30 min. The title compound from Step A (0.059 g, 0.21 mmol) was
added. The whole mixture was stirred at 0.degree. C. for 1 h and
warmed to room temperature for 4 h. The reaction was quenched with
saturated ammonium chloride. The organic was extracted with ethyl
acetate (3.times.15 ml). The combined ethyl acetate layers were
washed with brine and dried over sodium sulfate. The title compound
was obtained after preparative TLC purification using
EtOAc:hexane=2:8 as the elute. .sup.1H NMR (CDCl.sub.3, 500 MHz)
.delta. 7.92 (s, 1H), 7.82 (s, 2H), 7.55 (d, J=8.5 Hz, 1H), 7.43
(d, J=2.5 Hz, 1H), 7.23 (dd, J=8.5, 2.5 Hz, 1H), 5.77 (d, J=8.0 Hz,
1H), 4.86 (d, J=16.0 Hz, 1H), 4.36 (d, J=16.0 Hz, 1H), 4.11 (m,
1H), 0.82 (d, J=6.5 Hz, 3H).
Step C.
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-chloro-4'-fluoro--
5'-isopropyl-2'-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
[0383] A mixture of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-chlorobenzyl)-4-m-
ethyl-1,3-oxazolidin-2-one (44 mg, 0.085 mmol),
(4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (Example 78, 23
mg, 0.11 mmol), potassium carbonate (25 mg, 0.18 mmol) and
catalytic amount of PdOAc in a 4:1 mixture of acetone/water was
heated to reflux for 1 h. Acetone was removed and water was added.
The organic was extracted with methylene chloride (3.times.15 ml).
The combined methylene chloride layers were washed with brine and
dried over sodium sulfate. The title compound was obtained as a
solid after preparative reverse phase HPLC. .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 1:1 mixture of rotamer 67.90 (s, 1H),
7.73 (s, 2H), 7.49 (m, 1H), 7.40 (m, 1H), 7.20 (m, 1H), 7.00 (m,
1H), 6.68 (dd, J=12.0, 3.0 Hz, 1H), 5.63 (d, J=8.0 Hz, 1/2H), 5.44
(d, J=8.0 Hz, 1/2H), 4.85 (d, J=10.0 Hz, 1/2H), 4.82 (d, J=10.0 Hz,
1/2H), 4.03 (d, J=16.0 Hz, 1/2H), 3.84 (m, 11/2H), 3.80 (s, 3H),
3.20 (m, 1H), 1.20 (m, 6H), 0.56 (d, J=6.5 Hz, 3/2H), 0.38 (d,
J=6.5H, 3/2H). LC-MS (M+1): 604.3, 4.61 min.
Example 80
##STR00116##
[0384]
5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one
Step A: 2-iodo-5-(trifluoromethyl)benzaldehyde
[0385] To a solution of 2-iodo-5-(trifluoromethyl)benzonitrile
(EXAMPLE 2, 42 g) in CH.sub.2Cl.sub.2 (300 mL) at -78.degree. C.
was added a solution of DIBAL in CH.sub.2Cl.sub.2 (175 mL, 1M) over
30 minutes. A precipitate formed. The reaction was warmed to
0.degree. C. An additional 25 mL of the DIBAL solution was added
dropwise over 30 minutes. The reaction was poured into 200 mL 2N
aqueous HCl, diluted with ether and stirred 1 hour. TLC analysis
indicates imine still present and an additional 100 mL 2N aqueous
was added and the reaction stirred overnight. Imine was still
present by TLC analysis and 200 mL 2N aqueous HCl was added and the
mixture stirred 2 hours. The layers were separated and the aqueous
layer back extracted with ether. The ether extracts were combined,
washed with brine, dried over anhydrous MgSO.sub.4, filtered and
concentrated. The product was purified by silica gel chromatography
eluting with 95:5 hexanes/EtOAc to give
2-Iodo-5-(trifluoromethyl)benzaldehyde as a white solid. .sup.1H
NMR (500 MHz, CDCl.sub.3): .delta. 10.00 (s, 1H), 8.12 (s, 1H),
8.11 (d, J=8 Hz, 1H), 7.53 (dd, J=2 Hz, 8 Hz, 1H).
Step B:
5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one
[0386] To a 0.degree. C. solution of 0.2 g of
2-iodo-5-(trifluoromethyl)benzaldehyde in 3 mL of EtOH was added
0.13 mL of nitromethane, then 0.28 mL of a 2.5 N solution of NaOH.
The mixture was stirred at 0.degree. C. for 3 h, and then
neutralized by addition of 2.1 .mu.L of a 0.33 N aqueous solution
of AcOH. The mixture was partitioned between 10 mL of water and 10
.mu.L of EtOAc. The aqueous phase was extracted with 2.times.5 mL
of EtOAc. The combined organics were washed with 10 mL of brine,
dried over Na.sub.2SO.sub.4, and concentrated. The residue was
dissolved in 4 mL of MeOH and 0.5 mL of 88% aqueous formic acid was
added. Approximately 200 mg of a Raney nickel slurry was added and
the mixture was flushed with H2, and stirred under an H2 balloon
for 4 h. The mixture was filtered through a pad of Celite, washing
with MeOH, and the filtrate was concentrated. The residue was
partitioned between 10 mL of 10% aqueous NH.sub.4OH and 20 mL of
EtOAc. The aqueous phase was extracted with 2.times.10 mL of EtOAc.
The combined organics were washed with 10 mL of brine, dried over
Na.sub.2SO.sub.4, and concentrated. The residue was dissolved in 2
mL of CH.sub.2Cl.sub.2. To the solution was added 0.114 mL of
diisopropylethylamine, then 0.065 g of triphosgene. The mixture was
stirred at 0.degree. C. for 30 min, then diluted with 10 mL of
EtOAc and 10 mL of saturated NaHCO.sub.3. The aqueous phase was
extracted with 2.times.10 mL of EtOAc. The combined organics were
washed with 10 mL of brine, dried over Na.sub.2SO.sub.4, and
concentrated. The residue was purified by flash chromatography on a
Biotage Horizon, 25S column, eluting with 1 CV of 4% EtOAc in
hexanes, followed by a linear gradient of EtOAc in hexanes from 4
to 100% over 10 CV to provide the title compound. Mass spectrum
(ESI) 350.0 (M+1). .sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 8.00
(d, J=8 Hz, 1H), 7.74 (br s, 1H), 7.33 (br d, J=8 Hz, 1H), 5.80
(dd, J=7 Hz, 9 Hz 1H), 5.05-5.50 (br, 1H), 4.28 (t, J=9 Hz, 1.5H),
3.36 (dd, J=7 Hz, 9 Hz, 1H).
Example 81
##STR00117##
[0387]
5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-ox-
azolidin-2-one
[0388] To a solution of 65 mg of
5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1,3-oxazolid-
in-2-one, 45 mg of (5-isopropyl-2-methoxyphenyl)boronic acid, and
66 mg of potassium carbonate in 6 mL of acetone and 1.5 mL of water
was added ca. 5 mg of palladium acetate. The mixture was heated to
reflux and stirred at this temperature for 1.5 h. Acetone was
removed by rotary evaporation and the residue was diluted with 10
mL of EtOAc and 10 mL of water. The aqueous phase was extracted
with 10 mL of EtOAc. The combined organics were washed with 10 mL
of brine, dried over Na.sub.2SO.sub.4, and concentrated. The
residue was purified by flash chromatography on a Biotage Horizon,
25S column, eluting with 1 CV of 10% EtOAc in hexanes, followed by
a linear gradient of EtOAc in hexanes from 10 to 100% over 10 CV to
provide the title compound. Spectral data are provided in EXAMPLE
49.
[0389] Following the procedures outlined in EXAMPLE 52 the
compounds listed in Table 2 were prepared:
TABLE-US-00003 TABLE 3 ##STR00118## LC/MS Data EXAMPLE R (M + 1) 82
##STR00119## 488.1 83 ##STR00120## 504.1 84 ##STR00121## 495.1 85
##STR00122## 476.2 86 ##STR00123## 484.2 87 ##STR00124## 484.2 88
##STR00125## 484.2 89 ##STR00126## 484.2
Example 90
##STR00127##
[0390]
5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
[0391] Following the procedure described in EXAMPLE 80 and using
nitroethane, 0.2 g of 2-iodo-5-(trifluoromethyl)benzaldehyde
provided 0.102 g of the desired product, which was separated into
the cis and trans diastereomers by flash chromatography Biotage
Horizon, 25S column, eluting with 1 CV of 10% EtOAc in hexanes,
followed by a linear gradient of EtOAc in hexanes from 10 to 100%
over 10 CV.
[0392]
trans-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin--
2-one: Mass spectrum (ESI) 372.1 (M+1). .sup.1H NMR (500 MHz,
CDCl.sub.3): .delta. 8.02 (d, J=8 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H),
7.32 (dd, J=2 Hz, 8 Hz, 1H), 6.16 (s, 1H), 5.39 (d, J=4 Hz, 1H),
3.76 (dq, J=6 Hz, 4.5 Hz, 1H), 1.62 (d, J=6 Hz, 3H).
[0393]
cis-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2--
one: Mass spectrum (ESI) 372.1 (M+1). .sup.1H NMR (500 MHz,
CDCl.sub.3): .delta. 7.98 (d, J=8 Hz, 1H), 7.60 (br s, 1H), 7.33
(dd, J=1.5 Hz, 8 Hz, 1H), 6.25 (s, 1H), 5.85 (d, J=8 Hz, 1H), 3.76
(dq, J=8 Hz, 7 Hz, 1H), 0.81 (d, J=7 Hz, 3H).
Example 91
##STR00128##
[0394]
trans-5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]--
4-methyl-1,3-oxazolidin-2-one (racemic)
[0395] To a solution of 0.036 g of
trans-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one,
0.024 g of (5-isopropyl-2-methoxyphenyl)boronic acid, and 0.04 g of
potassium carbonate in 2 mL of acetone and 0.5 mL of water was
added ca. 2 mg of palladium acetate. The mixture was heated to
reflux and stirred at this temperature for 1.5 h. Acetone was
removed by rotary evaporation and the residue was diluted with 10
mL of EtOAc and 10 mL of water. The aqueous phase was extracted
with 10 mL of EtOAc. The combined organics were washed with 10 mL
of brine, dried over Na.sub.2SO.sub.4, and concentrated. The
residue was purified by flash chromatography on a Biotage Horizon,
25S column, eluting with 1 CV of 10% EtOAc in hexanes, followed by
a linear gradient of EtOAc in hexanes from 10 to 100% over 10 CV to
provide the title compound. Mass spectrum (ESI) 394.2 (M+1).
.sup.1H NMR signals are doubled because of atropoisomerism. .sup.1H
NMR (500 MHz, CDCl.sub.3): .delta. 7.80, 7.78 (s, 1H), 7.64, 7.63
(d, J=8 Hz, 1H), 7.35 (d, J=7.5 Hz, 1H), 7.27, 7.26 (d, J=8 Hz 1H),
7.00, 6.95 (d, J=2.5 Hz, 1H), 6.93, 6.92 (d, J=8 Hz, 1H), 5.87,
5.81 (s, 1H), 5.16, 5.10 (d, J=5 Hz, 1H), 3.70-3.78 (m, 3.5H), 3.49
(m, 0.5H), 2.89 (m, 1H), 1.24 (m, 6H), 0.90, 0.70 (d, J=6.5 Hz,
3H).
Example 92
##STR00129##
[0396]
cis-5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4--
methyl-1-1,3-oxazolidin-2-one (racemic)
[0397] Following the procedure described in EXAMPLE 91, 0.046 g of
cis-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
provided the desired product. Mass spectrum (ESI) 394.2 (M+1).
.sup.1H NMR signals are doubled because of atropoisomerism. .sup.1H
NMR (500 MHz, CDCl.sub.3): .delta. 7.89, 7.88 (s, 1H), 7.65, 7.64
(d, J=7.5 Hz, 1H), 7.34, 7.32 (d, J=8 Hz, 1H), 7.26 (d, J=8.5 Hz,
1H), 6.98, 6.86 (d, J=2.5 Hz, 1H), 6.91, 6.89 (d, J=8 Hz, 1H),
5.83, 5.75 (s, 1H), 5.69, 5.61 (d, J=8 Hz, 1H), 3.75 (s, 1.8H),
3.58-3.70 (m, 2H), 3.32 (m, 0.6H), 2.88 (m, 1H), 1.23 (m, 6H),
0.89, 0.71 (d, J=6.5 Hz, 3H).
Example 93
##STR00130##
[0398]
trans-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-isopropyl-2'-methoxy-
-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one
(racemic)
[0399] To a 0.degree. C. solution of 30 mg of
trans-5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-meth-
yl-1,3-oxazolidin-2-one in 1 mL of DMF was added 8 mg of sodium
hydride. The mixture was stirred 10 min at room temperature, and
then 32 mg of 3,5-bis(trifluoromethyl)benzyl bromide was added. The
mixture was stirred overnight at room temperature, then diluted
with 10 mL of EtOAc and 10 mL of water. The phases were separated
and the aqueous phase was extracted with 5 mL of EtOAC. The
combined organics were washed with 5 mL of brine, dried
(Na.sub.2SO.sub.4), and concentrated. The residue was purified by
flash chromatography on a Biotage Horizon, 25S column, eluting with
1 CV of 4% EtOAc in hexanes, followed by a linear gradient of EtOAc
in hexanes from 4 to 100% over 10 CV to provide the title compound.
Mass spectrum (ESI) 620.2 (M+1). .sup.1H NMR signals are doubled
because of atropoisomerism. .sup.1H NMR (500 MHz, CDCl.sub.3):
.delta. 7.53-7.80 (m, 5H), 7.33 (d, J=8 Hz, 1H), 7.21-7.29 (m, 1H),
7.00, 6.76 (d, J=2.5 Hz, 1H), 6.91, 6.86 (d, J=8.5 Hz, 0.4H), 5.15,
5.10 (d, J=4.5 Hz, 1H), 4.80, 4.74 (d, J=16 Hz, 1H), 4.25, 4.21 (d,
16 Hz, 1H), 3.76 (s, 2H), 3.49 (s, 1H), 3.43 (m, 0.4H), 3.18 (m,
0.5H), 2.77-2.98 (m, 1H), 1.24 (m, 3H), 1.16 (m, 3H), 0.78, 0.61
(d, J=6.5 Hz, 3H).
Example 94
##STR00131##
[0400]
cis-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-isopropyl-2'-methoxy-4-
-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one
(racemic)
[0401] Following the procedure described in EXAMPLE 93, 40 mg of
cis-5-[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-
-1,3-oxazolidin-2-one and 42 mg of 3,5-bis(trifluoromethyl)benzyl
bromide gave the title compound. Mass spectrum (ESI) 620.2 (M+1).
.sup.1H NMR signals are doubled because of atropoisomerism. .sup.1H
NMR (500 MHz, CDCl.sub.3): .delta. 7.82-7.94 (m, 2H), 7.62-7.74 (m,
3H), 7.39, 7.37 (d, J=8 Hz, 1H), 7.25, 7.17 (br d, J=8.5 Hz, 1H),
7.00, 6.78 (s, 1H), 6.87, 6.84 (d, J=8.5 Hz, 1H), 5.59, 5.56 (d,
J=4.5 Hz, 1H), 4.96 (d, J=16 Hz, 1H), 4.22, 4.11 (d, J=16 Hz, 1H),
3.76 (s, 2H), 3.58 (s, 1H), 3.40 (m, 0.4H), 2.85-3.00 (m, 1H), 2.78
(m, 0.5H), 1.23 (d, J=7 Hz, 3H), 1.06 (m, 3H), 0.88, 0.69 (d, J=6.5
Hz, 3H).
Example 95
##STR00132##
[0402]
(4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidi-
n-2-one
Step A:
(4S)-4-benzyl-3-{(2R,3S)-3-hydroxy-3-[2-iodo-5-(trifluoromethyl)ph-
enyl]-2-methylpropanoyl}-1,3-oxazolidin-2-one
##STR00133##
[0404] A mixture of 1.8 g of
5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde
(EXAMPLE 80, Step A), 1.16 g of
(4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one, 0.048 g of
magnesium chloride, 1.40 mL of triethylamine, and 0.91 mL of
chlorotrimethylsilane in 10 mL of EtOAc was stirred at r.t. for 24
h, then filtered through a 10.times.10 cm plug of silica gel,
eluting with 400 mL of Et.sub.2O. The filtrate was concentrated,
and 10 mL of MeOH was added along with 2 drops of trifluoroacetic
acid. This solution was stirred at r.t. for 30 min and concentrated
to a pale yellow oil. The residue was purified by flash
chromatography on a Biotage Horizon, 65i column, eluting with 15 CV
of 10% acetone in hexanes to provide the title compound. Mass
spectrum (ESI) 516.2 (M-OH). .sup.1H NMR (500 MHz, CDCl.sub.3):
.delta. 8.00 (d, J=8.5 Hz, 1H), 7.76 (d, J=2 Hz, 1H), 7.22-7.32 (m.
4H), 7.07 (br d, J=6.5 Hz, 2H), 5.18 (dd, J=6.5 Hz, 7.5 Hz, 1H),
4.67 (m, 1H), 4.46 (dq, J=6.5 Hz, 7.5 Hz, 1H), 4.17 (t, J=9 Hz,
1H), 4.11 (dd, J=3 Hz, 9 Hz, 1H), 3.97 (d, J=8 Hz, 1H), 3.19 (dd,
J=7 Hz, 13.5 Hz, 1H), 2.57 (dd, J=9.5 Hz, 13.5 Hz, 1H), 1.34 (d,
J=7.5 Hz, 3H).
B:
(4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2--
one
[0405] To a 0.degree. C. solution of 0.65 g of
(4S)-4-benzyl-3-{(2R,3S)-3-hydroxy-3-[2-iodo-5-(trifluoromethyl)phenyl]-2-
-methylpropanoyl}-1,3-oxazolidin-2-one in 6 mL of 3:1
tetrahydrofuran-water was added 0.102 g of lithium hydroxide in 1.5
mL of water, then 0.554 mL of a 30% aqueous solution of hydrogen
peroxide. The solution was stirred 1 h at 0.degree. C., at which
point LC/MS analysis showed no starting material. A 1.5 M solution
of sodium sulfite (3.7 mL) was added to the cold solution, which
was then poured into a separatory funnel and extracted with
2.times.10 mL of CH.sub.2Cl.sub.2. The combined CH.sub.2Cl.sub.2
extracts were back-extracted with 20 mL of 3:1 water-saturated
aqueous NaHCO.sub.3. The combined aqueous layers were acidified
(pH<1) with 6 N HCl and extracted with 4.times.10 mL of EtOAc.
The combined EtOAc extracts were washed with 10 mL of brine, dried
over Na.sub.2SO.sub.4, and concentrated. The residue was dissolved
in 10 mL of toluene. Diphenylphosphoryl azide (0.315 mL) and 0.24
mL of triethylamine were added and the mixture was stirred
overnight at 100.degree. C., then cooled and concentrated. The
residue was purified by flash chromatography on a Biotage Horizon,
40S column, eluting with 1 CV of 5% EtOAc in hexanes, followed by a
linear gradient of EtOAc in hexanes from 5 to 100% over 10 CV to
provide the title compound. Mass spectrum (ESI) 372.1 (M+1).
.sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 8.02 (d, J=8 Hz, 1H),
7.61 (d, J=1.5 Hz, 1H), 7.32 (dd, J=2 Hz, 8 Hz, 1H), 6.16 (s, 1H),
5.39 (d, J=4 Hz, 1H), 3.76 (dq, J=6 Hz, 4.5 Hz, 1H), 1.62 (d, J=6
Hz, 3H). Analytical HPLC on Chiralpak AD 4.6.times.250 mm, eluting
with 4% ethanol in heptane at 0.75 mL/min (t.sub.R=21.5.sup.6 min
for R,R; t.sub.R=18.00 min for S,S) showed 98% e.e.
Example 96
##STR00134##
[0406]
(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluorome-
thyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
[0407] To a 0.degree. C. solution of 95 mg of
(4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-on-
e in 1 mL of DMF was added 20 mg of sodium hydride. The mixture was
stirred 10 min at 0.degree. C.; then 94 mg of
3,5-bis(trifluoromethyl)benzyl bromide was added. The mixture was
stirred 10 min at 0.degree. C., then diluted with 10 mL of EtOAc
and 10 mL of water. The phases were separated and the aqueous phase
was extracted with 10 mL of EtOAc. The combined organic phases were
washed with 10 mL of brine, dried over Na.sub.2SO.sub.4, and
concentrated. The residue was purified by flash chromatography on a
Biotage Horizon, 25M column, eluting with 1 CV of 2% EtOAc in
hexanes, followed by a linear gradient of EtOAc in hexanes from 2
to 100% over 10 CV to provide the title compound. Mass spectrum
(ESI) 598.1 (M+1). .sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 8.00
(d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.58 (br s, 3H), 7.34 (dd, J=1.5
Hz, 8 Hz, 1H), 5.36 (d, J=4 Hz, 1H), 4.89 (d, J=16 Hz, 1H), 4.31
(d, J=16 Hz, 1H), 4.48 (dq, J=6 Hz, 4 Hz, 1H), 1.55 (d, J=6.5 Hz,
3H).
Example 97
##STR00135##
[0408]
(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-isopropyl-2'-metho-
xy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one
[0409] Following the procedure described in EXAMPLE 81, 41 mg of
(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)p-
henyl]-4-methyl-1,3-oxazolidin-2-one and 17 mg of
(5-isopropyl-2-methoxyphenyl)boronic acid gave title compound. Mass
spectrum (ESI) 620.4 (M+1). .sup.1H NMR signals are doubled because
of atropoisomerism. .sup.1H NMR (500 MHz, CDCl.sub.3): .delta.
7.53-7.80 (m, 5H), 7.33 (d, J=8 Hz, 1H), 7.21-7.29 (m, 1H), 7.00,
6.76 (d, J=2.5 Hz, 1H), 6.91, 6.86 (d, J=8.5 Hz, 0.4H), 5.15, 5.10
(d, J=4.5 Hz, 1H), 4.80, 4.74 (d, J=16 Hz, 1H), 4.25, 4.21 (d, 16
Hz, 1H), 3.76 (s, 2H), 3.49 (s, 1H), 3.43 (m, 0.4H), 3.18 (m,
0.5H), 2.77-2.98 (m, 1H), 1.24 (m, 3H), 1.16 (m, 3H), 0.78, 0.61
(d, J=6.5 Hz, 3 Hz).
Example 98
##STR00136##
[0410]
(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[4'-fluoro-5'-isopropy-
l-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-o-
ne
[0411] Following the procedure described in EXAMPLE 81, 38.5 mg of
(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)p-
henyl]-4-methyl-1,3-oxazolidin-2-one and 18 mg of
(4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (EXAMPLE 78)
gave the title compound. Mass spectrum (ESI) 638.3 (M+1). .sup.1H
NMR signals are doubled because of atropoisomerism. .sup.1H NMR
(500 MHz, CDCl.sub.3): .delta. 7.55-7.80 (m, 5H), 7.29 (d, J=8 Hz,
1H), 7.00, 6.77 (d, J=8.5 Hz, 1H), 6.68, 6.63 (d, J=12 Hz, 1H),
5.08, 5.04 (d, J=5 Hz, 1H), 4.81, 4.75 (d, J=16 Hz, 1H), 4.26, 4.23
(d, 15.5 Hz, 1H), 3.75 (s, 2H), 3.50 (s, 1H), 3.43 (m, 0.5H),
3.12-3.24 (m, 1.5H), 1.24, 1.22 (d, J=5 Hz, 3H), 1.17, 1.06 (d, J=7
Hz, 3H), 0.84, 0.70 (d, J=6 Hz, 3H).
Example 99
##STR00137##
[0412]
(4S,5S)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidi-
n-2-one
Step A:
(4R)-4-benzyl-3-{(2S,3R)-3-hydroxy-3-[2-iodo-5-(trifluoromethyl)ph-
enyl]-2-methylpropanoyl}-1,3-oxazolidin-2-one
##STR00138##
[0414] Following the procedure described in EXAMPLE 95, Step A,
0.72 g of
5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde
(EXAMPLE 80, Step A), 0.466 g of
(4R)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one, 0.02 g of magnesium
chloride, 0.56 mL of triethylamine, and 0.38 mL of
chlorotrimethylsilane provided the title compound. Mass spectrum
(ESI) 516.2 (M-OH). .sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 8.00
(d, J=8.5 Hz, 1H), 7.76 (d, J=2 Hz, 1H), 7.22-7.32 (m. 4H), 7.07
(br d, J=6.5 Hz, 2H), 5.18 (dd, J=6.5 Hz, 7.5 Hz, 1H), 4.67 (m,
1H), 4.46 (dq, J=6.5 Hz, 7.5 Hz, 1H), 4.17 (t, J=9 Hz, 1H), 4.11
(dd, J=3 Hz, 9 Hz, 1H), 3.97 (d, J=8 Hz, 1H), 3.19 (dd, J=7 Hz,
13.5 Hz, 1H), 2.57 (dd, J=9.5 Hz, 13.5 Hz, 1H), 1.34 (d, J=7.5 Hz,
3H).
Step B:
(4S,5S)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolid-
in-2-one
[0415] Following the procedure described in EXAMPLE 95, Step B,
0.214 g of
(4R)-4-benzyl-3-{(2S,3R)-3-hydroxy-3-[2-iodo-5-(trifluoromethyl)phenyl]-2-
-methylpropanoyl}-1,3-oxazolidin-2-one, 0.034 g of lithium
hydroxide, 0.16 mL of a 30% aqueous solution of hydrogen peroxide,
0.1 mL of diphenylphosphoryl azide, and 0.072 mL of triethylamine
provide the title compound. Mass spectrum (ESI) 372.1 (M+1).
.sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 8.02 (d, J=8 Hz, 1H),
7.61 (d, J=1.5 Hz, 1H), 7.32 (dd, J=2 Hz, 8 Hz, 1H), 6.16 (s, 1H),
5.39 (d, J=4 Hz, 1H), 3.76 (dq, J=6 Hz, 4.5 Hz, 1H), 1.62 (d, J=6
Hz, 3H). Analytical HPLC on Chiralpak AD 4.6.times.250 mm, eluting
with 4% ethanol in heptane at 0.75 mL/min (t.sub.R=210.56 min for
R,R; t.sub.R=18.00 min for S,S) showed 99% e.e.
Example 100
##STR00139##
[0416]
(4S,5S)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluorome-
thyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
[0417] Following the procedure described in EXAMPLE 96, 0.108 g of
(4S,5S)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-on-
e, 23 mg of sodium hydride, and 107 mg of
3,5-bis(trifluoromethyl)benzyl bromide provided the title compound.
Mass spectrum (ESI) 598.1 (M+1). .sup.1H NMR (500 MHz, CDCl.sub.3):
.delta. 8.00 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.58 (br s, 3H), 7.34
(dd, J=1.5 Hz, 8 Hz, 1H), 5.36 (d, J=4 Hz, 1H), 4.89 (d, J=16 Hz,
1H), 4.31 (d, J=16 Hz, 1H), 4.48 (dq, J=6 Hz, 4 Hz, 1H), 1.55 (d,
J=6.5 Hz, 3H).
Example 101
##STR00140##
[0418]
(4S,5S)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-isopropyl-2'-metho-
xy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one
[0419] Following the procedure described in EXAMPLE 81, 40 mg of
(4S,5S)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)p-
henyl]-4-methyl-1,3-oxazolidin-2-one and 17 mg of
(5-isopropyl-2-methoxyphenyl)boronic acid gave the title compound.
Mass spectrum (ESI) 620.4 (M+1). .sup.1H NMR signals are doubled
because of atropoisomerism. .sup.1H NMR (500 MHz, CDCl.sub.3):
.delta. 7.53-7.80 (m, 5H), 7.33 (d, J=8 Hz, 1H), 7.21-7.29 (m, 1H),
7.00, 6.76 (d, J=2.5 Hz, 1H), 6.91, 6.86 (d, J=8.5 Hz, 0.4H), 5.15,
5.10 (d, J=4.5 Hz, 1H), 4.80, 4.74 (d, J=16 Hz, 1H), 4.25, 4.21 (d,
16 Hz, 1H), 3.76 (s, 2H), 3.49 (s, 1H), 3.43 (m, 0.4H), 3.18 (m,
0.5H), 2.77-2.98 (m, 1H), 1.24 (m, 3H), 1.16 (m, 3H), 0.78, 0.61
(d, J=6.5 Hz, 3 Hz).
Example 102
##STR00141##
[0420]
(4R,5R)-5-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)bip-
henyl-2-yl]-4-methyl-1,3-oxazolidin-2-one
[0421] Following the procedure described in EXAMPLE 81, 240 mg of
(4R,5R)-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-on-
e and 171 mg of (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid
(EXAMPLE 78) gave the title compound. Mass spectrum (ESI) 412.3
(M+1). .sup.1H NMR signals are doubled because of atropoisomerism.
.sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 7.79, 7.77 (s, 1H),
7.64, 7.62 (dd, J=2.5 Hz, 8 Hz, 1H), 7.32, 7.31 (d, J=8 Hz, 1H),
7.00, 6.95 (d, J=8.5 Hz, 1H), 6.70, 6.67 (d, J=12 Hz, 1H), 6.47,
6.43 (s, 1H), 5.08, 5.04 (d, J=5 Hz, 0.1H), 3.68-3.80 (m, 3.5H),
3.53 (m, 0.5H), 3.21 (m, 1H), 1.19-1.30 (m, 6H), 0.95, 0.77 (d, J=6
Hz, 3H).
[0422] Following the procedures outlined in EXAMPLE 96 the
compounds listed in Table 4 were prepared from
(4R,5R)-5-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl--
2-yl]-4-methyl-1,3-oxazolidin-2-one:
TABLE-US-00004 TABLE 4 ##STR00142## LC/MS Data EXAMPLE R (M + 1)
103 ##STR00143## 520.3 104 ##STR00144## 520.3 105 ##STR00145##
520.3 106 ##STR00146## 538.4 107 ##STR00147## 516.4 108
##STR00148## 516.4 109 ##STR00149## 503.3 110 ##STR00150##
571.4
Example 111
##STR00151##
[0423]
((4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5'-isopropyl-2'-met-
hoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methylimidazolidin-2-ylide-
ne)cyanamide
[0424] To a solution of
(1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-N.sup.2-{[5'-isopropyl-2'-meth-
oxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}propane-1,2-diamine
(25.1 mg, 0.0424 mmol) in dichloroethane (1.5 mL) was added
triethylamine (15 .mu.L, 0.105 mmol) and diphenyl
cyanocarbonimidate (13 mg, 0.053 mmol). The reaction was heated at
60.degree. C. overnight, cooled to room temperature, filtered, and
loaded directly onto a silica gel column for purification by flash
chromatography with 10 to 40% EtOAc/hexanes to afford
((4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[5'-isopropyl-2'-me-
thoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methylimidazolidin-2-ylid-
ene)cyanamide. R.sub.f=0.20 (25% EtOAc/hexanes). LCMS=643.3
(M+1).sup.+. .sup.1H NMR(C.sub.6D.sub.6, 500 MHz; atropisomers
present, doubling of some peaks) .delta. 6.53-8.83 (m, 10H),
3.61-4.91 (m, 3H), 3.28-2.70 (m, 5H), 1.14-1.25 (m, 6H),
-0.39--0.26 (m, 3H).
[0425] Following the general procedures outlined above, the
compounds in Table 5 were prepared:
TABLE-US-00005 TABLE 5 ##STR00152## LCMS Compound A.sup.3 A.sup.2 Z
(M + 1) 112 ##STR00153## ##STR00154## CO 515.1 113 ##STR00155##
##STR00156## CO 537.3 114 ##STR00157## ##STR00158## CO 615.3 115
##STR00159## ##STR00160## CO 569.3 116 ##STR00161## ##STR00162## CO
637.3 117 ##STR00163## ##STR00164## CO 673.3
##STR00165##
(4S,5R)-5-(3,5-difluorophenyl)-4-methyl-1,3-oxazolidin-2-one
Step A: benzyl
[(1S)-2-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate
[0426] To a -15.degree. C. solution of benzyl
{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (1.96
g, 7.36 mmol) in THF (9.4 mL) was added i-propyl magnesium chloride
(3.6 mL of a 2M solution in Et.sub.2O, 7.2 mmol). The reaction was
stirred at -15.degree. C. for 15 minutes and then
3,5-difluorophenylmagnesium bromide (29.44 mL of a 0.5 M solution
in THF, 14.72 mmol) was added. The reaction was warmed to room
temperature and stirred for 24 hours. The reaction was then poured
into saturated NH.sub.4Cl (100 mL) and extracted with EtOAc
(3.times.100 mL). The organic extracts were washed with water and
brine (100 mL each), dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification of the residue by flash chromatography
on silica gel (15% EtOAc/hexanes) afforded benzyl
[(1S)-2-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate.
R.sub.f=0.34 (15% EtOAc/hexanes). LCMS=342.3 (M+Na).sup.+.
Step B: benzyl
[(1S,2S)-2-(3,5-difluorophenyl)-2-hydroxy-1-methylethyl]carbamate
[0427] To a -78.degree. C. solution of benzyl
[(1S)-2-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate. (1.35
g, 4.23 mmol) in THF (75 mL) was added L-Selectride (6.35 mL of a
1M solution in THF, 6.35 mmol). After stirring at -78.degree. C.
for 1 hour, the reaction was poured into 1N HCl (50 mL). The
mixture was extracted with EtOAc (2.times.100 mL). The organic
extracts were washed with water and brine (50 mL each), dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography on silica gel (5 to 40%
EtOAc/hexanes) afforded benzyl
[(1S,2S)-2-(3,5-difluorophenyl)-2-hydroxy-1-methylethyl]carbamate
(major product). LCMS=322.3 (M+1).sup.+.
Step C:
(4S,5R)-5-(315-difluorophenyl)-4-methyl-1,3-oxazolidin-2-one
[0428] To a solution of
[(1S,2S)-2-(3,5-difluorophenyl)-2-hydroxy-1-methylethyl]carbamate
(900 mg, 2.80 mmol) in THF (28.6 mL) was added MeOH (14.3 mL) and
7.5 N KOH (7.2 mL). The reaction was stirred at room temperature
for 4 hours and then extracted with EtOAc (2.times.75 mL). The
organic extracts were washed with water and brine (50 mL each),
dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Purification of the residue by flash chromatography on silica gel
(10 to 75% EtOAc/hexanes) afforded
(4S,5S)-5-(3,5-difluorophenyl)-4-methyl-1,3-oxazolidin-2-one.
R.sub.f=0.07 (25% EtOAc/hexanes). LCMS=214.3 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 6.89-6.93 (m, 2H), 6.82 (m, 1H),
6.24 (bs, 1H), 5.01 (d, J=6.8 Hz, 1H), 3.79 (m, 1H), 1.42 (d, J=6.2
Hz, 3H).
##STR00166##
6-chloro-5-fluoro-2-iodopyridin-3-ol
[0429] To a solution of 6-chloro-5-fluoropyridin-3-ol (307.8 mg,
2.08 mmol) in water (11 mL) was added Na.sub.2CO.sub.3 (441 mg,
4.16 mmol) and 12 (549 mg, 2.08 mmol). After 2 hours, the reaction
mixture was acidified with 1 N HCl to pH 3, diluted with EtOAc (100
mL), and washed with aq. NaHSO.sub.3 and brine (50 mL each). The
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated to afford 6-chloro-5-fluoro-2-iodopyridin-3-ol.
LCMS=273.9 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.
7.11 (d, J=8.5 Hz, 1H), 5.47 (d, J=1.4 Hz, 1M).
##STR00167##
2-bromo-6-isopropenyl-3-methoxypyridine
[0430] In a tube were placed 2-bromo-6-iodo-3-methoxypyridine (700
mg, 2.236 mmol), isopropenylboronic acid (212 mg, 2.460 mmol), DME
(7.5 n-L), EtOH (2.8 mL), and 1M aq. Na.sub.2CO.sub.3 (5.6 mL). The
mixture was degassed with N.sub.2. Next, Pd(PPh.sub.3).sub.4 (206
mg, 0.179 mmol) was added and the mixture was degassed again with
N.sub.2. The tube was sealed and heated at 80.degree. C. for 16
hours. The reaction was then cooled to room temperature, diluted
with EtOAc (100 mL), and washed with saturated NaHCO.sub.3 and
brine (50 mL each). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography on silica gel (0 to 15%
EtOAc/hexanes) afforded 2-bromo-6-isopropenyl-3-methoxypyridine.
R.sub.f=0.38 (25% EtOAc/hexanes). LCMS=230.0 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta.7.36 (d, J=8.5 Hz, 1H), 7.07 (d,
J=9.4 Hz, 1H), 5.81 (s, 1H), 5.21 (s, 1H), 3.92 (s, 3H), 2.16 (s,
3H).
##STR00168##
2-iodo-3-methoxypyridine
[0431] To a solution of 2-iodopyridin-3-ol (45.3 mg, 0.205 mmol) in
DMF (3 mL) was added Cs.sub.2CO.sub.3 (334 mg, 1.030 mmol) and MeI
(25 .mu.L, 0.410 mmol). After 1 hour, the reaction was poured into
water (10 mL), diluted with EtOAc (20 mL), washed with water
(3.times.10 mL) and brine (10 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated to afford
2-iodo-3-methoxypyridine. LCMS=236.1 (M+1).sup.+. .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 8.00 (dd, J=1.4, 4.6 Hz, 1H), 7.20
(dd, J=4.6, 8.0 Hz, 1H), 7.00 (dd, 1.4, 8.3 Hz, 1H), 3.90 (s,
3H).
##STR00169##
2-bromo-6-iodopyridin-3-ol
[0432] To a solution of 2-bromopyridin-3-ol (1.00 g, 5.80 mmol) in
water (30 mL) was added Na.sub.2CO.sub.3 (1.23 g, 11.60 mmol) and
12 (1.53 g, 5.80 mmol). After 1 hour, the reaction was quenched
with 1 N HCl (20 mL), extracted with EtOAc (2.times.100 mL), and
washed with aq. NaHSO.sub.3 and brine (50 mL each). The organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated.
Purification of the residue by flash chromatography on silica gel
(20 to 40% EtOAc/hexanes) afforded 2-bromo-6-iodopyridin-3-ol.
R.sub.f=0.44 (25% EtOAc/hexanes). LCMS=301.9 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 7.56 (d, J=8.3 Hz, 1H), 6.99 (d,
J=8.3 Hz, 1H), 5.65 (s, 1H).
##STR00170##
1-(2-bromo-1,3-thiazol-5-yl)ethanol
[0433] To a 0.degree. C. solution of 2-bromo-5-formylthiazole
(100.6 mg, 0.524 mmol) in THF (5 mL) was added MeMgBr (175 .mu.L of
a 3M solution in Et.sub.2O, 0.524 mmol). After 30 minutes,
additional MeMgBr (50 .mu.L of a 3M solution in Et.sub.2O, 0.150
mmol) was added. After 30 more minutes, the reaction was quenched
by pouring into saturated NH.sub.4Cl (20 mL). The mixture was
extracted with EtOAc (50 mL) and the organic layer was washed with
water and brine (25 mL each). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography (0 to 80% EtOAc/hexanes) afforded
1-(2-bromo-1,3-thiazol-5-yl)ethanol. R.sub.f=0.13 (25%
EtOAc/hexanes). LCMS=210.0 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3,
500 MHz) .delta. 7.40 (s, 1H), 5.12 (q, J=6.4 Hz, 1H), 1.59 (d,
J=6.4 Hz, 3H).
##STR00171##
4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-iodo-1,3-thiazole
Step A: 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-thiazole
[0434] To a solution of 1,3-thiazol-4-ylmethanol (311.4 mg, 2.7
mmol) in CH.sub.2Cl.sub.2 (15 mL) was added Et.sub.3N (1.9 mL, 13.6
mmol). The solution was cooled to -78.degree. C. and TBSOTf (776
.mu.L, 3.38 mmol) was added. The reaction was warmed to room
temperature and stirred for 1 hour. Next, the reaction was diluted
with EtOAc (75 mL) and washed with saturated NaHCO.sub.3, brine, 1N
HCl, and brine (20 mL each). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by flash chromatography on silica gel (0 to 15%
EtOAc/hexanes) to afford
4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-thiazole.
R.sub.f=0.28 (15% EtOAc/hexanes). LCMS=230.1 (M+1).sup.+.
.sup.1HNMR (CDCl.sub.3, 600 MHz) .delta. 8.77 (d, J=2.0 Hz, 1H),
7.25 (m, 1H), 4.93 (d, J=1.1 Hz, 2H), 0.95 (s, 9H), 0.12 (s,
6H).
Step B:
4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-iodo-1,3-thiazole
[0435] To a -78.degree. C. solution of
4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-thiazole (106.4 mg,
0.465 mmol) in THF (5 mL) was added dropwise a solution of n-BuLi
(465 .mu.L of a 1.6M solution in hexanes, 0.744 mmol). The reaction
was stirred at -78.degree. C. for 30 minutes, and then a solution
of iodine (295 mg, 1.16 mmol) in THF (5 mL) was added by cannula.
The reaction was warmed to room temperature for 15 minutes and then
quenched by pouring into aq. NaHSO.sub.3 (20 mL). The mixture was
extracted with EtOAc (60 mL) and the organic layer was washed with
brine, saturated NaHCO.sub.3, and brine (20 mL each). The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Purification of the residue by flash chromatography (15%
EtOAc/hexanes) afforded
4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-iodo-1,3-thiazole.
R.sub.f=0.55 (15% EtOAc/hexanes). LCMS=356.0 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 600 MHz) .delta. 7.16 (s, 1H), 4.86 (s, 2H), 0.93
(s, 9H), 0.10 (s, 6H).
##STR00172##
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetrame-
thyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2--
one
[0436] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)b-
enzyl]-4-methyl-1,3-oxazolidin-2-one (975 mg, 1.633 mmol) in DMSO
(16 mL) were added bis(pinacolato)diboron (1.24 g, 4.899 mmol),
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
with dichloromethane (1:1) (133 mg, 0.1633 mmol), and KOAc (320 mg,
3.266 mmol). The mixture was degassed with N.sub.2, and then heated
at 80.degree. C. for 16 hours. The reaction was then cooled to room
temperature, diluted with EtOAc (200 mL), and washed with saturated
NaHCO.sub.3 and brine (80 mL each). The organic layer was dried
over Na.sub.2SO.sub.4, filtered through a plug of silica, and
concentrated. Purification of the residue by reverse-phase
chromatography (C-18, 10 to 95% MeCN/water with 0.1% TFAA) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetrame-
thyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2--
one. LCMS=598.1 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz)
.delta. 7.98 (d, J=7.8 Hz, 1H), 7.88 (s, 1H), 7.78 (s, 2H), 7.67
(s, 1H), 7.57 (d, J=7.8 Hz, 1H), 5.68 (d, J=7.5 Hz, 1H), 5.01 (d,
J=15.6 Hz, 1H), 4.76 (d, J=15.5 Hz, 1H), 3.98-3.93 (m, 1H), 1.35
(d, J=6.9 Hz, 12H), 0.77 (d, J=6.7 Hz, 3H).
Example 118
##STR00173##
[0437]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3'-isopropyl-4-(trif-
luoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
[0438] In a tube were placed
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)b-
enzyl]-4-methyl-1,3-oxazolidin-2-one (52.5 mg, 0.0879 mmol),
3-isopropylbenzeneboronic acid (17.3 mg, 0.106 mmol), DME (370
.mu.L), EtOH (120 .mu.L), and 1M aqueous Na.sub.2CO.sub.3 (264
.mu.L, 0.264 mmol). The mixture was degassed with N.sub.2. Next,
Pd(PPh.sub.3).sub.4 (10.2 mg, 8.8.times.10.sup.-3 mmol) was added
and the mixture was degassed again with N.sub.2. The tube was
sealed and heated at 100.degree. C. for two hours. The reaction was
then cooled to room temperature, diluted with EtOAc (50 mL), and
washed with water and brine (15 mL each). The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Purification of the residue by flash chromatography on silica gel
(0 to 15% EtOAc/hexanes) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3'-isopropyl-4-(trifluorom-
ethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.
R.sub.f=0.29 (15% EtOAc/hexanes). LCMS=590.1 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 7.85 (s, 1H), 7.72 (s, 1H), 7.68
(s, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.39 (t,
J=7.6 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.15 (bs, 1H), 7.11 (bd,
J=7.5 Hz, 1H), 5.46 (d, J=8.0 Hz, 1H), 4.91 (d, J=15.7 Hz, 1H),
4.21 (d, J=15.8 Hz, 1H), 3.69 (m, 1H), 2.96 (m, 1H), 1.26-1.28 (m,
6H), 0.38 (d, J=6.4 Hz, 3H).
Example 119
##STR00174##
[0439]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-3'-isoprop-
enyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-on-
e
[0440] In a tube was placed
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3'-chloro-4'-fluoro-4-(tri-
fluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
(Example 146) (30.2 mg, 0.0504 mmol), isopropenylboronic acid (27
mg, 0.31 mmol), 1,1-bis(di-t-butylphosphino)ferrocene palladium
chloride (5.5 mg, 8.4.times.10.sup.-3 mmol), THF (350 .mu.L) and 1
M aq. K.sub.2CO.sub.3 (350 .mu.L). The tube was degassed with
nitrogen, sealed, and heated at 100.degree. C. for 5 hours. The
reaction was then cooled to room temperature, diluted with EtOAc
(50 mL) and washed with water and brine (15 mL each). The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Purification of the residue by flash chromatography on silica gel
(0 to 15% EtOAc/hexanes) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-3'-isopropenyl-4-
-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.
R.sub.f=0.29 (15% EtOAc/hexanes). LCMS=606.2 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 7.86 (s, 1H), 7.70 (s, 3H), 7.64
(d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.23 (dd, J=7.8, 2.0 Hz,
1H), 7.12-7.17 (m, 2H), 5.54 (d, J=8.0 Hz, 1H), 5.28 (s, 1H), 5.26
(s, 1H), 4.90 (d, J=15.8 Hz, 1H), 4.18 (d, J=15.8 Hz, 1H), 3.78 (m,
1H), 2.16 (s, 3H), 0.47 (d, J=6.7 Hz, 3H).
Example 120
##STR00175##
[0441]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1H-pyrrol-
-3-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one
[0442] To a 0.degree. C. solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-{5-(trifluoromethyl-
)-2-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]benzyl}-1,3-oxazolidin-2-one
(Example 149) (22.6 mg, 0.0326 mmol) in THF (2 mL) was added TBAF
(65 .mu.L of a 1M solution in THF, 0.065 mmol). After 30 minutes,
the reaction was quenched with saturated NH.sub.4Cl (5 mL). The
mixture was extracted with EtOAc (35 mL) and the organic layer was
washed with water and brine (15 mL each). The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Purification of the residue by flash chromatography on silica gel
(25 to 60% EtOAc/hexanes) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1H-pyrrol-3-yl)-
-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one. R.sub.f=0.11 (25%
EtOAc/hexanes). LCMS=537.1 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3,
600 MHz) .delta. 8.49 (s, 1H), 7.85 (s, 1H), 7.71 (s, 2H), 7.64 (s,
1H), 7.58 (d, J=8.1 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 6.88-6.91 (m,
2H), 6.33 (d, J=1.6 Hz, 1H), 5.53 (d, J=8.0 Hz, 1H), 5.02 (d,
J=15.7 Hz, 1H), 4.46 (d, J=15.6 Hz, 1H), 3.80 (m, 1H), 0.49 (d,
J=6.6 Hz, 3H).
Example 121
##STR00176##
[0443]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1-isopropyl-1H-pyr-
rol-3-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
[0444] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1H-pyrrol-3-yl)-
-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (6.8 mg, 0.0127
mmol) (Example 120) in DMSO (300 .mu.L) was added powdered KOH (3.6
mg, 0.0643 mmol). After stirring for 15 minutes, 2-iodopropane (3.2
.mu.L, 0.032 mmol) was added. After 1.5 hours of stirring at room
temperature, water (5 mL) was added, and the mixture was extracted,
first with CH.sub.2Cl.sub.2 (2.times.15 mL) and then with EtOAc
(2.times.15 mL). The combined organics were dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by PTLC (25% EtOAc/hexanes) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1-isopropyl-1H--
pyrrol-3-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one.
R.sub.f=0.33 (25% EtOAc/hexanes). LCMS=579.2 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 7.85 (s, 1H), 7.71 (s, 2H), 7.61
(s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 6.83 (t,
J=2.1 Hz, 1H), 6.79 (t, J=2.5 Hz, 1H), 6.24 (t, J=2.3 Hz, 1H), 5.49
(d, J=8.0 Hz, 1H), 5.04 (d, J=15.5 Hz, 1H), 4.48 (d, J=15.6 Hz,
1H), 4.27 (m, 1H), 3.76 (m, 1H), 1.48 (d, J=6.6 Hz, 6H), 0.49 (d,
J=6.6 Hz, 3H).
Example 122
##STR00177##
[0445]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-5'-nitro--
4-(trifluoromethyl)biphenyl
2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
[0446] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-4-(trifluoromet-
hyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (example
143) (159.4 mg, 0.276 mmol) in HOAc (5 mL) was added HNO.sub.3 (1.5
mL). After 45 minutes, additional HNO.sub.3 (1.5 mL) was added. 45
minutes later, the reaction was quenched by pouring into ice water
(30 mL). The mixture was extracted with EtOAc (75 mL), and the
organic layer was washed with 1 N NaOH, saturated NaHCO.sub.3, and
brine (25 mL each). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography on silica gel (8 to 40%
EtOAc/hexanes) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-5'-nitro-4-(tri-
fluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.
R.sub.f=0.11 (25% EtOAc/hexanes). LCMS=623.1 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz, rotamers present) .delta. 8.34 (m, 1H),
8.10 (m, 1H), 7.85 (d, J=6.9 Hz, 1H), 7.61-7.71 (m, 4H), 7.40 (m,
1H), 7.11 (m, 1H), 5.66 (d, J=8.0 Hz), 5.28 (d, J=8.2 Hz),
4.89-4.94 (m, 1H), 3.74-4.09 (m, 5H), 0.61 (d, J=6.6 Hz), 0.47 (d,
J=6.5 Hz).
Example 123
##STR00178##
[0447]
(4S,5R)-3-{[5'-amino-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]me-
thyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
[0448] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-5'-nitro-4-(tri-
fluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
(example 122) (48.2 mg, 0.077 mmol) in EtOAc (4 mL) was added
PtO.sub.2 (12 mg) and the reaction was placed under an atmosphere
of hydrogen (balloon) and stirred vigorously. After 45 minutes, the
catalyst was removed by filtration through a plug of silica gel
with 100% EtOAc. The filtrate was concentrated to afford
(4S,5R)-3-[{methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3,5-bis(t-
rifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. R.sub.f=0.20
(40% EtOAc/hexanes). LCMS=593.2 (M+1).sup.+. .sup.1H NMR
(CDCl.sub.3, 500 MHz, rotamers present) .delta. 7.85 (s, 1H),
7.60-7.70 (m, 4H), 7.36 (d, J=7.8 Hz, 1H), 6.74-6.84 (m, 2H), 6.56
(s, 1H), 5.45-5.54 (m, 1H), 4.82-4.87 (m, 1H), 3.64-4.17 (m, 2H),
3.70 (s, 3H), 0.43-0.53 (m, 3H).
Example 124
##STR00179##
[0449]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-5'-(methy-
lthio)-4-(trifluoromethyl)biphenyl-2-yl]methyl.ident.-4-methyl-1,3-oxazoli-
din-2-one
[0450] To a solution of
(4S,5R)-3-{[5'-amino-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}--
5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
(Example 123) (40 mg, 0.0676 mmol) in CHCl.sub.3 (1 mL) that had
been degassed with N.sub.2 was added methyl disulfide (10 .mu.L,
0.101 mmol) and t-butyl nitrite (16 .mu.L, 0.135 mmol). The
reaction was stirred at room temperature for 30 minutes and then
heated to reflux for 2 hours. The reaction was then cooled to room
temperature and diluted with hexanes (3 mL). The solution was
loaded directly onto a silica gel column and eluted with 25%
EtOAc/hexanes. Fractions containing the desired product were
combined and repurified by silica gel chromatography with 5 to 25%
EtOAc/hexanes to afford
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-5'-(methylthio)-
-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.
R.sub.f=0.52 (40% EtOAc/hexanes). LCMS=624.1 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 600 MHz, rotamers present) .delta. 6.94-7.85 (m,
9H), 5.58 (d, J=8.1 Hz) 5.25 (d, J=7.8 Hz), 4.94 (d, J=15.8 Hz),
4.85 (d, J=15.7 Hz), 3.65-4.12 (m, 5H), 2.47 (s), 2.44 (s), 0.54
(d, J=6.6 Hz), 0.40 (d, J=6.6 Hz).
Example 125
##STR00180##
[0451]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-5'-(methy-
lsulfinyl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidi-
n-2-one
[0452] To a -60.degree. C. solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-5'-(methylthio)-
-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
(example 124) (32.5 mg, 0.0522 mmol) in CH.sub.2Cl.sub.2 (5 mL) was
added m-CPBA (14.6 mg, 77% purity, 0.0652 mmol). The reaction was
warmed slowly to -20.degree. C. and then diluted with EtOAc (35
mL), washed with aq. NaHSO.sub.3, brine, saturated NaHCO.sub.3, and
brine (15 mL each). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography on silica gel (20 to 100%
EtOAc/hexanes) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-5'-(methylsulfi-
nyl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-on-
e. R.sub.f=0.10 (75% EtOAc/hexanes). LCMS=640.1 (M+1).sup.+.
.sup.1H NMR (CDCl.sub.3, 600 MHz) .delta. 7.10-7.86 (m, 9H),
4.87-5.59 (m, 2H), 3.56-4.14 (m, 5H), 2.79 (s), 2.75 (s), 2.73 (s),
0.61 (d, J=6.5 Hz), 0.57 (d, J=6.4 Hz), 0.46 (d, J=6.4 Hz), 0.43
(d, J=6.5 Hz).
Example 126
##STR00181##
[0453]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-5'-(methy-
lsulfonyl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidi-
n-2-one
[0454] To a 0.degree. C. solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[{2'-methoxy-5'-(methylthio)-
-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
(example 124) (7.8 mg, 0.013 mmol) in CH.sub.2Cl.sub.2 (1 mL) was
added m-CPBA (14 mg, 77% purity, 0.063 mmol). The reaction was
stirred at room temperature for 30 minutes and then diluted with
EtOAc (35 mL), washed with aq. NaHSO.sub.3, brine, saturated
NaHCO.sub.3, and brine (15 mL each). The organic layer was dried
over Na.sub.2SO.sub.4, filtered, and concentrated. Purification of
the residue by PTLC (50% EtOAc/hexanes) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-5'-(me-
thylsulfonyl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazol-
idin-2-one. R.sub.f=0.11 (40% EtOAc/hexanes). LCMS=656.2
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 600 MHz, rotamers present)
.delta. 7.99-8.02 (m, 1H), 7.84-7.86 (m, 1H), 7.75-7.78 (m, 1H),
7.58-7.72 (m, 4H), 7.38-7.42 (m, 1H), 7.15-7.18 (m, 1H), 5.55 (d,
J=8.0 Hz), 5.26 (d, J=8.1 Hz), 4.91-4.97 (m, 1H), 3.63-4.03 (m,
5H), 3.12 (s), 3.10 (s), 0.62 (d, J=6.6 Hz), 0.48 (d, J=6.6
Hz).
Example 127
##STR00182##
[0455]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(6-isopropenylpyrid-
in-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
Step A: 2-bromo-6-isopropenylpyridine
[0456] In a tube were placed 2,6-dibromopyridine (100 mg, 0.422
mmol), isopropenylboronic acid (40 mg, 0.464 mmol), DME (1.5 mL),
EtOH (500 .mu.L), and 1M aqueous Na.sub.2CO.sub.3 (1 mL, 1.0 mmol).
The mixture was degassed with N.sub.2. Next, Pd(PPh.sub.3).sub.4
(37 mg, 0.032 mmol) was added and the mixture was degassed again
with N.sub.2. The tube was sealed and heated at 100.degree. C. for
1 hour. The reaction was then cooled to room temperature, diluted
with EtOAc (50 mL), and washed with water and brine (15 mL each).
The organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification of the residue by flash chromatography
on silica gel (5% EtOAc/hexanes) afforded
2-bromo-6-isopropenylpyridine. R.sub.f=0.45 (15% EtOAc/hexanes).
LCMS=200.0 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.
7.49 (t, J=7.8 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.0 Hz,
1H), 5.93 (s, 1H), 5.32 (m, 1H), 2.17 (s, 3H).
Step B:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(6-isopropenylpyri-
din-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
[0457] In a tube were placed 2-bromo-6-isopropenylpyridine (17.5
mg, 0.0878 mmol),
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetrame-
thyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2--
one (26.2 mg, 0.0439 mmol), DME (190 .mu.L), EtOH (62 .mu.L), and
1M aqueous Na.sub.2CO.sub.3 (100 .mu.L, 0.1 mmol). The mixture was
degassed with N.sub.2. Next, Pd(PPh.sub.3).sub.4 (9 mg,
7.8.times.10.sup.-3 mmol) was added and the mixture was degassed
again with N.sub.2. The tube was sealed and heated at 100.degree.
C. for 2 hours. The reaction was then cooled to room temperature,
diluted with EtOAc (50 mL), and washed with water and brine (15 mL
each). The organic layer was dried over Na.sub.2SO.sub.4, filtered,
and concentrated. Purification of the residue by flash
chromatography on silica gel (5 to 25% EtOAc/hexanes) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(6-isopropenylpyridin-2-y-
l)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one.
R.sub.f=0.15 (15% EtOAc/hexanes). LCMS=589.1 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 7.81-7.85 (m, 2H), 7.74 (s, 1H),
7.69-7.69 (m, 3H), 7.58 (d, J=8.0 Hz, 1H), 7.53 (d, J=7.7 Hz, 1H),
7.34 (d, J=7.6 Hz, 1H), 5.94 (s, 1H), 5.48 (d, J=7.7 Hz, 1H), 5.36
(s, 1H), 5.06 (d, J=16.0 Hz, 1H), 4.47 (d, J=16.1 Hz, 1H), 3.91 (m,
1H), 2.23 (s, 3H), 0.50 (d, J=6.6 Hz, 3H).
Example 128
##STR00183##
[0458]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(3-methoxy-6-methyl-
-1-oxidopyridin-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-
-one
[0459] To a 0.degree. C. solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(3-methoxy-6-methylpyridi-
n-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
(Example 174) (7.6 mg, 0.0128 mmol) in CH.sub.2Cl.sub.2 (1.3 mL)
was added m-CPBA (5.8 mg, 77% purity, 0.0256 mmol). The reaction
was stirred at room temperature for 1 hour and then diluted with
CH.sub.2Cl.sub.2 (10 mL), washed with aq. NaHSO.sub.3, saturated
K.sub.2CO.sub.3, and brine (5 mL each). The organic layer was dried
over Na.sub.2SO.sub.4, filtered, and concentrated. Purification of
the residue by PTLC (50% Et.sub.2O/CH.sub.2Cl.sub.2) afforded the
title compound. R.sub.f=0.23 (50% Et.sub.2O/CH.sub.2Cl.sub.2).
LCMS=609.2 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.
7.85 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.70 (s, 2H), 7.62 (s, 1H),
7.53 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.9 Hz, 1H), 7.04 (d, J=9.2 Hz,
1H), 5.74 (d, J=8.3 Hz, 1H), 4.88 (d, J=14.8 Hz, 1H), 4.11-3.96 (m,
1H), 3.88 (d, J=14.9 Hz, 1H), 3.86 (s, 3H), 2.49 (s, 3H), 0.65 (d,
J=6.6 Hz, 3H).
Example 129
##STR00184##
[0460]
(4S,5R)-3-[2-(3-amino-6-isopropylpyridin-2-yl)-5-(trifluoromethyl)b-
enzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
[0461] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(6-isopropenyl-3-nitropyr-
idin-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
(example 177) (19.3 mg, 0.0305 mmol) in EtOH (300 .mu.L) was added
10% Pd/C (5 mg). The reaction was placed under a H.sub.2 atmosphere
(balloon) and stirred vigorously. After 90 minutes, the mixture was
loaded on to a PTLC plate and purified (30% EtOAc/hexanes,
developed twice), affording
(4S,5R)-3-[2-(3-amino-6-isopropylpyridin-2-yl)-5-(trifluoromethyl)benzyl]-
-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one.
R.sub.f=0.63 (30% EtOAc/hexanes, developed twice). LCMS=606.2
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 7.84 (s,
1H), 7.78 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.69 (s, 2H), 7.55 (d,
J=8.0 Hz, 1H), 7.09-7.05 (m, 2H), 5.53-5.52 (m, 1H), 4.92 (d, J=5.5
Hz, 1H), 4.15-4.10 (m, 1H), 3.89-3.78 (m, 1H), 3.48 (s, 2H),
3.00-2.95 (m, 1H), 1.26-1.23 (m, 6H), 0.44 (d, J=5.1 Hz, 3H).
Example 130
##STR00185##
[0462]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(3-chloro-6-isoprop-
ylpyridin-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
[0463] To a solution of CuCl.sub.2 (9.3 mg) and t-butyl nitrite
(6.6 .mu.L, 0.0559 mmol) in MeCN (300 .mu.L) was added
(4S,5R)-3-[2-(3-amino-6-isopropylpyridin-2-yl)-5-(trifluoromethyl)benzyl]-
-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
(Example 129) (16.9 mg, 0.0279 mmol) in MeCN (300 .mu.L) via
cannula. The reaction was heated at 60.degree. C. for 1 hour and
then cooled to room temperature, diluted with EtOAc (20 mL) and
washed with water and brine (8 mL each). The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Purification of the residue by PTLC (30% EtOAc/hexanes) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(3-chloro-6-isop-
ropylpyridin-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-on-
e. R.sub.f=0.56 (30% EtOAc/hexanes). LCMS=625.1 (M+1).sup.+.
.sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 7.85 (s, 1H), 7.78 (d,
J=8.3 Hz, 1H), 7.73-7.71 (m, 2H), 7.68 (s, 2H), 7.53 (d, J=7.8 Hz,
1H), 7.24 (d, J=8.2 Hz, 1H), 5.55 (d, J=7.7 Hz, 1H), 5.05 (d,
J=15.4 Hz, 1H), 3.97 (d, J=15.4 Hz, 1H), 3.88-3.82 (m, 1H),
3.17-3.08 (m, 1H), 1.30-1.32 (m, 6H), 0.53 (d, J=6.7 Hz, 3H).
Example 131
##STR00186##
[0464]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-isopropenyl-1,3--
thiazol-4-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
Step A: 4-bromo-2-isopropenyl-1,3-thiazole
[0465] In a tube were placed 2,4-dibromothiazole (100 mg, 0.411
mmol), isopropenylboronic acid (39 mg, 0.452 mmol), DME (1.625 mL),
EtOH (563 .mu.L), and 1M aqueous Na.sub.2CO.sub.3 (1.03 mL, 1.03
mmol). The mixture was degassed with N.sub.2. Next,
Pd(PPh.sub.3).sub.4 (24 mg, 0.0206 mmol) was added and the mixture
was degassed again with N.sub.2. The tube was sealed and heated at
100.degree. C. for 2 hours. The reaction was then cooled to room
temperature, diluted with EtOAc (50 mL), and washed with water and
brine (15 mL each). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography on silica gel (0 to 15%
EtOAc/hexanes) afforded 4-bromo-2-isopropenyl-1,3-thiazole; NMR
showed an impurity present that was not removed. R.sub.f=0.53 (15%
EtOAc/hexanes). LCMS=206.0 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3,
500 MHz) .delta. 7.13 (s, 1H), 5.87 (s, 1H), 5.33 (d, J=1.3 Hz,
1H), 2.21 (s, 3H).
Step B:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-isopropenyl-1,3-
-thiazol-4-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
[0466] In a tube were placed 4-bromo-2-isopropenyl-1,3-thiazole (20
mg, 0.097 mmol),
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetrame-
thyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2--
one (29.4 mg, 0.0492 mmol), THF (340 .mu.L), 1M aqueous
K.sub.2CO.sub.3 (340 .mu.L), and
1,1-bis(di-t-butylphosphino)ferrocene palladium chloride (3.2 mg,
4.9.times.10.sup.-3 mmol). The mixture was degassed with N.sub.2.
The tube was sealed and heated at 100.degree. C. for 1.5 hours. The
reaction was then cooled to room temperature, diluted with EtOAc
(50 mL), and washed with water and brine (15 mL each). The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Purification of the residue by flash chromatography on silica gel
(5 to 25% EtOAc/hexanes) and then by PTLC (90%
CH.sub.2Cl.sub.2/hexanes) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-isopropenyl-1,3-thiazo-
l-4-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one.
R.sub.f=0.16 (15% EtOAc/hexanes). LCMS=595.1 (M+1).sup.+. .sup.1H
NMR (CD.sub.2Cl.sub.2, 500 MHz) .delta. 7.90 (s, 1H), 7.64-7.76 (m,
5H), 7.38 (s, 1H), 5.89 (s, 1H), 5.60 (d, J=8.1 Hz, 1H), 5.37 (d,
J=1.2 Hz, 1H), 4.99 (d, J=16.0 Hz, 1H), 4.66 (d, J=16.0 Hz, 1H),
3.94 (m, 1H), 2.25 (s, 3H), 0.59 (d, J=6.4 Hz, 3H).
Example 132
##STR00187##
[0467]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(hydroxymethyl)--
1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
[0468] To a 0.degree. C. solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-({[tert-butyl(dimethyl-
)silyl]oxy}methyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1-
,3-oxazolidin-2-one (Example 178) (54.0 mg, 0.0774 mmol) in THF (10
mL) was added TBAF (194 .mu.L of a 1M solution in THF, 0.194 mmol).
The reaction was stirred at 0.degree. C. for 30 minutes and then
quenched by pouring into saturated NH.sub.4Cl (15 mL). The mixture
was extracted with EtOAc (60 mL) and the organic layer was washed
with water and brine (15 mL each). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography on silica gel (60% EtOAc/hexanes)
afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(hydroxymethyl)-1,3-th-
iazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one.
R.sub.f=0.11 (40% EtOAc/hexanes). LCMS=585.1 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 7.85 (s, 1H), 7.81 (d, J=8.0 Hz,
1H), 7.70-7.73 (m, 4H), 7.36 (s, 1H), 5.52 (d, J=8.0 Hz, 1H), 5.39
(d, J=15.3 Hz, 1H), 4.81 (s, 2H), 4.55 (d, J=15.3 Hz, 1H), 3.87 (m,
1H), 0.69 (d, J=6.7 Hz, 3H).
Example 133
##STR00188##
[0469]
2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,-
3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazole-4-carbal-
dehyde
[0470] To a 0.degree. C. solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(hydroxymethyl)-1,3-th-
iazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
(Example 132) (40.9 mg, 0.070 mmol) in CH.sub.2Cl.sub.2 (5 mL) was
added DMP (59.4 mg, 0.140 mmol). The reaction was warmed to room
temperature and stirred for 45 minutes. Next the reaction was
diluted with EtOAc (40 mL) and washed with 1N NaOH (2.times.15 mL)
and brine (2.times.15 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography on silica gel (50% EtOAc/hexanes)
afforded
2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxaz-
olidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazole-4-carbaldehyde-
. R.sub.f=0.24 (40% EtOAc/hexanes). LCMS=583.1 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 10.09 (s, 1H), 8.33 (s, 1H), 7.87
(s, 2H), 7.82 (d, J=8.2 Hz, 1H), 7.79 (s, 2H), 7.72, (d, J=8.1 Hz,
1H), 5.70 (d, J=8.0 Hz, 1H), 5.13 (d, J=16.0 Hz, 1H), 4.83 (d,
J=16.0 Hz, 1H), 4.23 (m, 1H), 0.75 (d, J=6.6 Hz, 3H).
Example 134
##STR00189##
[0471]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxyethyl)-
-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-on-
e
[0472] To a -40.degree. C. solution of
2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxaz-
olidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazole-4-carbaldehyde
(Example 133) (43.9 mg, 0.075 mmol) in Et.sub.2O (7.5 mL) was added
MeMgBr (30 .mu.L of a 3M solution in Et.sub.2O, 0.10 mmol). The
reaction was monitored closely by TLC and additional MeMgBr was
added dropwise until nearly all starting aldehyde was consumed. At
this point, the reaction was quenched by pouring it into saturated
NH.sub.4Cl (15 mL). The mixture was extracted with EtOAc (50 mL)
and the organic layer was washed with water and brine (15 mL each).
The organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification of the residue by flash chromatography
on silica gel (5 to 50% EtOAc/hexanes) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxyeth-
yl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-
-one. R.sub.f=0.17 (40% EtOAc/hexanes). LCMS=599.1 (M+1).sup.+.
.sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 7.70-7.86 (m, 6H),
7.31-7.32 (m, 1H), 5.53-5.55 (m, 1H), 5.35-5.41 (m, 1H), 5.06 (m,
1H), 4.57-4.62 (m, 1H), 3.88 (m, 1H), 1.61-1.63 (m, 3H), 0.69 (d,
J=6.7 Hz, 3H).
Example 135
##STR00190##
[0473]
(4S,5R)-3-[2-(4-acetyl-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-
-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
[0474] To a 0.degree. C. solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxyethyl)-1,3-t-
hiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
(Example 134) (31.0 mg, 0.052 mmol) in CH.sub.2Cl.sub.2 (6 mL) was
added DMP (55 mg, 0.130 mmol). The reaction was warmed to room
temperature and stirred for 45 minutes. Next, the reaction was
diluted with EtOAc (40 mL) and washed with 1N NaOH (2.times.15 mL)
and brine (2.times.15 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography on silica gel (40% EtOAc/hexanes)
afforded
(4S,5R)-3-[2-(4-acetyl-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,-
5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one.
R.sub.f=0.26 (40% EtOAc/hexanes). LCMS=597.1 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 600 MHz) .delta. 8.27 (s, 1H), 7.89 (s, 1H),
7.77-7.82 (m, 4H), 7.71 (d, J=7.9 Hz, 1H), 5.68 (d, J=7.9 Hz, 1H),
5.22 (d, J=16.3 Hz, 1H), 4.85 (d, J=16.4 Hz, 1H), 4.08 (m, 1H),
2.70 (s, 3H), 0.71 (d, J=6.6 Hz, 3H).
Example 136
##STR00191##
[0475]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxy-1-met-
hylethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazol-
idin-2-one
[0476] To a -40.degree. C. solution of
(4S,5R)-3-[2-(4-acetyl-1,3-thiazol-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,-
5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
(Example 135) (38.1 mg, 0.064 mmol) in THF/heptanes (1:1, 8 mL) was
added MeMgBr (21 .mu.L of a 3M solution in Et.sub.2O, 0.07 mmol).
The temperature was maintained between -40.degree. C. and
-20.degree. C. and the reaction was monitored closely by TLC;
additional MeMgBr was added dropwise until nearly all starting
ketone was consumed. At this point, the reaction was quenched by
pouring it into saturated NH.sub.4Cl (15 mL). The mixture was
extracted with EtOAc (50 mL) and the organic layer was washed with
water and brine (15 mL each). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography on silica gel (10 to 60%
EtOAc/hexanes) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxy-1-methyleth-
yl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-
-one. R.sub.f=0.20 (40% EtOAc/hexanes). LCMS=613 (M+1).sup.+.
.sup.1H NMR (CD.sub.2Cl.sub.2, 500 MHz) .delta.7.90 (s, 1H), 7.85
(d, J=8.0 Hz, 1H), 7.77 (s, 3H), 7.71 (d, J=8.3 Hz, 1H), 7.32 (s,
1H), 5.59 (d, J=8.0 Hz, 1H), 5.28 (d, J=15.8 Hz, 1H), 4.74 (d,
J=15.8 Hz, 1H), 3.89 (m, 1H), 3.01 (bs, 1H), 1.63 (s, 3H), 1.62 (s,
3H), 0.64 (d, J=6.5 Hz, 3H).
Example 137
##STR00192##
[0477]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(4-isopropenyl-1,3--
thiazol-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
[0478] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxy-1-methyleth-
yl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-
-one (example 136) (9.5 mg, 0.015 mmol) in toluene (4 mL) was added
p-toluenesulfonic acid monohydrate (20 mg, 0.105 mmol). The
reaction was heated to 80.degree. C. for 30 minutes and then cooled
to room temperature, diluted with EtOAc (35 mL), and washed with
saturated NaHCO.sub.3 and brine (15 mL each). The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Purification of the residue by flash chromatography on silica gel
(25% EtOAc/hexanes) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(4-isopropenyl-1,3-thiazo-
l-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one.
R.sub.f=0.55 (40% EtOAc/hexanes). LCMS=595.1 (M+1).sup.+. .sup.1H
NMR (CD.sub.2Cl.sub.2, 500 MHz) .delta. 7.91 (s, 1H), 7.78-7.83 (m,
4H), 7.68 (d, J=8.5 Hz, 1H), 7.33 (s, 1H), 5.95 (d, J=0.9 Hz, 1H),
5.66 (d, J=8.0 Hz, 1H), 5.24 (m, 1H), 5.07 (d, J=16.4 Hz, 1H), 5.00
(d, J=16.3 Hz, 1H), 4.03 (m, 1H), 2.17 (s, 3H), 0.63 (d, J=6.4 Hz,
3H).
Example 138
##STR00193##
[0479]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-3'-isoprop-
yl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
[0480] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-3'-isopropenyl-4-
-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
(Example 119) (18.8 mg, 0.031 mmol) in EtOH (4.5 mL) was added 10%
Pd/C (15 mg). The reaction was placed under a H.sub.2 atmosphere
(balloon) and stirred vigorously. After 45 minutes, the catalyst
was removed by filtration. The filtrate was concentrated, and the
residue was purified by flash chromatography on silica gel with 15%
EtOAc/hexanes. Further purification by PTLC with 75%
CH.sub.2Cl.sub.2/hexanes afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-3'-isopropyl-4-(-
trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.
R.sub.f=0.35 (15% EtOAc/hexanes). LCMS=608.2 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 7.86 (s, 1H), 7.71 (s, 1H), 7.70
(s, 2H), 7.64 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.15 (m,
1H), 7.08-7.12 (m, 2H), 5.52 (d, J=8.0 Hz, 1H), 4.89 (d, J=15.7 Hz,
1H), 4.18 (d, J=15.8 Hz, 1H), 3.76 (m, 1H), 3.28 (m, 1H), 1.25-1.29
(m, 6H), 0.42 (d, J=6.4 Hz, 3H).
Example 139
##STR00194##
[0481]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[5-(1-methoxyethyl)-
-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-on-
e
[0482] To a 0.degree. C. solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[5-(1-hydroxyethyl)-1,3-t-
hiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
(Example 154) (13.2 mg, 0.0221 mmol) in THF (1 mL) was added NaHMDS
(26.5 .mu.L of a 1M solution in THF, 0.0265 mmol) followed by MeI
(1 drop). After 1.5 hours, additional NaHMDS (15 .mu.L of a 1M
solution in THF, 0.015 mmol) and MeI (1 drop) were added to the
reaction. The reaction was warmed to room temperature for 20
minutes and then quenched by pouring into saturated NH.sub.4Cl (10
mL). The mixture was extracted with EtOAc (35 mL) and the organic
layer was washed with water and brine (15 mL each). The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated.
Purification of the residue by flash chromatography on silica gel
(15 to 75% EtOAc/hexanes) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[5-(1-methoxyethyl)-1,3-t-
hiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one.
R.sub.f=0.37 (40% EtOAc/hexanes). LCMS=613.0 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 7.87 (s, 1H), 7.74-7.82 (m, 5H),
7.67 (d, J=8.0 Hz, 1H), 6.63-5.66 (m, 1H), 5.08-5.14 (m, 1H),
4.83-4.88 (m, 1H), 4.64-4.68 (m, 1H), 4.01-4.08 (m, 1H), 3.34 (m,
3H), 1.60 (d, J=6.4 Hz, 3H), 0.69 (d, J=6.7 Hz, 3H).
Examples 140 and 141
##STR00195##
[0483]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1-oxido-1-
-benzothien-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one
and
(4S,5R)-5-[35-bis(trifluoromethyl)phenyl]-3-[2-(1,1-dioxido-1-benzothien--
2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
[0484] To a solution of
(4S,5R)-3-[2-(1-benzothien-2-yl)-5-(trifluoromethyl)benzyl]-5-[3,5-bis(tr-
ifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (Example 150)
(14.5 mg, 0.024 mmol) in CH.sub.2Cl.sub.2 (2 mL) was added m-CPBA
(16 mg, 77% purity, 0.071 mmol). The reaction was stirred at room
temperature for 3 hours, and then diluted with EtOAc (40 mL) and
washed with aq. NaHSO.sub.3 (15 mL), saturated NaHCO.sub.3 (15 mL)
and brine (15 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by PTLC (25% EtOAc/hexanes, 2 elutions) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1,1-dioxido-1-benzothien-
-2-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one and
2.2 mg (15%) of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1-oxid-
o-1-benzothien-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one.
Data for 141: R.sub.f=0.09 (25% EtOAc/hexanes). LCMS=636.2
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 7.96 (d,
J=8.0 Hz, 1H), 7.83 (s, 1H), 7.68-7.77 (m, 5H), 7.63 (m, 1H), 7.57
(m, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.28 (s, 1H), 5.75 (d, J=8.0 Hz,
1H), 5.21 (d, J=15.8 Hz, 1H), 4.21 (d, J=15.8 Hz, 1H), 4.01 (m,
1H), 0.70 (d, J=6.7 Hz, 3H). Data for 140: R.sub.f=0.06 (25%
EtOAc/hexanes). LCMS=620.2 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3,
500 MHz) .delta. 7.15-7.95 (m, 1H), 5.72-5.75 (m, 1H), 5.36 (d,
J=15.6 Hz), 5.07 (d, J=15.8 Hz), 4.41 (d, J=16.0 Hz), 4.22 (d,
J=15.8 Hz), 3.88-4.08 (m, 1H), 0.68 (d, J=6.6 Hz), 0.61 (d, J=6.6
Hz).
Example 142
##STR00196##
[0485]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isoprop-
yl-2'-methoxy-4-(trifluoromethoxy)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazo-
lidin-2-one
Step A: 2-(bromomethyl)-1-nitro-4-(trifluoromethoxy)benzene
[0486] Fuming nitric acid (5 mL) was cooled to 0.degree. C. and
3-(trifluoromethoxy)benzyl bromide (1 mL, 6.16 mmol) was added.
After 15 minutes, the reaction was poured into ice water (100 mL)
and extracted with EtOAc (200 mL). The organic layer was washed
with water, saturated NaHCO.sub.3, and brine (75 mL each). The
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Purification of the residue by flash chromatography
on silica gel (0 to 15% EtOAc/hexanes) afforded
2-(bromomethyl)-1-nitro-4-(trifluoromethoxy)benzene R.sub.f=0.54
(15% EtOAc/hexanes). .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 8.14
(d, J=8.9 Hz, 1H), 7.43 (m, 1H), 7.31 (m, 1H), 4.82 (s, 2H).
Step B:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-nitro-5-(-
trifluoromethoxy)benzyl]-1,3-oxazolidin-2-one
[0487] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
(840 mg, 2.68 mmol) in DMA (25 mL) was added NaHMDS (2.68 mL of a
1M solution in THF, 2.68 mmol). The reaction was stirred at room
temperature for 5 minutes, and then
2-(bromomethyl)-1-nitro-4-(trifluoromethoxy)benzene (967 mg, 3.22
mmol) was added by cannula in DMA (5 mL). After 15 minutes, the
reaction was poured into saturated NH.sub.4Cl (50 mL). The mixture
was extracted with EtOAc (150 mL) and the organic layer was washed
with water and brine (40 mL each). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography on silica gel (5 to 25%
EtOAc/hexanes) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-nitro-5-(trifluo-
romethoxy)benzyl]-1,3-oxazolidin-2-one. R.sub.f=0.10 (15%
EtOAc/hexanes). LCMS=533.2 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3,
500 MHz) .delta. 8.16 (d, J=8.9 Hz, 1H), 7.92 (s, 1H), 7.80 (s,
2H), 7.44 (s, 1H), 7.33 (d, J=8.9 Hz, 1H), 5.78 (d, J=7.8 Hz, 1H),
4.94 (d, J=17.0 Hz, 1H), 4.79 (d, J=16.9 Hz, 1H), 4.25 (m, 1H),
0.81 (d, J=6.7 Hz, 3H).
Step C:
(4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluor-
omethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
[0488] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-nitro-5-(trifluo-
romethoxy)benzyl]-1,3-oxazolidin-2-one (1.07 g, 2.01 mmol) in EtOAc
(30 mL) was added PtO.sub.2 (100 mg, 0.44 mmol). The reaction was
placed under a H.sub.2 atmosphere (balloon) and stirred vigorously.
After 1 hour, the catalyst was removed by filtration, and the
filtrate was concentrated. Purification of the residue by flash
chromatography (5 to 40% EtOAc/hexanes) afforded
(4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl-
)phenyl]-4-methyl-1,3-oxazolidin-2-one. R.sub.f=0.45 (40%
EtOAc/hexanes). LCMS=503.2 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3,
600 MHz) .delta. 7.89 (s, 1H), 7.75 (s, 2H), 7.03 (dd, J=8.7, 2.0
Hz, 1H), 6.90 (d, J=2.1 Hz, 1H), 6.67 (d, J=8.7 Hz, 1H), 5.67 (d,
J=8.5 Hz, 1H), 4.73 (d, J=15.4 Hz, 1H), 4.35 (bs, 2H), 4.09 (d,
J=15.4 Hz, 1H), 4.04 (m, 1H), 0.78 (d, J=6.6 Hz, 3H).
Step D:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluorom-
ethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one
[0489] To a solution of
(4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl-
)phenyl]-4-methyl-1,3-oxazolidin-2-one (582 mg, 1.16 mmol) in
CHCl.sub.3 (35 mL) was added t-butyl nitrite (275 .mu.L, 2.32
mmol). After 10 minutes, 12 (736 mg, 2.9 mmol) was added. The
reaction was stirred at room temperature for 30 minutes, and then
heated to 65.degree. C. for 2 hours. The reaction was then cooled
to room temperature, diluted with EtOAc (150 mL) and washed with
aqueous NaHSO.sub.3, water, brine, saturated NaHCO.sub.3, and brine
(50 mL each). The organic layer was dried over Na.sub.2SO.sub.4,
filtered, and concentrated. Purification of the residue by flash
chromatography on silica gel (2 to 15% EtOAc/hexanes) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethoxy)-
benzyl]-4-methyl-1,3-oxazolidin-2-one. R.sub.f=0.30 (15%
EtOAc/hexanes). LCMS=614.1 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3,
500 MHz) .delta. 7.89-7.91 (m, 2H), 7.79 (s, 2H), 7.23 (m, 1H),
6.95 (m, 1H), 5.75 (d, J=8.0 Hz, 1H), 4.81 (d, J=15.8 Hz, 1H), 4.32
(d, J=15.8 Hz, 1H), 4.07 (m, 1H), 0.78 (d, J=6.6 Hz, 3H).
Step E:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopro-
pyl-2'-methoxy-4-(trifluoromethoxy)biphenyl-2-yl]methyl}-4-methyl-1,3-oxaz-
olidin-2-one
[0490] In a microwave tube were placed
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethoxy)-
benzyl]-4-methyl-1,3-oxazolidin-2-one (41.6 mg, 0.0679 mmol),
(4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (18 mg, 0.085
mmol), DME (305 .mu.L), EtOH (100 .mu.L), and 1M aqueous
Na.sub.2CO.sub.3 (140 .mu.L, 0.140 mmol). The mixture was degassed
with N.sub.2. Next, Pd(PPh.sub.3).sub.4 (4 mg, 3.4.times.10.sup.-3
mmol) was added and the mixture was degassed again with N.sub.2.
The tube was sealed and irradiated in a microwave for 10 minutes at
150.degree. C. and 200 W. The reaction was then cooled to room
temperature, diluted with EtOAc (40 mL), and washed with water and
brine (15 mL each). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated. Purification of the
residue by flash chromatography on silica gel (2 to 15%
EtOAc/hexanes) afforded
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isop-
ropyl-2'-methoxy-4-(trifluoromethoxy)biphenyl-2-yl]methyl}-4-methyl-1,3-ox-
azolidin-2-one. R.sub.f=0.24 (15% EtOAc/hexanes). LCMS=654.3
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz, rotamers present)
.delta. 7.85 (s, 1H), 7.69 (s, 2H), 7.21-7.30 (m, 4H), 6.95-7.00
(m, 1H), 6.65-6.68 (m, 1H), 5.59 (d, J=8.0 Hz), 5.41 (d, J=8.0 Hz),
4.74-4.81 (m, 1H), 3.75-4.09 (m, 5H), 3.19 (m, 1H), 1.16-1.27 (m,
6H), 0.51 (d, J=6.7 Hz), 0.36 (d, J=6.6 Hz).
[0491] Following the general procedures outlined above, the
compounds in Table 6 were prepared:
TABLE-US-00006 TABLE 6 ##STR00197## Example A.sup.3 LCMS (M +
1).sup.+ 143 ##STR00198## 578.1 144 ##STR00199## 596.1 145
##STR00200## 566.1 146 ##STR00201## 600.1 147 ##STR00202## 582.2
148 ##STR00203## 600.1 149 ##STR00204## 693.3 150 ##STR00205##
604.2 151 ##STR00206## 604.2 152 ##STR00207## 637.2 153
##STR00208## 593.2 154 ##STR00209## 599.1 155 ##STR00210## 617.1
156 ##STR00211## 612.2 157 ##STR00212## 549.3 158 ##STR00213##
549.2 159 ##STR00214## 550.2 160 ##STR00215## 550.4 161
##STR00216## 563.3 162 ##STR00217## 563.3 163 ##STR00218## 563.4
164 ##STR00219## 583.1 165 ##STR00220## 563.2 166 ##STR00221##
579.2 167 ##STR00222## 563.2 168 ##STR00223## 567.2 169
##STR00224## 583.1 170 ##STR00225## 618.1 171 ##STR00226## 583.1
172 ##STR00227## 585.2 173 ##STR00228## 597.2 174 ##STR00229##
593.2 175 ##STR00230## 619.2 176 ##STR00231## 631.1 177
##STR00232## 634.1 178 ##STR00233## 699.2 179 ##STR00234## 597.1
180 ##STR00235## 613.1 181 ##STR00236## 595.1 182 ##STR00237##
591.2 183 ##STR00238## 597.1 184 ##STR00239## 597.1 185
##STR00240## 597.1 186 ##STR00241## 621.2 187 ##STR00242## 639.2
188 ##STR00243## 620.2 189 ##STR00244## 636.2
[0492] Following the general procedures outlined above, the
compounds in Table 7 were prepared:
TABLE-US-00007 TABLE 7 ##STR00245## LCMS Example A.sup.3 A.sup.2 (M
+ 1).sup.+ 190 ##STR00246## ##STR00247## 586.3 191 ##STR00248##
##STR00249## 566.1 192 ##STR00250## ##STR00251## 554.3 193
##STR00252## ##STR00253## 554.3 194 ##STR00254## ##STR00255## 632.2
195 ##STR00256## ##STR00257## 640.2
##STR00258##
[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]metha-
nol
[0493] A mixture of [2-iodo-5-(trifluoromethyl)phenyl]methanol
(EXAMPLE 69) (3.09 g, 10.2 mmol),
(4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (4.34 g, 20.5
mmol), (Ph.sub.3P).sub.4Pd (1.42 g, 1.23 mmol) and Na.sub.2CO.sub.3
(9.11 g, 85.9 mmol) in benzene/EtOH/H.sub.2O (7:1:3, 250 mL) was
heated at reflux for 24 h under N.sub.2. After cooling to room
temperature, the aqueous phase was separated and extracted with
CH.sub.2Cl.sub.2 (3.times.50 mL). The combined organic layers were
dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give the
crude product. This was purified by flash chromatography (Si,
65.times.200 mm, 0-20% EtOAc in hexanes gradient) to afford
4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methan-
ol. R.sub.f=0.50 (20% EtOAc in hexanes). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.86 (s, 1H), 7.59 (d, J=6.7 Hz, 1H), 7.30 (d,
J=7.9 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 6.68 (d, J=12.0 Hz, 1H),
4.52 (br s, 1H), 4.46 (br s, 1H), 3.73 (s, 3H), 3.25-3.17 (m, 1H),
1.82 (br s, 1H), 1.24 (d, J=6.8 Hz, 6H).
##STR00259##
2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphe-
nyl
[0494] A solution of triphenylphosphine (3.11 g, 11.8 mmol) in dry
CH.sub.2Cl.sub.2 (7 mL) was added by cannula to a stirred solution
of carbon tetrabromide (3.93 g, 11.8 mmol) and
4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methan-
ol (3.38 g, 9.87 mmol) in dry CH.sub.2Cl.sub.2 (56 mL) at 0.degree.
C. under N.sub.2. The reaction was allowed to warm to room
temperature. After 2 h, the reaction mixture was concentrated in
vacuo to give the crude product. This was purified by flash
chromatography (Si, 65.times.200 mm, 0-20% EtOAc in hexanes
gradient) to afford
2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphe-
nyl. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.83 (s, 1H), 7.61
(d, J=8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H),
6.72 (d, J=12.0 Hz, 1H), 4.43 (br d, J=10.0 Hz, 1H), 4.30 (br d,
J=10.2 Hz, 1H), 3.76 (s, 3H), 3.30-3.22 (m, 1H), 1.29 (d, J=6.9 Hz,
6H).
##STR00260##
5-[35-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-
-(trifluoromethyl)biphenyl-2-yl]methyl}-4,4-dimethyl-1,3-oxazolidin-2-one
Step A: benzyl
{2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate
[0495] N-Methylmorpholine (682 mg, 741 .mu.L, 6.74 mmol) and
isobutylchloroformate (460 mg, 441 .mu.L, 3.37 mmol) were added
successively to a stirred solution of
N-carbobenzyloxy-2-methylalanine (0.64 g, 2.69 mmol) in dry
CH.sub.2Cl.sub.2 at 0.degree. C. under N.sub.2. The resulting
cloudy mixture was stirred at 0.degree. C. for 90 min.
N,O-Dimethylhydroxylamine hydrochloride (316 mg, 3.24 mmol) was
added portionwise and the mixture was warmed to room temperature
and stirred for 3 h. The mixture was poured into 1N HCl (30 mL) and
extracted with CH.sub.2Cl.sub.2 (3.times.40 mL). The combined
extracts were washed with 1N HCl (30 mL), dried (Na.sub.2SO.sub.4)
and concentrated in vacuo to give the crude product. This was
purified by flash chromatography (Si, 40.times.160 mm, 0-80% EtOAc
in hexanes gradient) to afford benzyl
{2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate.
R.sub.f=0.47 (50% EtOAc in hexanes). LCMS calc.=303.1; found=303.2
(M+Na).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.37-7.29
(m, 5H), 5.82 (s, 1H), 5.09 (s, 2H), 3.60 (s, 3H), 3.18 (s, 3H),
1.60 (s, 6H).
Step B: benzyl (1,1-dimethyl-2-oxoethyl)carbamate
[0496] Diisobutylaluminum hydride (1.77 mL, 1M solution in toluene,
0.708 mmol) was added to a stirred solution of benzyl
{2-[methoxy(methyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate (198.5
mg, 0.708 mmol) in dry THF (7.1 mL) at -78.degree. C. under
N.sub.2. The reaction was stirred at -78.degree. C. for 4 h. MeOH
(100 .mu.L) and 1N HCl (250 .mu.L) were added and the reaction was
allowed to warm to room temperature. The mixture was diluted with
Et.sub.2O (50 mL) and washed with 1N HCl (2.times.50 mL), 50%
saturated NaHCO.sub.3 (50 mL) and water (50 mL), then dried
(MgSO.sub.4) and concentrated in vacuo to give benzyl
(1,1-dimethyl-2-oxoethyl)carbamate. R.sub.f=0.40 (20% EtOAc in
hexanes). LCMS calc.=244.1; found=244.1 (M+Na).sup.+. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 9.43 (s, 1H), 7.38-7.30 (m, 5H), 5.34
(s, 1H), 5.09 (s, 2H), 1.37 (s, 6H).
Step C: benzyl
{2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate
[0497] Ethylmagnesium bromide (1.63 mL, 1M in THF, 1.63 mmol) was
added dropwise to a stirred solution of
1-iodo-3,5-bis(trifluoromethyl)benzene (608 mg, 317 .mu.L, 1.79
mmol) in dry THF (1 mL) at room temperature under N.sub.2 and the
reaction was stirred for 30 min. The resulting solution was added
to a stirred solution of benzyl (1,1-dimethyl-2-oxoethyl)carbamate
(163.5 mg, 0.739 mmol) in dry THF (1 mL) at -20.degree. C. and the
reaction was allowed to warm to room temperature over 3 h.
Saturated NH.sub.4Cl (10 mL) and water (10 mL) were added and the
mixture was extracted with EtOAc (3.times.20 mL). The combined
extracts were dried (Na.sub.2SO.sub.4) and concentrated in vacuo to
give the crude product. This was purified by flash chromatography
(Si, 25.times.160 mm, 0-40% EtOAc in hexanes gradient) to afford
benzyl
{2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate-
. R.sub.f=0.40 (20% EtOAc in hexanes). LCMS calc.=436.1;
found=436.0 (M+1).sup.+. .sup.1H NMR (600 MHz, CDCl.sub.3) .delta.
7.80 (s, 1H), 7.77 (s, 2H), 7.39-7.33 (m, 5H), 5.12-5.08 (m, 2H),
1.36 (s, 1H), 4.90 (d, J=4.4 Hz, 1H), 4.81 (s, 1H), 1.36 (s, 3H),
1.23 (s, 3H).
##STR00261##
benzyl
[(1S)-2-(4-chloropyridin-2-yl)-1-methyl-2-oxoethyl]carbamate
[0498] A solution of 2-(dimethylamino)ethanol (471 mg, 531 mL, 5.28
mmol) in dry hexanes (3.3 mL) was cooled to -5.degree. C. and
n-butyllithium (1.6 M in hexanes, 6.60 mL, 10.6 mmol) was added
dropwise under N.sub.2. After 30 min at 0.degree. C., the solution
was cooled to -78.degree. C. and a solution of 4-chloropyridine
(obtained by washing a solution of the corresponding HCl salt (264
mg, 1.76 mmol) in CH.sub.2Cl.sub.2 (20 mL) with saturated
K.sub.2CO.sub.3 (10 mL), then back extracting with CH.sub.2Cl.sub.2
(2.times.20 mL), combining the organic layers, drying
(Na.sub.2SO.sub.4) and concentrating in vacuo) in hexanes (3.3 mL)
was added dropwise by cannula. The solution became dark red in
color and after 1 h at -78.degree. C., a solution of the
electrophile (prepared by adding isopropylmagnesium chloride (2M in
THF, 1.29 mL, 2.59 mmol) to a solution of benzyl
{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (702
mg, 2.64 mmol) in dry THF (3.5 mL) at -15.degree. C. under N.sub.2
and stirring for 15 min) was added by cannula. The reaction was
allowed to warm slowly to room temperature overnight. Water (25 mL)
and saturated NH.sub.4Cl (50 mL) were added and the mixture was
extracted with EtOAc (3.times.50 mL). The combined extracts were
dried (MgSO.sub.4) and concentrated in vacuo to give the crude
product. This was purified by flash chromatography (Si,
40.times.160 mm, 0-30% EtOAc in hexanes gradient) to afford benzyl
[(1S)-2-(4-chloropyridin-2-yl)-1-methyl-2-oxoethyl]carbamate.
R.sub.f=0.46 (20% EtOAc in hexanes). LCMS calc.=319.1; found=319.3
(M+1).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.58 (d,
J=5.0 Hz, 1H), 8.04 (s, 1H), 7.47 (dd, J=5.2, 2.0 Hz, 1H),
7.35-7.30 (m, 5H), 5.78 (s, 1H), 5.72 (m, 1H), 5.11 (m, 2H), 1.47
(d, J=7.0 Hz, 3H).
##STR00262##
benzyl [(1S)-1-methyl-2-oxo-2-(1,3-thiazol-2-yl)ethyl]carbamate
[0499] n-Butyllithium (1.6M in hexanes, 1.76 mL, 2.83 mmol) was
added dropwise to a stirred solution of 2-bromothiazole (462 mg,
251 .mu.L, 2.82 mmol) in dry THF (13 mL) at -78.degree. C. under
N.sub.2 and the reaction was stirred at -78.degree. C. for 45 min.
Separately, isopropylmagnesium chloride (2M in THF, 0.94 mL, 1.99
mmol) was added to a stirred solution of benzyl
{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (500
mg, 1.88 mmol) in dry THF (4 mL) at -15.degree. C. under N.sub.2.
This solution was stirred for 15 min at -15.degree. C. and was
added dropwise to the above 2-lithiothiazole solution at
-78.degree. C. The reaction was allowed to warm to room temperature
overnight and saturated NH.sub.4Cl (20 mL) and water (10 mL) were
added and the mixture was extracted with EtOAc (3.times.30 mL). The
combined extracts were washed with brine, dried (Na.sub.2SO.sub.4)
and concentrated in vacuo to give the crude product. This was
purified by flash chromatography (Si, 25.times.160 mm, 0-50% EtOAc
in hexanes gradient) to afford benzyl
[(1S)-1-methyl-2-oxo-2-(1,3-thiazol-2-yl)ethyl]carbamate.
R.sub.f=0.28 (20% EtOAc in hexanes). LCMS calc.=291.1; found=291.3
(M+1).sup.+. .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 8.03 (s,
1H), 7.70 (d, J=3.1 Hz, 1H), 7.34-7.29 (m, 5H), 5.79 (d, J=6.6 Hz,
1H), 5.53-5.49 (m, 1H), 5.14-5.08 (m, 2H), 1.55 (d, J=6.4 Hz,
3H).
##STR00263##
Benzyl
[(1S)-1-methyl-2-(1-methyl-1H-imidazol-4-yl)-2-oxoethyl]carbamate
[0500] A solution of benzyl
{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (64
mg, 0.24 mmol) in CH.sub.2Cl.sub.2 (1 mL) was cooled to -20.degree.
C. under N.sub.2, and isopropylmagnesium chloride (120 .mu.L of a
2.0 M solution in THF) was added dropwise. The mixture was stirred
at -20.degree. C. for 20 min. In a separate flask ethylmagnesium
bromide (480 .mu.L of a 2.0 M solution in Et.sub.2O) was added to a
solution of 4-iodo-1-methyl-1-H-imidazole (109 mg, 0.48 mmol) in
dry CH.sub.2Cl.sub.2 (1.5 mL) at room temperature. The resulting
mixture was stirred for 20 min and then added by cannula to the
solution above slowly. The resulting solution was left to stir
overnight. Saturated NH.sub.4Cl was added to the reaction solution.
The mixture was diluted with water and the aqueous phase was
extracted with CH.sub.2Cl.sub.2 (2.times.25 mL). The combined
organic extracts were dried (Na.sub.2SO.sub.4) and concentrated in
vacuo. Flash chromatography of the residue yielded benzyl
[(1S)-1-methyl-2-(1-methyl-1H-imidazol-4-yl)-2-oxoethyl]carbamate.
LCMS calc.=288.14; found=288.3 (M+1).sup.+. .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.65 (s, 1H); 7.47 (s, 1H); 7.35-7.28 (m, 5H);
5.93 (d, J=6.9 Hz, 1H); 5.29-5.25 (m, 1H); 5.13 (s, 2H); 3.73 (s,
3H); 1.26 (d, J=7.1 Hz, 3H).
##STR00264##
Benzyl
((1S)-2-{1-[(benzyloxy)methyl]-1H-imidazol-2-yl}-1-methyl-2-oxoeth-
yl)carbamate
Step A: 1-[(benzyloxy)methyl]-1H-imidazole
[0501] A mixture of chloromethylether (4.3 mL, 29 mmol) and
imidazole (6 g, 58 mmol) in acetonitrile (200 mL) was heated at
reflux for 3.5 h. The solvent was removed in vacuo. The resulting
oily residue was partitioned between CH.sub.2Cl.sub.2 (300 mL) and
water (150 mL). Then the organic extract was washed with water
(2.times.150 mL), dried (Na.sub.2SO.sub.4) and concentrated in
vacuo to yield 1[(benzyloxy)methyl]-1H-imidazole used without
further purification. LCMS calc.=189.10; found=189.1 (M+1).sup.+.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.63 (s, 1H); 7.40-7.30
(m, 5H); 7.16 (t, J=6.5 Hz, 1H); 7.09 (t, J=10.6 Hz, 1H); 5.34 (s,
2H); 4.45 (s, 2H).
Step B: benzyl
((1S)-2-{1-[(benzyloxy)methyl]-1H-imidazol-2-yl}-1-methyl-2-oxoethyl)carb-
amate
[0502] To a solution of 1-[(benzyloxy)methyl]-1H-imidazole (706 mg,
3.75 mmol) in THF (4 mL) at -78.degree. C. under N.sub.2, was added
n-Butyllithium (2.3 mL of a 1.6 M solution in hexanes). The mixture
was stirred at -78.degree. C. for 30 min. To a solution of benzyl
{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (200
mg, 0.75 mmol) in THF (2 mL) under N.sub.2 at -15.degree. C., was
added isopropylmagnesium chloride (375 .mu.L of a 2.0 M solution in
THF). The resulting mixture was stirred at -15.degree. C. for 15
min. This mixture was then added, by cannula to the solution above
at -78.degree. C. The mixture stirred at -78.degree. C. for about 3
h, then warmed up gradually to room temperature and stirred
overnight. The mixture was quenched with saturated NH.sub.4Cl. The
aqueous layer was extracted with CH.sub.2Cl.sub.2 (3.times.25 mL).
The organic layers were combined, dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. The residue was purified by flash
chromatography to afford benzyl
((1S)-2-{1-[(benzyloxy)methyl]-1H-imidazol-2-yl}-1-methyl-2-oxoethyl)carb-
amate contaminated with about 30% of the unreacted starting
material benzyl
{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate. The
mixture was carried forward to the next step without further
purification. LCMS calc.=394.18; found=394.2 (M+1).sup.+.
##STR00265##
2-bromo-4,5-dichloro-1-methyl-1H-imidazole
[0503] A mixture of 2-bromo-4,5-dichloroimidazole (1 g, 4.6 mmol),
methyl iodide (346 .mu.L, 5.56 mmol), potassium carbonate (1.27 g,
9.2 mmol) and tetrabutylammonium bromide (148 mg, 0.46 mmol) in
acetonitrile (2 mL) was stirred vigorously at 70-80.degree. C. for
1.0 h. After cooling to room temperature, the inorganic salts were
filtered off and washed with acetonitrile. The filtrate was
evaporated and the residue was purified by flash chromatography
(Si) to afford 2-bromo-4,5-dichloro-1-methyl-1H-imidazole as a
white solid. LCMS calc.=230.89; found=230.9 (M+1).sup.+. .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 3.61 (s, 3H).
##STR00266##
4-iodo-1-methyl-1H-pyrazole
[0504] To a solution of 18-crown-6 (132 mg, 0.5 mmol) in Et.sub.2O
(8 mL) under N.sub.2, was added potassium tert-butoxide (616 mg,
5.5 mmol). The mixture was stirred while 4-iodopyrazole (1 g, 5
mmol) was introduced in a single portion at room temperature. The
reaction was cooled to 0.degree. C. and a solution of iodomethane
(342 .mu.L, 5.5 mmol) in Et.sub.2O (2 mL) was added dropwise at
0.degree. C. The resulting mixture was warmed to room temperature
and stirred overnight. The reaction was then diluted with water and
extracted with Et.sub.2O (2.times.50 mL). The combined organic
layers were washed with brine (45 mL), dried over anhydrous
Na.sub.2SO.sub.4 and concentrated in vacuo. Flash chromatography
gave 4-iodo-1-methyl-1H-pyrazole. LCMS calc.=208.96; found=209.0
(M+1).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.52 (s,
1H); 7.43 (s, 1 H); 3.95 (s, 3H).
##STR00267##
3-iodo-1-methyl-1H-pyrazole
[0505] 1-methyl-1-H-pyrazole-3-amine (250 mg, 2.57 mmol) was heated
at reflux for 3 h with tert-butylnitrite (336 .mu.L, 2.83 mmol) in
diiodomethane (5 mL). The solvent and volatile material was removed
in vacuo and the resulting residue was purified by flash
chromatography (Si) to yield 3-iodo-1-methyl-1H-pyrazole. LCMS
calc.=208.96; found=209.0 (M+1).sup.+. .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.21 (d, J=2.1 Hz, 1H); 6.42 (d, J=2.2 Hz, 1H);
3.94 (s, 3H).
##STR00268##
(4S,5S)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]methyl}-4-methyl-5-(1-methyl-1H-tetrazol-5-yl)-1,3-oxazolidin-2-one
and
(4S,5S)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biph-
enyl-2-yl]methyl}-4-methyl-5-(2-methyl-2H-tetrazol-5-yl)-1,3-oxazolidin-2--
one
Step A: benzyl
[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(1H-tetrazol-5-yl)-
ethyl]carbamate and benzyl
[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(2H-tetrazol-5-yl)-
ethyl]carbamate
[0506] A mixture of benzyl
((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyano-1-methylethyl)carbama-
te (106.6 mg, 0.306 mmol), triethylamine hydrochloride (211 mg,
1.53 mmol) and sodium azide (99.4 mg, 1.56 mmol) in dry toluene (6
mL) was heated at relux under N.sub.2 for 20 h and at room
temperature for 2 days. The reaction was diluted with 1N HCl (20
mL) and extracted with EtOAc (3.times.20 mL). The combined extracts
were dried (Na.sub.2SO.sub.4) and concentrated in vacuo to afford
the crude product. This was carried forward with no further
purification. LCMS calc.=392.2; found=392.1 (M+1).sup.+.
Step B: benzyl
[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(1-methyl-1H-tetra-
zol-5-yl)ethyl]carbamate and benzyl
[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(2-methyl-2H-tetra-
zol-5-yl)ethyl]carbamate
[0507] (Trimethylsilyl)diazomethane (2M in hexanes, 459 .mu.L,
0.918 mmol) was added dropwise to a solution of the crude benzyl
[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(1H-tetrazol-5-yl)-
ethyl]carbamate and benzyl
[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(2H-tetrazol-5-yl)-
ethyl]carbamate in CH.sub.2Cl.sub.2/MeOH (3:2, 5 mL) at room
temperature under N.sub.2. After 15 min and gas evolution had
ceased, the reaction mixture was concentrated in vacuo to give the
crude product. This was purified by flash chromatography (Si,
12.times.160 mm, 0-70% EtOAc in hexanes gradient) to afford benzyl
[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(1-methyl-1H-tetra-
zol-5-yl)ethyl]carbamate and benzyl
[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(2-methyl-2H-tetra-
zol-5-yl)ethyl]carbamate, as a 2:1 mixture of regioisomers. LCMS
calc.=406.2; found=406.2 (M+1).sup.+.
Step C: benzyl
[(1S,2S)-2-hydroxy-1-methyl-2-(1-methyl-1H-tetrazol-5-yl)ethyl]carbamate
and benzyl
[(1S,2S)-2-hydroxy-1-methyl-2-(2-methyl-2H-tetrazol-5-yl)ethyl]carbamate
[0508] Tetrabutylammonium fluoride (1M, in THF, 177 .mu.L, 0.177
mmol) was added dropwise to a stirred solution of benzyl
[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(1-methyl-1H-tetra-
zol-5-yl)ethyl]carbamate and benzyl
[(1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-2-(2-methyl-2H-tetra-
zol-5-yl)ethyl]carbamate (2:1 mixture of regioisomers, 65.2 mg,
0.161 mmol) in THF (2 mL) at 0.degree. C. The reaction was stirred
for 2 h at 0.degree. C., diluted with saturated NH.sub.4Cl (10 mL)
and extracted with EtOAc (3.times.30 mL). The combined extracts
were dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give the
crude product. This was purified by flash chromatography (Si,
12.times.160 mm, 0-80% EtOAc in hexanes gradient) to afford benzyl
[(1S,2S)-2-hydroxy-1-methyl-2-(2-methyl-2H-tetrazol-5-yl)ethyl]carbamate
and benzyl
[(1S,2S)-2-hydroxy-1-methyl-2-(1-methyl-1H-tetrazol-5-yl)ethyl]carbamate.
2-methyl isomer (INTERMEDIATE 20): LCMS calc.=292.1; found=292.1
(M+1).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.33-7.29
(m, 5H), 5.59 (d, J=8.5 Hz, 1H), 5.09-5.00 (m, 5H), 4.49 (m, 1H),
4.26 (s, 3H), 1.07 (d, J=6.9 Hz, 3H). 1-methyl isomer (INTERMEDIATE
19): LCMS calc.=292.1; found=292.1 (M+1).sup.+. .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 7.33-7.29 (m, 5H), 5.72 (s, 1H), 5.07 (m,
3H), 4.99 (m, 2H), 4.18 (m, 1H), 4.10 (s, 3H), 1.24 (d, J=6.7 Hz,
3H).
Example 196
##STR00269##
[0509]
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)bi-
phenyl-2-yl]methyl}-4-methyl-5-pyridin-4-yl-1,3-oxazolidin-2-one
Step A: benzyl
[(1S)-1-methyl-2-oxo-2-pyridin-4-ylethyl]carbamate
[0510] A solution of isopropylmagnesium chloride (1.6 mL, 1M in
THF, 3.23 mmol) was added dropwise to a stirred solution of benzyl
{(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate
(EXAMPLE 17, Step 1) (879 mg, 3.30 mmol) in dry THF (4.2 mL) at
-15.degree. C. under N.sub.2. The reaction was stirred at
-15.degree. C. for 30 min then a suspension of 4-pyridylmagnesium
bromide in dry THF (prepared by adding ethyl magnesium bromide (6
mL, 2M in THF, 6.00 mmol) to a stirred solution of 4-iodopyridine
(1.35 g, 6.60 mmol) in dry THF (45 mL) at room temperature under
N.sub.2 and stirring for 30 min) was added dropwise by cannula. The
reaction was allowed to warm to room temperature and was stirred
for 5 h. 1N HCl (15 mL) was added to quench the reaction and the
mixture was adjusted to basic pH with saturated NaHCO.sub.3. The
mixture was extracted with EtOAc (2.times.50 mL) and
CH.sub.2Cl.sub.2 (3.times.50 mL). The EtOAc and CH.sub.2Cl.sub.2
extracted were washed with brine separately, dried
(Na.sub.2SO.sub.4), combined and concentrated in vacuo to give the
crude product. This was purified by flash chromatography (Si,
40.times.160 mm, 0-100% EtOAc in hexanes gradient) to afford benzyl
[(2R)-1-methyl-2-oxo-2-pyridin-4-ylethyl]carbamate, as a colorless
solid. R.sub.f=0.33 (50% EtOAc/hexanes). LCMS calc.=285.1;
found=285.3 (M+1).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.85 (d, J=3.3 Hz, 2H), 7.76 (d, J=5.5 Hz, 2H), 7.36-7.32 (m, 5H),
5.70 (d, J=6.8 Hz, 1H), 5.31-5.25 (m, 1H), 5.13 (s, 2H), 1.43 (s,
3H).
Step B: benzyl
[(1S,2R)-2-hydroxy-1-methyl-2-pyridin-4-ylethyl]carbamate
[0511] Lithium tri-tert-butoxyaluminum hydride (964 mg, 3.79 mmol)
was added to a solution of benzyl
[(2R)-1-methyl-2-oxo-2-pyridin-4-ylethyl]carbamate (539.1 mg, 1.90
mmol) in dry EtOH (40 mL) at -78.degree. C. under N.sub.2. The
reaction was stirred at -78.degree. C. for 2 h. 2% Aqueous acetic
acid was added to quench the reaction and the mixture was adjusted
to basic pH with saturated NaHCO.sub.3 (.about.50 mL). The mixture
was extracted with EtOAc (3.times.100 mL) and the combined extracts
were washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and
concentrated in vacuo to give the crude product. This was purified
by flash chromatography (Si, 40.times.160 mm, 0-100% EtOAc in
hexanes gradient) to afford benzyl
[(1S,2R)-2-hydroxy-1-methyl-2-pyridin-4-ylethyl]carbamate as a
colorless solid. R.sub.f=0.49 (EtOAc). LCMS calc.=287.1;
found=287.3 (M+1).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.
8.41 (d, J=5.7 Hz, 2H), 7.36-7.32 (m, 7H), 5.27 (d, J=7.4 Hz, 1H),
5.10 (s, 2H), 4.89 (s, 1H), 4.02 (br s, 1H), 0.96 (d, J=6.7 Hz,
3H).
Step C:
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)b-
iphenyl-2-yl]methyl}-4-methyl-5-pyridin-4-yl-1,3-oxazolidin-2-one
[0512] Sodium hydride (52.4 mg, 60% dispersion in mineral oil, 1.31
mmol) was added to a solution of benzyl
[(1S,2R)-2-hydroxy-1-methyl-2-pyridin-4-ylethyl]carbamate 150 mg,
0.524 mmol) in dry THF (6 mL) at room temperature under N.sub.2.
After stirring for 30 min at room temperature a solution of
2-(bromomethyl)-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl
(255 mg, 0.629 mmol) in dry THF (3 mL) was added by cannula. The
reaction mixture was stirred overnight at room temperature.
Saturated NH.sub.4Cl (10 mL) was added and the mixture was
extracted with EtOAc (3.times.20 mL). The combined extracts were
dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give the
crude product. This was purified by flash chromatography (Si,
25.times.160 mm, 0-70% EtOAc in hexanes gradient) to afford
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)b-
iphenyl-2-yl]methyl}-4-methyl-5-pyridin-4-yl-1,3-oxazolidin-2-one
as a colorless oil. R.sub.f=0.49 (EtOAc). LCMS calc.=503.2;
found=503.3 (M+1).sup.+. .sup.1H NMR (600 MHz, CDCl.sub.3, 1:1
mixture of atropisomers) .delta. 8.61 (d, J=4.1 Hz, 2H), 7.68 (s,
0.5H), 7.61 (s, 1H), 7.60 (s, 0.5H), 7.33 (dd, J=7.4, 3.8, Hz 1H),
7.16 (br s, 2H), 6.97 (dd, J=17.8, 8.4 Hz, 1H), 6.67 (dd, J=12.0,
3.4 Hz, 1H), 5.44 (d, J=8.2 Hz, 0.5H), 5.28 (d, J=8.0 Hz, 0.5H),
4.79 (d, J=15.8 Hz, 0.5H), 4.76 (d, J=15.8 Hz, 0.5H), 4.15-4.09 (m,
1H), 3.88 (d, J=15.8 Hz, 0.5H), 3.79-3.70 (m, 0.5H), 3.74 (s, 3H),
3.23-3.17 (m, 1H), 1.26-1.16 (m, 6H), 0.52 (d, J=6.5 Hz, 1.5H),
0.38 (d, J=6.5 Hz, 1.5H).
Example 197
##STR00270##
[0513]
(4S,5S)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)bi-
phenyl-2-yl]methyl}-4-methyl-5-(4-methyl-1,3-thiazol-2-yl)-1,3-oxazolidin--
2-one
Step A: benzyl [(1S)-1-methyl-2-oxoethyl]carbamate
[0514] Dimethylsulfoxide (1.01 g, 918 .mu.L, 12.9 mmol) was added
dropwise to a stirred solution of oxalyl chloride (790 mg, 543
.mu.L, 6.23 mmol) in dry CH.sub.2Cl.sub.2 (12.6 mL) at -78.degree.
C. under N.sub.2 and the reaction was stirred for 15 min. A
solution of benzyl [(1S)-2-hydroxy-1-methylethyl]carbamate (965 mg,
4.61 mmol) in dry CH.sub.2Cl.sub.2 (12.6 mL) was added dropwise by
cannula and the mixture was stirred at -78.degree. C. for 30 min.
Triethylamine (1.34 g, 1.85 mL, 13.2 mmol) was added and the
reaction was allowed to warm to room temperature and was stirred
for 2 h. Water (15 mL) was added and the aqueous phase was
separated and extracted with CH.sub.2Cl.sub.2 (3.times.15 mL). The
combined organic extracts were washed with saturated NaHCO.sub.3
and brine, then dried (MgSO.sub.4) and concentrated in vacuo to
afford benzyl [(1S)-1-methyl-2-oxoethyl]carbamate as a colorless
oil. R.sub.f=0.75 (50% EtOAc in hexanes). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 9.58 (s, 1H), 7.39-7.35 (m, 5H), 5.39 (br s,
1H), 5.15 (s, 2H), 4.33 (m, 1H), 1.40 (d, J=7.1 Hz, 3H).
Step B: benzyl [(1S)-2-cyano-2-hydroxy-1-methylethyl]carbamate
[0515] Diethylaluminum cyanide (4.53 mL, 1M in toluene, 4.53 mmol)
was added dropwise to a stirred solution of benzyl
[(1S)-1-methyl-2-oxoethyl]carbamate (0.853 g, 4.12 mmol) in dry
toluene (33 mL) at -78.degree. C. under N.sub.2. The mixture was
stirred at -78.degree. C. for 6 h and then allowed to warm to room
temperature overnight. Saturated NH.sub.4Cl (20 mL) and water (10
mL) were added then the mixture was extracted with EtOAc
(3.times.50 mL). The combined extracts were dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to afford the crude
product. This was purified by flash chromatography (Si,
40.times.160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl
[(1S)-2-cyano-2-hydroxy-1-methylethyl]carbamate as a 3:1 mixture of
diastereoisomers. R.sub.f=0.63 (50% EtOAc in hexanes). LCMS
calc.=257.1; found=257.1 (M+1).sup.+. .sup.1H NMR (500 MHz,
CDCl.sub.3) major diastereoisomer: .delta. 7.39-7.31 (m, 5H), 5.11
(m, 2H), 4.60 br (s, 1H), 3.96 (m, 1H), 1.34 (d, J=6.7 Hz, 3H),
minor diastereoisomer: .delta. 7.39-7.31 (m, 5H), 5.14 (m, 2H),
4.50 br (s, 1H), 4.10 (m, 1H), 1.30 (d, J=7.0 Hz, 3H).
Step C: benzyl
((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyano-1-methylethyl)carbama-
te tert-Butyldimethylsilyl chloride (471 mg, 3.12 mmol) and
imidazole (483 mg, 7.10 mmol) were added successively to a stirred
solution of benzyl [(1S)-2-cyano-2-hydroxy-1-methylethyl]carbamate
(665 mg, 2.84 mmol) in dry CH.sub.2Cl.sub.2 (13 mL) at room
temperature under N.sub.2 and the mixture was stirred overnight.
Water (30 mL) was added and the mixture was extracted with
Et.sub.2O (3.times.30 mL). The combined extracts were dried
(MgSO.sub.4) and concentrated in vacuo to give the crude product.
This was purified by flash chromatography (Si, 40.times.160 mm,
0-15% EtOAc in hexanes gradient) to afford benzyl
((1S,2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyano-1-methylethyl)carbama-
te and benzyl
((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyano-1-methylethyl)carbama-
te. (1S,2R)-diastereoisomer: R.sub.f=0.29 (10% EtOAc in hexanes).
LCMS calc.=349.2; found=349.1 (M+1).sup.+. .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.39-7.33 (m, 5H), 5.16 (d, J=12.1 Hz, 1H),
5.07 (d, J=12.1 Hz, 1H), 4.89 (br d, J=6.6 Hz, 1H), 4.68 (br, d,
3.6 Hz, 1H), 3.92 (m, 1H), 1.31 (d, J=6.7 Hz, 3H), 0.91 (s, 9H),
0.21 (s, 3H), 0.17 (s, 3H). (1S,2S)-diastereoisomer: R.sub.f=0.24
(10% EtOAc in hexanes). LCMS calc.=349.2; found=349.1 (M+1).sup.+.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.38-7.32 (m, 5H), 5.10
(s, 2H), 4.76 (br d, J=6.9 Hz, 1H), 4.63 (br s, 1H), 4.00 (m, 1H),
1.31 (d, J=6.8 Hz, 3H), 0.90 (d, J=2.9 Hz, 9H), 0.17 (s, 3H), 0.08
(s, 3H).
Step D: benzyl
((1S,2S)-3-amino-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-3-thioxoprop-
yl)carbamate
[0516] A mixture of benzyl
((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyano-1-methylethyl)carbama-
te (115.6 mg, 0.287 mmol), diethyldithiophosphate (1 mL) and water
(3 drops) was stirred overnight at room temperature. The reaction
mixture was partitioned between saturated NaHCO.sub.3 (40 mL) and
EtOAc (40 mL). The aqueous layer was separated and extracted with
EtOAc (2.times.40 mL). The combined extracts were dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to give the crude
product. This was purified by flash chromatography (Si,
12.times.160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl
((1S,2S)-3-amino-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-3-thioxoprop-
yl)carbamate as a colorless oil. R.sub.f=0.30 (20% EtOAc in
hexanes). LCMS calc.=383.2; found=383.1 (M+1).sup.+. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 8.36 (s, 1H), 7.87 (s, 1H), 7.37-7.29
(m, 5H), 5.13 (m, 2H), 4.85 (d, J=8.2 Hz, 1H), 4.72 (s, 1H), 4.47
(m, 1H), 1.05 (d, J=6.7 Hz, 3H), 0.96 (s, 9H), 0.08 (s, 3H), 0.07
(s, 3H).
Step E: benzyl
[(1S,2S)-2-hydroxy-1-methyl-2-(4-methyl-1,3-thiazol-2-yl)ethyl]carbamate
[0517] A solution of benzyl
((1S,2S)-3-amino-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methyl-3-thioxoprop-
yl)carbamate (96.8 mg, 0.253 mmol) and chloroacetone (117 mg, 101
.mu.L, 1.27 mmol) in dry EtOH (5 mL) was heated at reflux under
N.sub.2 for 20 h, then stirred at room temperature for 2 days. The
reaction mixture was concentrated in vacuo to give the crude
product. This was purified by flash chromatography (Si,
12.times.160 mm, 0-100% EtOAc in hexanes gradient) to afford benzyl
[(1S,2S)-2-hydroxy-1-methyl-2-(4-methyl-1,3-thiazol-2-yl)ethyl]carbamate.
R.sub.f=0.44 (50% EtOAc in hexanes). LCMS calc.=307.1; found=307.1
(M+1).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.31 (m,
5H), 6.80 (s, 1H), 5.49 (br s, 1H), 5.06 (m, 3H), 4.26-4.18 (m,
1H), 2.38 (s, 3H), 1.09 (d, J=6.5 Hz, 3H).
Step F:
(4S,5S)-4-methyl-5-(4-methyl-1,3-thiazol-2-yl)-1,3-oxazolidin-2-on-
e
[0518] A solution of benzyl
[(1S,2S)-2-hydroxy-1-methyl-2-(4-methyl-1,3-thiazol-2-yl)ethyl]carbamate
(53.4 mg, 0.174 mmol) in 7.5 N aqueous KOH (1 mL), MeOH, (2 mL) and
THF (4 mL) was stirred at room temperature overnight. The reaction
mixture was acidified with 3N HCl and extracted with EtOAc
(3.times.20 mL). The combined extracts were washed with brine,
dried (Na.sub.2SO.sub.4) and concentrated in vacuo to afford the
product. LCMS calc.=199.1; found=199.1 (M+1).sup.+. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. 6.92 (s, 1H), 6.82 (s, 1H), 5.91 (d,
J=8.2 Hz, 1H), 4.39-4.35 (m, 1H), 2.44 (s, 3H), 0.95 (d, J=6.4 Hz,
3H).
Step G:
(4S,5S)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)b-
iphenyl-2-yl]methyl}-4-methyl-5-(4-methyl-1,3-thiazol-2-yl)-1,3-oxazolidin-
-2-one
[0519] Sodium hydride (60% dispersion in mineral oil, 8.1 mg, 0.202
mmol) was added to a stirred solution of
(4S,5S)-4-methyl-5-(4-methyl-1,3-thiazol-2-yl)-1,3-oxazolidin-2-one
(33.4 mg, 0.168 mmol) in dry THF (1 mL) at room temperature under
N.sub.2. The reaction was stirred for 15 min then a solution of
2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphe-
nyl (81.0 mg, 0.202 mmol) in dry THF (2 mL) was added by cannula.
The reaction was stirred at room temperature overnight. Saturated
NH.sub.4Cl (10 mL) was added and the mixture was extracted with
EtOAc (3.times.20 mL). The combined extracts were dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to give the crude
product. This was purified by flash chromatography (Si,
25.times.160 mm, 0-70% EtOAc in hexanes gradient) and chiral HPLC
(IA column, 20.times.250 mm, 5% i-PrOH in heptane) to afford
(4S,5S)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]methyl}-4-methyl-5-(4-methyl-1,3-thiazol-2-yl)-1,3-oxazolidin-2-one.
R.sub.f=0.18 (20% EtOAc in hexanes). LCMS calc.=523.2; found=523.1
(M+1).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3, 1:1 mixture of
atropisomers) .delta. 7.68 (s, 0.5H), 7.63 (s, 0.5H), 7.59 (d,
J=8.0 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 6.99 (d, J=8.5 Hz, 0.5H),
6.95 (d, J=8.5 Hz, 0.5H), 6.88 (s, 1H), 6.68 (d, J=5.0 Hz, 0.5H),
6.66 (d, J=4.9 Hz, 0.5H), 5.70 (d, J=8.3 Hz, 0.5H), 5.55 (d, J=8.2
Hz, 0.5H), 4.72 (d, J=15.9 Hz, 0.5H), 4.64 (d, J=15.9 Hz, 0.5H),
4.20 (d, J=15.9 Hz, 0.5H), 3.95 (d, J=15.9 Hz, 0.5H), 3.91-3.83 (m,
1H), 3.75 (s, 1.5H), 3.74 (s, 1.5H), 3.23-3.15 (m, 1H), 2.40 (s,
3H), 1.26-1.18 (m, 6H), 0.65 (d, J=6.5 Hz, 1.5H), 0.55 (d, J=6.5
Hz, 1.5H).
[0520] Following the general procedures outlined above, the
compounds in Table 8 were prepared. Example 198 was made as a
reference compound.
TABLE-US-00008 TABLE 8 ##STR00271## Example R LCMS (M + 1).sup.+
198 ##STR00272## 426.1 199 ##STR00273## 570.2,572.1,574.2 200
##STR00274## 520.3 201 ##STR00275## 516.3 202 ##STR00276## 536.3
203 ##STR00277## 532.3 204 ##STR00278## 570.3 205 ##STR00279##
586.3 206 ##STR00280## 527.3 207 ##STR00281## 527.3 208
##STR00282## 548.3 209 ##STR00283## 545.4 210 ##STR00284## 588.5
211 ##STR00285## 546.3 212 ##STR00286## 538.3 213 ##STR00287##
554.3 214 ##STR00288## 538.3 215 ##STR00289## 554.3 216
##STR00290## 562.4 217 ##STR00291## 556.3 218 ##STR00292## 584.3
219 ##STR00293## 624.3 220 ##STR00294## 652.2 221 ##STR00295##
508.4 222 ##STR00296## 494.4 223 ##STR00297## 503.2 224
##STR00298## 503.3 225 ##STR00299## 503.3 226 ##STR00300## 503.3
227 ##STR00301## 508.3 228 ##STR00302## 508.3 229 ##STR00303##
542.3,544.3 230 ##STR00304## 504.3 231 ##STR00305## 504.3 232
##STR00306## 537.3,539.3 233 ##STR00307## 509.2 234 ##STR00308##
504.4 235 ##STR00309## 523.1 236 ##STR00310## 508.1 237
##STR00311## 508.1 238 ##STR00312## 506.4 239 ##STR00313## 506.3
240 ##STR00314## 506.2 241 ##STR00315## 520.3 242 ##STR00316##
520.3 243 ##STR00317## 574.1 244 ##STR00318## 612.3 245
##STR00319## 506.2 246 ##STR00320## 506.2 247 ##STR00321## 506.2
248 ##STR00322## 520.2 249 ##STR00323## 574.2 250 ##STR00324##
574.2 251 ##STR00325## 507.2 252 ##STR00326## 507.2
Example 253, 254
##STR00327##
[0521]
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)bi-
phenyl-2-yl]methyl}-4-methyl-5-[3-(methylsulfinyl)phenyl]-1,3-oxazolidin-2-
-one (EXAMPLE 253)
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl--
2-yl]methyl}-4-methyl-5-[3-(methylsulfonyl)phenyl]-1,3-oxazolidin-2-one
(EXAMPLE 254)
[0522] To a solution of
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]methyl}-4-methyl-5-[3-(methylthio)phenyl]-1,3-oxazolidin-2-one
(EXAMPLE 208) (25 mg, 0.0457 mmol) in dry dichloromethane (1.5 mL)
under N.sub.2 at 0.degree. C., was added dropwise a solution of
3-chloroperoxybenzoic acid (77%, 26 mg, 0.114 mmol) in
CH.sub.2Cl.sub.2 (0.5 mL). After addition the mixture was left to
warm to room temperature and stirred for 2 h. The reaction mixture
was quenched with saturated Na.sub.2SO.sub.3 (15 mL). The aqueous
layer was extracted with Et.sub.2O (3.times.20 mL). The combined
organic extracts were washed with saturated NaHCO.sub.3, dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. The crude material
was purified by flash chromatography (Si, 12.times.160 mm, 0-60%
EtOAc in hexanes gradient) to afford
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]methyl}-4-methyl-5-[3-(methylsulfinyl)phenyl]-1,3-oxazolidin-2-one
and
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biph-
enyl-2-yl]methyl}-4-methyl-5-[3-(methylsulfonyl)phenyl]-1,3-oxazolidin-2-o-
ne. EXAMPLE 253: LCMS calc.=564.19; found=564.3 (M+1).sup.+.
.sup.1H NMR (500 MHz, CDCl.sub.3, 1:1 mixture of atropisomers)
.delta. 7.73 (s, 0.5H); 7.66-7.52 (m, 4.5H); 7.42 (s, 0.5H); 7.40
(s, 0.5H); 7.37 (d, J=3.4 Hz, 0.5H); 7.36 (d, J=3.5 Hz, 0.5H); 7.02
(d, J=8.4 Hz, 0.5H); 6.99 (d, J=8.4 Hz, 0.5H); 6.71 (d, J=3.1 Hz,
0.5H); 6.69 (d, J=2.9 Hz, 0.5H); 5.59 (d, J=5.9 Hz, 0.5H); 5.57 (d,
J=5.9 Hz, 0.5H); 5.42 (t, J=8.4 Hz, 1H); 4.85 (d, J=3.4 Hz, 0.5H);
4.82 (d, J=3.4 Hz, 0.5H); 4.80 (d, J=7.8 Hz, 0.5H); 4.77 (d, J=7.7
Hz, 0.5H); 4.16 (d, J=15.8 Hz, 0.5H); 3.92 (d, J=15.8 Hz, 0.5H);
3.76 (s, 3H); 3.85-3.72 (m, 1H); 3.26-3.19 (m, 1H); 2.73 (d, J=4.7
Hz, 3H); 1.30-1.26 (m, 4.5H); 1.20 (d, J=6.9 Hz, 1.5H); 0.55 (d,
J=6.7 Hz, 0.75H); 0.52 (d, J=6.7 Hz, 0.75H); 0.41 (d, J=4.0 Hz,
0.75H); 0.39 (d, J=4.1 Hz, 0.75H). EXAMPLE 254: LCMS calc.=580.17;
found=580.3 (M+1).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3, 1:1
mixture of atropisomers) .delta. 7.95 (s, 0.5H); 7.94 (s, 0.5H);
7.81 (s, 0.5H); 7.80 (s, 0.5H); 7.73 (s, 0.5H); 7.65-7.58 (m, 3H);
7.57 (s, 0.5H); 7.38 (d, J=3.5 Hz, 0.5H); 7.36 (d, J=3.8 Hz, 0.5H);
7.02 (d, J=8.4 Hz, 0.5H); 6.99 (d, J=8.4 Hz, 0.5H); 6.72 (s, 0.5H);
6.69 (s, 0.5H); 5.58 (d, J=8.1 Hz, 0.5H); 5.42 (d, J=8.0 Hz, 0.5H);
4.86 (d, J=15.9 Hz, 0.5H); 4.81 (d, J=15.9 Hz, 0.5H); 4.17 (d,
J=15.8 Hz, 0.5H); 3.91 (d, J=15.8 Hz, 0.5H); 3.81-3.75 (m, 1H);
3.78 (s, 3H); 3.27-3.19 (m, 1H); 3.07 (s, 3H); 1.30-1.26 (m, 4.5H);
1.21 (t, J=8.7 Hz, 1.5H); 0.53 (d, J=6.5 Hz, 1.5H); 0.39 (d, J=6.5
Hz, 1.5H).
Example 255
##STR00328##
[0523]
3-((4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl-
)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde
[0524] The solution of
(4S,5R)-5-[3-(1,3-dioxan-2-yl)phenyl]-3-{[4'-fluoro-5'-isopropyl-2'-metho-
xy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
(EXAMPLE 210) (380 mg, 0.647 mmol) in THF and 1N HCl (3:1) (4 mL)
was stirred at room temperature for 2 h. The reaction mixture was
diluted with EtOAc and washed with NaHCO.sub.3 and brine. The
organic layer was dried and concentrated in vacuo. The crude
material was purified by flash chromatography (Si) to provide
3-((4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphe-
nyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde.
LCMS calc.=530.19; found=530.4 (M+1).sup.+. .sup.1H NMR (500 MHz,
CDCl.sub.3, 1:1 mixture of atropisomers) .delta. 10.03 (s, 1H);
7.88 (s, 0.5H); 7.87 (s, 0.5H); 7.77-7.52 (m, 5H); 7.37 (d, J=3.5
Hz, 0.5H); 7.36 (d, J=3.4 Hz, 0.5H); 7.02 (d, J=8.4 Hz, 0.5H); 6.99
(d, J=8.4 Hz, 0.5H); 6.71 (d, J=3.5 Hz, 0.5H); 6.69 (d, J=3.4 Hz,
0.5H); 4.17 (d, J=15.8 Hz, 0.5H); 6.98 (d, J=15.8 Hz, 0.5H); 3.78
(s, 3H); 3.85-3.71 (m, 1H); 3.26-3.19 (m, 1H); 1.30-1.26 (m, 4.5H);
1.19 (d, J=6.9 Hz, 1.5H); 0.53 (d, J=6.6 Hz, 1.5H); 0.40 (d, J=6.6
Hz, 1.5H).
Example 256
##STR00329##
[0525]
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)bi-
phenyl-2-yl]methyl}-5-[3-(hydroxy)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-
-(trifluoromethyl)biphenyl-2-yl]methyl}-5-[3-(hydroxy
[0526] To a solution of
3-((4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphe-
nyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde
(12 mg, 0.023 mmol) in anhydrous EtOH (1 .mu.L) at 0.degree. C.
under N.sub.2, was added NaBH.sub.4 (4.5 mg, 0.119 mmol) as a
powder. The solution was warmed to room temperature and stirred for
1 h. The mixture was quenched with 2% HOAc and diluted with water.
The aqueous layer was extracted with EtOAc (3.times.10 mL). The
combined organic extracts were washed with saturated NaHCO.sub.3
(12 mL) and brine (12 mL), dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. The crude material was purified by flash
chromatography to yield
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]methyl}-5-[3-(hydroxy)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trif-
luoromethyl)biphenyl-2-yl]methyl}-5-[3-(hydroxy. LCMS calc.=532.0;
found=532.4 (M+1).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3, 1:1
mixture of atropisomers) .delta. 7.73 (s, 0.5H); 7.67 (s, 0.5H);
7.64 (s, 0.5H); 7.62 (s, 0.5H); 7.42-7.32 (m, 3H); 7.24 (s, 1H);
7.15 (s, 0.5H); 7.14 (s, 0.5H); 7.01 (d, J=8.4 Hz, 0.5H); 6.98 (d,
J=8.5 Hz, 0.5H); 6.71 (s, 0.5H); 6.68 (s, 0.5H); 5.51 (d, J=8.1 Hz,
0.5H); 5.37 (d, J=8.0 Hz, 0.5H); 4.81 (d, J=15.9 Hz, 0.5H); 4.74
(d, J=16 Hz, 0.5H); 4.73 (s, 2H); 4.15 (d, J=15.9 Hz, 1H); 3.92 (d,
J=15.9 Hz, 1H); 3.77 (s, 3.0H); 3.79-3.74 (m, 0.5H); 3.74-3.68 (m,
0.5H); 3.25-3.18 (m, 1H); 1.29-1.25 (m, 4.5H); 1.19 (d, J=6.9 Hz,
1.5H); 0.53 (d, J=6.4 Hz, 1.5H); 0.40 (d, J=6.4 Hz, 1.5H).
Example 257
##STR00330##
[0527]
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)bi-
phenyl-2-yl]methyl}-5-[3-(1-hydro)-xyethyl)phenyl]-4-methyl-1,3-oxazolidin-
-2-one
[0528] To a solution of
3-((4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphe-
nyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde
(11 mg, 0.021 mmol) in THF (1 mL) at -78.degree. C. under N.sub.2,
was added methylmagnesium bromide (30 .mu.L of a 3.0 M solution in
Et.sub.2O). The mixture was stirred at -78.degree. C. for 2 h. The
mixture was quenched with saturated NH.sub.4Cl (10 mL). The aqueous
layer was extracted with EtOAc (3.times.10 mL). The combined
organic layers were washed with brine (15 mL), dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to give the crude
product. This was purified by flash chromatography (Si) to afford
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]methyl}-5-[3-(1-hydro)-xyethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one-
. LCMS calc.=546.22; found=546.4 (M+1).sup.+. .sup.1H NMR (500 MHz,
CDCl.sub.3, 1:1 mixture of atropisomers) .delta. 7.74 (s, 0.5H);
7.67 (s, 0.5H); 7.64 (s, 0.5H); 7.63 (s, 0.5H); 7.36 (m, 3H); 7.24
(s, 1H); 7.15 (s, 0.5H); 7.14 (s, 0.5H); 7.01 (d, J=8.5 Hz, 0.5H);
6.99 (d, J=8.5 Hz, 0.5H); 6.71 (s, 0.5H); 6.68 (s, 0.5H); 5.52 (d,
J=8.0 Hz, 0.5H); 5.36 (d, J=7.9 Hz, 0.5H); 4.92 (q, J=6.4 Hz, 1H);
4.83 (d, J=15.7, 0.5H); 4.77 (d, J=16.0, 0.5H); 4.16 (d, J=15.5 Hz,
0.5H); 3.92 (d, J=15.5 Hz, 0.5H); 3.77 (d, J=7.1 Hz, 3H); 3.81-3.68
(m, 1H); 3.25-3.18 (m, 1H); 1.64 (br, s, 1H); 1.49 (d, J=6.4 Hz,
3H); 1.30-1.26 (m, 4.5H); 1.19 (d, J=6.9 Hz, 1.5H); 0.53 (d, J=6.5
Hz, 1.5H); 0.40 (d, J=6.5 Hz, 1.5H).
[0529] Following the general procedures outlined above, the
compounds in Table 9 were prepared:
TABLE-US-00009 TABLE 9 ##STR00331## LCMS Example R (M + 1).sup.+
258 Et 560.4 259 n-Pr 574.4
Example 260
##STR00332##
[0530]
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)bi-
phenyl-2-yl]methyl}-4-methyl-5-{3-[(methylamino)methyl]phenyl}-1,3-oxazoli-
din-2-one
[0531] To a solution of
3-((4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphe-
nyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde
(15 mg, 0.028 mmol) in 1,2-dichloroethane (1 mL) was added
methylamine (1 mL of a 2.0 M solution in THF). The resulting
mixture was treated with sodium triacetoxyborohydride (34.8 mg,
0.16 mmol) and AcOH (0.05 mL). The mixture was stirred under
N.sub.2 at room temperature for 5 days. The reaction mixture was
quenched with 1N NaOH and the aqueous layer was extracted with
ether (3.times.15 mL). The ether extracts were washed with brine,
dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The residue was
purified by flash chromatography (Si) to afford
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]methyl}-4-methyl-5-{3-[(methylamino)methyl]phenyl}-1,3-oxazolidin-2--
one. LCMS calc.=545.23; found=545.4 (M+1).sup.+. .sup.1H NMR (500
MHz, CDCl.sub.3, 1:1 mixture of atropisomers) .delta. 7.74 (s,
0.5H); 7.67 (s, 0.5H); 7.64 (s, 0.5H); 7.62 (s, 0.5H); 7.33 (m,
3H); 7.20 (s, 1H); 7.13 (s, 0.5H); 7.12 (s, 0.5H); 7.01 (d, J=8.4
Hz, 0.5H); 6.98 (d, J=8.5 Hz, 0.5H); 6.71 (d, J=2.9 Hz, 0.5H); 6.68
(d, J=2.8 Hz, 0.5H); 5.51 (d, J=8.1 Hz, 0.5H); 5.37 (d, J=8.0 Hz,
0.5H); 4.82 (d, J=15.9 Hz, 0.5H); 4.75 (d, J=15.9 Hz, 0.5H); 4.16
(d, J=15.9 Hz, 0.5H); 3.92 (d, J=15.9 Hz, 0.5H); 3.77 (m, 5.5H);
3.70 (t, J=6.6 Hz, 0.5H); 3.25-3.18 (m, 1H); 2.45 (s, 3H); 1.93
(br, s, 1H); 1.27 (m, 4.5H); 1.19 (d, J=6.9 Hz, 1.5H); 0.53 (d,
J=6.5 Hz, 1.5H); 0.40 (d, J=6.5 Hz, 1.5H).
Example 261
##STR00333##
[0532]
(4S,5R)-5-{3-[(dimethylamino)methyl]phenyl}-3-{[4'-fluoro-5'-isopro-
pyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazo-
lidin-2-one
[0533] To a solution of
3-((4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphe-
nyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde
(15 mg, 0.028 mmol) in EtOH (1 mL) was added dimethylamine (140
.mu.L of a 2.0 M solution in MeOH) and titanium isopropoxide (79
.mu.L, 0.28 mmol). The resulting white suspension was stirred
overnight. Sodium borohydride (7.1 mg, 0.188 mmol) was added and
the mixture was stirred overnight. The reaction was quenched by
pouring the mixture into 2N aqueous ammonia (2 mL). The resulting
inorganic precipitate was filtered and washed with dichloromethane.
The combined filtrates were extracted with dichloromethane
(2.times.15 mL). The extracts were dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. The residue was purified by flash
chromatography (Si) to give
(4S,5R)-5-{3-[(dimethylamino)methyl]phenyl}-3-{[4'-fluoro-5'-isopropyl-2'-
-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin--
2-one. LCMS calc.=559.25; found=559.4 (M+1).sup.+. .sup.1H NMR (500
MHz, CDCl.sub.3, 1:1 mixture of atropisomers) .delta. 7.74 (s,
0.5H); 7.67 (s, 0.5H); 7.64 (s, 0.5H); 7.62 (s, 0.5H); 7.37-7.29
(m, 3H); 7.18 (s, 1H); 7.16 (s, 0.5H); 7.13 (s, 0.5H); 7.01 (d,
J=8.4 Hz, 0.5H); 6.99 (d, J=8.5 Hz, 0.5H); 6.71 (d, J=3.0 Hz,
0.5H); 6.68 (d, J=2.9 Hz, 0.5H); 5.52 (d, J=8.1 Hz, 0.5H); 5.37 (d,
J=8.0 Hz, 0.5H); 4.82 (d, J=15.9 Hz, 0.5H); 4.77 (d, J=16.0 Hz,
0.5H); 4.15 (d, J=16.0 Hz, 0.5H); 3.91 (d, J=15.9 Hz, 0.5H); 3.76
(s, 3H); 3.80-3.73 (m, 0.5H); 3.72-3.68 (m, 0.5H); 3.43 (s, 2H);
3.25-3.18 (m, 1H); 2.23 (s, 6H); 1.27 (m, 4.5H); 1.19 (d, J=6.9 Hz,
1.5H); 0.53 (d, J=6.5 Hz, 1.5H); 0.39 (d, J=6.6 Hz, 1.5H).
Example 262
##STR00334##
[0534]
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)bi-
phenyl-2-yl]methyl}-5-(1H-imidazol-2-yl)-4-methyl-1,3-oxazolidin-2-one
[0535] A mixture of
(4S,5S)-5-{1-[(benzyloxy)methyl]-1H-imidazol-2-yl}-3-{[4'-fluoro-5'-isopr-
opyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxaz-
olidin-2-one (EXAMPLE 244) (16.9 mg, 0.028 mmol), 20% palladium
hydroxide on carbon (8.3 mg) and 1N HCl (28 uL) in MeOH (1 mL) was
stirred under hydrogen (balloon) overnight, after which time it was
filtered through Celite and concentrated in vacuo. The crude
material was purified by flash chromatography to afford
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]methyl}-5-(1H-imidazol-2-yl)-4-methyl-1,3-oxazolidin-2-one.
LCMS calc.=492.18; found=492.2 (M+1).sup.+. .sup.1H NMR (500 MHz,
CDCl.sub.3, 1:1 mixture of atropisomers) .delta. 7.71 (s, 0.5H);
7.67 (s, 0.5H); 7.65 (s, 0.5H); 7.64 (s, 0.5H); 7.37 (d, J=3.2 Hz,
0.5H); 7.35 (d, J=3.3 Hz, 0.5H); 7.09 (d, 2H); 7.02 (d, J=8.4 Hz,
0.5H); 6.99 (d, J=8.5 Hz, 0.5H); 6.72 (d, J=4.3 Hz, 0.5H); 6.69 (d,
J=4.2 Hz, 0.5H); 5.76 (d, J=8.3 Hz, 0.5H); 5.64 (d, J=8.7 Hz,
0.5H); 4.72 (d, J=15.8 Hz, 0.5H); 4.68 (d, J=15.8 Hz, 0.5H); 4.20
(d, J=15.7 Hz, 0.5H); 4.01 (d, J=15.7 Hz, 0.5H); 3.90 (br, s, 1H);
3.79-3.72 (m, 4H); 3.25-3.18 (m, 1H); 1.28-1.22 (m, 6H); 0.67 (d,
J=6.5 Hz, 1.5H); 0.59 (d, J=6.5 Hz, 1.5H).
Example 263
##STR00335##
[0536]
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)bi-
phenyl-2-yl]methyl}-4-methyl-5-(1-oxidopyridin-4-yl)-1,3-oxazolidin-2-one
[0537] m-Chlorobenzoic acid (77%, 47.9 mg, 0.214 mmol) was added to
a solution of
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]methyl}-4-methyl-5-pyridin-4-yl-1,3-oxazolidin-2-one (53.7,
0.107 mmol) in dry CH.sub.2Cl.sub.2 (10.8 mL) at 0.degree. C. After
15 min at 0.degree. C., the reaction was stirred at room
temperature for 3 h. The reaction was diluted with CH.sub.2Cl.sub.2
(40 mL) and washed with saturated Na.sub.2SO.sub.3 (20 mL) and
saturated K.sub.2CO.sub.3 (2.times.20 mL). The organic layer was
dried (Na.sub.2SO.sub.4) and concentrated in vacuo to afford
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]methyl}-4-methyl-5-(1-oxidopyridin-4-yl)-1,3-oxazolidin-2-one
as an oil. LCMS calc.=519.2; found=519.3 (M+1).sup.+.
Example 264
##STR00336##
[0538]
4-((4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl-
)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)pyridine-2-carbo-
nitrile
[0539] Trimethylsilyl cyanide (39.9 mg, 54 .mu.L, 0.402 mmol) was
added to a stirred solution of
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]methyl}-4-methyl-5-(1-oxidopyridin-4-yl)-1,3-oxazolidin-2-one
(37.9 mg, 0.0732 mmol) in dry CH.sub.2Cl.sub.2 (2 mL) at room
temperature under N.sub.2. The reaction was stirred for 5 min and
benzoyl chloride (20.5 mg, 17 .mu.L, 0.146 mmol) was added. The
reaction was stirred at room temperature overnight. 50% Saturated
K.sub.2CO.sub.3 (10 mL) was added and the mixture was diluted with
CH.sub.2Cl.sub.2 (20 mL). The aqueous layer was separated and
extracted with CH.sub.2Cl.sub.2 (2.times.10 mL). The combined
organic extracts were dried (K.sub.2CO.sub.3) and concentrated in
vacuo to give the crude product. This was purified by flash
chromatography (Si, 12.times.160 mm, 0-70% EtOAc in hexanes
gradient) to afford the product (11.6 mg, 30%), as a colorless oil.
This was resolved into its enantiomers by chiral HPLC (AD column,
20.times.250 mm, 10% i-PrOH in heptane) to give
4-((4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphe-
nyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)pyridine-2-carbonitril-
e and
4-((4R,5S)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)-
biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)pyridine-2-carbon-
itrile. R.sub.f=0.72 (50% EtOAc in hexanes). LCMS calc.=528.2;
found=528.3 (M+1).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3, 1:1
mixture of atropisomers) .delta. 8.73 (s, 1H), 7.67-7.59 (m, 2H),
7.55 (d, J=3.3 Hz, 1H), 7.40 (d, J=4.2 Hz, 1H), 7.35 (dd, J=7.8,
3.3 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.69
(d, J=3.1 Hz, 1H), 6.67 (d, J=3.1 Hz, 1H), 5.47 (d, J=8.1 Hz,
0.5H), 5.30 (d, J=8.1 Hz, 0.5H), 4.81 (t, J=15.1 Hz, 1H), 4.11 (d,
J=15.8 Hz, 0.5H), 3.89 (d, J=15.8 Hz, 0.5H), 3.83-3.73 (m, 1H),
3.76 (s, 3H), 3.24-3.16 (m, 1H), 1.27-1.17 (m, 6H), 0.54 (d, J=6.5
Hz, 1.5H), 0.39 (d, J=6.5 Hz, 1.5H).
Example 265
##STR00337##
[0540]
(4S,5R)-5-(2-chloropyridin-4-yl)-3-{[4'-fluoro-5'-isopropyl-2'-meth-
oxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
[0541] A solution of
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]methyl}-4-methyl-5-(1-oxidopyridin-4-yl)-1,3-oxazolidin-2-one
(53.7 mg, 0.104 mmol) in phosphorous oxychloride (4 mL) was heated
at reflux under N.sub.2 for 2 h. The reaction mixture was cooled to
room temperature, concentrated in vacuo, diluted with EtOAc (20 mL)
and water (5 mL), then washed with saturated NaHCO.sub.3 (10 mL).
The aqueous layer was extracted with EtOAc (2.times.20 mL). The
combined organic layers were dried (Na.sub.2SO.sub.4) and
concentrated in vacuo to give the crude product. This was purified
by flash chromatography (Si, 12.times.160 mm, 0-70% EtOAc in
hexanes gradient) to afford the product as a colorless oil. This
was resolved into its enantiomers by chiral HPLC (AD column,
20.times.250 mm, 5% i-PrOH in heptane) to afford
(4S,5R)-5-(2-chloropyridin-4-yl)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4--
(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one.
R.sub.f=0.17 (20% EtOAc in hexanes). LCMS calc.=537.2; found=537.3
(M+1).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3, 1:1 mixture of
atropisomers) .delta. 8.40 (br s, 1H), 7.70 (s, 0.5H), 7.63 (s,
1.5H), 7.37 (m, 1H), 7.24 (br s, 1H), 7.10 (br s, 1H), 7.01 (d,
J=8.2 Hz, 0.5H), 6.98 (d, J=8.2 Hz, 0.5H), 6.72-6.68 (m, 1H), 5.44
(d, J=8.1 Hz, 0.5H), 5.29 (d, J=8.1 Hz, 0.5H), 4.81 (t, J=16.9 Hz,
1H), 4.14 (d, J=15.9 Hz, 0.5H), 3.91 (d, J=15.9 Hz, 0.5H),
3.81-3.71 (m, 1H), 3.76 (s, 3H), 3.27-3.19 (m, 1H), 1.29-1.19 (m,
6H), 0.58 (d, J=6.5 Hz, 1.55H), 0.44 (d, J=6.5 Hz, 1.55H).
Example 266
##STR00338##
[0542]
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)bi-
phenyl-2-yl]methyl}-4-methyl-5-(2-methylpyridin-4-yl)-1,3-oxazolidin-2-one
[0543] A solution of
(4S,5R)-5-(2-chloropyridin-4-yl)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4--
(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
(20.9 mg, 0.0389 mmol), trimethylboroxine (14.7 mg, 16 .mu.L, 0.116
mmol), Cs.sub.2CO.sub.3 (38.0 mg, 0.117 mmol) and
(Ph.sub.3P).sub.4Pd (9.0 mg, 0.00778 mmol) in dry 1,4-dioxane (1
mL) was heated at reflux overnight. The reaction mixture was
filtered through a plug of Celite and washed with EtOAc. The
filtrate was concentrated in vacuo to afford the crude product.
This was purified by flash chromatography (Si, 12.times.160 mm,
0-70% EtOAc in hexanes gradient) to afford the product as a
colorless oil. This was resolved into its enantiomers by chiral
HPLC (AD column, 20.times.250 mm, 10% i-PrOH in heptane) to afford
(4S,5R)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]methyl}-4-methyl-5-(2-methylpyridin-4-yl)-1,3-oxazolidin-2-one
and
(4R,5S)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]methyl}-4-methyl-5-(2-methylpyridin-4-yl)-1,3-oxazolidin-2-one.
R.sub.f=0.22 (50% EtOAc in hexanes). LCMS calc.=517.2; found=517.1
(M+1).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3, 1:1 mixture of
atropisomers) .delta. 8.48 (d, J=4.9 Hz, 1H), 7.69 (s, 0.5H), 7.61
(s, 1H), 7.60 (s, 0.5H), 7.33 (m, 1H), 7.05 (s, 1H), 6.99-6.93 (m,
2H), 6.69 (d, J=3.2 Hz, 1H), 6.66 (d, J=3.2 Hz, 1H), 5.40 (d, J=8.1
Hz, 0.5H), 5.24 (d, J=8.1 Hz, 0.5H), 4.79 (d, J=15.9 Hz, 0.5H),
4.74 (d, J=15.9 Hz, 0.5H), 4.13 (d, J=15.9 Hz, 0.5H), 3.89 (d,
J=15.9 Hz, 0.5H), 3.78-3.66 (m, 1H), 3.75 (s, 3H), 3.23-3.17 (m,
1H), 2.56 (s, 3H), 1.25-1.17 (m, 6H), 0.53 (d, J=6.5 Hz, 1.5H),
0.39 (d, J=6.5 Hz, 1.5H).
[0544] Following the general procedures outlined above, the
compounds in Table 10 were prepared:
TABLE-US-00010 TABLE 10 ##STR00339## LCMS Example R (M + 1).sup.+
267 ##STR00340## 519.3 268 ##STR00341## 537.3, 539.2
[0545] Following the general procedures outlined above, the
compounds in Table 11 were prepared:
TABLE-US-00011 TABLE 11 ##STR00342## LCMS Example R A.sup.3 (M +
1).sup.+ 269 ##STR00343## ##STR00344## 546.1, 548.1,550.1 270
##STR00345## ##STR00346## 548.1, 550.1,552.1, 554.1 271
##STR00347## ##STR00348## 514.2, 516.2 272 ##STR00349##
##STR00350## 516.2, 518.1,520.2
[0546] Following the general procedures outlined above, the
compounds in Table 12 were prepared:
TABLE-US-00012 TABLE 12 ##STR00351## LCMS Example R (M + 1).sup.+
273 ##STR00352## 518.2 274 ##STR00353## 572.2 275 ##STR00354##
492.1 276 ##STR00355## 506.2 277 ##STR00356## 495.0, 497.0 278
##STR00357## 502.0, 504.0,506.1 279 ##STR00358## 495.0, 497.0 280
##STR00359## 489.0, 491.0
Example 281
##STR00360##
[0547]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-2'-hydroxy-
-5'-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazol-
idin-2-one
Step A:
4-fluoro-2'-(iodomethyl)-5-isopropyl-4'-(trifluoromethyl)biphenyl--
2-ol
[0548] A solution of
[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]metha-
nol (71.5 mg, 0.209 mmol) and iodine (610 mg, 2.40 mmol) in
phenyltrimethylsilane (877 .mu.L) was heated at 110.degree. C. in a
sealed tube overnight. The reaction was cooled to room temperature,
diluted with 1N HCl (10 mL) and extracted with EtOAc (3.times.20
mL). The combined extracts were washed with 10%
Na.sub.2S.sub.2O.sub.3 (20 mL), dried (Na.sub.2SO.sub.4) and
concentrated in vacuo to give the crude product. This was purified
by flash chromatography (Si, 12.times.160 mm, 0-20% EtOAc in
hexanes gradient) to afford
4-fluoro-2'-(iodomethyl)-5-isopropyl-4'-(trifluoromethyl)biphenyl-2-ol.
R.sub.f=0.65 (20% EtOAc in hexanes). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.81 (s, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.34 (d,
J=7.9 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.69 (d, J=11.1 Hz, 1H),
4.82 (s, 1H), 4.41 (d, J=9.4 Hz, 1H), 4.23 (d, J=9.3 Hz, 1H),
3.27-3.19 (m, 1H), 1.27 (br s, 6H).
Step B:
2-{[4-fluoro-2'-(iodomethyl)-5-isopropyl-4'-(trifluoromethyl)biphe-
nyl-2-yl]oxy}tetrahydro-2H-pyran
[0549] p-Toluenesulfonic acid (2.8 mg, 0.0145 mmol) was added to a
solution of
4-fluoro-2'-(iodomethyl)-5-isopropyl-4'-(trifluoromethyl)biphenyl-2-ol
(63.4 mg, 0.145 mmol) and 3,4-dihydro-2H-pyran (60.8 mg, 66 .mu.L,
0.723 mmol) in dry CH.sub.2Cl.sub.2 (7.2 mL) at room temperature
under N.sub.2 and the reaction was stirred for 3 days. The reaction
mixture was diluted with saturated NaHCO.sub.3 (20 mL) and
extracted with CH.sub.2Cl.sub.2 (3.times.20 mL). The combined
extracts were dried (Na.sub.2SO.sub.4) and concentrated in vacuo to
give the crude product. This was purified by flash chromatography
(Si, 12.times.160 mm, 0-20% EtOAc in hexanes gradient) to afford
2-{[4-fluoro-2'-(iodomethyl)-5-isopropyl-4'-(trifluoromethyl)biphenyl-2-y-
l]oxy}tetrahydro-2H-pyran. R.sub.f=0.74 (10% EtOAc in hexanes).
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.75 (s, 1H), 7.62 (d,
J=8.3 Hz, 0.5H), 7.59 (d, J=8.3 Hz, 0.5H), 7.53 (t, J=7.3 Hz,
0.5H), 7.41 (s, 0.5H), 7.32 (d, J=7.9 Hz, 0.5H), 7.25 (d, J=7.9 Hz,
0.5H), 7.15 (t, J=9.4 Hz, 0.5H), 6.99 (d, J=12.2 Hz, 0.5H), 6.94
(d, J=12.2 Hz, 0.5H), 6.69 (d, J=11.0 Hz, 0.5H), 5.37 (s, 0.5H),
5.23 (s, 0.5H), 5.13 (s, 1H), 4.45 (d, J=9.6 Hz, 0.5H), 4.40 (d,
J=9.6 Hz, 0.5H), 4.31 (d, J=9.6 Hz, 0.5H), 4.23 (d, J=9.6 Hz, 0.5H)
3.76 (m, 0.5H), 3.66-3.54 (m, 1.5H), 3.29-3.21 (m, 1H), 1.68-1.44
(m, 4H) 1.32-1.26 (m, 6H).
Step C:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-2'-hydrox-
y-5'-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazo-
lidin-2-one
[0550] Sodium hydride (60% dispersion in mineral oil, 1.9 mg,
0.0485 mmol) was added to a stirred solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
in dry DMF (1 mL) and the reaction was stirred for 30 min, A
solution of
2-{[4-fluoro-2'-(iodomethyl)-5-isopropyl-4'-(trifluoromethyl)biphenyl-2-y-
l]oxy}tetrahydro-2H-pyran (16.9 mg, 0.324 mmol) in dry DMF (1 mL)
was added by cannula and the reaction was stirred at room
temperature overnight. The reaction was diluted with saturated
NH.sub.4Cl (10 mL) and water (5 mL) and extracted with EtOAc
(3.times.20 mL). The combined extracts were dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to give the crude
product. A solution of the crude product and p-toluenesulfonic acid
(0.6 mg, 0.00324 mmol) in MeOH (5 mL) was stirred at room
temperature overnight. The reaction mixture was concentrated in
vacuo to give the crude product. This was purified by flash
chromatography (Si, 12.times.160 mm, 0-35% EtOAc in hexanes
gradient) to afford
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-2'-hydroxy-5'-is-
opropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-
-one. R.sub.f=0.33 (20% EtOAc in hexanes). LCMS calc.=624.2;
found=624.3 (M+1).sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3, 1:1
mixture of atropisomers) .delta. 7.86 (s, 1H), 7.67 (m, 4H), 7.42
(d, J=7.1 Hz, 0.5H), 7.41 (d, J=7.1 Hz, 0.5H), 6.95 (d, J=7.3 Hz,
0.5H), 6.94 (d, J=7.3 Hz, 0.5H), 6.70 (d, J=5.6 Hz, 0.5H), 6.68 (d,
J=5.6 Hz, 0.5H), 5.66 (d, J=8.0 Hz, 0.5H), 5.36 (d, J=8.1 Hz,
0.5H), 4.93 (d, J=15.8 Hz, 0.5H), 4.88 (d, J=15.8 Hz, 0.5H), 4.18
(d, J=15.8 Hz, 0.5H), 4.00 (d, J=15.8 Hz, 0.5H), 3.87-3.83 (m,
0.5H), 3.77-3.71 (m, 0.5H), 3.22-3.14 (m, 1H), 1.77 (br s, 1H),
1.27-1.17 (m, 6H), 0.57 (d, J=6.5 Hz, 1.5H), 0.45 (d, J=6.5 Hz,
1.5H).
[0551] Following the general procedures outlined above, the
compounds in Table 13 were prepared:
TABLE-US-00013 TABLE 13 LCMS Example R (M + 1).sup.+ 282
##STR00361## 624.3
Example 283
##STR00362##
[0552]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-3'-hydroxy-
-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-
-1,3-oxazolidin-2-one
Step A:
tert-butyl{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)b-
iphenyl-2-yl]methoxy}dimethylsilane
[0553] tert-Butyldimethylsilyl chloride (0.48 g, 3.21 mmol) and
imidazole (0.50 g, 7.30 mmol) were added successively to a stirred
solution of
[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]metha-
nol (1.00 g, 2.93 mmol) in dry CH.sub.2Cl.sub.2 (13.4 mL) at room
temperature under N.sub.2 and the reaction was stirred overnight.
Water (50 mL) was added and the mixture was extracted with EtOAc
(3.times.50 mL). The combined extracts were dried (MgSO.sub.4) and
concentrated in vacuo to give the crude product. This was purified
by flash chromatography (Si, 25.times.160 mm, 1% EtOAc in hexanes)
to afford
tert-butyl{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]methoxy}dimethylsilane as a colorless oil. R.sub.f=0.16 (1%
EtOAc in hexanes). LCMS calc.=457.2; found=457.2 (M+1).sup.+.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 7.94 (s, 1H), 7.57 (d,
J=7.8 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 6.69
(d, J=12.1 Hz, 1H), 4.63 (br s, 1H), 4.50 (br s, 1H), 3.75 (s, 3H),
3.29-3.21 (m, 1H), 1.28 (d, J=6.9 Hz, 6H), 0.93 (s, 9H), 0.03 (s,
6H).
Step B:
2'-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-fluoro-5-isopropyl-2-
-methoxy-4'-(trifluoromethyl)biphenyl-3-ol
[0554] n-Butyllithium (1.6M in hexanes, 261 .mu.L, 0.417 mmol) was
added dropwise over 30-45 min with a syringe pump to a stirred
solution of
tert-butyl{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]methoxy}dimethylsilane (200 mg, 0.438 mmol) in dry THF (0.5
mL) at -78.degree. C. under N.sub.2. The reaction was stirred for a
further 2 h at -78.degree. C. after the addition to give a violet
colored solution. Trimethyl borate (43.4 mg, 47 .mu.L, 0.417 mmol)
was added dropwise and the reaction was stirred at -78.degree. C.
for 3 h. The reaction mixture was warmed to 0.degree. C. and acetic
acid (25.1 mg, 24 .mu.L, 0.626 mmol) was added quickly followed by
30% aqueous hydrogen peroxide (52 .mu.L, 0.459 mmol) dropwise. The
reaction was stirred at room temperature overnight, diluted with
water (10 mL) and extracted with Et.sub.2O (3.times.20 mL). The
combined extracts were washed with 50% saturated FeSO.sub.4 (20
mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give the
crude product. This was purified by flash chromatography (Si,
12.times.160 mm, 0-100% EtOAc in hexanes gradient) to afford
2'-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-fluoro-5-isopropyl-2-methox-
y-4'-(trifluoromethyl)biphenyl-3-ol. R.sub.f=0.32 (10% EtOAc in
hexanes). LCMS calc.=473.1; found=473.2 (M+1).sup.+. .sup.1H NMR
(600 MHz, CDCl.sub.3) .delta. 7.95 (s, 1H), 7.56 (d, J=7.8 Hz, 1H),
7.35 (d, J=7.9 Hz, 1H), 6.53 (d, J=7.8 Hz, 1H), 5.65 (s, 1H), 4.68
(br s, 1H), 4.54 (br s, 1H), 3.42 (s, 3H), 3.26-3.20 (m, 1H), 1.25
(d, J=6.9 Hz, 6H), 0.90 (s, 9H), 0.02 (s, 6H).
Step C:
4-fluoro-2'-(hydroxymethyl)-5-isopropyl-2-methoxy-4'-(trifluoromet-
hyl)biphenyl-3-ol
[0555] tert-Butylammonium fluoride (1M in THF, 179 .mu.L, 0.179
mmol) was added dropwise to a stirred solution of
2'-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-fluoro-5-isopropyl-2-methox-
y-4'-(trifluoromethyl)biphenyl-3-ol (76.8 mg, 0.163 mmol) in THF (2
mL) at 0.degree. C. and the reaction was allowed to warm to room
temperature overnight. Saturated NH.sub.4Cl (10 ml) was added and
the mixture was extracted with EtOAc (3.times.20 mL). The combined
extracts were dried (Na.sub.2SO.sub.4) and concentrated in vacuo to
give the crude product. This was purified by flash chromatography
(Si, 12.times.160 mm, 0-40% EtOAc in hexanes gradient) to afford
4-fluoro-2'-(hydroxymethyl)-5-isopropyl-2-methoxy-4'-(trifluoromethyl)bip-
henyl-3-ol. R.sub.f=0.26 (20% EtOAc in hexanes). .sup.1H NMR (600
MHz, CDCl.sub.3) .delta. 7.85 (s, 1H), 7.63 (d, J=7.9 Hz, 1H), 7.41
(d, J=8.0 Hz, 1H), 6.53 (d, J=7.7 Hz, 1H), 4.50 (br s, 1H), 4.47
(s, 1H), 3.42 (s, 3H), 3.25-3.19 (m, 1H), 1.24 (br s, 6H).
Step D:
2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethy-
l)biphenyl-3-ol
[0556] A solution of triphenylphosphine (102.8 mg, 0.392 mmol) in
dry CH.sub.2Cl.sub.2 (2 mL) was added by cannula to a stirred
solution of carbon tetrabromide (130 mg, 0.392 mmol) and
4-fluoro-2'-(hydroxymethyl)-5-isopropyl-2-methoxy-4'-(trifluoromethyl)bip-
henyl-3-ol (58.5 mg, 0.163 mmol) in dry CH.sub.2Cl.sub.2 (2 mL) at
0.degree. C. under N.sub.2 and the reaction was stirred at room
temperature overnight. The reaction mixture was concentrated in
vacuo to give the crude product. This was purified by flash
chromatography (Si, 12.times.160 mm, 0-40% EtOAc in hexanes
gradient) to afford
2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphe-
nyl-3-ol. R.sub.f=0.55 (20% EtOAc in hexanes). .sup.1H NMR (600
MHz, CDCl.sub.3) .delta. 7.84 (s, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.42
(d, J=8.0 Hz, 1H), 6.69 (d, J=7.8 Hz, 1H), 5.59 (s, 1H), 4.50 (d,
J=9.6 Hz, 1H), 4.39 (d, J=9.7 Hz, 1H), 3.47 (s, 3H), 3.29-3.23 (m,
1H), 1.27 (d, J=6.9 Hz, 6H).
Step E:
2-{[2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluorom-
ethyl)biphenyl-3-yl]oxy}tetrahydro-2H-pyran
[0557] 3,4-Dihydro-2H-pyran (51.9 mg, 56 .mu.L, 0.617 mmol) was
added to a stirred solution of p-toluenesulfonic acid (2.3 mg,
0.0123 mmol) and
2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphe-
nyl-3-ol (52.0 mg, 0.123 mmol) in dry CH.sub.2Cl.sub.2 (6.1 mL) at
room temperature under N.sub.2 and the reaction was stirred
overnight. The reaction mixture was diluted with CH.sub.2Cl.sub.2
(45 mL) and washed with saturated NaHCO.sub.3 (5 mL) and 30%
saturated Na.sub.2SO.sub.3 (5 mL), dried (Na.sub.2SO.sub.4) and
concentrated in vacuo to give the crude product. This was purified
by flash chromatography (Si, 12.times.160 mm, 0-40% EtOAc in
hexanes gradient) to afford
2-{[2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)b-
iphenyl-3-yl]oxy}tetrahydro-2H-pyran. R.sub.f=0.59 (20% EtOAc in
hexanes). .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 7.82 (s, 1H),
7.60 (d, J=7.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 6.67 (d, J=7.8 Hz,
1H), 5.77 (s, 1H), 4.97 (dd, J=4.9, 2.9 Hz, 1H), 4.49 (d, J=9.8 Hz,
1H), 4.37 (d, J=9.8 Hz, 1H), 3.89-3.87 (m, 1H), 3.61-3.49 (m, 1H),
3.46 (s, 3H), 3.27-3.21 (m, 1H), 1.89-1.83 (m, 1H), 1.78-1.70 (m,
1H) 1.64-1.48 (m, 3H), 1.26 (d, J=6.8 Hz, 6H).
Step F:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-3'-hydrox-
y-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methy-
l-1,3-oxazolidin-2-one
[0558] Sodium hydride (60% dispersion in mineral oil, 14.7 mg,
0.368 mmol) was added to a stirred solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
(57.7 mg, 0.184 mmol) in dry THF (2 mL) at room temperature. After
30 min a solution of
2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphe-
nyl-3-ol (62.0 mg, 0.123 mmol) in dry THF (2 mL) was added by
cannula and the reaction mixture was stirred overnight. Saturated
NH.sub.4Cl (10 mL) was added and the mixture was extracted with
EtOAc (3.times.20 mL). The combined extracts were dried
(Na.sub.2SO.sub.4) and concentrated in vacuo to give the crude
product. This was purified by flash chromatography (Si,
12.times.160 mm, 0-40% EtOAc in hexanes gradient) to afford
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-3'-hydroxy-5'-is-
opropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-o-
xazolidin-2-one. R.sub.f=0.25 (20% EtOAc in hexanes). LCMS
calc.=654.2; found=654.2 (M+1).sup.+. .sup.1H NMR (500 MHz,
CDCl.sub.3, 1:1 mixture of atropisomers) .delta. 7.86 (m, 1H),
7.73-7.63 (m, 4H) 7.44 (m, 1H), 6.55 (d, J=7.6 Hz, 0.5H), 6.52 (d,
J=7.7 Hz, 0.5H), 5.71 (br s, 1H), 5.60 (d, J=8.0 Hz, 0.5H), 5.54
(d, J=8.0 Hz, 0.5H), 4.87 (d, J=16.0 Hz, 0.5H), 4.72 (d, J=16.1 Hz,
0.5H), 4.23 (d, J=16.1 Hz, 0.5H), 3.98 (d, J=15.9 Hz, 0.5H),
3.93-3.85 (m, 0.5H), 3.77-3.71 (m, 0.5H), 3.51 (s, 1.5H), 3.47 (s,
1.5H), 3.25-3.17 (m, 1H), 1.26-1.18 (m, 6H), 0.58 (d, J=6.5 Hz,
1.5H), 0.38 (d, J=6.6 Hz, 1.5H).
Example 284
##STR00363##
[0559]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-2',3'-dihy-
droxy-5'-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-o-
xazolidin-2-one
[0560] Boron tribromide (17.4 mg, 6.6 .mu.L, 0.0692 mmol) was added
to a stirred solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-3'-hydroxy-5'-is-
opropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-o-
xazolidin-2-one (22.6 mg, 0.0346 mmol) in dry CH.sub.2Cl.sub.2 (1
mL) at -78.degree. C. at room temperature under N.sub.2 and the
reaction was stirred for 8 h. The reaction was diluted with water
(5 mL) and extracted with EtOAc (3.times.20 mL). The combined
extracts were dried (Na.sub.2SO.sub.4) and concentrated in vacuo to
give the crude product. This was purified by chiral HPLC (IA
column, 20.times.250 mm, 15% i-PrOH in heptane) to afford
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-2',3'-dihydroxy--
5'-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazoli-
din-2-one. R.sub.f=0.24 (20% EtOAc in hexanes). LCMS calc.=640.2;
found=640.2 (M+1).sup.+. .sup.1H NMR (600 MHz, CDCl.sub.3, 1:1
mixture of atropisomers) .delta. 7.85 (s, 1H), 7.70-7.62 (m, 4H),
7.41 (m, 1H), 6.52 (s, 0.5H), 6.51 (s, 0.5H), 6.20 (br s, 2H), 5.65
(d, J=7.9 Hz, 0.5H), 5.38 (d, J=8.0 Hz, 0.5H), 5.00 (d, J=15.5 Hz,
0.5H), 4.92 (d, J=15.6 Hz, 0.5H), 4.15 (d, J=15.5 Hz, 0.5H), 4.02
(d, J=15.6 Hz, 0.5H), 3.88 (t, J=6.7 Hz, 0.5H), 3.77 (t, J=6.7 Hz,
0.5H), 3.19-3.13 (m, 1H), 1.26-1.17 (m, 6H), 0.59 (d, J=6.1 Hz,
1.5H), 0.48 (d, J=6.2 Hz, 1.5H).
##STR00364##
Step A: 2-(2-fluoro-3,4-dimethoxyphenyl)propan-2-ol
[0561] A solution of methylmagnesium chloride (3M in THF, 1.74 mL,
5.22 mmol) was added dropwise to a stirred solution of
1-(2-fluoro-3,4-dimethoxyphenyl)ethanone (J. Chem. Soc. Perkin
Trans. 2 1994, 547-555) (646 mg, 3.26 mmol) in heptane (3.1 mL) and
THF (1.4 mL) at -20.degree. C. under N.sub.2. The reaction was
allowed to warm to room temperature and was stirred for 4 h. 50%
Saturated NH.sub.4Cl (20 mL) was added and the mixture was
extracted with EtOAc (3.times.20 mL). The combined extracts were
dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give
2-(2-fluoro-3,4-dimethoxyphenyl)propan-2-ol as a colorless oil.
LCMS calc.=197.1; found=197.1 (M-OH).sup.+.
[0562] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 7.14 (t, J=8.8 Hz,
1H), 6.61 (dd, J=8.8, 1.4 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H),
2.56-2.25 (br s, 1H), 1.58 (s, 6H).
Step B: 2-fluoro-1-isopropyl-3,4-dimethoxybenzene
[0563] A suspension of 10% palladium on carbon (69.8 mg) in a
solution of 2-(2-fluoro-3,4-dimethoxyphenyl)propan-2-ol (698 mg,
3.26 mmol) in 5N HCl (0.7 mL) and EtOH (5.6 mL) was stirred at room
temperature under H.sub.2 (15 psi) overnight. The mixture was
filtered through a plug of Celite and washed with Et.sub.6Ac
(.about.75 mL). The filtrate was washed with 50% saturated brine
(10 mL), dried (MgSO.sub.4) and concentrated in vacuo to afford
2-fluoro-1-isopropyl-3,4-dimethoxybenzene. .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 6.86 (t, J=8.3 Hz, 1H), 6.63 (dd, J=8.7, 1.5
Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.19-3.11 (m, 1H), 1.22 (d,
J=6.8 Hz, 6H).
Step C: 1-bromo-3-fluoro-2-isopropyl-4,5-dimethoxybenzene
[0564] Bromine (80.6 mg, 26 .mu.L, 0.504 mmol) was added to a
solution of 2-fluoro-1-isopropyl-3,4-dimethoxybenzene (50.0 mg,
0.252 mmol) and potassium acetate (49.5 mg, 0.504 mmol) in acetic
acid (1 mL) at room temperature and the reaction was stirred
overnight. The reaction was diluted with water (10 mL) and
saturated Na.sub.2SO.sub.3 (10 mL), then extracted with EtOAc
(3.times.20 mL). The combined extracts were washed with saturated
NaHCO.sub.3 (2.times.10 mL), dried (MgSO.sub.4) and concentrated in
vacuo to afford 1-bromo-3-fluoro-2-isopropyl-4,5-dimethoxybenzene.
.sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 6.86 (d, J=2.0 Hz, 1H),
3.87 (s, 3H), 3.81 (s, 3H), 3.43-3.34 (m, 1H), 1.31-1.29 (dd,
J=7.1, 1.4 Hz, 6H).
[0565] Following the general procedures outlined above, the
compounds in Table 14 were prepared:
TABLE-US-00014 TABLE 14 ##STR00365## LCMS Example A.sup.3 (M +
1).sup.+ 285 ##STR00366## 668.1 286 ##STR00367## 668.1 287
##STR00368## 640.1 288 ##STR00369## 640.1
Example 289
##STR00370##
[0566]
5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-(difluoromethyl)-2'-metho-
xy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one
Step A:
2'-({5-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-1,3-oxazolidin-3-yl}-
methyl)-6-methoxy-4'-(trifluoromethyl)biphenyl-3-carbaldehyde
[0567] A mixture of
5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-1-
,3-oxazolidin-2-one (Example 66, 50 mg; 0.0858 mmol),
5-formyl-2-methoxyphenyl boronic acid (46 mg; 0.257 mmol),
tetrakis(triphenylphosphine)palladium (0) (12 mg; 0.0103 mmol), and
sodium carbonate (74 mg) in benzene/ethanol/water (2.8/0.4/1.2 mL)
was heated at reflux for 60 h. The reaction was diluted with EtOAc
(30 mL) and washed successively with H.sub.2O (10 mL) and brine (10
mL), dried over MgSO.sub.4, filtered, and concentrated in vacuo.
The crude product was purified by flash silica gel chromatography
(0-50% EtOAc/hexanes gradient) to afford
2'-({5-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-1,3-oxazolidin-3-yl}methyl)-
-6-methoxy-4'-(trifluoromethyl)biphenyl-3-carbaldehyde as a yellow
oil. LCMS=592.1 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz,
mixture of atropisomers): .delta. 9.98 (s, 1H), 7.99-7.96 (m, 1H),
7.90 (s, 1H), 7.75 (s, 2H), 7.69-7.64 (m, 2 Hz), 7.53 (s, 1H),
7.41-7.38 (m, 1H), 7.17-7.14 (m, 1H), 5.37 (t, J=8.2 Hz, 1H), 4.59
(d, J=15.3 Hz, 1H), 4.37 (d, J=15.6 Hz, 1H), 3.92 (s, 3H),
3.67-3.64 (m, 1 Hz), 3.19-3.16 (m, 1H).
Step B:
5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-(difluoromethyl)-2'-meth-
oxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one
[0568] Diethylaminosulfur trifluoride (22 .mu.L, 0.1675 mmol) was
added dropwise to a stirred solution of
2'-({5-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-1,3-oxazolidin-3-yl}methyl)-
-6-methoxy-4'-(trifluoromethyl)biphenyl-3-carbaldehyde (Step A, 50
mg, 0.0838 mmol) in CH.sub.2Cl.sub.2 (1 mL) at 0.degree. C. The
reaction stirred at room temperature for 14 h. The reaction was
quenched with H.sub.2O at 0.degree. C., diluted with
CH.sub.2Cl.sub.2 (10 mL), washed with H.sub.2O (10 mL) and brine
(10 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in
vacuo. The crude product was purified by flash silica gel
chromatography (0-25% EtOAc/hexanes gradient) to afford
5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-(difluoromethyl)-2'-methoxy-4-(-
trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one as a
clear glass. LCMS=594.2 (M-19).sup.+. .sup.1H NMR (benzene-d.sub.6,
500 MHz, mixture of atropisomers): .delta. 7.64 (s, 1H), 7.38-7.36
(m, 2H), 7.30-7.26 (m, 2H), 7.14-7.11 (m, 2H), 6.85 (d, J=8 Hz,
1H), 6.45 (d, J=8.5 Hz, 1H), 6.37-6.13 (m, 1H), 4.46-4.38 (m, 2H),
3.79-3.76 (m, 1H), 3.21 (s, 3H), 2.36 (t, J=8.7 Hz, 1H), 2.05 (t,
J=8.4 Hz, 1H).
[0569] This compound was separated into its enantiomers
(5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-(difluoromethyl)-2'-methox-
y-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one and
(5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5'-(difluoromethyl)-2'-methox-
y-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one
using chiral HPLC (15% IPA/heptane, AS column).
Example 290
##STR00371##
[0570]
5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-4,5'-bis(trifluor-
omethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one
Step A: 2-iodo-1-methoxy-4-(trifluoromethyl)benzene
[0571] To a stirred solution of
2-methoxy-5-(trifluoromethyl)aniline (500 mg, 2.62 mmol) in
CH.sub.2Cl.sub.2 (10 mL) was added t-butyl nitrite (467 .mu.L, 3.93
mmol). The reaction was stirred for 5 min prior to addition of
iodine (1.3 g, 5.24 mmol), and then heated at 70.degree. C. for 2
h. The reaction was cooled, diluted with CH.sub.2Cl.sub.2 (10 mL),
washed with sat. Na.sub.2S.sub.2O.sub.3 (10 mL) and brine (10 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The crude product was purified by flash silica gel chromatography
(hexanes) to afford 2-iodo-1-methoxy-4-(trifluoromethyl)benzene as
a light yellow solid. .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.
8.05 (d, J=2 Hz, 1H), 7.61 (dd, J=8.7, 1.8 Hz, 1H), 6.89 (d, J=8.7
Hz, 1H), 3.97 (s, 3H).
Step B: [2-methoxy-5-(trifluoromethyl)phenyl]boronic acid
[0572] n-Butyl lithium (1.6M in hexanes, 456 .mu.L, 0.729 mmol) was
added dropwise to a stirred solution of
2-iodo-1-methoxy-4-(trifluoromethyl)benzene (Step A, 200 mg, 0.662
mmol) in THF (1.5 mL) at -78.degree. C. under an atmosphere of
nitrogen. The reaction stirred at -78.degree. C. for 30 min prior
to the addition of triisopropyl borate (458 .mu.L, 1.986 mmol). The
reaction stirred an additional 2 h at -78.degree. C. and was
quenched with sat. NH.sub.4Cl. The mixture was extracted with
CH.sub.2Cl.sub.2 and the organic phase was washed with NaHCO.sub.3
(15 mL) and brine (15 mL), dried (Na.sub.2SO.sub.4), filtered,
conc. in vacuo to afford
[2-methoxy-5-(trifluoromethyl)phenyl]boronic acid which was carried
on without purification.
Step C:
5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-4,5'-bis(trifluo-
romethyl)-biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one
[0573]
5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)ben-
zyl]-1,3-oxazolidin-2-one (Example 66, 100 mg; 0.171 mmol) was
treated with [2-methoxy-5-(trifluoromethyl)phenyl] boronic acid
(Step B, 113 mg; 0.514 mmol), tetrakis(triphenylphosphine)palladium
(0) (24 mg; 0.0206 mmol), and sodium carbonate (148 mg) as
described in Example 291 to afford
5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-4,5'-bis(trifluo-
romethyl)-biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one as a clear
glass. LCMS=612.1 (M-19).sup.+. .sup.1H NMR (benzene-d.sub.6, 500
MHz, mixture of atropisomers): .delta. 7.61 (s, 1H), 7.40-7.36 (m,
1H), 7.31 (s, 1H), 7.27-7.23 (m, 4H), 6.74-6.72 (m, 1H), 6.35 (d,
J=8.7 Hz, 1H), 4.42-4.32 (m, 2H), 3.70 (d, J=15.8 Hz, 1H), 3.14 (s,
3H), 2.28 (t, J=8.7 Hz, 1H), 1.98 (t, J=8.2 Hz, 1H).
[0574] This compound was separated into its enantiomers
(5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-4,5'-bis(trifluoro-
methyl)-biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one and
(5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-methoxy-4,5'-bis(trifluoro-
methyl)-biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one using chiral
HPLC (5% EtOHi/heptane, AS column).
##STR00372##
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)b-
enzyl]-4-methyl-1,3-oxazolidin-2-one
[0575]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin--
2-one (400 mg, 1.28 mmol) was treated with NaH (60% in oil, 128 mg,
3.2 mmol) and 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene
(Example 70, 466 mg, 1.28 mmol) as described in Example 66 to
afford
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)b-
enzyl]-4-methyl-1,3-oxazolidin-2-one as a white solid. LCMS=598.0
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta. 8.06 (d,
J=8.2 Hz, 1H), 7.93 (s, 1H), 7.82 (s, 2H), 7.61 (s, 1H), 7.33 (dd,
J=8.2, 1.4 Hz, 1H), 5.79 (d, J=7.8 hz, 1H), 4.91 (d, J=16 Hz, 1H),
4.40 (d, J=16 Hz, 1H), 4.16-4.06 (m, 1H), 0.83 (d, J=6.4 Hz,
3H).
Example 291
##STR00373##
[0576]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-methoxy-5-methyl-
-3-thienyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
Step A: 3,5-dibromo-2-methoxythiophene
[0577] To a stirred solution of 2-methoxythiophene (1 g, 8.76 mmol)
in CH.sub.2Cl.sub.2 (18 mL) at 0.degree. C. was added
N-bromosuccinimide (3.12 g, 17.52 mmol) slowly. The reaction was
allowed to warm to room temperature and stirred for 14 h. The
reaction was cooled in an ice bath and filtered. The filtrate was
washed with sat. NaHCO.sub.3 (2.times.25 mL). The aqueous layer was
neutralized with 1N HCl and extracted with CHCl.sub.3 (3.times.25
mL). The combined organic layers were washed with brine (25 mL),
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The
crude product was purified by flash silica gel chromatography
(hexanes) to afford 3,5-dibromo-2-methoxythiophene as a pale pink
oil. LCMS=272.9 (M.sup.+).sup.+.
Step B: 3-bromo-2-methoxy-5-methylthiophene
[0578] n-Butyl lithium (2.0M in pentane, 0.97 mL, 1.93 mmol) was
added to a stirred solution of 3,5-dibromo-2-methoxythiophene (Step
A, 500 mg, 1.84 mmol) in THF (5 mL) at -78.degree. C. under an
atmosphere of N.sub.2. The reaction stirred at -78.degree. C. for 1
h prior to addition of methyl iodide (114 .mu.L, 1.84 mmol). The
reaction was allowed to warm to room temperature and stirred for 20
h. The solvent was removed under reduced pressure and the residue
was partitioned between EtOAc (15 mL0 and H.sub.2O (15 mL). The
aqueous layer was re-extracted with ether (2.times.15 mL) and the
combined organic layers were washed with H.sub.2O (15 mL) and brine
(15 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo.
The crude product was purified by flash silica gel chromatography
(hexanes) to afford 3-bromo-2-methoxy-5-methylthiophene as a yellow
oil. .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta. 6.44 (s, 1H), 3.95
(s, 3H), 2.41 (s, 3H).
Step C: (2-methoxy-5-methyl-3-thienyl)boronic acid
[0579] A stirred mixture of 3-bromo-2-methoxy-5-methylthiophene
(Step B, 296 mg, 1.43 mmol) and triisopropyl borate (396 .mu.L,
2.15 mmol) in toluene/THF (2.3/0.6 mL) was cooled to -70.degree. C.
under an atmosphere of N.sub.2. n-Butyl lithium (2.0M in pentane,
1.07 mL, 2.15 mmol) was added dropwise via a syringe pump over 1 h.
The reaction stirred at -70.degree. C. for 40 min more and was
quenched with 2N HCl (2 mL) at -20.degree. C. The reaction was
partitioned between EtOAc (15 mL) and H.sub.2O (15 mL). The aqueous
layer was extracted with EtOAc (10 mL); the combined organic layers
were washed with brine (15 mL), dried (Na.sub.2SO.sub.4), filtered,
and concentrated in vacuo to afford
(2-methoxy-5-methyl-3-thienyl)boronic acid as a yellow oil. This
material was used without further purification.
Step D:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-methoxy-5-methy-
l-3-thienyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
[0580]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluorome-
thyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (Intermediate 21, 13 mg;
0.0219 mmol) was treated with (2-methoxy-5-methyl-3-thienyl)boronic
acid (Step C, 10.4 mg; 0.0657 mmol),
tetrakis(triphenylphosphine)palladium (0) (3 mg; 0.0026 mmol), and
sodium carbonate (20 mg) as described in Example 291 to afford
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-methoxy-5-methyl-3-thi-
enyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one as a
yellow glass. LCMS=598.2 (M+1).sup.+. .sup.1H NMR (benzene-d.sub.6,
500 MHz): .delta. 7.75 (s, 1H), 7.57 (s, 1H), 7.31-29 (m, 1H), 7.24
(s, 2H), 7.12-7.10 (m, 1H), 6.14 (s, 1H), 4.96 (d, J=16 Hz, 1H),
4.57 (d, J=8 Hz, 1H), 3.99 (d, J=15.8 Hz, 1H), 3.30 (s, 3H),
2.95-2.92 (m, 1H), 2.05 (s, 3H), -0.28 (d, J=6.7 Hz, 3H).
[0581] Following the general procedures outlined above, the
compounds in Table 15 were prepared:
TABLE-US-00015 TABLE 15 ##STR00374## LCMS Compound A.sup.3 (M +
1).sup.+ 292 ##STR00375## 608.1(M - 19).sup.+ 293 ##STR00376##
610.1(M + 1).sup.+ 294 ##STR00377## 614.2(M + 1).sup.+ 295
##STR00378## 682.1(M + 42).sup.+ 296 ##STR00379## 622.2(M +
1).sup.+ 297 ##STR00380## 584.2(M + 1).sup.+
Example 298
##STR00381##
[0582]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-2'-methoxy-
-5'-(2-methyl-1,3-dioxolan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}--
4-1,3-oxazolidin-2-one
[0583] A mixture of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)b-
enzyl]-4-methyl-1,3-oxazolidin-2-one (Intermediate 21, 7.34 g,
12.29 mol),
[4-fluoro-2-methoxy-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]boronic
acid (5.5 g, 21.48 mol), tetrakis(triphenylphosphine)palladium (0)
(1.7 g; 1.47 mol), and sodium carbonate (10 g) in
benzene/EtOH,/H.sub.2O (203/29/86 mL) was heated at reflux for 14
h. The reaction was quenched with H.sub.2O and partitioned between
EtOAc (250 mL) and H.sub.2O (75 mL). The aqueous layer was
re-extracted with EtOAc (3.times.200 mL). The combined extracts
were washed with brine (100 mL), dried (MgSO.sub.4), filtered, and
concentrated in vacuo. The crude product was purified by flash
silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-2'-methoxy-5'-(2-
-methyl-1,3-dioxolan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-1,3--
oxazolidin-2-one as an amorphous solid. LCMS=682.2 (M+1).sup.+.
.sup.1H NMR (CDCl.sub.3, 500 MHz, mixture of atropisomers): .delta.
7.86 (s, 1H), 7.71 (S, 3H), 7.65-7.61 (m, 1H), 7.37-7.34 (m, 1H),
7.32-7.28 (m, 1H), 6.75 (dd, J=12.4, 3.6 Hz, 1H), 5.58 (d, J=8.1
Hz, 1H), 4.89 (d, J=15.8 Hz, 1H), 4.08-4.04 (m, 2H), 3.91-3.76 (m,
7H), 1.73 (d, J=10.5 Hz, 3H), 0.4 (d, J=6.5 Hz, 3H).
Example 299
##STR00382##
[0584]
(4S,5R)-3-{[5'-acetyl-4'-fluoro-2'-methoxy-4-(trifluoromethyl)biphe-
nyl-2-yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidi-
n-2-one
[0585] To a stirred solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-2'-methoxy-5'-(2-
-methyl-1,3-dioxolan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-1,3--
oxazolidin-2-one (8 g, 0.0118 mol) in acetone (400 mL) was added
p-toluenesulfonic acid monohydrate (670 mg, 0.0035 mol). The
reaction stirred at room temperature for 14 h. The reaction was
partitioned between EtOAc (250 mL) and sat. NaHCO.sub.3 (250 mL).
The aqueous layer was re-extracted with EtOAc (3.times.250 mL) and
the combined organic layers were washed with brine (200 mL), dried
(MgSO.sub.4), filtered, and concentrated in vacuo. The crude
product was purified by flash silica gel chromatography (0-25%
EtOAc/hexanes gradient) to afford
(4S,5R)-3-{[5'-acetyl-4'-fluoro-2'-methoxy-4-(trifluoromethyl)biphenyl-2--
yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-on-
e as a yellow solid. LCMS=638.2 (M+1).sup.+. .sup.1H NMR
(CDCl.sub.3, 500 MHz, mixture of atropisomers): .delta. 7.87 (s,
1H), 7.81-7.79 (m, 1H), 7.74 (s, 1H), 7.70 (s, 2H), 7.59 (s, 1H),
7.39 (d, J=8 Hz, 1H), 6.80 (d, J=12.8 Hz, 1H), 5.27 (d, J=8.2 Hz,
1H), 4.97 (d, J=15.3 Hz, 1H), 4.04 (d, J=15.5 Hz, 1H), 3.94 (s,
3H), 3.72-3.66 (m, 1H), 2.67-2.64 (m, 3H), 0.62 (d, J=6.4 Hz,
3H).
Example 300
##STR00383##
[0586]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isoprop-
enyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxaz-
olidin-2-one
[0587] Methyl magnesium iodide (29 .mu.L, 0.085 mmol) was added
dropwise to a solution of
(4S,5R)-3-{[5'-acetyl-4'-fluoro-2'-methoxy-4-(trifluoromethyl)biphenyl-2--
yl]methyl}-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-on-
e (30 mg, 0.047 mmol) in diethyl ether (2 mL) at room temperature.
The reaction was carefully heated at reflux 4 h. Additional methyl
magnesium iodide (63 .mu.L, 0.19 mmol) and ether (1 mL) was added
and the reaction was refluxed for 3 h. The reaction was quenched
with sat. NH.sub.4Cl and extracted with EtOAc (3.times.25 mL). The
combined extracts were washed with brine (25 mL), dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
product was purified by flash silica gel chromatography (0-25%
EtOAc/hexanes gradient) to afford
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropenyl-2-
'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-
-2-one as a clear glass. L CMS=636.3 (M+1).sup.+. .sup.1H NMR
(benzene-d.sub.6, 500 MHz, mixture of atropisomers): .delta. 7.59
(s, 1H), 7.55 (s, 1H), 7.35 (d, J=8 Hz, 1H), 7.30-7.27 (m, 2H),
6.99-6.96 (m, 2H), 6.45 (d, J=12.9 Hz, 1H), 5.32 (d, J=16.9 Hz,
1H), 5.16-5.15 (m, 1H), 4.90 (d, J=16.3 Hz, 1H), 4.48 (d, J=7.7 Hz,
1H), 3.70 (d, J=6.4 Hz, 1H), 3.16 (s, 3H), 2.85-2.79 (m, 1H), 2.12
(s, 3H), -0.025 (d, J=6.5 Hz, 3H).
Example 301
##STR00384##
[0588]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-2'-hydroxy-
-5'-isopropenyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxaz-
olidin-2-one
[0589] To a stirred solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropenyl-2-
'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-
-2-one (Example 300, 50 mg, 0.078 mmol) in DMF (450 .mu.L) was
added lithium chloride (13.4 mg, 0.315 mmol). The vial was sealed
and the reaction was heated at 160.degree. C. for 14 h. 10% NaOH
(10 mL) was added and the resultant solution was extracted with
ether (3.times.10 mL). The aqueous layer was acidified to
pH.about.3 with 3N HCl and was re-extracted with ether (3.times.25
mL). The combined organic extracts were washed with brine (25 mL),
dried (MgSO.sub.4), filtered, and concentrated in vacuo. The crude
product was purified by flash silica gel chromatography (0-25%
EtOAc/hexanes gradient) to afford
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-2'-hydroxy-5'-is-
opropenyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-
-2-one as a clear glass. LCMS=622.1 (M+1).sup.+. .sup.1H NMR
(CDCl.sub.3, 500 MHz, mixture of atropisomers): .delta. 7.90 (s,
1H), 7.76-7.70 (m, 4H), 7.48-7.45 (m, 1H), 7.11-7.07 (m, 1H), 6.75
(d, J=11.7 Hz, 1H), 5.71 (d, J=7.8 Hz, 1H), 5.59-5.56 (m, 1H),
5.25-5.21 (m, 2H), 4.81 (d, J=15.4 Hz, 1H), 4.04 (d, J=15.6 Hz,
1H), 3.97-3.92 (m, 1H), 2.13 (s, 3H), 0.58 (d, J=6.6 Hz, 3H).
Example 302
##STR00385##
[0590]
(4S)-4-benzyl-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromet-
hyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one
[0591] A stirred suspension of sodium hydride (60% in oil, 37 mg,
0.926 mmol) in THF (1 mL) was treated at 0.degree. C. with
(S)-4-benzyl-2-oxazolidinone (33 mg, 0.185 mmol) dissolved in THF
(1 mL), under an atmosphere of N.sub.2. The reaction was stirred
for 20 min and a solution of
2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphe-
nyl (Intermediate 10, 50 mg, 0.124 mmol) in THF (1 mL) was added
dropwise. The reaction was stirred at room temperature for 60 h.
The reaction was quenched with H.sub.2O (1 mL) and partitioned
between EtOAc (25 mL) and H.sub.2O (10 mL). The aqueous phase was
re-extracted with EtOAc (3.times.15 mL) and the combined organic
extracts were washed with brine (25 mL), dried (MgSO.sub.4) and
concentrated in vacuo to give the crude product. This was purified
by flash silica-gel chromatography (0-25% EtOAc/hexanes gradient)
to afford
(4S)-4-benzyl-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)bi-
phenyl-2-yl]methyl}-1,3-oxazolidin-2-one as a clear glass.
LCMS=502.3 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz, mixture
of atropisomers) .delta. 7.69-7.64 (m, 1H), 7.58 (s, 1H), 7.39-7.36
(m, 1H), 7.29-7.24 (m, 3H), 7.06 (d, J=8.5 Hz, 1H), 6.97-6.91 (m,
2H), 6.73 (d, J=11.7, 1H), 4.79 (d, J=15.8 Hz, 1H), 4.30 (d, J=15.8
Hz, 1H), 4.08-4.05 (m, 1H), 3.99-3.97 (m, 1H), 3.76 (s, 3H),
3.65-3.58 (m, 1H), 3.27-3.17 (m, 1H), 2.81 (dd, J=13.5, 4.1 Hz,
1H), 2.45-2.40 (m, 1H), 1.30-1.4 (m, 6H).
Example 303
##STR00386##
[0592]
(4S)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphe-
nyl-2-yl]methyl}-4-(4-methylbenzyl)-1,3-oxazolidin-2-one
Step A: (2S)-2-amino-3-(4-methylphenyl)propan-1-ol
[0593] A mixture of lithium aluminum hydride (254 mg, 6.696 mmol)
in THF (20 mL) was heated at reflux for 1 h, then cooled in an ice
bath. (S)-4-Methylphenylalanine (500 mg, 2.79 mmol) was added
portionwise and the resultant mixture was heated at reflux for 14
h. The excess lithium aluminum hydride was decomposed by successive
addition of H.sub.2O (1 mL), 10% aq. NaOH (10 mL) and H.sub.2O (2.5
mL). The mixture was filtered and the solid was washed with THF.
The filtrate was concentrated in vacuo and the residue was
dissolved in CHCl.sub.3 (50 mL), washed with 5% aq. NaOH (25 mL),
H.sub.2O (25 mL) and brine (25 mL), dried (MgSO.sub.4), filtered,
and concentrated in vacuo to afford
(2S)-2-amino-3-(4-methylphenyl)propan-1-ol as an off-white solid.
.sup.1H NMR (CD.sub.3OD, 500 MHz) .delta. 7.13-7.09 (m, 4H), 3.52
(dd, J=10.7, 4.6 Hz, 1H), 3.36 (dd, J=10.7, 6.9 Hz, 1H), 3.04-2.99
(m, 1H), 2.73 (dd, J=13.5, 6.2 Hz, 1H), 2.53 (dd, J=13.5, 7.7 Hz,
1H), 2.30 (s, 3H).
Step B: (4S)-4-(4-methylbenzyl)-1,3-oxazolidin-2-one
[0594] A stirred solution of
(2S)-2-amino-3-(4-methylphenyl)propan-1-ol (Step A, 460 mg, 2.79
mmol) in CH.sub.2Cl.sub.2 (20 mL) at 0.degree. C. was treated with
diisopropylethylamine (2.92 mL, 16.74 mmol) and triphosgene (414
mg, 1.39 mmol) under an atmosphere of N.sub.2. The reaction stirred
at 0.degree. C. for 3 h. The reaction was quenched with sat.
NaHCO.sub.3 (10 mL) and extracted with EtOAc (4.times.20 mL). The
combined organic layers were washed with brine (25 mL), dried
(MgSO.sub.4), filtered and concentrated in vacuo. The crude product
was purified by flash silica gel chromatography (0-70%
EtOAc/hexanes gradient) to afford
(4S)-4-(4-methylbenzyl)-1,3-oxazolidin-2-one as a white solid.
LCMS=192.2 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.
7.17 (d, J=8 Hz, 2H), 7.09 (d, J=7.7 Hz, 2H), 5.39 (br s, 1H), 4.48
(t, J=8.4 Hz, 1H), 4.37 (dd, J=8.6, 5.6 Hz, 1H), 4.11-4.06 (m, 1H),
2.86 (d, J=7.1 Hz, 2H), 2.36 (s, 3H).
Step C:
(4S)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biph-
enyl-2-yl]methyl}-4-(4-methylbenzyl)-1,3-oxazolidin-2-one
[0595] (4S)-4-(4-methylbenzyl)-1,3-oxazolidin-2-one (Step B, 14 mg,
0.074 mmol) was treated with sodium hydride (60% in oil, 6.2 mg,
0.154 mmol) and
2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)b-
iphenyl (Intermediate 10, 25 mg, 0.062 mmol) as described in
Example 305 to afford
(4S)-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)b-
iphenyl-2-yl]methyl}-4-(4-methylbenzyl)-1,3-oxazolidin-2-one as
clear gum. LCMS=516.4 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500
MHz, mixture of atropisomers) .delta. 7.65-7.60 (m, 1H), 7.53 (s,
1H), 7.35-7.32 (m, 1H), 7.06-7.20 (m, 2H), 6.82-6.75 (m, 2H), 6.69
(d, J=11.7 Hz, 1H), 4.67 (d, J=15.8 Hz, 1H), 4.06 (d, J=15.8 Hz,
1H), 4.04-4.00 (m, 1H), 3.96-3.93 (m, 1H), 3.73 (s, 3H), 3.55-3.48
(m, 1H), 3.23-3.15 (m, 1H), 2.63 (dd, J=13.5, 3.6 Hz, 1H), 2.35 (d,
J=13.5 Hz, 1H), 2.29 (s, 3H), 1.25-1.13 (m, 6H).
[0596] Following the general procedures outlined above, the
compounds in Table 16 were prepared:
TABLE-US-00016 TABLE 16 ##STR00387## LCMS Compound A.sup.2 (M +
1).sup.+ 304 ##STR00388## 516.4 305 ##STR00389## 516.4 306
##STR00390## 532.3 307 ##STR00391## 532.3 308 ##STR00392## 520.4
309 ##STR00393## 520.3 310 ##STR00394## 536.3 311 ##STR00395##
536.3 312 ##STR00396## 536.3 313 ##STR00397## 516.4 314
##STR00398## 516.4 315 ##STR00399## 516.4 316 ##STR00400##
516.4
Example 317
##STR00401##
[0597]
(4S,5S)-4-benzyl-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoro-
methyl)biphenyl-2-yl]methyl}-5-methyl-1,3-oxazolidin-2-one
Step A: tert-butyl[1(S)-1-benzyl-2-oxopropyl]carbamate
[0598] A stirred solution of
N-(tert-butoxycarbonyl)-N-methoxy-N-methyl-L-phenylalaninamide (500
mg, 1.62 mmol) in THF (3 mL) at -15.degree. C. was treated with
methyl magnesium bromide (540 .mu.L, 1.62 mmol) under an atmosphere
of N.sub.2. The reaction stirred at -15.degree. C. for 15 min prior
to dropwise addition of methyl magnesium bromide (1.08 mL, 3.24
mmol). The reaction stirred for 14 h at room temperature and was
quenched with 1N HCl (5 mL). The mixture was partitioned between
H.sub.2O (15 mL) and EtOAc (20 mL) and the aqueous layer was
re-extracted with EtOAc (2.times.20 mL). The combined organic
layers were washed with H.sub.2O (20 mL) and brine (20 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The crude
product was purified by flash silica gel chromatography to afford
tert-butyl[1(S)-1-benzyl-2-oxopropyl]carbamate as a white solid.
LCMS=164.2 (M-BOC).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.
7.34-7.26 (m, 3H), 7.18 (d, J=7.1 Hz, 2H), 5.15 (br s, 1H),
4.59-4.56 (m, 1H), 3.14-2.99 (m, 2H), 2.16 (s, 3H), 1.44 (s,
9H).
Step B: tert-butyl[1(S)-1-benzyl-2-hydroxypropyl]carbamate
[0599] A stirred solution of
tert-butyl[1(S)-1-benzyl-2-oxopropyl]carbamate (Step A, 150 mg,
0.57 mmol) in dry MeOH (5 mL) at -20.degree. C. was treated with
sodium borohydride (44.2 mg, 1.169 mmol). The reaction stirred at
-20.degree. C. for 1 h and was quenched with H.sub.2O (1 mL) and
concentrated in vacuo. The residue was dissolved in EtOAc (25 mL)
and washed sequentially with H.sub.2O (15 mL) and brine (15 mL),
dried (Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The
crude product was purified by preparatory thin-layer
chromatography, eluting with 15% acetone/hexanes to afford
tert-butyl[(1S,2R)-1-benzyl-2-hydroxypropyl]carbamate (45 mg) and
tert-butyl[(1S,2S)-1-benzyl-2-hydroxypropyl]carbamate as white
solids. tert-butyl[(1S,2R)-1-benzyl-2-hydroxypropyl]carbamate:
LCMS=166.2 (M-BOC).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.
7.34-7.31 (m, 2H), 7.26-7.23 (m, 3H), 4.81 (br s, 1H), 3.83 (dq,
J=6.4, 2.7 Hz, 1H), 3.71-3.69 (m, 1H), 2.90 (d, J=7.3 Hz, 2H), 1.43
(s, 9H), 1.22 (d, J=6.5 Hz, 3H).
tert-butyl[(1S,2S)-1-benzyl-2-hydroxypropyl]carbamate: LCMS=166.2
(M-BOC).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 7.34-7.31
(m, 2H), 7.26-7.23 (m, 3H), 4.58 (br s, 1H), 3.3.93-3.85 (m, 2H),
2.90 (dd, J=14.2, Hz, 1H), 2.82-2.73 (m, 1H), 1.40 (s, 9H), 1.25
(d, J=6.4 Hz, 3H).
Step C:
(4S,5S)-4-benzyl-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluor-
omethyl)biphenyl-2-yl]methyl}-5-methyl-1,3-oxazolidin-2-one
[0600] tert-butyl[(1S,2R)-1-benzyl-2-hydroxypropyl]carbamate (Step
B, 39 mg, 0.148 mmol) was treated with sodium hydride (60% in oil,
12 mg, 0.309 mmol) and
2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluorome-
thyl)biphenyl (Intermediate 10, 50 mg, 0.123 mmol) as described in
Example 305 to afford
(4S,5S)-4-benzyl-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl-
)biphenyl-2-yl]methyl}-5-methyl-1,3-oxazolidin-2-one as a clear
glass. LCMS=516.4 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz,
mixture of atropisomers) .delta. 7.68 (d, J=11.5 Hz, 1H), 7.66-7.63
(m, 1H), 7.39-7.36 (m, 1H), 7.28-7.23 (m, 3H), 7.07 (d, J=8.5 Hz,
1H), 6.94 (d, J=6.9 Hz, 2H), 6.73 (d, J=4.8 Hz, 1H), 4.81 (d, J=16
Hz, 1H) 4.38 (d, J=16.1 Hz, 1H), 4.28-4.23 (m, 1H), 3.78 (s, 3H),
3.29-3.17 (m, 2H), 2.81 (dd, J=13.3, 3.9 Hz, 1H), 2.38-2.28 (m,
1H), 1.29-1.13 (m, 6H), 0.98 (d, J=6.2 Hz, 3H).
Example 318
##STR00402##
[0601]
(4S,5R)-4-benzyl-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoro-
methyl)biphenyl-2-yl]methyl}-5-methyl-1,3-oxazolidin-2-one
[0602] tert-butyl[(1S,2S)-1-benzyl-2-hydroxypropyl]carbamate
(Example 317, Step B, 39 mg, 0.148 mmol) was treated with sodium
hydride (60% in oil, 12 mg, 0.309 mmol) and
2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphe-
nyl (Intermediate 10, 50 mg, 0.123 .mu.mmol) as described in
Example 305 to afford
(4S,5R)-4-benzyl-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifl-
uoromethyl)biphenyl-2-yl]methyl}-5-methyl-1,3-oxazolidin-2-one as a
clear glass. LCMS=516.4 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500
MHz, mixture of atropisomers) .delta. 7.64-759 (m, 2H), 7.33-7.30
(m, 1H), 7.28-7.21 (m, 2H), 7.16 (s, 1H), 7.00-6.91 (m, 3H), 6.67
(d, J=3 Hz, 1H), 4.70 (d, J=2.7 Hz, 1H), 4.52-4.47 (m, 1H), 3.95
(d, J=15.8 Hz, 1H), 3.70 (s, 3H), 3.68-3.62 (m, 1H), 3.24-3.18 (m,
1H), 2.72-2.53 (m, 2H), 1.28-1.21 (m, 6H), 1.19 (d, J=6.8 Hz,
3H).
Example 319
##STR00403##
[0603]
(4R)-4-benzyl-3-{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphen-
yl-2-yl]methyl}-1,3-oxazolidin-2-one
[0604] The title compound was prepared according to the procedure
described in Example 67 starting from (R)-4-benzyl-2-oxazolidinone
(49 mg, 0.27 mmol) and
2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (100 mg, 0.27
mmol) to afford the title compound as a colorless oil. R.sub.f=0.35
(15% EtOAc/hexanes). LCMS 484 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3,
500 MHz) (atropisomers present) .delta. 7.72 (br s 1H), 7.65 (br s,
1H), 7.42 (m, 1H), 7.32-7.22 (m, 3H), 7.08 (m, 1H), 6.90-6.84 (m,
3H), 4.81 (d, J=15.8 Hz, 1H), 4.35 (d, J=15.8 Hz), 4.28 (t, J=8.7
Hz, 1H), 3.96-3.92 (m, 3H), 3.78 (s, 3H), 3.62-3.52 (m, 1H),
2.94-2.86 (m, 1H), 2.82 (dd, J=9.4, 3.9 Hz, 1H), 2.42 (dd, J=9.6,
3.9 Hz), 1.26 (s, 3H), 1.10 (s, 3H).
Example 320
##STR00404##
[0606] Example 322 was prepared according to the procedure
described in Example 14 starting from
(S)-4-benzyl-5,5-dimethyl-2-oxazolidinone (10 mg, 0.05 mmol) and
2-(bromomethyl)-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl
(20 mg, 0.05 mmol) to afford the title compound as a colorless oil.
LCMS 512 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz)
(atropisomers present) .delta. 7.72 (br s 1H), 7.31 (br s, 1H),
7.12-7.02 (m, 2H), 6.85-6.82 (m, 3H), 6.45-6.35 (m, 4H), 4.61 (d,
J=15.8 Hz, 1H), 4.21 (d, J=15.8 Hz), 3.21 (s, 2H), 3.16 (s, 3H),
2.62-2.52 (m, 1H), 2.42-218 (m, 1H), 1.98 (m, 2H), 1.22 (d, J=7.1
Hz), 1.05 (d, J=7.1 Hz), 0.98 (s, 3H), 0.88 (s, 3H).
Example 321
##STR00405##
[0607]
(4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[4'-fluoro-5'-isoprop-
yl]-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-pyrrolidi-
n-2-one
Step A: ethyl 3-[3,5-bis(trifluoromethyl)phenyl]acrylate
[0608] To a suspension of NaH (60% suspension in oil, 168 mg, 4.96
mmol) in THF (3 mL) was added a solution of triethyl
phosphonoacetate (0.5 mL, 2.52 mmol) at 0.degree. C., under an
atmosphere of nitrogen. The reaction was allowed to stir for 30 min
at 0.degree. C. and 3,5-bis(trifluoromethyl)benzaldehyde (609 mg,
2.52 mmol) was added. The reaction was allowed to warm to ambient
temperature, stirred for an additional 2 h and then concentrated in
vacuo. The residue was diluted with EtOAc (20 mL), washed with
H.sub.2O, brine, dried over MgSO.sub.4, concentrated and purified
by flash chromatography with 10% EtOAc/hexanes to afford the title
compound as a white solid. LCMS 313 (M+1).sup.+.
Step B. methyl
3-[3,5-bis(trifluoromethyl)phenyl]-4-nitropentanoate
[0609] Ethyl 3-[3,5-bis(trifluoromethyl)phenyl]acrylate (170 mg,
0.54 mmol) and nitromethane (736 uL, 10.29 mmol) were treated with
a solution of tetrabutylammonium hydroxide (1.0 M solution in MeOH,
1.5 mL) and the mixture heated to reflux for 3 h, diluted with 10%
aqueous ammonium chloride (10 mL) and extracted with EtOAC
(4.times.30 mL). The combined organic extracts were washed with 10%
ammonium chloride (20 mL), dried over MgSO.sub.4, concentrated in
vacuo to give the crude product. This was purified by flash
chromatography using 10% EtOAC/hexanes to afford methyl
3-[3,5-bis(trifluoro methyl)phenyl]-4-nitropentanoate as a
colorless oil. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 7.82 (br s
1H), 7.64 (br s, 2H), 4.91 (m, 1H), 3.91 (m, 1H), 3.61 (s, 3H),
2.82 (m, 2H), 1.42 (d, J=6.7 Hz, 3H).
Step C:
4-[3,5-bis(trifluoromethyl)phenyl]-5-methylpyrollidin-2-one
[0610] A suspension of Raney Nickel (50% w/v slurry in H.sub.2O,
200 mg) was added to a solution of methyl
3-[3,5-bis(trifluoromethyl)phenyl]-4-nitropentanoate in absolute
EtOH (5 mL) and the resultant mixture was stirred at room
temperature overnight under a balloon atmosphere of H.sub.2. The
reaction mixture was filtered through a pad of Celite and the
filtrate was concentrated in vacuo to remove the EtOH. The residue
was purified by flash chromatography using 75% EtOAC/hexanes to
afford
threo-4-[3,5-bis(trifluoromethyl)phenyl]-5-methylpyrollidin-2-one
and
erythro-4-[3,5-bis(trifluoromethyl)phenyl]-5-methylpyrollidin-2-one
as white solids. erythro-diastereomer: LCMS 353 (M+1).sup.+.
.sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 7.82 (br s 1H), 7.64 (br
s, 2H), 5.72 (br s, 1H), 3.85 (m, 1H), 3.31 (dd, J=8.9, 8.2 Hz,
1H), 2.61 (dd, J=8.9, 8.2 Hz, 1H), 1.34 (d, J=6.1 Hz, 3H).
erythro-diastereomer: LCMS 353 (M+1).sup.+. .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 7.82 (br s 1H), 7.64 (br s, 2H), 5.76
(br s, 1H), 4.20 (m, 1H), 3.90 (m, 1H), 2.81 (dd, J=8.5, 8.2 Hz,
1H), 2.73 (dd, J=8.5, 8.2 Hz, 1H), 0.88 (d, J=6.7 Hz, 3H).
Step D:
(4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[4'-fluoro-5'-isopro-
pyl]-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-pyrrolid-
in-2-one
[0611] To a stirred suspension of NaH (60% in oil, 4.4 mg, 0.11
mmol) in THF (3 mL), was added a solution of
erythro-4-[3,5-bis(trifluoromethyl)phenyl]-5-methylpyrollidin-2-one
(16 mg, 0.051 mmol) in THF (1 mL) at 0.degree. C. under an
atmosphere of nitrogen. The resultant mixture was allowed to stir
for 30 min at 0.degree. C. before the addition of
2'-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphe-
nyl (16 mg, 0.051 mmol). After 3 h, the reaction was diluted with
15 mL EtOAc and 5 mL H.sub.2O. The phases were separated and the
organic phase was washed with H.sub.2O, brine, dried (MgSO.sub.4),
and concentrated. The residue was purified by flash chromatography
using 10% EtOAC/hexanes to afford the title compound as a colorless
oil. LCMS 636 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz)
(atropisomers present) .sup.1H NMR .delta. 7.82 (br s 1H), 7.80 (br
s, 1H), 7.45-7.36 (m, 3H), 7.32-7.22 (m, 3H), 7.08 (d, J=10.1 Hz,
1H), 6.60 (m, 1H), 5.05 (m, 1H), 4.01 (d, J=15.5 Hz), 3.78 (s, 3H),
3.71-3.52 (m, 2H), 3.24 (m, 1H), 1.32-1.20 (m, 6H), 0.56 (d, J=6.4
Hz, 3H). This compound was separated into its two enantiomers
(4R,5S)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[4'-fluoro-5'-isopropyl]-2'-
-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-pyrrolidin-2-on-
e and
(4S,5R)-4-[3,5-bis(trifluoromethyl)phenyl]-1-{[4'-fluoro-5'-isopropy-
l]-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-pyrrolidin-
-2-one using chiral HPLC (IA column, 20.times.250 mm, 3% i-PrOH in
heptane).
[0612] Following the general procedures outlined above, the
compounds in Table 17 were prepared:
TABLE-US-00017 TABLE 17 ##STR00406## LCMS Example R (M + 1).sup.+
322 ##STR00407## 534.2 323 ##STR00408## 534.2 324 ##STR00409##
584.2 325 ##STR00410## 568.1 326 ##STR00411## 568.1
Example 327
##STR00412##
[0613]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isoprop-
yl-2'-methoxy-6-methyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1-
,3-oxazolidin-2-one
Step A: [2,6-dimethyl-4-(trifluoromethyl)phenyl]amine
[0614] A mixture of 2,6-dibromo-4-trifluoromethyl aniline (1.00 g,
3.14 mmol), trimethylboroxine (1.16 ml, 1.04 g, 8.33 mmol),
potassium carbonate (1.15 g, 8.33 mmol) and catalytic amount (10%)
Pd(PPh.sub.3).sub.4 in DMF (5 ml) was heated to 90.degree. C. for
14 h. Water (10 ml) was added. The mixture was extracted with ethyl
acetate (3.times.20 ml). The combined EtOAc layers were washed with
brine and dried over sodium sulfate. The titled compound was
obtained as a colorless oil after a flash column using EtOAc:hexane
(1:9) as the elute. .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta. 7.28
(s, 1H), 7.22 (s, 1H), 3.88 (br s, 2H), 2.21 (s, 6H).
Step B: 2-iodo-1,3-dimethyl-5-(trifluoromethyl)benzene
[0615] A mixture of the titled compound from Step A (0.27 g, 1.43
mmol), n-pentyl nitrite (0.50 g, 2.86 mmol) and 12 (0.72 g, 2.86
mmol) in chloroform (10 ml) was refluxed for 1 h. The mixture was
diluted with methylene chloride (20 ml) and washed with saturated
sodium thiosulfate solution, and brine. The organic layer was dried
over sodium sulfate. The titled compound was obtained as a light
yellow liquid after flash column using hexane as the elute. .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 7.31 (s, 2H), 2.58 (s, 6H).
Step C:
1-(bromomethyl)-2-iodo-3-methyl-5-(trifluoromethyl)benzene
[0616] A mixture of the titled compound from Step B (0.26 g, 0.87
mmol), NBS (0.154 g, 0.87 mmol) and catalytic amount of AIBN in
CCl.sub.4 was refluxed for 6 h. TLC (hexane) showed a mixture of
starting material and a new spot. Upon addition of more AIBN the
reaction was allowed to reflux for another 2 h. No change was
observed. The reaction mixture was cooled to room temperature and
the solvent was removed. The titled compound was obtained as a
white solid along with the starting material after preparative TLC
purification using hexane as the elute. .sup.1H NMR (CDCl.sub.3,
500 MHz): .delta. 7.54 (s, 1H), 7.42 (s, 1H), 4.67 (s, 2H), 2.60
(s, 3H).
Step D.
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-3-methyl-5-(t-
rifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
[0617] To a solution of oxazolidone from Example xx, step xx,
(0.058 g, 0.186 mmol) in THF (5 ml) at 0.degree. C., NaH was added.
The mixture was stirred for 30 min at 0.degree. C. A solution of
benzyl bromide from Step C (0.064 g, 0.169 mmol) in THF (5 ml) was
added via syringe. The mixture was then allowed to stirred at room
temperature for 12 h. The reaction was quenched with saturated
ammonium chloride solution. The mixture was extracted with ethyl
acetate (3.times.15 ml). The combined EtOAc layers were washed with
brine and dried over sodium sulfate. The titled compound was
obtained after a preparative TLC plate using EtOAc:hexane=1:9 as
the elute. .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta. 7.92 (s, 1H),
7.82 (s, 2H), 7.49 (s, 1H), 7.38 (s, 1H), 5.77 (d, J=8 Hz, 1H),
4.93 (d, J=16 Hz, 1H), 4.45 (d, J=16 Hz, 1H), 4.05 (m, 1H), 2.60
(s, 3H), 0.81 (d, J=6.5 Hz, 3H).
Step E:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopro-
pyl-2'-methoxy-6-methyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl--
1,3-oxazolidin-2-one
[0618] A mixture of the titled compound from Step D (0.07 g, 0.11
mmol), 2-methoxy-4-fluoro-5-isopropyl phenyl boronic acid (0.036 g,
0.17 mmol), sodium carbonate (0.024 g, 0.23 mmol) and catalytic
amount of Pd(PPh.sub.3).sub.4 in a mixture of 2:1:4
EtOH/H.sub.2O/toluene was heated to reflux for 3 h. The solvents
were removed and the aqueous was extracted with methylene chloride
(3.times.20 ml). The combined methylene chloride layers were washed
with brine, and dried over sodium sulfate. The titled compound was
obtained after a preparative TLC plate using EtOAc:hexane=1:9 as
the elute. Two diastereomeric atropisomers of the titled compound
were separated by a chiral OD column using EtOH/n-Heptane as the
elute. Isomer A (faster elute): .sup.1H NMR (CDCl.sub.3, 500 MHz):
.delta. 7.89 (s, 1H), 7.75 (s, 2H), 7.52 (s, 2H), 6.85 (d, J=8.5
Hz, 1H), 6.71 (d, J=12 Hz, 1H), 5.63 (d, J=8 Hz, 1H), 4.71 (d, J=16
Hz, 1H), 3.93 (m, 1H), 3.87 (d, J=16 Hz, 1H), 3.72 (s, 3H), 3.22
(m, 1H), 2.09 (s, 3H), 1.26 (m, 6H), 0.53 (d, J=6.5 Hz, 3H); LC-MS
(M+1): 652.3. Isomer B (slower elute): .sup.1H NMR (CDCl.sub.3, 500
MHz): .delta. 7.89 (s, 1H), 7.73 (s, 2H), 7.53 (s, 2H), 6.90 (d,
J=8.5 Hz, 1H), 6.73 (d, J=12 Hz, 1H), 5.60 (d, J=8 Hz, 1H), 4.69
(d, J=15.5 Hz, 1H), 3.88 (m, 1H), 3.86 (d, J=15.5 Hz, 1H), 3.76 (s,
3H), 3.22 (m, 1H), 2.11 (s, 3H), 1.23 (m, 6H), 0.48 (d, J=6.5 Hz,
3H); LC-MS (M+1): 652.3.
Example 328
##STR00413##
[0619]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-chloro-4'-fluoro-5-
'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1-
,3-oxazolidin-2-one
Step A: [2-chloro-6-methyl-4-(trifluoromethyl)phenyl]amine
[0620] A mixture of 2-bromo-6-chloro-4-trifluoromethyl aniline
(1.00 g, 3.64 mmol), trimethylboroxine (0.66 ml, 0.59 g, 4.47
mmol), potassium carbonate (1.00 g, 7.30 mmol) and catalytic amount
(10%) Pd(PPh.sub.3).sub.4 in DMF (5 ml) was heated to 90.degree. C.
for 14 h. Water (20 ml) was added. The mixture was extracted with
ethyl acetate (3.times.50 ml). The combined EtOAc layers were
washed with brine and dried over sodium sulfate. The titled
compound was obtained as a colorless oil after a flash column using
EtOAc:hexane (1:9) as the elute. .sup.1H NMR (CDCl.sub.3, 500 MHz):
.delta. 7.43 (s, 1H), 7.24 (s, 1H), 4.38 (br s, 2H), 2.22 (s,
3H).
Step B [2-chloro-6-(iodomethyl)-4-(trifluoromethyl)phenyl]amine
[0621] A mixture of the titled compound from Step A (0.67 g, 3.20
mmol), n-pentyl nitrite (0.75 g, 6.41 mmol) and 12 (1.05 g, 4.17
mmol) in chloroform (10 ml) was refluxed for 1 h. The mixture was
diluted with methylene chloride (20 ml) and washed with saturated
sodium thiosulfate solution, and brine. The organic layer was dried
over sodium sulfate. 2-Iodo-3-chloro-4-trifluoromethyl benzyl
iodide were obtained as after flash column using hexane as the
elute. .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta. 7.60 (s, 2H),
4.65 (s, 2H).
Step C.
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[3-chloro-2-iodo-5-(t-
rifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one
[0622] To a solution of oxazolidone from Example xx, step xx,
(0.058 g, 0.186 mmol) in THF (5 ml) at 0.degree. C., NaH was added.
The mixture was stirred for 30 min at 0.degree. C. A solution of
2-iodo-3-chloro-4-trifluoromethyl benzyl iodide from Step B (0.226
g, 0.51 mmol) in THF (5 ml) was added via syringe. The mixture was
then allowed to stir at room temperature for 3 h. The reaction was
quenched with saturated ammonium chloride solution. The mixture was
extracted with ethyl acetate (3.times.20 ml). The combined EtOAc
layers were washed with brine and dried over sodium sulfate. The
titled compound was obtained after a flash column using
EtOAc:hexane=1:9 as the elute. LC-MS (M+1): 432.0.
Step D:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-chloro-4'-fluoro--
5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl--
1,3-oxazolidin-2-one
[0623] A mixture of the titled compound from Step C (0.10 g, 0.16
mmol), 2-methoxy-4-fluoro-5-isopropyl phenyl boronic acid (0.067 g,
0.32 mmol), sodium carbonate (0.034 g, 0.32 mmol) and catalytic
amount of Pd(PPh.sub.3).sub.4 in a mixture of 2:1:4
EtOH/H2O/toluene was heated to reflux for 4 h. The solvents were
removed and the aqueous was extracted with methylene chloride
(3.times.15 ml). The combined methylene chloride layers were washed
with brine, and dried over sodium sulfate. The titled compound was
obtained after a preparative TLC plate using EtOAc:hexane=1:9 as
the elute. Two diastereomeric atropisomers of the titled compound
were separated by a chiral AD column using i-PrOH/n-Heptane as the
elute. Isomer A (faster elute): .sup.1H NMR (CDCl.sub.3, 500 MHz):
.delta. 7.91 (s, 1H), 7.75 (s, 3H), 7.61 (s, 1H), 6.92 (d, J=8.5
Hz, 1H), 6.73 (d, J=12 Hz, 1H), 5.64 (d, J=8 Hz, 1H), 4.72 (d, J=16
Hz, 1H), 3.95 (d, J=16 Hz, 1H), 3.93 (m, 1H), 3.78 (s, 3H), 3.22
(m, 1H), 1.23 (m, 6H), 0.55 (d, J=7 Hz, 3H); LC-MS (M+1): 672.1.
Isomer B (slower elute): .sup.1H NMR (CDCl.sub.3, 500 MHz): .delta.
7.89 (s, 1H), 7.75 (s, 1H), 7.73 (s, 2H), 7.62 (s, 1H), 6.98 (d,
J=8.5 Hz, 1H), 6.74 (d, J=12 Hz, 1H), 5.61 (d, J=8.5 Hz, 1H), 4.72
(d, J=16 Hz, 1H), 3.91 (d, J=16 Hz, 1H), 3.87 (m, 1H), 3.79 (s,
3H), 3.22 (m, 1H), 1.22 (m, 6H), 0.48 (d, J=6.5 Hz, 3H); LC-MS
(M+1): 672.1.
Intermediate 22
##STR00414##
[0624]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-fluorobenzy-
l)-4-methyl-1,3-oxazolidin-2-one
[0625] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
(2.0 g, 6.39 mmol) in THF (40 mL) at 0.degree. C., NaH (285 mg, 60
w/w % in mineral oil, 7.13 mmol, 1.1 eq.) was added in one portion.
The resulting foaming mixture was stirred in an ice bath.
Additional THF (50 mL) was added into the reaction. The mixture was
stirred at 0.degree. C. for 30 min. A solution of
2-bromo-5-fluorobenzyl bromide (1.712 g, 6.39 mmol) in THF (20 mL)
was added. The resulting mixture was stirred cold for 30 min and
then allowed to warm to ambient. The reaction was completed in 3 h,
monitored by LC-MS. The reaction was quenched with saturated aq.
NH.sub.4Cl (80 mL). Volatiles were removed in vacuo. Crude mixture
was extracted with EtOAc, and dried over Na.sub.2SO.sub.4. The
resulting clear gel was purified by SiO.sub.2 (Biotage 40+M
cartridge, EtOAc/hexane, gradient). The titled compound was
obtained as a clear oil. LC-MS: 500.09 (M+1).sup.+. .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 7.88 (s, 1H), 7.79 (s, 2H), 7.55 (dd,
J=8.8, 5.2 Hz, 1H), 7.17 (dd, J=8.7, 4.5 Hz, 1H), 6.95 (m, 1H),
5.74 (d, J=8.0 Hz, 1H), 4.83 (d, J=15.8, 1H), 4.54 (d, J=16.0 Hz,
1H), 4.11 (m, 1H), 0.80 (d, J=6.6 Hz, 3H).
Example 329
##STR00415##
[0626]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4,4'-difluoro-5'-iso-
propyl-2'-methoxybiphenl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
[0627] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-fluorobenzyl)-4-m-
ethyl-1,3-oxazolidin-2-one (1.0 g, 2.0 mmol) in 1,4-dioxane (6 mL)
was added (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (509
mg, 2.4 mmol), [1,1'-bis(diphenylphosphino) ferrocene]
dichloropalladium (II) (82 mg, 5 mol %) and aq. potassium hydroxide
(1.3 mL, 3M, 2 eq.). The reaction mixture was purged with nitrogen
and then sealed in a microwave vessel. The reaction vessel was
subject to microwave irradiation at 150.degree. C. for 40 min.
Crude mixture was worked up with water. Volatiles were evaporated.
The resulting mixture was extracted with EtOAc. The combined
extracts were dried over Na.sub.2SO.sub.4. The resulting purple
residue was purified by SiO.sub.2 (Biotage 40+M cartridge, eluted
by EtOAc/hexane, gradient; 5% to 25%). The titled compound was
obtained as clear solid. LC-MS:588.23 (M+1).sup.+. .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 6:4 mixture of rotamers .delta. 7.85
(s, 1H), 7.69 (s, 2H), 7.16-7.21 (m, 1.5H), 7.04-7.13 (m, 1.5H),
6.96 (dd, J=14.3, 8.80 Hz, 1H), 6.65 (d, J=10.0 Hz, 1H), 5.59 (d,
J=8.0 Hz, 0.6H), 5.43 (d, J=8.0 Hz, 0.4H), 4.85 (d, J=15.8 Hz,
0.6H), 4.82 (d, J=15.8 Hz, 0.4H), 4.02 (d, J=15.8 Hz, 0.6H), 3.85
(m, 0.6H), 3.76-3.81 (m, 0.8H), 3.75 (s, 1.8H), 3.73 (s, 1.2H),
3.19 (m, 1H), 1.14-1.26 (m, 6H), 0.56 (d, J=6.6 Hz, 1.2H), 0.38 (d,
J=6.6 Hz, 1.8H).
Intermediate 23
##STR00416##
[0628]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-chloro-4-fluorobenz-
yl)-4-methyl-1,3-oxazolidin-2-one
[0629] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
(1.0 g, 3.19 mmol)/THF (40 mL) at 0.degree. C., was added NaH (153
mg, 60 w/w % in mineral oil, 3.83 mmol, 1.2 eq.) in one portion.
The resulting foaming mixture was stirred in an ice bath for 30
min, followed by addition of 2-chloro-4-fluorobenzyl chloride (572
mg, 3.19 mmol). The resulting mixture was stirred at 0.degree. C.
for 30 min then warmed to ambient overnight. The reaction failed to
proceed at room temperature and it was warmed in a 60.degree. C.
oil bath for 20 h. An aliquot indicated that the reaction was over.
It was quenched with aq. NH.sub.4Cl (50 mL). Volatiles were
evaporated. The resulting mixture was extracted with EtOAc. The
combined extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to a yellow oil. The oil was purified by
SiO.sub.2 (Biotage 40+M cartridge, eluted by EtOAc/hexanes,
gradient; 5% to 40%). The titled compound was obtained as a
colorless glassy material. LC-MS: 456.12 (M+1).sup.+. .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 7.89 (s, 1H), 7.77 (s, 2H), 7.46 (dd,
J=8.7, 6.0 Hz, 1H), 7.17 (dd, J=8.4, 2.5 Hz, 1H), 7.03 (m, 1H),
5.68 (d, J=8.2 Hz, 1H), 4.83 (d, J=15.6, 1H), 4.36 (d, J=15.3 Hz,
1H), 4.06 (m, 1H), 0.79 (d, J=6.4 Hz, 3H).
Example 330
##STR00417##
[0630]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4',5-difluoro-5'-iso-
propyl-2'-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
[0631] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-chloro-4-fluorobenzyl)-4--
methyl-1,3-oxazolidin-2-one (100 mg, 0.22 mmol) in 1,4-dioxane (1
mL) was added (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid
(55.8 mg, 0.26 mmol), palladium(II) acetate (10 mg, 20 mol %),
potassium hydroxide aqueous solution (147 .mu.L, 3M, 2 eq.) and
tri-tert-butylphosphine (13.4 mg, 0.066 mmol, 30 mol % as a 10% w/w
hexane solution). The resulting reaction mixture was N.sub.2 purged
and sealed in a microwave vessel. The vessel was subject to
microwave irradiation at 140.degree. C. for 40 min. LC-MS indicated
the formation of desired product. It was quenched with water (50
mL). Volatiles were evaporated. The resulting mixture was extracted
with EtOAc. The combined extracts were dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo to an oil. The titled compound
was obtained after two purifications with silica gel and one
reversed phase prep-HPLC. LC-MS:588.25 (M+1).sup.+.
##STR00418##
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-chloro-6-fluorobenzyl)-4--
methyl-1,3-oxazolidin-2-one
[0632] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
(1.0 g, 3.19 mmol) in THF (40 mL) at 0.degree. C., was added NaH
(153 mg, 60 w/w % in mineral oil, 3.83 mmol, 1.2 eq.) in one
portion. The resulting foaming mixture was stirred in an ice bath
for 30 min followed by addition of benzyl chloride (572 mg, 3.19
mmol). The resulting mixture was stirred at 0.degree. C. for 30 min
then warmed to 60.degree. C. for 30 hr. An aliquot indicated about
10% of starting
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
left. The reaction was cooled and quenched with saturated
NH.sub.4Cl (50 mL). Volatiles were evaporated. The resulting
mixture was extracted with EtOAc. The combined extracts were dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to a
yellow oil. The titled compound was obtained as a colorless glassy
material after purification by SiO.sub.2 (Biotage 40+M, eluted by
EtOAc/hex, gradient; 5% to 40%). LC-MS: 456.11 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 7.87 (s, 1H), 7.77 (s, 2H),
7.22-7.34 (m, 2H), 7.01-7.09 (m, 1H), 5.62 (d, J=8.2 Hz, 1H), 5.01
(dd, J=14.8, 2.0 Hz, 1H), 4.45 (d, J=14.6 Hz, 1H), 3.91 (m, 1H),
0.81 (d, J=6.4 Hz, 3H).
Example 331
##STR00419##
[0633]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3,4'-difluoro-5'-iso-
propyl-2'-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
[0634] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-chloro-6-fluorobenzyl)-4--
methyl-1,3-oxazolidin-2-one (327 mg, 0.72 mmol) in 1,4-dioxane (4
mL) was added (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid
(228 mg, 1.08 mmol), Palladium(II) acetate (33 mg, 20 mol %),
potassium hydroxide (588 .mu.L, 3M, 2.5 eq.) and
tri-tert-butylphosphine (44 mg, 0.22 mmol, 30 mol % as a 10% w/w
hexane solution). The resulting reaction mixture was purged with
nitrogen and sealed in a microwave vessel. The vessel was subject
to microwave irradiation at 135.degree. C. for 50 min. LC-MS
indicated the starting material/product ratio was about 55:45. The
reaction mixture was re-submitted to reaction conditions (.mu.w at
135.degree. C. for 50 min). The LC-MS trace indicated that no
progress was made from the 2.sup.nd irradiation. More palladium(II)
acetate (33 mg, 20 mol %) and tri-tert-butylphosphine (44 mg, 0.22
mmol, 30 mol % as a 10% w/w hexane solution) were added into
reaction mixture. The mixture was resubmitted to reaction
conditions (.mu.w at 135.degree. C., 1 hr). Again, the LC-MS
indicated no significant progress. The reaction mixture was
quenched with H.sub.2O. The volatiles were removed under reduced
pressure. The resulting mixture was extracted with EtOAc. The
combined extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to a yellow oil. The oil was dissolved in
DMSO and purified twice by a reversed phase prep-HPLC (column:
Kromasil, 100-5C18, 100.times.21.1 mm) eluted by 10% to 90%
H.sub.2O (0.1% TFA, v/v)/MeCN (0.1% TFA, v/v). The resulting glassy
material was then purified on a prep-TLC plate by 100%
dichloromethane to afford the titled compound. LC-MS: 588.21
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1:1 mixture
of rotamers .delta. 7.83 (s, 1H), 7.67 (s, 1H) 7.65 (s, 1H),
7.32-7.41 (m, 1H), 7.09-7.16 (m, 1H), 6.96-7.06 (m, 1H), 6.64-6.70
(m, 1H), 5.47 (d, J=8.0 Hz, 0.5H), 5.19 (d, J=7.8 Hz, 0.5H), 4.96
(d, J=14.9 Hz, 0.5H), 4.80 (d, J=15.1 Hz, 0.5H), 4.31 (d, J=15.1
Hz, 0.5H), 3.91 (d, J=15.1 Hz, 0.5H), 3.78 (s, 1.5H), 3.75 (s,
1.5H), 3.62-3.69 (m, 1H), 3.15-3.26 (m, 1 H), 1.14-1.25 (m, 6H),
0.54 (d, J=6.6 Hz, 1.5H), 0.33 (d, J=6.4 Hz, 1.5H).
Example 332
##STR00420##
[0635] Step A: 2-bromo-5-nitrophenyl)methanol
[0636] Methyl 2-bromo-5-nitrobenzoate (10 g, 38.46 mmol) was
dissolved in THF (100 mL) and cooled to internal
temperature=-15.about.-10.degree. C. To this mixture was added
diisobutylaluminum hydride solution (1.0 M in toluene, 57 mL, 57
mmol) slowly while maintaining internal temperature <0.degree.
C. The resulting mixture was stirred at ambient for 1 hour then
quenched with aq. NH.sub.4Cl (150 mL). The crude mixture was
diluted with EtOAc (100 mL) and then filtered. Volatiles were
removed under reduced pressure. The resulting residue was extracted
with EtOAc (200 mL.times.2). The combined extracts were dried over
Na.sub.2SO.sub.4, filtered and evaporated to an oil. The resulting
oil was purified by SiO.sub.2 (Biotage 65i, EtOAc/hexanes,
gradient; 10% to 15%). The titled compound was obtained as a yellow
crystalline solid. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 8.44
(d, J=2.74 Hz 1H), 8.02 (dd, J=8.7, 2.8 Hz. 1H), 7.72 (d, J=8.7,
1H), 4.83 (s, 3H).
Step B: 1-bromo-2-(bromomethyl)-4-nitrobenzene
[0637] To a solution of 2-bromo-5-nitrophenyl)methanol (4.746 g,
20.45 mmol) in anhydrous dichloromethane (150 mL), was added
triphenylphosphine (6.43 g, 24.5 mmol) and carbon tetrabromide
(8.15 g, 24.5 mmol). The mixture was stirred at 0.degree. C. for 30
min then at 20.degree. C. for 1 h. TLC showed complete consumption
of starting material. Volatiles were removed under reduced
pressure. The resulting oil was purified by SiO.sub.2 (Biotage 40M,
eluted by EtOAc/hexanes, gradient) to afford the titled compound as
a colorless solid. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 8.33
(d, J=2.74 Hz 1H), 8.03 (dd, J=8.7, 2.5 Hz. 1H), 7.78 (d, J=8.7,
1H), 4.63 (s, 3H).
Step C:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzy-
l)-4-methyl-1,3-oxazolidin-2-one
[0638] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
(5.3 g, 16.95 mmol) in THF (100 mL) at 0.degree. C., NaH (746 mg,
60 w/w % in mineral oil, 18.65 mmol, 1.1 eq.) was added in one
portion. The resulting foaming mixture was stirred in an ice bath.
Additional THF (100 mL) was added into the reaction. The mixture
was stirred at 0.degree. C. for 30 min. A solution of
1-bromo-2-(bromomethyl)-4-nitrobenzene (5.0 g, 16.95 mmol) in THF
(25 mL) was added. The resulting mixture was stirred cold for 30
min and then allowed to warn to ambient. The reaction was completed
in 1.5 h. The reaction was quenched with sat. aqueous NH.sub.4Cl
(100 mL). Crude mixture was extracted with EtOAc, and dried over
Na.sub.2SO.sub.4. The resulting clear gel was purified by SiO.sub.2
(Biotage 40M cartridge, EtOAc/hexane, gradient, 25% to 45%). The
titled compound was obtained as a crystalline solid. LC-MS: 529.11
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 8.24 (d,
J=2.5 Hz, 1H), 8.07 (dd, J=8.7, 2.8 Hz, 1H), 7.91 (s, 1H),
7.79-7.83 (m, 3H), 5.82 (d, J=7.8 Hz, 1H), 4.82 (d, J=16.2 Hz, 1H),
4.44 (d, J=16.3, 1H), 4.11-4.20 (m, 1H), 0.84 (d, J=6.6 Hz,
3H).
Step D:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4'-fluoro-5'-isopro-
pyl-2'-methoxy-4
nitrobiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
[0639] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzyl)-4-me-
thyl-1,3-oxazolidin-2-one (3.877 g, 7.35 mmol) in a toluene (24
mL): ethanol (12 mL): water (6 mL) mixture was added
(4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (2.337 g, 11.03
mmol), tetrakis (triphenylphosphine) palladium(0) (425 mg, 5 mol %)
and sodium carbonate (1.56 g, 14.72 mmol). The resulting mixture
was bubbled with nitrogen and then heated in a 90.degree. C. oil
bath for 10 h. An aliquot showed complete consumption of the
starting material. The reaction was quenched with brine. The
resulting mixture was extracted with EtOAc and dried over
Na.sub.2SO.sub.4. The resulting glassy mixture was purified by
SiO.sub.2 (Biotage 40S cartridge, EtOAc/hexane, gradient). The
titled compound was obtained as a crystalline solid. LC-MS: 615.26
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1:1 mixture
of rotamers .delta. 8.31 (s, 1H), 8.20-8.26 (m, 1H), 7.86 (s, 1H),
7.70 (s, 2H), 7.39-7.43 (m, 1H), 6.96-7.01 (m, 1H), 6.67-6.72 (m,
1H), 5.64 (d, J=8.0 Hz, 0.5H), 5.48 (d, J=8.0 Hz, 0.5H), 4.90 (d,
J=16.3 Hz, 0.5H), 4.86 (d, J=16.3 Hz, 0.5H), 4.10-4.16 (m, 0.5H),
3.84-3.94 (m, 1.5H), 3.77 (s, 1.5H), 3.75 (s, 1.5H), 3.15-3.26 (m,
1H), 1.15-1.29 (m, 6H), 0.57 (d, J=6.6 Hz, 1.5H), 0.40 (d, J=6.6
Hz, 1.5H).
Example 333
##STR00421##
[0640]
(4S,5R)-3-[(4-amino-4'-fluoro-5'-isopropyl-2'-methoxybiphenyl-2-yl)-
methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
[0641] A solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4'-fluoro-5'-isopropyl-2'--
methoxy-4-nitrobiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
(1.94 g, 3.16 mmol) in methanol (20 mL) was subject to H.sub.2 (40
psi., Parr shaker) at 20.degree. C. for 1.5 h. LCMS indicated the
presence of trace starting material. The crude mixture was filtered
through a bed of Celite (521). The filtrate was evaporated in vacuo
to afford a glass as the product. LC-MS: 585.32 (M+1).sup.+.
.sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1:1 mixture of rotamers
.delta. 7.83 (s, 1H), 7.67 (s, 2H), 6.93-7.06 (m, 2H), 6.87 (s,
0.5H), 6.72-6.82 (m, 1.5H), 5.57 (d, J=8.0 Hz, 0.5H), 5.36 (d,
J=8.0 Hz, 0.5H), 4.77 (d, J=5.5 Hz, 0.5H), 4.74 (d, J=6.5 Hz,
0.5H), 3.95 (d, J=15.5 Hz, 0.5H), 3.75-3.86 (m, 1.5H), 3.73 (s,
3H), 3.12-3.24 (m, 1H), 1.11-1.29 (m, 6H), 0.47 (d, J=6.5 Hz,
1.5H), 0.29 (d, J=6 Hz, 1.5H).
Example 334
##STR00422##
[0642]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4'-fluoro-5'-
-isopropyl-2'-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
[0643] To a solution
(4S,5R)-3-[(4-amino-4'-fluoro-5'-isopropyl-2'-methoxybiphenyl-2-yl)methyl-
]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
(526 mg, 0.90 mmol) in bromoform (2.5 mL) was added tert-butyl
nitrite (186 mg, 1.80 mmol). The resulting mixture was stirred at
80.degree. C. for 20 min. An aliquot indicated completion of the
reaction. The reaction crude was purified silica gel to afford the
title compound as a yellow glass. LC-MS: 650.09 (M+1).sup.+.
.sup.1H NMR (CDCl.sub.3, 500 MHz) a 1:1 mixture of rotamers .delta.
7.85 (s, 1H), 7.69 (s, 2H), 7.60 (s, 0.5H), 7.48-7.53 (m, 1.5H),
7.07-7.11 (m, 1H), 6.93-6.99 (m, 1H), 6.62-6.67 (m, 1H), 5.59 (d,
J=8.0 Hz, 0.5H), 5.39 (d, J=7.0 Hz, 0.5H), 4.82 (d, J=6.5 Hz,
0.5H), 4.75 (d, J=6.5 Hz, 0.5H), 3.98 (d, J=16.0 Hz, 0.5H),
3.76-3.85 (m, 1.5H), 3.75 (s, 1.5H), 3.74 (s, 1.5H), 3.13-3.23 (m,
1H), 1.13-1.29 (m, 6H), 0.52 (d, J=6.5 Hz, 1.5H), 0.34 (d, J=7.0
Hz, 1.5H).
Example 335
##STR00423##
[0644]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-cyclopropyl-4'-flu-
oro-5'-isopropyl-2'
methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
[0645] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4'-fluoro-5'-isopr-
opyl-2'-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
(100 mg, 0.15 mmol) in 1,4-dioxane (0.5 mL) was added
cyclopropylboronic acid (10 mg, 0.19 mmol),
[1,1'-bis(diphenylphosphino) ferrocene]-dichloropalladium (II) (82
mg, 8 mol %), bis(tri-tert-butylphosphine)palladium (0) (10 mg, 13
mol %) and aqueous potassium hydroxide (78 .mu.L, 3M, 1.5 eq.). The
reaction mixture was purged with nitrogen and then sealed in a
microwave vessel. The reaction vessel was subject to microwave
irradiation at 150.degree. C. for 30 min. An aliquot indicated
complete consumption of starting material. Reaction crude was
worked up with water. The resulting mixture was extracted with
EtOAc and dried over Na.sub.2SO.sub.4. The titled compound was
obtained as a glassy material after two preparative TLC plates
using respectively 20% EtOAc in hexanes and 5% EtOAc in
dichloromethane as the eluent. LC-MS: 610.26 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 1:1 mixture of rotamers .delta.
7.84 (s, 1H), 7.65-7.70 (m, 2H), 7.21 (s, 0.5H), 7.08-7.14 (m,
1.5H), 6.95-7.04 (m, 2H), 6.61-6.67 (m, 1H), 5.52 (d, J=8.5 Hz,
0.5H), 5.27 (d, J=8.0 Hz, 0.5H), 4.85 (d, J=15.5 Hz, 0.5H), 4.81
(d, J=15.5 Hz, 0.5H), 4.00 (d, J=15.5 Hz, 0.5H), 3.69-3.81 (m,
4.5H), 3.13-3.24 (m, 1H), 1.90-1.99 (m, 1H), 1.12-1.30 (m, 6H),
0.98-1.15 (m, 2H), 0.71-0.77 (m, 2H), 0.48 (d, J=6.5 Hz, 1.5H),
0.29 (d, J=6.5 Hz, 1.5H).
Example 336
##STR00424##
[0646]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isoprop-
yl-2'-methoxy-4-(methylthio)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin--
2-one
[0647] To a solution
(4S,5R)-3-[(4-amino-4'-fluoro-5'-isopropyl-2'-methoxybiphenyl-2-yl)methyl-
]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
(200 mg, 0.34 mmol) in methyl disulfide (2 mL) was added tert-butyl
nitrite (70 mg, 0.68 mmol). The resulting mixture was stirred at
80.degree. C. for 30 min. An aliquot indicated completion of the
reaction. The titled compound was obtained as a glassy material
after two preparative TLC plates using respectively 20% EtOAc in
hexanes and 10% EtOAc in dichloromethane as the eluent. LC-MS:
616.21 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1:1
mixture of rotamers .delta. 7.84 (s, 1H), 7.67 (s, 2H), 7.35 (s,
0.5H), 7.22-7.28 (m, 1.5H), 7.12-7.19 (m, 1H), 6.94-7.02 (m, 1H),
6.61-6.68 (m, 1H), 5.55 (d, J=8.0 Hz, 0.5H), 5.31 (d, J=9.5 Hz,
0.5H), 4.85 (d, J=16.0 Hz, 0.5H), 4.83 (d, J=15.5 Hz, 0.5H), 3.99
(d, J=15.5 Hz, 0.5H), 3.69-3.81 (m, 4.5H), 3.12-3.24 (m, 1H), 2.54,
(s, 1.5H), 2.53 (s, 1.5H), 1.11-1.27 (m, 6H), 0.50 (d, J=6.5 Hz,
1.5H), 0.31 (d, J=7.0 Hz, 1.5H).
Example 337
##STR00425##
[0648]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isoprop-
yl-2'-methoxy-4-(methylsulfonyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazoli-
din-2-one
[0649] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropyl-2'--
methoxy-4-(methylthio)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one
(156 mg, 0.25 mmol) in dichloromethane (3 mL) was added
3-chloroperbenzoic acid (175 mg, 1.01 mmol). The resulting mixture
was stirred at 20.degree. C. for 1 h. An aliquot indicated
completion of the reaction. Reaction crude was partitioned between
water and dichloromethane. The organic layer was separated and
dried over Na.sub.2SO.sub.4. The titled compound was obtained as a
glassy material after three preparative TLC plates using
respectively 50% EtOAc in hexanes, 20% EtOAc in dichloromethane and
dichloromethane as the eluent. LC-MS: 648.29 (M+1).sup.+. .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 1:1 mixture of rotamers .delta.
7.99 (s, 0.5H), 7.92-7.96 (m, 1.5H), 7.86 (s, 1H), 7.70 (s, 2H),
7.42-7.46 (m, 1H), 6.96-7.00 (m, 1H), 6.69 (d, J=12 Hz, 1H), 5.64
(d, J=8.0 Hz, 0.5H), 5.45 (d, J=8.0 Hz, 0.5H), 4.93 (d, J=6.0 Hz,
0.5H), 4.90 (d, J=6.5 Hz, 0.5H), 4.09 (d, J=16 Hz, 0.5H), 3.88 (d,
J=16 Hz, 0.5H), 3.80-3.88 (m, 1H), 3.78 (s, 1.5H), 3.75 (s, 1.5H),
3.16-3.25 (m, 1H), 3.14 (s, 1.5H), 3.13 (s, 1.5H), 1.22-1.28 (m,
6H), 0.57 (d, J=6.5 Hz, 1.5H), 0.38 (d, J=6.5 Hz, 1.5H).
Example 338
##STR00426##
[0650]
2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-o-
xazolidin-3-yl}methyl)-4'-fluoro-5'-isopropyl-2'-methoxybiphenyl-4-carboni-
trile
[0651] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4'-fluoro-5'-isopr-
opyl-2'-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
(100 mg, 0.15 mmol) in N,N-dimethylformamide (1.5 mL) was added
copper(I) cyanide (17 mg, 0.19 mmol). The resulting reaction
mixture was N.sub.2 purged and sealed in a microwave vessel. The
vessel was subject to microwave irradiation at 150.degree. C. for
30 min. LC-MS indicated only the starting bromide was present.
Added tetrakis(triphenylphosphine)palladium(0) (10 mg, 6 mol %)
into the reaction mixture. Repeated microwave irradiation at
150.degree. C. for 30 min. An aliquot indicated the desired product
was formed and all starting bromide was consumed. Reaction crude
was partitioned between water and hexanes. The aqueous phase was
back extracted with diethyl ether. The combined extracts were dried
over Na.sub.2SO.sub.4. The titled compound was obtained as a glassy
material after two preparative TLC plates developed respectively by
20% EtOAc in hexanes and 4% EtOAc in dichloromethane. LC-MS: 595.03
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1:1 mixture
of rotamers .delta. 7.86 (s, 1H), 7.61 (S, 0.5H), 7.67-7.71 (m,
2.5H), 7.64-7.68 (m, 1H), 7.32-7.36 (m, 1H), 6.98 (d, J=8.5 Hz,
0.5H), 6.95 (d, J=8.5 Hz, 0.5H), 6.68 (d, J=12 Hz, 1H), 5.62 (d,
J=8.0 Hz, 0.5H), 5.46 (d, J=8.0 Hz, 0.5H), 4.85 (d, J=16.0 Hz,
0.5H), 4.80 (d, J=16.0 Hz, 0.5H), 4.06 (d, J=16 Hz, 0.5H),
3.79-3.86 (m, 1H), 3.70-3.78 (m, 3.5H), 3.16-3.24 (m, 1H), 3.75 (s,
1.5H), 3.16-3.25 (m, 1H), 3.14 (s, 1.5H), 3.13 (s, 1.5H), 1.15-1.27
(m, 6H), 0.54 (d, J=7.0 Hz, 1.5H), 0.37 (d, J=6.5 Hz, 1.5H).
Example 339
##STR00427##
[0652]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4'-fluoro-5'-isoprop-
yl-2'-methoxy-4-methylbiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
[0653] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4'-fluoro-5'-isopr-
opyl-2'-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
(82.5 mg, 0.13 mmol) in 1,4-dioxane (1 mL) was added
trimethylboroxine (39 mg, 0.31 mmol), Pd(PPh.sub.3).sub.4 (15 mg,
10 mol %) and potassium carbonate (35 mg, 0.25 mmol). The resulting
reaction mixture was purged with nitrogen and sealed in a microwave
vessel. The vessel was subject to microwave irradiation at
130.degree. C. for 15 min. The crude mixture was diluted with brine
and extracted with EtOAc. The combined organic extracts were dried
over Na.sub.2SO.sub.4. The titled compound was obtained as a glassy
material after two preparative TLC plates developed respectively by
20% EtOAc in hexanes and dichloromethane. LC-MS: 584.08
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1:1 mixture
of rotamers .delta. 7.84 (s, 1H), 7.65-7.70 (m, 2H), 7.29 (s, 0.5),
7.18-7.22 (m, 1.5H), 7.10-7.15 (m, 1H), 7.01 (d, J=8.0 Hz, 0.5H),
6.98 (d, J=8.5 Hz, 0.5H), 6.66 (d, J=5.0 Hz, 0.5H), 6.64 (d, J=5.5
Hz, 0.5H), 5.54 (d, J=8.5 Hz, 0.5H), 5.31 (d, J=8.0 Hz, 0.5H), 4.82
(d, J=15.5 Hz, 1H), 4.02 (d, J=15 Hz, 0.5H), 3.71-3.82 (m, 5H),
3.15-3.24 (m, 1H), 2.42 (s, 1.5H), 2.41 (s, 1.5H), 1.13-1.27 (m,
6H), 0.48 (d, J=6.5 Hz, 1.5H), 0.31 (d, J=6.5 Hz, 1.5H).
Example 340
##STR00428##
[0654]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4'-fluoro-4-isoprope-
nyl-5'-isopropyl-2'-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-
-one
[0655] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4'-fluoro-5'-isopr-
opyl-2'-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
(38 mg, 0.059 mmol) in 1,4-dioxane (0.5 mL) was added
(2-chloro-5-isopropylphenyl)boronic acid (10 mg, 0.12 mmol),
[1,1'-bis(diphenylphosphino) ferrocene] dichloropalladium (II) (2.4
mg, 5 mol %) and aqueous potassium hydroxide (40 .mu.L, 3M, 2 eq.).
The reaction mixture was purged with nitrogen and then sealed in a
microwave vessel. The reaction vessel was subject to microwave
irradiation at 140.degree. C. for 20 min. Crude mixture was worked
up with water and EtOAc. The combined organic extracts were dried
over Na.sub.2SO.sub.4 and concentrated in vacuo to give the crude
product. This was purified by preparative TLC plate eluted by 20%
EtOAc in hexanes to give the titled compound. LC-MS: 610.04
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1:1 mixture
of rotamers .delta.7.84 (s, 1H), 7.64-7.70 (m, 2H), 7.56 (s, 0.5),
7.45-7.50 (m, 1.5H), 7.18-7.23 (m, 1H), 7.02 (d, J=9.0 Hz, 0.5H),
6.99 (d, J=8.5 Hz, 0.5H), 6.67 (d, J=7.0 Hz, 0.5H), 6.64 (d, J=5.5
Hz, 0.5H), 5.52 (d, J=8.0 Hz, 0.5H), 5.43 (d, J=8.5 Hz, 1H), 5.26
(d, J=8.0 Hz, 0.5H), 5.13-5.17 (m, 1H), 4.91 (d, J=15.0 Hz, 0.5H),
4.86 (d, J=15.5 Hz, 0.5H), 4.04 (d, J=15.5 Hz, 0.5H), 3.83 (d,
J=15.5, 0.5H), 3.70-3.78 (m, 3H), 3.14-3.25 (m, 1H), 2.18-2.22 (m,
3H), 1.14-1.29 (m, 6H), 0.50 (d, J=6.5 Hz, 1.5H), 0.31 (d, J=6.5
Hz, 1.5H).
Example 341
##STR00429##
[0656]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4'-fluoro-4,5'-diiso-
propyl-2'-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
[0657] A solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4'-fluoro-4-isopropenyl-5'-
-isopropyl-2'-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
(15 mg, 0.025 mmol) in methanol (1 .mu.L) was subject to H.sub.2
(ballon atmosphere) at 20.degree. C. overnight. The crude mixture
was filtered through a syringe filter. The filtrate was evaporated
in vacuo and purified by preparative TLC plates developed by 20%
EtOAc in hexanes to give the titled compound. LC-MS: 612
(M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1:1 mixture
of rotamers .delta. 7.84 (s, 1H), 7.64-7.68 (m, 2H), 7.30 (s, 0.5),
7.20-7.27 (m, 1.5H), 7.13-7.17 (m, 1H), 7.02 (d, J=8.5 Hz, 0.5H),
6.99 (d, J=8.0 Hz, 0.5H), 6.65 (d, J=6.0 Hz, 0.5H), 6.63 (d, J=6.0
Hz, 0.5H), 5.52 (d, J=8.0 Hz, 0.5H), 5.25 (d, J=8.0 Hz, 1H), 4.87
(d, J=15.5 Hz, 0.5H), 4.82 (d, J=15.5 Hz, 0.5H), 4.03 (d, J=15.0
Hz, 0.5H), 3.81 (d, J=15.0 Hz, 0.5H), 3.69-3.77 (m, 4H), 3.14-3.24
(m, 1H), 2.92-3.02 (m, 1H), 1.14-1.33 (m, 12H), 0.48 (d, J=6.5 Hz,
1.5H), 0.30 (d, J=7.0 Hz, 1.5H).
##STR00430##
(4S,5R)-3-(5-amino-2-bromobenzyl)-5-[3,5-bis(trifluoromethyl)phenyl]-4-me-
thyl-1,3-oxazolidin-2-one
[0658] A mixture of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzyl)-4-me-
thyl-1,3-oxazolidin-2-one (614 mg, 1.17 mmol), tin(II) chloride
dehydrate (1.314 g, 5.823 mmol) and ethanol (3 mL) was stirred at
20.degree. C. for 36 h. Reaction crude was worked up with water.
The resulting mixture was extracted with EtOAc and dried over
Na.sub.2SO.sub.4. The titled compound was obtained as a glassy
material after SiO.sub.2 purification (Biotage 40+M, gradient, 0%
to 35% EtOAc in hexanes). LC-MS: 499.05 (M+1).sup.+. .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 7.88 (s, 1H), 7.77 (s, 2H), 7.31 (d,
J=8.5, 1H), 6.77 (d, J=2.7, 1H), 6.54 (dd, J=8.5, 2.7 Hz, 1H), 5.69
(d, J=8.0 Hz, 1H), 4.77 (d, J=15.3, 1H), 4.29 (d, J=15.3 Hz, 1H),
4.05-4.12 (m, 1H), 0.79 (d, J=6.4 Hz, 3H).
##STR00431##
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-bromo-5-(methylthio)benzy-
l]-4-methyl-1,3-oxazolidin-2-one
[0659] To a solution of
(4S,5R)-3-(5-amino-2-bromobenzyl)-5-[3,5-bis(trifluoromethyl)phenyl]-4-me-
thyl-1,3-oxazolidin-2-one (457 mg, 0.92 mmol) in methyl disulfide
(4 mL) was added tert-butyl nitrite (182 .mu.L, d=0.867, 1.38
mmol). The resulting mixture was stirred at 80.degree. C. for 1 h.
An aliquot indicated completion of the reaction. The titled
compound was obtained as a glassy material after preparative TLC
plates eluted by 25% EtOAc in hexanes. LC-MS: 529.71
(M+1).sup.+.
Example 342
##STR00432##
[0660]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2'-chloro-4'-fluoro--
5'-isopropyl-4-(methylthio)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-
-one
[0661] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-bromo-5-(methylthio)benzy-
l]-4-methyl-1,3-oxazolidin-2-one (60 mg, 0.114 mmol) in 1,4-dioxane
(1 mL) was added (2-chloro-4-fluoro-5-isopropylphenyl)boronic acid
(10 mg, 0.12 mmol), [1,1'-bis(diphenylphosphino) ferrocene]
dichloropalladium (II) (28 mg, 30 mol %) and aqueous potassium
hydroxide (95 .mu.L, 3M, 2 eq.). The reaction mixture was purged
with nitrogen and then sealed in a microwave vessel. The reaction
vessel was subject to microwave irradiation at 150.degree. C. for
30 min. Crude mixture was worked up with water and EtOAc. The
combined organic extracts were dried over Na.sub.2SO.sub.4 and
concentrated in vacuo to give the crude product. This was purified
by preparative TLC plate to afford the titled compound. LC-MS:
619.95 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) a 1:1 mixture
of rotamers .delta. 7.83-7.88 (m, 1H), 7.72 (s, 1H) 7.68 (s, 1H),
7.30-7.35 (m, 1H), 7.24-7.29 (m, 1H), 7.11-7.19 (m, 2.5H),
7.04-7.07 (m, 0.5H), 5.62 (d, J=8.2 Hz, 0.5H), 5.24 (d, J=8.0 Hz,
0.5H), 4.87 (d, J=15.3 Hz, 0.5H), 4.70 (d, J=15.8 Hz, 0.5H),
3.79-3.98 (m, 2H), 3.18 (m, 1H), 2.55 (s, 1.5H), 2.54 (s, 1.5H),
1.20-1.29 (m, 6H), 0.53 (d, J=6.4 Hz, 1.5H), 0.47 (d, J=6.6 Hz,
1.5H).
Example 343
##STR00433##
[0662]
(4S,5R)-5-[3,5-bis(trifluormethyl)phenyl]-3-[(2'-chloro-5'-isopropy-
l-4-nitrobiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
[0663] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-(2-bromo-5-nitrobenzyl)-4-me-
thyl-1,3-oxazolidin-2-one (950 mg, 1.80 mmol) in a toluene (5.2
mL):ethanol (2.6 mL):water (1.3 mL) mixture was added
(2-chloro-5-isopropylphenyl) boronic acid (325 mg, 1.64 mmol),
tetrakis(triphenylphosphine)palladium(0) (188 mg, 10 mol %) and
sodium carbonate (346 mg, 3.26 mmol). The resulting mixture was
heated in an 80.degree. C. oil bath for 12 h. The reaction crude
was evaporated into dryness. The resulting residue was taken up by
a mixture of water and EtOAc. The combined organic extracts were
dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give the
crude product, which was purified by SiO.sub.2 (Biotage 40+S
cartridge, EtOAc/hexane, gradient) to afford the titled compound.
LC-MS: 601.19 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz)
.delta. 1:1 mixture of rotamers .delta. 8.31-8.30 (m, 1H),
8.24-8.28 (m, 1H), 7.85-7.89 (m, 1H), 7.68-7.76 (m, 2H), 7.42-7.48
(m, 2H), 7.26-7.30 (m, 1H), 7.04-7.11 (m, 1H), 5.74 (d, J=7.8 Hz,
0.5H), 5.58 (d, J=8.0 Hz, 0.5H), 4.92 (d, J=15.8 Hz, 0.5H), 4.76
(d, J=16.2 Hz, 0.5H), 3.97-4.04 (m, 1.5H), 3.82 (dt, J=8.0, 6.6 Hz,
0.5H), 2.89-2.99 (m, 1H) 1.22-1.29 (m, 6H), 0.60 (d, J=6.4 Hz,
1.5H), 0.52 (d, J=6.6 Hz, 1.5H).
Example 344
##STR00434##
[0664]
(4S,5R)-3-[(4-amino-2'-chloro-5'-isopropylbiphenyl-2-yl)methyl]-5-[-
3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
[0665] A solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(2'-chloro-5'-isopropyl-4-n-
itrobiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (425 mg,
0.71 mmol) in methanol (10 mL) was subject to H.sub.2 (40 psi.,
Parr shaker) at 20.degree. C. for 6 h. The crude mixture was
filtered through a bed of Celite (521). The filtrate was evaporated
in vacuo to afford a glass. The titled compound was obtained after
a preparative TLC plate developed by 20% EtOAc in hexanes. LC-MS:
571.22 (M+1).sup.+. .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 6:4
mixture of rotamers .delta. 7.82-7.86 (m, 1H), 7.65-7.71 (m, 2H),
7.34-7.38 (m, 1H), 7.11-7.17 (m, 2H), 7.02-7.06 (m, 1H), 6.76-6.82
(m, 1H), 6.68-6.74 (m, 1H), 5.58 (d, J=8.0 Hz, 0.4H), 5.51 (d,
J=8.2 Hz, 0.6H), 4.82 (d, J=15.3 Hz, 0.6H), 4.70 (d, J=15.6 Hz,
0.4H), 3.69-4.00 (m, 4H), 2.84-2.94 (m, 1H), 1.19-1.28 (m, 6H),
0.45 (d, J=6.6 Hz, 1.2H), 0.40 (d, J=6.6 Hz, 1.8H).
Example 345
##STR00435##
[0666]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-2'-chloro-5'-
-isopropylbiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
[0667] To a solution of
(4S,5R)-3-[(4-amino-2'-chloro-5'-isopropylbiphenyl-2-yl)methyl]-5-[3,5-bi-
s(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (100 mg,
0.175 mmol) in bromoform (0.5 mL) and dichloromethane (1 mL) was
added t-butyl nitrite (23 .mu.L, d=0.867, 90% pure, 0.193 mmol).
The resulting mixture was stirred at 50.degree. C. for 1 h. An
aliquot indicated completion of the reaction. The reaction crude
was deposited on 2 prep-TLC plates eluted by dichloromethane to
afford the title compound. LC-MS: 635.80 (M+1).sup.+. .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 6:4 mixture of rotamers .delta.
7.84-7.88 (m, 1H), 7.67-7.74 (m, 2H), 7.60-7.63 (m, 1
[0668] H), 7.51-7.57 (m, 1H), 7.38-7.42 (m, 1H), 7.19-7.23 (m, 1H),
7.11-7.16 (m, 1H), 7.09 (d, J=2.3 Hz, 0.6H), 7.03 (d, J=2.3 Hz,
0.4H), 5.66 (d, J=8.0 Hz, 0.4H), 5.55 (d, J=8.0 Hz, 0.6H), 4.86 (d,
J=15.6 Hz, 0.6H), 4.70 (d, J=15.6 Hz, 0.4H), 3.77-4.00 (m, 2H),
2.87-2.95 (m, 1H), 1.20-1.28 (m, 6H), 0.53 (d, J=6.6 Hz, 1.2H),
0.45 (d, J=6.4 Hz, 1.8H).
Example 346
##STR00436##
[0669]
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(2'-chloro-4-cyclopro-
pyl-5'-isopropylbiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one
[0670] To a solution of
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-2'-chloro-5'-isopr-
opylbiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (27 mg,
0.043 mmol) in 1,4-dioxane (1 mL) was added cyclopropylboronic acid
(9 mg, 0.10 mmol), [1,1'-bis(diphenylphosphino)
ferrocene]dichloropalladium (II) (10.4 mg, 30 mol %) and aqueous
potassium hydroxide (42 .mu.L, 3M, 3 eq.). The reaction mixture was
purged with nitrogen and then sealed in a microwave vessel. The
reaction vessel was subject to microwave irradiation at 120.degree.
C. for 20 min. Crude mixture was worked up with water and EtOAc.
The combined organic extracts were dried over Na.sub.2SO.sub.4 and
concentrated in vacuo to give the crude product. This was purified
by preparative TLC plate eluted by 20% EtOAc in hexanes to afford
the titled compound. LC-MS: 595.99 (M+1).sup.+. .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 6:4 mixture of rotamers .delta.
7.82-7.86 (m, 1H), 7.66-7.72 (m, 2H), 7.36-7.40 (m, 1H), 7.21-7.23
(m, 0.5H), 7.11-7.19 (m, 3H), 7.01-7.08 (m, 1.5H), 5.58 (d, J=8.0
Hz, 0.4H), 5.50 (d, J=8.0 Hz, 0.6H), 4.88 (d, J=15.1 Hz, 0.6H),
4.71 (d, J=15.6 Hz, 0.4H), 3.76-3.95 (m, 2H), 2.84-2.95 (m, 1H),
1.92-2.00 (m, 1H), 1.18-1.29 (m, 6H), 1.00-1.07 (m, 2H), 0.71-0.82
(m, 2H), 0.47 (d, J=6.6 Hz, 1.2 H), 0.42 (d, J=6.6 Hz, 1.8H).
[0671] Following the procedures outlined in EXAMPLE 96 the
compounds listed in Table 18 were prepared from
(4R,5R)-5-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)-biphenyl-
-2-yl]-4-methyl-1,3-oxazolidin-2-one:
TABLE-US-00018 TABLE 18 ##STR00437## LC/MS Data EXAMPLE R (M + 1)
347 ##STR00438## 570.3 348 ##STR00439## 538.4 349 ##STR00440##
511.4 350 ##STR00441## 532.4 351 ##STR00442## 508.4 352
##STR00443## 562.4 353 ##STR00444## 643.5 354 ##STR00445## 570.4
355 ##STR00446## 586.4 356 ##STR00447## 503.4 357 ##STR00448##
503.4 358 ##STR00449## 618.5 359 ##STR00450## 518.4
Example 360
##STR00451##
[0672]
(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5'-isopropyl-2'-(trif-
luoromethoxy)-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2--
one
[0673] To a solution of 80 mg of
(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluoromethyl)p-
henyl]-4-methyl-1,3-oxazolidin-2-one in 2 mL of benzene, 1 mL of
water, and 0.5 mL ethanol was added 100 mg of
5-isopropyl-2-(trifluoromethoxy)phenyl boronic acid, 0.15 mL of 2M
aqueous sodium carbonate, and 21 mg of Pd(PPh.sub.3).sub.4. A
reflux condenser was attached, and the mixture was heated to
100.degree. C. The mixture was stirred at 100.degree. C. for 24
hours, and then was diluted with 10 mL of EtOAc and 10 mL of water.
The phases were separated and the aqueous phase was extracted with
10 mL of EtOAc. The combined organic phases were washed with 10 mL
of brine, dried over Na.sub.2SO.sub.4, and concentrated. The
residue was purified by flash chromatography on a Biotage Horizon,
25M column, eluting with 1 CV of 2% EtOAc in hexanes, followed by a
linear gradient of EtOAc in hexanes from 2 to 100% over 10 CV. The
product was repurified using the same conditions to provide the
title compound. Mass spectrum (ESI) 674.4 (M+1).
[0674] Following the general procedures described above the
compounds listed in Table 19 were prepared.
TABLE-US-00019 TABLE 19 ##STR00452## LC/MS Data EXAMPLE A.sup.3 (M
+ 1) 361 ##STR00453## 580.3 362 ##STR00454## 642.4 363 ##STR00455##
614.3 364 ##STR00456## 616.3 365 ##STR00457## 634.4 366
##STR00458## 650.3 367 ##STR00459## 674.4 368 ##STR00460##
623.9
##STR00461##
(4R,5R)-4-ethyl-5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one
Step A: (4S)-4-benzyl-3-butyryl-1,3-oxazolidin-2-one
[0675] To a -78.degree. C. solution of S-benzyl-oxazolidinone in 15
mL of THF was added n-BuLi over ca. 1 min, and then butyryl
chloride. The mixture was stirred for 30 min at -78.degree. C., and
then allowed to warm to r.t. over ca. 30 min. Excess acid chloride
was quenched by addition of 3 mL of saturated aqueous NH.sub.4Cl,
and then the bulk of the solvent was removed by rotary evaporation.
The residue was diluted with 17 mL of saturated aqueous NH.sub.4Cl
and 30 mL of CH.sub.2Cl.sub.2. The phases were separated and the
aqueous phase was extracted with 20 mL of CH.sub.2Cl.sub.2. The
combined organic extracts were washed with 20 mL of 1 N NaOH
solution and 20 mL of brine, dried (Na.sub.2SO.sub.4), and
concentrated. The residue was purified by flash chromatography on a
Biotage Horizon, 40M column, eluting with 1 CV of 2% EtOAc in
hexanes followed by a linear gradient of 2.fwdarw.100% EtOAc in
hexanes over 10 CV. The residue was stored in the freezer
overnight, where it crystallized. The resulting solid was
triturated with hexanes, filtered, and dried under high vacuum.
Mass spectrum (ESI) 178.2 (M-C.sub.3H.sub.7CO).
Step B:
(4S)-4-benzyl-3-((2R)-2-{(S)-hydroxy[2-iodo-5-trifluoromethyl)phen-
yl]methyl}butanoyl)-1,3-oxazolidin-2-one
[0676] Following the procedure described in EXAMPLE 95, Step A, the
title compound was prepared from
5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde
(EXAMPLE 80, Step A) and
(4S)-4-benzyl-3-butyryl-1,3-oxazolidin-2-one. Mass spectrum (ESI)
530.1 (M-OH).
Step C:
(4R,5R)-4-ethyl-5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolidi-
n-2-one
[0677] Following the procedure described in EXAMPLE 95, Step B, the
title compound was prepared from
(4S)-4-benzyl-3-((2R)-2-{(S)-hydroxy[2-iodo-5-(trifluoromethyl)phenyl]met-
hyl}butanoyl)-1,3-oxazolidin-2-one. Mass spectrum (ESI) 386.2
(M+1).
##STR00462##
(4R,5R)-4-benzyl-5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolidin-2-on-
e
Step A:
(4S)-4-benzyl-3-(3-phenylpropanoyl)-1,3-oxazolidin-2-one
[0678] Following the procedure described in INTERMEDIATE 27, Step
A, the title compound was prepared from S-benzyl-oxazolidinone and
hydrocinnamoyl chloride. Mass spectrum (ESI) 178.2
(M-PhC2H4CO).
Step B:
(4S)-4-benzyl-3-{(2R,3S)-2-benzyl-3-hydroxy-3-[2-iodo-5-(trifluoro-
methyl)phenyl]propanoyl}-1,3-oxazolidin-2-one
[0679] Following the procedure described in EXAMPLE 95, Step A, the
title compound was prepared from
5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldehyde
(EXAMPLE 80, Step A) and
(4S)-4-benzyl-3-(3-phenylpropanoyl)-1,3-oxazolidin-2-one. Mass
spectrum (ESI) 592.3 (M-OH).
Step C:
(4R,5R)-4-benzyl-5-[2-iodo-5-(trifluoromethyl)phenyl]-1,3-oxazolid-
in-2-one
[0680] Following the procedure described in EXAMPLE 95, Step B, the
title compound was prepared from
(4S)-4-benzyl-3-{(2R,3S)-2-benzyl-3-hydroxy-3-[2-iodo-5-(trifluoromethyl)-
phenyl]propanoyl}-1,3-oxazolidin-2-one. Mass spectrum (ESI) 448.2
(M+1).
[0681] Following the general procedures outlined above, the
compounds in Table 20 were prepared:
TABLE-US-00020 TABLE 20 ##STR00463## LC/MS Data EXAMPLE A.sup.3
R.sub.2 R.sub.3 (M + 1) 369 ##STR00464## Et ##STR00465## 652.4 370
##STR00466## Et ##STR00467## 584.4 371 ##STR00468## Et ##STR00469##
639.2
Example 372
Alternate Procedure for Making
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'isopropyl-2'-m-
ethoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2--
one (Example 73)
[0682] The compound of Example 73 can be made by the procedure
shown below:
##STR00470##
Step 1: Suzuki Coupling Reaction of Boronic Acid 1 and aryl
chloride 2:
[0683] A 3 M K.sub.2CO.sub.3 solution is prepared by adding 4.71 kg
of solid K.sub.2CO.sub.3 to 10.3 L water. Cooling is applied to
keep the solution at 20-25.degree. C. THF (12 L), aryl chloride 2
(2.69 kg), and the boronic acid 1 that was made in Example 78 (2.74
kg) are added to the K.sub.2CO.sub.3 followed by a 1 L THF rinse.
HPLC analysis is used to confirm the 1.00/1.00 ratio of 1/2. The
solution is degassed by sparging with nitrogen gas for 70 min. The
catalyst, 1,1 bis(di-tert-butylphosphino)ferrocene palladium
dichloride (42 g) is added as a solid and is followed by a degassed
THF rinse (1.5 L). The organic layer turns dark brown immediately.
The biphasic mixture is aged at 36.degree.-40.degree. C. with
vigorous stirring. After HPLC reveals complete conversion (15-18
h), the mixture is cooled to rt and the aqueous layer is removed.
To the organic layer is added heptane (25.6 L) and water (25.6 L)
and the layers are cut. The organic layer is washed with water (19
L). The organic layer is treated with 680 g Darco KB-B at rt for 60
min and filtered through solka-floc with a 10% THF/Heptane rinse
(.about.15 L). The solvent is switched to heptane (.about.35 L) at
.about.45-50.degree. C. until <0.5 v % of THF is left. More
heptane is added to bring the total volume to .about.45-50 L. The
solution is seeded with crystals obtained from earlier runs if no
seed bed forms. The slurry is slowly cooled to rt and then to
-15.degree. C. After aging at -15.degree. C. for 1-2 h, after LC of
the supernatant shows .about.2 g/l loss of the product in the
supernatant, the slurry is filtered and the product is washed with
cold heptane (.about.25 L), providing compound 3.
Step 2: Chlorination of 3 to 4:
[0684] To a solution of biaryl 3 (3.4 kg) in DMF (17 L) which was
maintained at 10.degree. C. was added thionyl chloride (940 ml),
and then the mixture was warmed to room temperature. The mixture
was aged until >99.8% conversion was measured by HPLC. Water
(3.4 L) was then added. Seed crystals (1 wt %) were added, and the
mixture was aged for 30 min more before slowly adding 5.1 L of
additional water over .about.1 hr. The solid was filtered and
washed with first 20 L 1:1 DMF:water and then 3.times.20 L water.
The solid product 4 was dried at 20.degree. C. until <0.1 wt %
water remained.
Step 3: Alkylation of the Product of Example 17 with Compound 4 to
Yield the Product of Example 73:
[0685] The chiral intermediate
(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
which was made in Example 17 is dissolved in DMF (2.8 kg in 32.7 L)
and cooled to -15.degree. C. 2.0 M N S (3.92 L, 1.05 eq) was then
added over 1.5 hr, followed by addition of the biaryl chloride 4
(2.8 kg) in DMF. The mixture was warmed to +12.degree. C. and was
aged until complete conversion took place. Then 5N HCl (3.4 L) was
added, followed by 16 L of 10% IPAC/Heptane and 34 L of water,
keeping the temperature between 10.degree. C. and 20.degree. C.
throughout. The layers were cut and the organic layer was washed
twice with 14 L of 1:1 DMF:water followed by two 14 L water washes.
The organic layer was assayed for yield and was then filtered
through 2.4 kg of silica gel to remove the excess oxazolidinone to
<0.5%. The silica was washed with 5% IPAC/Heptane. The combined
organic solutions were distilled to remove IPAC to <1%. The warm
heptane solution was then transferred slowly into a 20.degree. C.
heptane solution containing 10 wt % seed. The slurry was then
cooled to -20.degree. C. and filtered. The filter cake was washed
with cold heptane and was then dried, yielding the compound that
was originally made in Example 73.
##STR00471##
(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-3-nitro-5-(trifluoro-
methyl)phenyl]-4-methyl-1,3-oxazolidin-2-one
[0686]
(4R,5R)-3-[3,5-Bis(trifluoromethyl)benzyl]-5-[2-iodo-5-(trifluorome-
thyl)phenyl]-4-methyl-1,3-oxazolidin-2-one was added in portions to
2 mL of fuming nitric acid at 0.degree. C. The reaction mixture was
stirred overnight at r.t., and then heated to 75.degree. C. for 4
h. The reaction mixture was cooled and then added dropwise to a
rapidly stirred mixture of 10 mL of water and 10 mL of EtOAc. The
phases were separated and the organic phase was washed with 10 mL
each of saturated NaHCO.sub.3 and brine, dried (Na.sub.2SO.sub.4),
and concentrated. The residue was purified by flash chromatography
on a Biotage Horizon, 25S column, eluting with 1 CV of 5% EtOAc in
hexanes followed by a linear gradient of 5.fwdarw.100% EtOAc in
hexanes over 10 CV, to provide the title compound. Mass spectrum
(ESI) 643 (M+1).
Example 373
##STR00472##
[0687]
(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[4'-fluoro-5'-isopropy-
l-2'-methoxy-6-nitro-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazol-
idin-2-one
[0688] Following the procedure described in EXAMPLE 81, 48 mg of
(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-3-nitro-5-(trifluoro-
methyl)phenyl]-4-methyl-1,3-oxazolidin-2-one and 48 mg of
(4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (EXAMPLE 78)
provided two atroposiomers, which were separable by flash
chromatography on a Biotage Horizon, 25S column, eluting with 1 CV
of 5% EtOAc in hexanes followed by a linear gradient of
5.fwdarw.100% EtOAc in hexanes over 10 CV, providing atropoisomer A
[mass spectrum (ESI) 683.4 (M+1)] and atropoisomer B [mass spectrum
(ESI) 683.3 (M+1)].
Example 374
##STR00473##
[0689]
(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[4'-fluoro-5'-isopropy-
l-2'-methoxy-6-iodo-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazoli-
din-2-one (atropoisomer A)
[0690] To a solution of 17 mg of
(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[4'-fluoro-5'-isopropyl-2'-m-
ethoxy-6-nitro-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-
-one, atropoisomer A (EXAMPLE 373), in 1 mL EtOAc was added 5 mg of
PtO.sub.2 (Adam's catalyst). The reaction mixture was flushed with
H.sub.2, and then stirred under an H.sub.2 balloon for 2 h, at
which point LC/MS analysis showed mostly the nitroso product. The
reaction mixture was filtered through Celite, washing liberally
with EtOAc, and the filtrate was concentrated and resubmitted to
reaction conditions overnight. The reaction mixture was filtered
through Celite, washing liberally with EtOAc, and the filtrate was
concentrated. The residue was dissolved in 0.5 mL of
CH.sub.2I.sub.2 and 6 .mu.L of t-butyl nitrite was added. The
reaction mixture was stirred for 1.5 h at 80.degree. C. The
reaction mixture was purified by preparative thin-layer
chromatography on a 1000 .mu.M plate, eluting with 20% EtOAc in
hexanes, to provide the title compound. Mass spectrum (ESI) 764.3
(M+1).
Example 375
##STR00474##
[0691]
(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[4'-fluoro-5'-isopropy-
l-2'-methoxy-6-iodo-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazoli-
din-2-one (atropoisomer B)
[0692] To a solution of 70 mg of
(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[2-iodo-3-nitro-4-(trifluoro-
methyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (intermediate 30) in 1
mL EtOH was added 124 mg of SnCl.sub.2. The reaction mixture was
stirred overnight at r.t.; then another 60 mg of SnCl.sub.2 was
added and the mixture was heated to 80.degree. C. and stirred
overnight. The reaction mixture was concentrated and the residue
was partitioned between 10 mL of CH.sub.2Cl.sub.2 and 10 mL of 1 N
NaOH. The aqueous phase was extracted with 2.times.10 mL of
CH.sub.2Cl.sub.2 and the combined organics were dried
(Na.sub.2SO.sub.4), and concentrated. Following the procedure
described in EXAMPLE 81, the residue from the reduction and 70 mg
of (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (EXAMPLE 78)
provided the corresponding biphenyl compound as a mixture of
atropoisomers. This mixture was dissolved in 0.5 mL of
CH.sub.2I.sub.2 and 14 .mu.L of t-butyl nitrite was added. The
reaction mixture was stirred for 1.5 h at 80.degree. C. and then
cooled and added directly to two 1000-.mu.M thin-layer
chromatography plates, eluting with 20% EtOAc in hexanes to provide
approximately equal amounts of atropoisomer A and B of the title
compound. Mass spectrum (ESI) 764.2 (M+1).
##STR00475##
4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldeh-
yde
[0693] Following the procedure described in EXAMPLE 81, 200 mg of
2-iodo-5-(trifluoromethyl)benzaldehyde (EXAMPLE 80, Step A) and 170
mg of (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (EXAMPLE
78) gave the title compound. Mass spectrum (ESI) 341.3 (M+1).
##STR00476##
5-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1--
(4-methoxybenzyl)imidazolidin-2-one
Step A:
[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-y-
l][(4-methoxybenzyl)amino]acetonitrile
[0694] To a solution of 203 mg of
4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbaldeh-
yde (INTERMEDIATE 31) in 2 mL of CH.sub.2Cl.sub.2 was added 100
.mu.L of TMSCN, and then 1 mg of ZnI.sub.2. The mixture was stirred
for 30 min at r.t. p-Methoxybenzylamine (157 .mu.L) in 2 mL of MeOH
was added and the mixture was heated to reflux for 1.5 h. The
reaction mixture was cooled and concentrated. The residue was
purified by flash chromatography on a Biotage Horizon, 25M column,
eluting with 1 CV of 2% EtOAc in hexanes followed by a linear
gradient of 2.fwdarw.100% EtOAc in hexanes over 10 CV to provide
the title compound. Mass spectrum (ESI) 487.2 (M+1).
Step B:
5-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-
-yl]-(4-methoxybenzyl)imidazolidin-2-one
[0695] To a 0.degree. C. solution of 100 mg of
[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl][(4-m-
ethoxybenzyl)amino]acetonitrile in 4 mL of THF was added 620 .mu.L
of a 1 M solution of LiAlH.sub.4 in Et.sub.2O. The cooling bath was
removed and the mixture was stirred for 45 min at r.t. The mixture
was recooled to 0.degree. C. and carefully quenched by dropwise
addition of 24 .mu.L of water, 24 .mu.L of 15% aqueous NaOH
solution, and 60 .mu.L of water. The solids were filtered, washing
liberally with Et.sub.2O, and the filtrate was concentrated. The
residue was dissolved in 2 mL of CH.sub.2Cl.sub.2 and cooled to
0.degree. C. Triethylamine (55 .mu.L) and then triphosgene (32 mg)
were added. The mixture was stirred for 45 min at 0.degree. C. The
reaction mixture was partitioned between 10 mL of EtOAc and 10 mL
of water. The aqueous was extracted with 10 mL of EtOAc and the
combined organics were washed with 10 mL of brine, dried
(Na.sub.2SO.sub.4), and concentrated. The residue was purified by
flash chromatography on a Biotage Horizon, 25S column, eluting with
1 CV of 15% EtOAc in hexanes followed by a linear gradient of
15.fwdarw.100% EtOAc in hexanes over 10 CV to provide the title
compound. Mass spectrum (ESI) 517.3 (M+1).
Example 376
##STR00477##
[0696]
1-[3,5-bis(trifluoromethyl)benzyl]-4-[4'-fluoro-5'-isopropyl-2'-met-
hoxy-4-(trifluoromethyl)biphenyl-2-yl]imidazolidin-2-one
Step A:
1-[3,5-bis(trifluoromethyl)benzyl]-4-[4'-fluoro-5'-isopropyl-2'-me-
thoxy-4-(trifluoromethyl)biphenyl-2-yl]-3-(4-methoxybenzyl)imidazolidin-2--
one
[0697] To a 0.degree. C. solution of 19 mg of
5-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1--
(4-methoxybenzyl)imidazolidin-2-one (INTERMEDIATE 32) in 1 mL of
DMF was added 3 mg of NaH (60% dispersion in oil). The solution was
stirred for 10 min at 0.degree. C. and then 8 .mu.L of
3,5-bistrifluoromethylbenzyl bromide was added and the mixture was
stirred for 3 h at 0.degree. C. The reaction mixture was quenched
with a drop of water and then filtered and purified by
reverse-phase HPLC [Waters XTerra C8 19.times.50 mm column, eluting
at 20 mL/min with 90% water (0.1% TFA) to 100% acetonitrile (0.1%
TFA) over 5.15 min, hold for 1.45 min, then back to 90% water over
0.5 min] to provide the title compound. Mass spectrum (ESI) 743.2
(M+1).
Step B:
1-[3,5-bis(trifluoromethyl)benzyl]-4-[4'-fluoro-5'-isopropyl-2'-me-
thoxy-4-(trifluoromethyl)biphenyl-2-yl]imidazolidin-2-one
[0698] A solution of 15 mg of
1-[3,5-bis(trifluoromethyl)benzyl]-4-[4'-fluoro-5'-isopropyl-2'-methoxy-4-
-(trifluoromethyl)biphenyl-2-yl]-3-(4-methoxybenzyl)imidazolidin-2-one
in 0.5 mL of TFA was stirred overnight at r.t. The reaction mixture
was concentrated and then purified by reverse-phase HPLC [Waters
XTerra C8 19.times.25 mm column, eluting at 20 mL/min with 90%
water (0.1% TFA) to 100% acetonitrile (0.1% TFA) over 5.15 min,
hold for 1.45 min, then back to 90% water over 0.5 min] to provide
the title compound. Mass spectrum (ESI) 623.4 (M+1).
Example 377
##STR00478##
[0699]
1-benzyl-4-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)bi-
phenyl-2-yl]imidazolidin-2-one
Step A:
1-benzyl-4-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)b-
iphenyl-2-yl]-3-(4-methoxybenzyl)imidazolidin-2-one
[0700] Following the procedure described in EXAMPLE 379, Step A, 31
mg of
5-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-1--
(4-methoxybenzyl)imidazolidin-2-one (INTERMEDIATE 32) and 9 .mu.L
of benzyl bromide gave the title compound. Mass spectrum (ESI)
607.5 (M+1).
Step B:
1-benzyl-4-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)b-
iphenyl-2-yl]imidazolidin-2-one
[0701] Following the procedure described in EXAMPLE 379, Step B, 5
mg of
1-benzyl-4-[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-
-2-yl]-3-(4-methoxybenzyl)imidazolidin-2-one gave the title
compound. Mass spectrum (ESI) 487.4 (M+1).
* * * * *