U.S. patent application number 11/538155 was filed with the patent office on 2007-05-10 for process for preparing oxazole intermediates.
This patent application is currently assigned to Pharmacia & Upjohn Company. Invention is credited to Rick J. Imbordino, Michael R. Reeder.
Application Number | 20070105921 11/538155 |
Document ID | / |
Family ID | 30003150 |
Filed Date | 2007-05-10 |
United States Patent
Application |
20070105921 |
Kind Code |
A1 |
Reeder; Michael R. ; et
al. |
May 10, 2007 |
Process for Preparing Oxazole Intermediates
Abstract
Disclosed are compounds of formula III and a process to prepare
a compound of formula III ##STR1## wherein R.sub.1, R.sub.2,
R.sub.3 and R.sub.6 are defined herein, using a zinc
chloride/optionally substituted oxazole adduct and an compound of
formula I. Further disclosed are methods of using compounds of
formula III to prepare compounds useful in the treatment of
Alzheimer's disease and related conditions.
Inventors: |
Reeder; Michael R.;
(Kalamazoo, MI) ; Imbordino; Rick J.; (Kalamazoo,
MI) |
Correspondence
Address: |
MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP
300 S. WACKER DRIVE
32ND FLOOR
CHICAGO
IL
60606
US
|
Assignee: |
Pharmacia & Upjohn
Company
|
Family ID: |
30003150 |
Appl. No.: |
11/538155 |
Filed: |
October 3, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10600100 |
Jun 20, 2003 |
7115747 |
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11538155 |
Oct 3, 2006 |
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60390285 |
Jun 20, 2002 |
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60450478 |
Feb 27, 2003 |
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Current U.S.
Class: |
514/374 ;
548/215 |
Current CPC
Class: |
A61P 25/28 20180101;
C07D 263/32 20130101 |
Class at
Publication: |
514/374 ;
548/215 |
International
Class: |
A61K 31/422 20060101
A61K031/422; A61K 31/421 20060101 A61K031/421; C07D 263/02 20060101
C07D263/02 |
Claims
1. A process for preparing a compound of the formula: ##STR26##
wherein: R.sub.1 is C.sub.1-C.sub.6 alkoxy or OH; R.sub.2 and
R.sub.3 are independently H, phenyl, or C.sub.1-C.sub.4 alkyl; or
R.sub.2 and R.sub.3 and the carbons to which they are attached form
a benzo ring, which is optionally substituted with C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, or dialkylamino; and R.sub.6 is
C.sub.1-C.sub.6 alkoxy or NR.sub.4R.sub.5; wherein R.sub.4 and
R.sub.5 are independently C.sub.1-C.sub.6 alkyl; comprising:
forming a reaction mixture comprising a compound of formula I:
##STR27## wherein X is Br, I, OTf, or OMs; a compound of formula
II: ##STR28## a catalyst and at least one solvent.
2. A process according to claim 1, wherein the catalyst is a
transition metal catalyst.
3-4. (canceled)
5. A process according to claim 1 wherein the method is conducted
in the presence of at one additional polar, aprotic solvent.
6. A process according to claim 5, wherein the polar, aprotic
solvent is tetrahydrofuran, tetramethyltetrahydrofuran, glyme,
methyl t-butyl ether, or a mixture thereof.
7. A process according to claim 6, wherein the polar, aprotic
solvent is tetrahydrofuran.
8. A process according to claim 1, wherein the reaction is
performed at a temperature of from about 25.degree. C. to about the
refluxing temperature of the solvent used.
9-10. (canceled)
11. A process according to claim 10, wherein the reaction mixture
is formed by combining I, II and the catalyst, and any additional
optional additives, at once or within a short time of each
other.
12. A process according to claim 10, wherein the reaction mixture
is formed over a period of about 0.5 hours to about 4 hours.
13-14. (canceled)
15. A process according to claim 1, wherein the transition metal
catalyst is present in 0.01 to 20 mole percent, based on the amount
of the compound of formula I.
16-17. (canceled)
18. A process according to claim 17, wherein the reaction mixture
is heated for about 24 hours.
19. A process according to claim 18, wherein the reaction mixture
is heated for about 0.5 to about 8 hours.
20-21. (canceled)
22. A process according to claim 1, wherein the compound of formula
II is used in an excess from 1.001 to 10 equivalents, based on the
compound of formula I.
23-24. (canceled)
25. A process according to claim 1, wherein X is Br; R.sub.2 and
R.sub.3 are independently H, methyl or ethyl; R.sub.6 is
NR.sub.4R.sub.5; wherein R.sub.4 and R.sub.5 are both C.sub.3
alkyl; and R.sub.1 is C.sub.1-C.sub.4 alkyl.
26. A compound of the formula: ##STR29## wherein: R.sub.1 is is OH,
imidazolyl, halogen, --OC(O)CH.sub.3, OC(O)CF.sub.3; ##STR30##
R.sub.2 and R.sub.3 are independently H or C.sub.1-C.sub.4 alkyl;
and R.sub.4 and R.sub.5 are independently C.sub.1-C.sub.6
alkyl.
27. A compound according to claim 26, wherein R.sub.2 and R.sub.3
are independently H or methyl.
28. A compound according to claim 27, wherein R.sub.4 and R.sub.5
are both C.sub.3 alkyl.
29-31. (canceled)
32. A compound according to claim 28, wherein R.sub.1 is
##STR31##
33. A process for preparing compounds of the formula: ##STR32##
wherein R.sub.10 is
--(CH.sub.2).sub.1-2--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl),
--CH.sub.2--CH.sub.2--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), or
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
groups independently selected from halogen, --F, --Cl, --Br, --I,
--OH, .dbd.O, --SH, --C.ident.N, --CF.sub.3, --C.sub.1-C.sub.3
alkoxy, amino, mono- or dialkylamino, --N(R)C(O)R'--,
--OC(.dbd.O)-amino and --OC(.dbd.O)-mono- or dialkylamino, or
C.sub.2-C.sub.6 alkenyl or C.sub.2-C.sub.6 alkynyl, each of which
is optionally substituted with 1, 2, or 3 groups independently
selected from halogen, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, amino, and mono-
or dialkylamino, or aryl, heteroaryl, heterocyclyl,
--C.sub.1-C.sub.6 alkyl-aryl, --C.sub.1-C.sub.6 alkyl-heteroaryl,
or --C.sub.1-C.sub.6 alkyl-heterocyclyl, where the ring portions of
each are optionally substituted with 1, 2, 3, or 4 groups
independently selected from halogen, --F, --Cl, --Br, --I, --OH,
--SH, --C.ident.N, -NR.sub.105R'.sub.105, --CO.sub.2R, --N(R)COR',
or --N(R)SO.sub.2R', --C(.dbd.O)--(C.sub.1-C.sub.4)alkyl,
--SO.sub.2-amino, --SO.sub.2-mono or dialkylamino,
--C(.dbd.O)-amino, --C(.dbd.O)-mono or dialkylamino,
--SO.sub.2--(C.sub.1-C.sub.4) alkyl, or C.sub.1-C.sub.6 alkoxy
optionally substituted with 1, 2, or 3 groups which are
independently selected from selected from halogen, or
C.sub.3-C.sub.7 cycloalkyl optionally substituted with 1, 2, or 3
groups independently selected from halogen, --F, --Cl, --Br, --I,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, amino,
--C.sub.1-C.sub.6 alkyl and mono- or dialkylamino, or
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
groups independently selected from halogen, --F, --Cl, --Br, --I,
--OH, --SH, --C.ident.N, --CF.sub.3, --C.sub.1-C.sub.3 alkoxy,
amino, mono- or dialkylamino and --C.sub.1-C.sub.3 alkyl, or
C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, each of which
is optionally substituted with 1, 2, or 3 groups independently
selected from halogen, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, amino,
C.sub.1-C.sub.6 alkyl and mono- or dialkylamino; and the
heterocyclyl group is optionally further substituted with oxo; R
and R' independently are hydrogen, C.sub.1-C.sub.10 alkyl,
C.sub.1-C.sub.10 alkylaryl or C.sub.1-C.sub.10 alkylheteroaryl;
R.sub.20 is selected from the group consisting of H;
C.sub.1-C.sub.6 alkyl, optionally substituted with 1, 2, or 3
substituents that are independently selected from the group
consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b; --(CH.sub.2).sub.0-4-aryl;
--(CH.sub.2).sub.0-4-heteroaryl; C.sub.2-C.sub.6 alkenyl;
C.sub.2-C.sub.6 alkynyl; --CONR.sub.N-2R.sub.N-3;
--SO.sub.2NR.sub.N-2R.sub.N-3; --CO.sub.2H; and
--CO.sub.2--(C.sub.1-C.sub.4 alkyl); wherein R.sub.1-a and
R.sub.1-b are independently --H or C.sub.1-C.sub.6 alkyl; R.sub.30
is selected from the group consisting of H; C.sub.1-C.sub.6 alkyl,
optionally substituted with 1, 2, or 3 substituents independently
selected from the group consisting of C.sub.1-C.sub.3 alkyl,
halogen, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b; --(CH.sub.2).sub.0-4-aryl;
--(CH.sub.2).sub.0-4-heteroaryl; C.sub.2-C.sub.6 alkenyl;
C.sub.2-C.sub.6 alkynyl; --CO--NR.sub.N-2R.sub.N-3;
--SO.sub.2--NR.sub.N-2R.sub.N3; --CO.sub.2H; and
--CO--O--(C.sub.1-C.sub.4 alkyl), or R.sub.20, R.sub.30 and the
carbon to which they are attached form a carbocycle of three thru
seven carbon atoms, wherein one carbon atom is optionally replaced
by a group selected from --O--, --S--, --SO.sub.2--, or
--NR.sub.N-2--; R.sub.N-2 and R.sub.N-3 at each occurrence are
independently selected from the group consisting of
--C.sub.1-C.sub.8 alkyl optionally substituted with 1, 2, or 3
groups independently selected from the group consisting of --OH,
--NH.sub.2, phenyl and halogen; --C.sub.3-C.sub.8 cycloalkyl;
--(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.8 cycloalkyl);
--(C.sub.1-C.sub.6 alkyl)-O+(C.sub.1-C.sub.3 alkyl);
--C.sub.2-C.sub.6 alkenyl; --C.sub.2-C.sub.6 alkynyl;
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond; aryl; heteroaryl; heterocycloalkyl; or R.sub.N-2, R.sub.N-3
and the nitrogen to which they are attached form a 5, 6, or 7
membered heterocycloalkyl or heteroaryl group, wherein said
heterocycloalkyl or heteroaryl group is optionally fused to a
benzene, pyridine, or pyrimidine ring, and said groups are
unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that at
each occurrence are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, halo C.sub.1-C.sub.6 alkyl, halo
C.sub.1-C.sub.6 alkoxy, --CN, --NO.sub.2, --NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl), N(C.sub.1-C.sub.6 alkyl)
(C.sub.1-C.sub.6 alkyl), --OH, --C(O)NH.sub.2,
--C(O)NH(C.sub.1-C.sub.6 alkyl), --C(O)N(C.sub.1-C.sub.6 alkyl)
(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 thioalkoxy, and C.sub.1-C.sub.6 thioalkoxy
C.sub.1-C.sub.6 alkyl; R.sub.c is hydrogen,
--(CR.sub.245R.sub.250).sub.0-4-aryl,
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl,
--(CR.sub.245R.sub.250).sub.0-4-heterocyclyl,
--(CR.sub.245R.sub.250).sub.0-4-aryl-heteroaryl,
--(CR.sub.245R.sub.250).sub.0-4-aryl-heterocyclyl,
--(CR.sub.245R.sub.250).sub.0-4-aryl-aryl,
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl-aryl,
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl-heterocyclyl,
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl-heteroaryl,
--(CR.sub.245R.sub.250).sub.0-4-heterocyclyl-heteroaryl,
--(CR.sub.245R.sub.250).sub.0-4-heterocyclyl-heterocyclyl,
--(CR.sub.245R.sub.250).sub.0-4-heterocyclyl-aryl,
--[C(R.sub.255)(R.sub.260)].sub.1-3--CO--N--(R.sub.255).sub.2,
--CH(aryl).sub.2, --CH(heteroaryl).sub.2, --CH(heterocyclyl).sub.2,
--CH(aryl)(heteroaryl), --(CH.sub.2).sub.0-1--CH(
CH.sub.2).sub.0-6--OH)--(CH.sub.2).sub.0-1aryl,
--(CH.sub.2).sub.0-1--CH((CH.sub.2).sub.0-6--OH--(CH.sub.2).sub.0-1-heter-
oaryl, --CH(-aryl or -heteroaryl)--CO--O(C.sub.1-C.sub.4 alkyl),
--CH(--CH.sub.2--OH)--CH(OH)-phenyl-NO.sub.2, (C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-OH;
--CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2-CH.sub.3).sub.2,
--(CH.sub.2).sub.0-6--C(.dbd.NR.sub.235)(NR.sub.235R.sub.240), or
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
groups independently selected from the group consisting of
R.sub.205, --OC.dbd.ONR.sub.235R.sub.240,
--S(.dbd.O).sub.0-2(C.sub.1-C.sub.6 alkyl), --SH,
--NR.sub.235C.dbd.ONR.sub.235R.sub.240,
--C.dbd.ONR.sub.235R.sub.240, and
--S(.dbd.O).sub.2NR.sub.235R.sub.240, or
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.8) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of R.sub.205,
--CO.sub.2H, and --CO.sub.2--(C.sub.1-C.sub.4 alkyl), or
cyclopentyl, cyclohexyl, or cycloheptyl ring fused to aryl,
heteroaryl, or heterocyclyl wherein one, two or three carbons of
the cyclopentyl, cyclohexyl, or cycloheptyl is optionally replaced
with a heteroatom independently selected from NH, NR.sub.215, O, or
S(.dbd.O).sub.0-2, and wherein the cyclopentyl, cyclohexyl, or
cycloheptyl group can be optionally substituted with one or two
groups that are independently R.sub.205, .dbd.O,
--CO--NR.sub.235R.sub.240, or --SO.sub.2--(C.sub.1-C.sub.4 alkyl),
or C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl, each of
which is optionally substituted with 1, 2, or 3 R.sub.205 groups,
wherein each aryl and heteroaryl is optionally substituted with 1,
2, or 3 R.sub.200, and wherein each heterocyclyl is optionally
substituted with 1, 2, 3, or 4 R.sub.210; R.sub.200 at each
occurrence is independently selected from --OH, --NO.sub.2,
halogen, --CO.sub.2H, C.ident.N,
--(CH.sub.2).sub.0-4--CO--NR.sub.220R.sub.225,
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl),
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl),
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl),
--(CH.sub.2).sub.0-4--CO--(C.sub.3-C.sub.7 cycloalkyl),
--(CH.sub.2).sub.0-4--CO-aryl, --(CH.sub.2).sub.0-4--CO-heteroaryl,
--(CH.sub.2).sub.0-4--CO-heterocyclyl,
--(CH.sub.2).sub.0-4--CO--O--R.sub.215,
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.220R.sub.225,
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl),
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.12 alkyl),
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.7 cycloalkyl),
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--CO--O--R.sub.215,
--(CH.sub.2).sub.0-4-N(H or R.sub.215)--CO--N(R.sub.215).sub.2,
--(CH.sub.2).sub.0-4--N--CS--N(R.sub.215).sub.2,
--(CH.sub.2).sub.0-4--N(--H or R.sub.215)--CO--R.sub.220,
--(CH.sub.2).sub.0-4--NR.sub.220R.sub.225,
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl),
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.240).sub.2,
--(CH.sub.2).sub.0-4--O--C--N(R.sub.215).sub.2,
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.215).sub.2,
--(CH.sub.2).sub.0-4--O--(R.sub.215),
--(CH.sub.2).sub.0-4--O--(R.sub.215)--COOH,
--(CH.sub.2).sub.0-4--S--(R.sub.215),
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, 3, or 5 --F), C.sub.3-C.sub.7 cycloalkyl,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)-SO.sub.2--R.sub.220,
--(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl, or
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
R.sub.205 groups, or C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10
alkynyl, each of which is optionally substituted with 1 or 2
R.sub.205 groups, wherein the aryl and heteroaryl groups at each
occurrence are optionally substituted with 1, 2, or 3 groups that
are independently R.sub.205, R.sub.210, or C.sub.1-C.sub.6 alkyl
substituted with 1, 2, or 3 groups that are independently R.sub.205
or R.sub.210, and wherein the heterocyclyl group at each occurrence
is optionally substituted with 1, 2, or 3 groups that are
independently R.sub.210; R.sub.205 at each occurrence is
independently selected from C.sub.1-C.sub.6 alkyl, halogen, --OH,
--O-phenyl, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy,
NH.sub.2, NH(C.sub.1-C.sub.6 alkyl) or N--(C.sub.1-C.sub.6 alkyl)
(C.sub.1-C.sub.6 alkyl); R.sub.210 at each occurrence is
independently selected from halogen, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, --NR.sub.220R.sub.225, OH, C.ident.N,
--CO--(C.sub.1-C.sub.4 alkyl), SO.sub.2--NR.sub.235R.sub.240,
--CO--NR.sub.235R.sub.240, --SO.sub.2--(C.sub.1-C.sub.4 alkyl),
.dbd.O, or C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl or C.sub.3-C.sub.7 cycloalkyl, each of
which is optionally substituted with 1, 2, or 3 R.sub.205 groups;
R.sub.215 at each occurrence is independently selected from
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.0-2-(aryl), C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.7 cycloalkyl, and
(CH.sub.2).sub.0-2-(heteroaryl),
--(CH.sub.2).sub.0-2-(heterocyclyl), wherein the aryl group at each
occurrence is optionally substituted with 1, 2, or 3 groups that
are independently R.sub.205 or R.sub.210, and wherein the
heterocyclyl and heteroaryl groups at each occurrence are
optionally substituted with 1, 2, or 3 R.sub.210; R.sub.220 and
R.sub.225 at each occurrence are independently selected from --H,
--C.sub.3-C.sub.7 cycloalkyl, --(C.sub.1-C.sub.2
alkyl)-(C.sub.3-C.sub.7 cycloalkyl), --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.3 alkyl), --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkyl chain with one
double bond and one triple bond, -aryl, -heteroaryl, and
-heterocyclyl, or --C.sub.1-C.sub.10 alkyl optionally substituted
with --OH, --NH.sub.2 or halogen, wherein the aryl, heterocyclyl
and heteroaryl groups at each occurrence are optionally substituted
with 1, 2, or 3 R.sub.270 groups R.sub.235 and R.sub.240 at each
occurrence are independently H, or C.sub.1-C.sub.6 alkyl; R.sub.245
and R.sub.25o at each occurrence are independently selected from
--H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkylaryl,
C.sub.1-C.sub.4 alkylheteroaryl, C.sub.1-C.sub.4 hydroxyalkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy,
--(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, and phenyl; or R.sub.245 and
R.sub.250 are taken together with the carbon to which they are
attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon atoms,
where one carbon atom is optionally replaced by a heteroatom
selected from --O--, --S--, --SO.sub.2--, and --NR.sub.220--;
R.sub.255 and R.sub.260 at each occurrence are independently
selected from --H,
--(CH.sub.2).sub.1-2--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl),
(C.sub.1-C.sub.4 alkyl)-aryl, --(C.sub.1-C.sub.4 alkyl)-heteroaryl,
--(C.sub.1-C.sub.4 alkyl)-heterocyclyl, -aryl, -heteroaryl,
-heterocyclyl,
--(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-aryl,
--(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-heteroaryl,
--(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-heterocyclyl,
or C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl or --(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl, each
of which is optionally substituted with 1, 2, or 3 R.sub.205
groups, wherein each aryl or phenyl is optionally substituted with
1, 2, or 3 groups that are independently R.sub.205, R.sub.210, or
C.sub.1-C.sub.6 alkyl substituted with 1, 2, or 3 groups that are
independently R.sub.205 or R.sub.210, and wherein each heterocyclyl
is optionally substituted with 1, 2, 3, or 4 R.sub.210; R.sub.265
at each occurrence is independently --O--, --S-- or
--N(C.sub.1-C.sub.6 alkyl)-; R.sub.270 at each occurrence is
independently R.sub.205, halogen C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, NR.sub.235R.sub.240, --OH, --C.ident.N,
--CO--(C.sub.1-C.sub.4 alkyl), _SO.sub.2NR.sub.235R.sub.240,
--CO--NR.sub.235R.sub.240, --SO.sub.2--(C.sub.1-C.sub.4 alkyl),
.dbd.O, or C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl or --(CH.sub.2).sub.0-4-C.sub.3-C.sub.7
cycloalkyl, each of which is optionally substituted with 1, 2, or 3
R.sub.205 groups; comprising forming a reaction mixture comprising
a compound of formula III ##STR33## wherein R.sub.1 is OH,
imidazolyl, halogen or ##STR34## R.sub.2 and R.sub.3 are
independently H, phenyl, or C.sub.1-C.sub.4 alkyl; or R.sub.2 and
R.sub.3 and the carbons to which they are attached form a benzene
ring; and R.sub.6 is C.sub.1-C.sub.6 alkoxy or NR.sub.4R.sub.5;
wherein R.sub.4 and R.sub.5 are independently C.sub.1-C.sub.6
alkyl; and a compound of formula VIII ##STR35## in a solvent.
34. (canceled)
35. A process according to claim 33 wherein the reaction mixture
comprises a base which is pyridine, collidine, di-tertiarybutyl
pyridine, triethylamine, diisopropylethylamine, dimethylamino
pyridine, or lutidine.
36. A process according to claim 35, wherein the reaction mixture
further comprises an additive which is 1, 2, or 3 of the following:
EDCI, HOBT, benzotriazole, HOAT, HATU, or DCC.
Description
[0001] This non-provisional application claims priority from U.S.
Provisional Application Ser. No. 60/390,285 filed Jun. 20, 2002,
and U.S. Provisional Application 60/450,478 filed Feb. 27,
2003.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates to processes for the preparation of
oxazolyl esters which are useful in preparing pharmaceutically
active compounds. The invention further comprises methods of
preparing the final active compounds. The invention further
comprises compounds useful in the preparation of compounds and
pharmaceutical compositions to treat Alzheimer's disease and
related conditions.
[0004] 2. Description of the Related Art
[0005] Synthesis 583 (1996) discloses the coupling of aryl halides
or aryl triflates with an oxazol-2-yl zinc chloride to provide the
corresponding aryl oxazolyl. The invention provides a method for
performing the coupling that unexpectedly affords improved yields
and in many cases, shorter reaction times.
[0006] The methods described herein are also suitable for the
preparation of compounds and/or intermediates disclosed in WO
02/02512.
SUMMARY OF INVENTION
[0007] In a first aspect, the invention provides processes for
preparing compounds of formula III: ##STR2## wherein: [0008]
R.sub.1 is C.sub.1-C.sub.6 alkoxy, or C.sub.1-C.sub.6 alkoxyphenyl;
[0009] R.sub.2 and R.sub.3 are independently H; phenyl optionally
substituted with C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or
dialkylamino; or C.sub.1-C.sub.4 alkyl; or [0010] R.sub.2 and
R.sub.3 and the carbons to which they are attached form a benzo
ring, which is optionally substituted with C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, or dialkylamino; and [0011] R.sub.6 is
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkoxyphenyl or
NR.sub.4R.sub.5; wherein [0012] R.sub.4 and R.sub.5 are
independently C.sub.1-C.sub.6 alkyl or -C.sub.1-C.sub.6
alkylphenyl; [0013] comprising forming a reaction mixture
comprising a compound of formula I: ##STR3## [0014] X is Br, I,
OTf, or OMs; [0015] a compound of formula II: ##STR4##
[0016] a catalyst, an optional additive, and at least one
solvent.
[0017] In a second aspect, the invention provides compounds of
formula III-a: ##STR5## wherein: [0018] R.sub.11 is OH, imidazolyl,
halogen, --OC(O)CH.sub.3, --OC(O)C.sub.2-C.sub.4 alkyl,
--OC(O)CF.sub.3, or ##STR6## [0019] R.sub.2 and R.sub.3 are
independently H; phenyl optionally substituted with C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, or dialkylamino; or C.sub.1-C.sub.4
alkyl; or [0020] R.sub.2 and R.sub.3 and the carbons to which they
are attached form a benzo ring, which is optionally substituted
with C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or
dialkylamino; and [0021] R.sub.6 is C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkoxyphenyl, or NR.sub.4R.sub.5 where R.sub.4 and
R.sub.5 are independently C.sub.1-C.sub.6 alkyl or -C.sub.1-C.sub.6
alkylphenyl.
[0022] Compounds of formula III-a are useful in preparing
pharmaceutically active compounds. For example, the compounds of
formula III-a are useful in preparing various compounds
pharmaceutically active compounds disclosed in published
international application WO 02/02512.
[0023] In a third aspect, the invention provides processes for
preparing compounds of formula XX: ##STR7## wherein [0024] R.sub.10
is --(CH.sub.2).sub.1-2--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), or
[0025] C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or
3 groups independently selected from halogen, --OH, .dbd.O, --SH,
--C.ident., --CF.sub.3,---C.sub.1-C.sub.3 alkoxy, amino, mono- or
dialkylamino, --N(R)C(O)R'--, --OC(.dbd.O)-amino and
--OC(.dbd.O)-mono- or dialkylamino, or [0026] C.sub.2-C.sub.6
alkenyl or C.sub.2-C.sub.6 alkynyl, each of which is optionally
substituted with 1, 2, or 3 groups independently selected from
halogen, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, amino, and mono- or dialkylamino, or [0027] aryl,
heteroaryl, heterocyclyl, --C.sub.1-C.sub.6 alkyl-aryl,
--C.sub.1-C.sub.6 alkyl-heteroaryl, or --C.sub.1-C.sub.6
alkyl.-heterocyclyl, where the ring portions of each are optionally
substituted with 1, 2, 3, or 4 groups independently selected from
halogen, --OH, --SH, --C.ident.N, --NR.sub.105R'.sub.105,
--CO.sub.2R, --NN(R)COR', or --N(R)SO.sub.2R',
--C(.dbd.O)--(C.sub.1-C.sub.4) alkyl, --SO.sub.2-amino,
--SO.sub.2-mono or dialkylamino, --C(.dbd.O)-amino,
--C(.dbd.O)-mono or dialkylamino, --SO.sub.2--(C.sub.1-C.sub.4)
alkyl, or [0028] C.sub.1-C.sub.6 alkoxy optionally substituted with
1, 2, or 3 groups which are independently selected from halogen, or
[0029] C.sub.3-C.sub.7 cycloalkyl optionally substituted with 1, 2,
or 3 groups independently selected from halogen, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, amino,
-C.sub.1C.sub.6 alkyl and mono- or dialkylamino, or [0030]
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
groups independently selected from halogen, --OH, --SH,
--C.ident.N, --CF.sub.3, --C.sub.1-C.sub.3 alkoxy, amino, mono- or
dialkylamino and --C.sub.1-C.sub.3 alkyl, or [0031]
C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl each of which
is optionally substituted with 1, 2, or 3 groups independently
selected from halogen, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, amino, C.sub.1-C.sub.6 alkyl and mono- or
dialkylamino; and the heterocyclyl group is optionally further
substituted with oxo; [0032] R and R' independently are hydrogen,
C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkylaryl or
C.sub.1-C.sub.10 alkylheteroaryl; [0033] R.sub.20 is selected from
the group consisting of H; C.sub.1-C.sub.6 alkyl, optionally
substituted with 1, 2, or 3 substituents that are independently
selected from the group consisting of C.sub.1-C.sub.3 alkyl,
halogen, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b; --(CH.sub.2).sub.0-4-aryl;
--(CH.sub.2).sub.0-4-heteroaryl; C.sub.2-C.sub.6 alkenyl;
C.sub.2-C.sub.6 alkynyl; --CONR.sub.N-2R.sub.N-3;
--SO.sub.2NR.sub.N-2R.sub.N-3; --CO.sub.2H; and
--CO.sub.2--(C.sub.1-C.sub.4 alkyl); wherein [0034] R.sub.1-a and
R.sub.1-b are independently --H or C.sub.1-C.sub.6 alkyl; [0035]
R.sub.30 is selected from the group consisting of H;
C.sub.1-C.sub.6 alkyl, optionally substituted with 1, 2, or 3
substituents independently selected from the group consisting of
C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b;
--(CH.sub.2).sub.0-4-aryl; --(CH.sub.2).sub.0-4-heteroaryl;
C.sub.2-C.sub.6 alkenyl; C.sub.2-C.sub.6 alkynyl;
--CO--NR.sub.N-2R.sub.N-3; --SO.sub.2--NR.sub.N-2R.sub.N-3;
--CO.sub.2H; and --CO--O--(C.sub.1-C.sub.4 alkyl); [0036] or [0037]
R.sub.20, R.sub.30 and the carbon to which they are attached form a
carbocycle of three thru seven carbon atoms, wherein one carbon
atom is optionally replaced by a group selected from --O--, --S--,
--SO.sub.2--, or --NR.sub.N-2--; [0038] R.sub.N-2 and R.sub.N-3 at
each occurrence are independently selected from the group
consisting of --C.sub.1-C.sub.8 alkyl optionally substituted with
1, 2, or 3 groups independently selected from the group consisting
of --OH, --NH.sub.2, phenyl and halogen; --C.sub.3-C.sub.8
cycloalkyl; --(C.sub.1-C.sub.2 alkyl)--(C.sub.3-C.sub.8
cycloalkyl); --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl);
--C.sub.2-C.sub.6 alkenyl; --C.sub.2-C.sub.6 alkynyl;
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond; aryl; heteroaryl; heterocycloalkyl; or [0039] R.sub.N-2,
R.sub.N-3 and the nitrogen to which they are attached form a 5, 6,
or 7 membered heterocycloalkyl or heteroaryl group, wherein said
heterocycloalkyl or heteroaryl group is optionally fused to a
benzene, pyridine, or pyrimidine ring, and said groups are
unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that at
each occurrence are independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, halo C.sub.1-C.sub.6 alkyl, halo
C.sub.1-C.sub.6 alkoxy, --CN, --NO.sub.2, --NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl) , N(C.sub.1-C.sub.6 alkyl)
(C.sub.1-C.sub.6 alkyl), --OH, --C(O)NH.sub.2,
--C(O)NH(C.sub.1-C.sub.6 alkyl), --C(O)N(C.sub.1-C.sub.6 alkyl)
(C.sub.1-C.sub.6 alkyl) , C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 thioalkoxy, and C.sub.1-C.sub.6 thioalkoxy
C.sub.1-C.sub.6 alkyl; [0040] R.sub.c is hydrogen,
--(CR.sub.245R.sub.250).sub.0-4-aryl,
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl,
--(CR.sub.245R.sub.250).sub.0-4-heterocyclyl,
--(CR.sub.245R.sub.250).sub.0-4-aryl-heteroaryl,
--(CR.sub.245R.sub.250).sub.0-4-aryl-heterocyclyl,
--(CR.sub.245R.sub.250).sub.0-4-aryl-aryl,
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl-aryl,
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl-heterocyclyl,
--(CR.sub.245R.sub.250).sub.0-4-heteroaryl-heteroaryl,
--(CR.sub.245R.sub.250).sub.0-4-heterocyclyl-heteroaryl,
--(CR.sub.245R.sub.250).sub.0-4-heterocyclyl-heterocyclyl,
--(CR.sub.245R.sub.250).sub.0-4-heterocyclyl-aryl, --[C (R.sub.255)
(R.sub.260)].sub.1-3--CO--N--(R.sub.255).sub.2, --CH(aryl).sub.2,
--CH(heteroaryl).sub.2, --CH(heterocyclyl).sub.2,
--CH(aryl)(heteroaryl),
--(CH.sub.2).sub.0-1--CH((CH.sub.2).sub.0-6--OH)--(CH.sub.2).sub.0-1-aryl-
,
--(CH.sub.2).sub.0-1-CH((CH.sub.2).sub.0-6--OH--(CH.sub.2).sub.0-1-heter-
oaryl, --CH(-aryl or -heteroaryl) --CO--O(C.sub.1-C.sub.4 alkyl),
--CH(--CH.sub.2--OH)--CH(OH)-phenyl-NO.sub.2, (C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-OH;
--CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2--CH.sub.3).sub.2,
--(CH.sub.2).sub.0-6--C(=NR.sub.235) (NR.sub.235R.sub.240), or
[0041] C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or
3 groups independently selected from the group consisting of
R.sub.205, --OC.dbd.ONR.sub.235R.sub.240,
--S(.dbd.O).sub.0-2(C.sub.1-C.sub.6 alkyl), --SH,
--NR.sub.235C.dbd.ONR.sub.235R.sub.240,
--C.dbd.ONR.sub.235R.sub.240, and
--S(.dbd.O).sub.2NR.sub.235R.sub.240, or [0042]
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.8) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of R.sub.205,
--CO.sub.2H, and --CO.sub.2--(C.sub.1-C.sub.4 alkyl), or [0043]
cyclopentyl, cyclohexyl, or cycloheptyl ring fused to aryl,
heteroaryl, or heterocyclyl wherein one, two or three carbons of
the cyclopentyl, cyclohexyl, or cycloheptyl is optionally replaced
with a heteroatom independently selected from NH, NR.sub.215, O, or
S(.dbd.).sub.0-2, and wherein the cyclopentyl, cyclohexyl, or
cycloheptyl group can be optionally substituted with one or two
groups that are independently R.sub.205, .dbd.O,
--CO--NR.sub.235R.sub.240, or --SO.sub.2--(C.sub.1-C.sub.4 alkyl),
or [0044] C.sub.2-C.sub.10 alkenyl or C.sub.2-C.sub.10 alkynyl,
each of which is optionally substituted with 1, 2, or 3 R.sub.205
groups, wherein [0045] each aryl and heteroaryl is optionally
substituted with 1, 2, or 3 R.sub.200, and wherein each
heterocyclyl is optionally substituted with 1, 2, 3, or 4
R.sub.210; [0046] R.sub.200 at each occurrence is independently
selected from --OH, --NO.sub.2, halogen, --CO.sub.2H, C.ident.N,
--(CH.sub.2).sub.0-4--CO--NR.sub.220R.sub.225,
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl),
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl),
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl),
--(CH.sub.2).sub.0-4--CO--(C.sub.3-C.sub.7 cycloalkyl),
--(CH.sub.2).sub.0-4--CO-aryl, --(CH.sub.2).sub.0-4--CO-heteroaryl,
--(CH.sub.2).sub.0-4--CO-heterocyclyl,
--(CH.sub.2).sub.0-4--CO--O--R.sub.215,
--(CH.sub.2).sub.0-4-SO.sub.2--NR.sub.220R.sub.225,
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl),
--(CH.sub.2).sub.0-4--SO.sub.2-(C.sub.1-C.sub.12 alkyl),
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.7 cycloalkyl),
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--CO--O--R.sub.215,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--CO--N(R.sub.215).sub.2,
--(CH.sub.2) .sub.0-4--N--CS--N(R.sub.215).sub.2,
--(CH.sub.2).sub.0-4--N(--H or R.sub.215)--CO--R.sub.220,
--(CH.sub.2).sub.0-4--NR.sub.220R.sub.225,
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl),
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.240).sub.2,
--(CH.sub.2).sub.0-4--O--CO--N(R.sub.215).sub.2,
--(CH.sub.2).sub.0-4--OCS--N(R.sub.215).sub.2,
--(CH.sub.2).sub.0-4--O--(R.sub.215),
--(CH.sub.2).sub.0-4--O--(R.sub.215)--COOH,
--(CH.sub.2).sub.0-4--S--(R.sub.215),
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, 3, or 5 --F), C.sub.3-C.sub.7 cycloalkyl,
--(CH.sub.2).sub.0-4--N(H or R.sub.215)--SO.sub.2--R.sub.220,
--(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl, or [0047]
C.sub.1-C.sub.10 alkyl optionally substituted with 1, 2, or 3
R.sub.205 groups, or [0048] C.sub.2-C.sub.10 alkenyl or
C.sub.2-C.sub.10 alkynyl, each of which is optionally substituted
with 1 or 2 R.sub.205 groups, wherein [0049] the aryl and
heteroaryl groups at each occurrence are optionally substituted
with 1, 2, or 3 groups that are independently R.sub.205, R.sub.210,
or [0050] C.sub.1-C.sub.6 alkyl substituted with 1, 2, or 3 groups
that are independently R.sub.205 or R.sub.210, and wherein the
heterocyclyl group at each occurrence is optionally substituted
with 1, 2, or 3 groups that are independently R.sub.210; [0051]
R.sub.205 at each occurrence is independently selected from
C.sub.1-C.sub.6 alkyl, halogen, --OH, --O-phenyl, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy, NH.sub.2,
NH(C.sub.1-C.sub.6 alkyl) or N--(C.sub.1-C.sub.6 alkyl)
(C.sub.1-C.sub.6 alkyl); [0052] R.sub.210 at each occurrence is
independently selected from halogen, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, --NR.sub.220R.sub.225, OH, C.ident.N,
--CO--(C.sub.1-C.sub.4 alkyl), _SO.sub.2--NR.sub.235R.sub.240,
--CO--NR.sub.235R.sub.240, --SO.sub.2--(C.sub.1-C.sub.4 alkyl),
.dbd.O, or [0053] C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl or C.sub.3-C.sub.7 lo cycloalkyl, each of
which is optionally substituted with 1, 2, or 3 R.sub.205 groups;
[0054] R.sub.215 at each occurrence is independently selected from
C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.0-2-(aryl), C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.7 cycloalkyl, and
--(CH.sub.2).sub.0-2-(heteroaryl),
--(CH.sub.2).sub.0-2-(heterocyclyl), wherein [0055] the aryl group
at each occurrence is optionally substituted with 1, 2, or 3 groups
that are independently R.sub.205 or R.sub.210, and wherein [0056]
the heterocyclyl and heteroaryl groups at each occurrence are
optionally substituted with 1, 2, or 3 R.sub.210; [0057] R.sub.220
and R.sub.225 at each occurrence are independently selected from
--H, --C.sub.3-C.sub.7 cycloalkyl, --(C.sub.1-C.sub.2
alkyl)-(C.sub.3-C.sub.7 cycloalkyl), --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.3 alkyl), --C.sub.2-C.sub.6 alkenyl,
--C.sub.2-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkyl chain with one
double bond and one triple bond, -aryl, -heteroaryl, and
-heterocyclyl, or [0058] --C.sub.1-C.sub.10 alkyl optionally
substituted with --OH, --NH.sub.2 or halogen, wherein [0059] the
aryl, heterocyclyl and heteroaryl groups at each occurrence are
optionally substituted with 1, 2, or 3 R.sub.270 groups [0060]
R.sub.235 and R.sub.240 at each occurrence are independently H, or
C.sub.1-C.sub.6 alkyl; [0061] R.sub.245 and R.sub.250 so at each
occurrence are independently selected from --H, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkylaryl, C.sub.1-C.sub.4 alkylheteroaryl,
C.sub.1-C.sub.4 hydroxyalkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 haloalkoxy, --(CH.sub.2).sub.0-4--C.sub.3-C.sub.7
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, and
phenyl; or [0062] R.sub.245 and R.sub.250 are taken together with
the carbon to which they are attached to form a carbocycle of 3, 4,
5, 6, or 7 carbon atoms, where one carbon atom is optionally
replaced by a heteroatom selected from --O--, --S--, --SO.sub.2--,
and --NR.sub.220--; [0063] R.sub.255 and R.sub.260 at each
occurrence are independently selected from --H,
--(CH.sub.2).sub.1-2--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl),
(C.sub.1-C.sub.4 alkyl) -aryl, --(C.sub.1-C.sub.4
alkyl)-heteroaryl, --(C.sub.1-C.sub.4 alkyl)-heterocyclyl, -aryl,
-heteroaryl, -heterocyclyl,
--(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-aryl,
--(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-heteroaryl,
--(CH.sub.2).sub.1-4--R.sub.265--(CH.sub.2).sub.0-4-heterocyclyl,
or [0064] C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl or --(CH.sub.2).sub.0-4--C.sub.3-C.sub.7
cycloalkyl, each of which is optionally substituted with 1, 2, or 3
R.sub.205 groups, wherein [0065] each aryl or phenyl is optionally
substituted with 1, 2, or 3 groups that are independently
R.sub.205, R.sub.210, or [0066] C.sub.1-C.sub.6 alkyl substituted
with 1, 2, or 3 groups that are independently R.sub.205 o
R.sub.210, and wherein [0067] each heterocyclyl is optionally
substituted with 1, 2, 3, or 4 R.sub.210; [0068] R.sub.265 at each
occurrence is independently --O--, --S-- or --N(C.sub.1-C.sub.6
alkyl)-; [0069] R.sub.270 at each occurrence is independently
R.sub.205, halogen C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkoxy, NR.sub.235R.sub.240, --OH, --C.ident.N,
--CO--(C.sub.1-C.sub.4 alkyl), _SO.sub.2--NR.sub.235R.sub.240,
--CO--NR.sub.235R.sub.240, --SO.sub.2--(C.sub.1-C.sub.4 alkyl),
.dbd.O, or [0070] C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl or --(CH.sub.2).sub.0-4--C.sub.3-C.sub.7
cycloalkyl, each of which is optionally substituted with 1, 2, or 3
R.sub.205 groups; [0071] comprising forming a reaction mixture
comprising a compound of formula III-a ##STR8## wherein [0072]
R.sub.1 is OH, imidazolyl, halogen, --OC(O)CH.sub.3,
--OC(O)CF.sub.3, or ##STR9## [0073] R.sub.2 and R.sub.3 are
independently H, phenyl, or C.sub.1-C.sub.4 alkyl; or [0074]
R.sub.2 and R.sub.3 and the carbons to which they are attached form
a benzo ring which is optionally substituted with C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, or dialkylamino; and [0075] R.sub.6
is C.sub.1-C.sub.6 alkoxy or NR.sub.4R.sub.5; wherein
[0076] R.sub.4 and R.sub.5 are independently C.sub.1-C.sub.6 alkyl;
[0077] and a compound of formula VIII ##STR10## [0078] in a solvent
with an optional base and an optional additive, such as, for
example, a ligand for the catalyst used in the formulation of
compounds of formula I.
[0079] Compounds of formula VIII can be prepared, for example, as
according to procedures described in published international
application WO 02/02512.
[0080] In still another aspect, the invention provides a process
for converting compounds of formula III into compounds of formula
III-a.
[0081] In yet another aspect, the invention provides compound of
formula III-a: ##STR11## wherein [0082] R.sub.1 is OH, imidazolyl,
halogen, --OC(O)CH.sub.3, --OC(O)CF.sub.3, or ##STR12## [0083]
R.sub.2 and R.sub.3 are independently H, phenyl, or C.sub.1-C.sub.4
alkyl; or [0084] R.sub.2 and R.sub.3 and the carbons to which they
are attached form a benzo ring which is optionally substituted with
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or dialkylamino; and
[0085] R.sub.6 is C.sub.1-C.sub.6 alkoxy or NR.sub.4R.sub.5;
wherein [0086] R.sub.4 and R.sub.5 are independently
C.sub.1-C.sub.6 alkyl.
[0087] The compounds of Formula III-a are useful in preparing the
pharmaceutically active compounds disclosed in WO 02/02512.
[0088] In another aspect, the invention provides a process for the
preparation of the zinc chloride/oxazole adduct of formula II.
DETAILED DESCRIPTION OF THE INVENTION
[0089] As noted above, in one aspect, the invention provides
methods of preparing compounds of formula III using compounds of
formula II.
[0090] In a preferred method for preparing compounds of formula III
using compounds of formula II, the catalyst is a transition metal
catalyst. More preferably, it is a Pt or Pd catalyst. Even more
preferably, it is a Pd(0) catalyst. Still more preferably, the
catalyst is Pd(PPh.sub.3).sub.4, PdCl.sub.2(PPh.sub.3).sub.2,
PdCl.sub.2, PdCl.sub.2 and PPh.sub.3, or Pd(OCOCH.sub.3).sub.2.
Most preferably the catalyst is Pd(PPh.sub.3).sub.4.
[0091] In a preferred method the reaction is carried out in a
solvent. More preferably, the method is carried out in at least one
polar, aprotic solvent. Still more preferably, the solvent is
tetrahydrofuran, tetramethyltetrahydrofuran, glyme, methyl t-butyl
ether, or mixtures thereof. Even more preferably, the solvent is
tetrahydrofuran.
[0092] In a preferred method the reaction is carried out at a
temperature of from about 25.degree. C. to about the refluxing
temperature of the solvent used. More preferably, the temperature
is about 30.degree. C. to about 75.degree. C. Even more preferably,
the temperature is about 40.degree. C. to about 60.degree. C. Still
more preferably, the temperature is 45-55.degree. C.
[0093] All of the reagents can preferably be combined at once,
i.e., at nearly the same time, or within a short time of each
other. In an alternative method, the reaction mixture is formed by
combining the compound of formula I, the compound of formula II,
the catalyst and any additional additive (if necessary) over a
period of about 0.5 hours to about 4 hours, wherein this period is
also known as the addition time. More preferably, the addition time
is about 1 hour to about 3 hours. Even more preferably, the
addition time is about 1.5 hours to about 2.5 hours. Most
preferably it is 2 hours. It should be noted that the compound of
formula I may be added to a mixture containing the compound of
formula II, or vice versa.
[0094] For example, the compound of formula II can be added to the
reaction mixture, e.g. a solution, comprising the compound of
formula I and the catalyst. Or, the compound of formula I, and the
catalyst, can be added to the reaction mixture, e.g. a solution,
comprising the compound of formula II.
[0095] In a preferred method the transition metal catalyst is
present in 0.01 to 20 mole percent, based on the amount of the
compound of formula I. More preferably the catalyst is present in
0.1 to 10 mole percent, based on the amount of the compound of
formula I. Even more preferably, the catalyst is present in 1 to 7
mole percent, based on the amount of the compound of formula I.
[0096] In a preferred method, after all of the compounds and
reagents have been combined, thereby forming the reaction mixture,
the reaction mixture is heated at the temperatures mentioned above
for about 0.5 to about 24 hours. More preferably, the reaction
mixture is heated for about 0.5 to about 4 hours. Even more
preferably, the reaction mixture is heated for about 0.5 to about
2.25 hours.
[0097] In a preferred method, the compound of formula II is used in
an excess from 1.001 to 10 equivalents, based on the amount of
compound of formula I. Preferably, the compound of formula II is
used in an excess from 1.01 to 5 equivalents, based on the amount
of compound of formula I. Even more preferably, the compound of
formula II is used in an excess from 1.05 to 4 equivalents, based
on the amount of compound of formula I. Still more preferably, the
second compound is used in an excess from 1.1 to 1.7 equivalents,
based on the amount of compound of formula I. In a most preferred
embodiment, about 3 equivalents are utilized.
[0098] In a preferred method of preparing compounds of formula III,
[0099] X is Br; [0100] R.sub.2 and R.sub.3 are independently H,
methyl or ethyl; [0101] R.sub.6 is NR.sub.4R.sub.5 where R.sub.4
and R.sub.5 are both C.sub.3 alkyl; and R.sub.1 is C.sub.1-C.sub.4
alkyl. In this aspect, R.sub.1 is more preferably methyl or
ethyl.
[0102] In another aspect, the invention provides an improved method
for preparing the zinc chloride/oxazole adduct of formula II.
[0103] In a preferred aspect, the compound of formula II is
prepared using solid ZnCl.sub.2. Preferably, 1.1 to about 10
equivalents of ZnCl.sub.2 based on the amount of the particular
oxazole used is used to prepare the compound of formula II. More
preferably, 1.1 to about 5 equivalents of ZnCl.sub.2 is used. Even
more preferably, about 2.5 to about 3.5 equivalents of ZnCl.sub.2
is used.
[0104] Preferred compounds of formula III and formula III-a include
compounds wherein R.sub.2 and R.sub.3 are independently H, methyl,
or phenyl; or R.sub.2, R.sub.3 and the carbons to which they are
attached form a benzo ring. More preferably, R.sub.2 and R.sub.3
are independently H or methyl. Even more preferably, R.sub.2 and
R.sub.3 are both H.
[0105] More preferred compounds of formula III and formula III-a
include compounds wherein R.sub.6 is NR.sub.4R.sub.5 where R.sub.4
and R.sub.5 are both C.sub.3 alkyl or R.sub.4 and R.sub.5 are
independently C.sub.1-C.sub.4 alkyl or benzyl. Preferably, R.sub.4
and R.sub.5 are both C.sub.3 alkyl. Alternatively, R.sub.4 and
R.sub.5 are independently C.sub.1-C.sub.4 alkyl or benzyl.
[0106] Even more preferred compounds of formula III-a include
compounds wherein R.sub.6 is NR.sub.4R.sub.5 where R.sub.4 and
R.sub.5 are both C.sub.3 alkyl or R.sub.4 and R.sub.5 are
independently C.sub.1-C.sub.4 alkyl or benzyl. Preferably R.sub.4
and R.sub.5 are both C.sub.3 alkyl. Alternatively, R.sub.4 and
R.sub.5 are independently C.sub.1-C.sub.4 alkyl or benzyl; and
R.sub.1 is OH.
[0107] Even more preferred compounds of formula III include
compounds wherein R.sub.6 is NR.sub.4R.sub.5 wherein R.sub.4-and
R.sub.5 are both C.sub.3 alkyl or R.sub.4 and R.sub.5 are
independently C.sub.1-C.sub.4 alkyl or benzyl. Preferably R.sub.4
and R.sub.5 are both C.sub.3 alkyl. Alternatively, R.sub.4 and
R.sub.5 are independently C.sub.1-C.sub.4 alkyl or benzyl; and
R.sub.1 is C.sub.1-C.sub.4 alkoxy, more preferably R.sub.1 is
methyl or ethyl. Even more preferably, R.sub.11 is methyl.
[0108] Even more preferred compounds of formula III-a include
compounds wherein R.sub.6 is NR.sub.4R.sub.5 where R.sub.4 and
R.sub.5 are both C.sub.3 alkyl or R.sub.4 and R.sub.5 are
independently C.sub.1-C.sub.4 alkyl or benzyl. Preferably R.sub.4
and R.sub.5 are both C.sub.3 alkyl. Alternatively, R.sub.4 and
R.sub.5 are independently C.sub.1-C.sub.4 alkyl or benzyl; and
R.sub.1 is halogen, more preferably R.sub.1 is chloro.
[0109] Even more preferred compounds of formula III-a include
compounds wherein [0110] R.sub.16 is NR.sub.4R.sub.5; wherein
[0111] R.sub.4 and R.sub.5 are both C.sub.3 alkyl or R.sub.4 and
R.sub.5 are independently C.sub.1-C.sub.4 alkyl or benzyl.
[0112] Preferably R.sub.4 and R.sub.5 are both C.sub.3 alkyl.
Alternatively, R.sub.4 and R.sub.5 are independently
C.sub.1-C.sub.4 alkyl or benzyl; and [0113] R.sub.1 is ##STR13##
--OC(O)CH.sub.3, or --OC(O)CF.sub.3.
[0114] In another aspect, preferred compounds of formula III and
formula III-a are those compounds wherein R.sub.6 is
C.sub.1-C.sub.6 alkoxy or C.sub.1-C.sub.6 alkoxyphenyl, more
preferably R.sub.6 is C.sub.1-C.sub.4 alkoxy or benzyloxy. Still
more preferably, R.sub.6 is methoxy or ethoxy. Even more
preferably, R.sub.6 is methoxy.
[0115] Other preferred compounds of formula III-a include those
where R.sub.2 and R.sub.3 are independently H, phenyl, or
C.sub.1-C.sub.4 alkyl; or R.sub.2 and R.sub.3 and the carbons to
which they are attached form a benzene ring which is optionally
substituted with C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or
dialkylamino; and R.sub.6 is C.sub.1-C.sub.6 alkoxy or
NR.sub.4R.sub.5; wherein R.sub.4 and R.sub.5 are independently
C.sub.1-C.sub.6 alkyl;
[0116] Still other preferred compounds of formula III-a include
those compounds wherein R.sub.2 and R.sub.3 are independently H,
phenyl, or C.sub.1-C.sub.4 alkyl.
[0117] Other preferred compounds of formula III-a are those wherein
R.sub.6 is NR.sub.4R.sub.5 wherein R.sub.4 and R.sub.5 are
C.sub.1-C.sub.6 alkyl.
[0118] Still other preferred compounds of formula III-a are those
wherein R.sub.2 and R.sub.3 are independently H, phenyl, or
C.sub.1-C.sub.4 alkyl; and R.sub.6 is NR.sub.4R.sub.5; wherein
R.sub.4 and R.sub.5 are C.sub.1-C.sub.6 alkyl.
[0119] Still other preferred compounds of formula III-a are those
wherein R.sub.1 is OH.
[0120] Still other preferred compounds of formula III-a are those
wherein R.sub.1 is OH; and R.sub.2 and R.sub.3 are independently H,
phenyl, or C.sub.1-C.sub.4 alkyl. More preferably when R.sub.1 is
OH, R.sub.2 and R.sub.3 are independently H, methyl or ethyl. Also
preferred when R.sub.1 is OH are compounds wherein R.sub.2 and
R.sub.3 are independently H or phenyl.
[0121] Still other preferred compounds of formula III-a are those
wherein R.sub.1 is OH; and R.sub.2 and R.sub.3 are independently H,
phenyl, or C.sub.1-C.sub.4 alkyl. More preferably R.sub.2 and
R.sub.3 are independently H, methyl or ethyl. Also preferred are
the compounds wherein R.sub.2 and R.sub.3 are independently H or
phenyl; and R.sub.6 is NR.sub.4R.sub.5; wherein R.sub.4 and R.sub.5
are C.sub.1-C.sub.6 alkyl. More preferably, R.sub.4 and R.sub.5 are
both C.sub.3 alkyl. Also preferred is when R.sub.4 and R.sub.5 are
both C.sub.2 alkyl. Also preferred is when R.sub.4 and R.sub.5 are
both C.sub.4 alkyl.
[0122] As noted above, the invention provides a process for
preparing a compound of formula XX.
[0123] In one aspect, the process for preparing compounds of
formula XX is carried out in a solvent. Preferably, the solvent is
THF, DMF, CH.sub.2Cl.sub.2, CHC.sub.13, or a mixture thereof.
Useful co-solvents include hexanes, heptane, n-methylpyrrolidine,
trifluoroethane, tetramethyltetrahydrofuran, and cyclohexane.
[0124] The optional base is typically an amine, preferably a
tertiary amine. Examples of suitable amine bases are selected from
pyridine, collidine, ditertiarybutyl pyridine, triethylamine,
diisopropylethylamine, dimethylamino pyridine, lutidine and
mixtures thereof.
[0125] The optional additive is typically am amide coupling agent.
Examples of suitable amide coupling agents are 1, 2, or 3 of the
following l-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (also known as EDC and/or EDCl),
1-hydroxybenzotriazole hydrate (HOBT), benzotriazole,
1-hydroxy-7-azabenzotriazole (HOAT),
O-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethyluronium
hexafluorophosphate (HATU),
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU), PYBop, Bop, BopCl, or
1,3-dicyclohexylcarbodiimide (DCC).
[0126] The reaction is preferably carried out for about 0.5 to
about 24 hours. More preferred reaction times are about 2 hours to
about 16 hours.
[0127] Preferably, the reaction is carried out a temperature of
about --5.degree. C. to about 70.degree. C. More preferably at a
temperature of about 0.degree. C. to about 50.degree. C. Even more
preferably, at a temperature of about 15.degree. C. to about
40.degree. C. Still more preferably at a temperature of about
20.degree. C to about 40.degree. C.
[0128] In another aspect, the compound of formula III-a is used in
excess, based on the amount of the compound of formula VIII.
Preferably about 1.01 to about 5 equivalents of the compound of
formula III-a are used. More preferably, from about 1.1 to about 3
equivalents of the compound of formula III-a are used.
[0129] In another aspect, when the optional base is present, it is
used 1) catalytically, 2) in a one to one ratio based on the amount
of the compound of formula III-a, or 3) in excess. If used
catalytically about 0.01 to about 0.99 equivalents based on the
amount of the compound of formula III-a can be used. If used in
excess, there are 1.0001 to about 30 equivalents of base are used.
More preferably, 1.001 to about 20 equivalents of base are used.
Still more preferably, 1.01 to about 10 equivalents of base are
used. More preferably, 1.1 to about 5 equivalents of base are used.
However, one skilled in the art will recognize that the exact
amount of base (or even substituting a different base) may be
varied without deviating from the scope of the invention.
[0130] If any of the additives are added, one skilled in the art
will recognize the appropriate amount of the additive that should
be added. The use of such reagents is known in the art of organic
synthesis and medicinal chemistry. It is also known in the art of
peptide synthesis and amide couplings.
DEFINITIONS
[0131] By "alkyl" and "C.sub.1-C.sub.6 alkyl" in the present
invention is meant straight or branched chain alkyl groups having
1-6 carbon atoms, such as, methyl, ethyl, propyl, isopropyl,
n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl,
neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. It is
understood that in cases where an alkyl chain of a substituent
(e.g. of an alkyl, alkoxy or alkenyl group) is shorter or longer
than 6 carbons, it will be so indicated in the second "C" as, for
example, "C.sub.1-C.sub.10" indicates a maximum of 10 carbons.
[0132] By "alkoxy" and "C.sub.1-C.sub.6 alkoxy" in the present
invention is meant straight or branched chain alkyl groups having
1-6 carbon atoms, attached through at least one divalent oxygen
atom, such as, for example, methoxy, ethoxy, propoxy, isopropoxy,
n-butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy,
hexoxy, and 3-methylpentoxy.
[0133] By the term "halogen" in the present invention is meant
fluorine, bromine, chlorine, and iodine.
[0134] By the term, "OTf" is meant --OSO.sub.2CF.sub.3.
[0135] By the term, "OMs" is meant --OSO.sub.2CH.sub.3.
[0136] By the term "halogen" in the present invention is meant
fluorine, bromine, chlorine, and/or iodine.
[0137] "Alkenyl" and "C.sub.2-C.sub.6 alkenyl" means straight and
branched hydrocarbon radicals having from 2 to 6 carbon atoms and
from one to three double bonds and includes, for example, ethenyl,
propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the
like.
[0138] "Alkynyl" and "C.sub.2-C.sub.6 alkynyl" means straight and
branched hydrocarbon radicals having from 2 to 6 carbon atoms and
one or two triple bonds and includes ethynyl, propynyl, butynyl,
pentyn-2-yl and the like.
[0139] As used herein, the term "cycloalkyl" refers to saturated
carbocyclic radicals having three to twelve carbon atoms. The
cycloalkyl can be monocyclic, or a polycyclic fused system.
Examples of such radicals include cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl. Preferred cycloalkyl groups are
cyclopentyl, cyclohexyl, and cycloheptyl. The cycloalkyl groups
herein are unsubstituted or, as specified, substituted in one or
more substitutable positions with various groups. For example, such
cycloalkyl groups may be optionally substituted with, for example,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, hydroxy,
cyano, nitro, amino, mono(C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkoxy, amino(C.sub.1-C.sub.6)alkyl,
mono(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl or
di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl.
[0140] By "aryl" is meant an aromatic carbocyclic group having a
single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or
multiple condensed rings in which at least one is aromatic, (e.g.,
1,2,3,4-tetrahydronaphthyl, naphthyl), which is optionally mono-,
di-, or trisubstituted. Preferred aryl groups of the present
invention are phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl,
dihydronaphthyl, tetralinyl or
6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. The aryl groups herein
are unsubstituted or, as specified, substituted in one or more
substitutable positions with various groups. For example, such aryl
groups may be optionally substituted with, for example,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, hydroxy,
cyano, nitro, amino, mono(C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkoxy, amino(C.sub.1-C.sub.6) alkyl,
mono(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl or
di(C.sub.1-C.sub.6) alkylamino (C.sub.1-C.sub.6) alkyl.
[0141] By "heteroaryl" is meant one or more aromatic ring systems
of 5-, 6-, or 7-membered rings-which includes fused ring systems of
9-11 atoms containing at least one and up to four heteroatoms
selected from nitrogen, oxygen, or sulfur. Preferred heteroaryl
groups of the present invention include pyridinyl, pyrimidinyl,
quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl,
pyrazinyl, isoindolyl-, isoquiliolyl, quinazolinyl, quinoxalinyl,
phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl,
thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl,
benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,
thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl,
imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl,
carbazolyl, beta-carbolinyl, isochromanyl, chromanyl,
tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl,
isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl,
pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,
purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl,
pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl,
dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,
dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl,
coumarinyl, isocoumarinyl, chromonyl, chromanonyl,
pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl,
dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl,
dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl,
benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide,
pyri.dazinyl N-oxide, pyrazinyl N-oxide, qiinolinyl N-oxide,
indolyl N-oxide, indolinyl N-oxide, isoquinolyl. N-oxide,
quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide,
imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl
N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl
N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl
N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, tetrazolyl
N-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide.
The heteroaryl groups herein are unsubstituted or, as specified,
substituted in one or more substitutable positions with various
groups. For example, such heteroaryl groups may be optionally
substituted with, for example, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, hydroxy, cyano, nitro, amino,
mono(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 haloalkoxy, amino(C.sub.1-C.sub.6)alkyl,
mono(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl or
di(C.sub.1-C.sub.6) alkylamino (C.sub.1-C.sub.6) alkyl.
[0142] By "heterocycle", "heterocycloalkyl" or "heterocyclyl" is
meant one or more carbocyclic ring systems of 4-, 5-, 6-, or
7-membered rings which includes fused ring systems of 9-11 atoms
containing at least one and up to four heteroatoms selected from
nitrogen, oxygen, or sulfur. Preferred heterocycles of the present
invention include morpholinyl, thiomorpholinyl, thiomorpholinyl
S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl,
pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl,
tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,
dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,
tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide. The
heterocycle groups herein are unsubstituted or, as specified,
substituted in one or more substitutable positions with various
groups. For example, such heterocycle groups may be optionally
substituted with, for example, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, hydroxy, cyano, nitro, amino,
mono(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 haloalkoxy, amino(C.sub.1-C.sub.6)alkyl,
mono(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
di(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl or .dbd.O.
[0143] The invention provides methods of converting compounds of
formula III into compounds of formula III-a. Such methods are
outlined in schemes B and C (wherein X.sub.1 is as defined below)
and are discussed in more detail below. Methods for converting an
ester into an amide are well known in the art. Such methods
include, for example, base hydrolysis using LiOH, NaOH, or KOH as
the base, or acid hydrolysis using HCl, H.sub.2SO.sub.4,
H.sub.3PO.sub.4, triflic acid, para-toluene sulfonic acid, or
HNO.sub.3. The invention also contemplates the use of two or more
acids in combination or two or more bases in combination to effect
the hydrolysis. Other methods will be readily apparent to one of
skill in the art.
[0144] The conversion of the acid into the acid chloride is
preferably accomplished by using SOCl.sub.2, SO.sub.2Cl.sub.2, or
oxalyl chloride. Other reagents known in the art can be
conveniently used to effect this transformation.
[0145] The conversion of the acid into the imidazolyl compound is
preferably carried out using carbonyl diimidazole (CDI.)
[0146] The conversion of the acid into an acid anhydride is
accomplished by treating the acid with another acid anhydride, such
as acetic anhydride (thereby forming a mixed anhydride), or the
conversion can be effected by dehydrating two acid molecules
through the use of heat or another dehydrating agent. Treatment
with an acid anhydride is more preferable. On an industrial scale,
heating is one preferred method of preparing the anhydride.
[0147] The processes of the invention are outlined in the following
Schemes. ##STR14## ##STR15## ##STR16## ##STR17## ##STR18##
##STR19##
[0148] The oxazolyl ester III can be used in situ or isolated.
Those skilled in the art when trying to remove zinc salts often add
acid so the zinc salts precipitate. Here if acid is added, the
desired oxazolyl ester III will protonate and will also
precipitate. Therefore, it is preferred to work-up the reaction by
adding saturated ammonium chloride solution to the crude reaction
mixture and extracting with a suitable organic solvent such as
ethyl acetate. This work up method allows for the partition of the
oxazolyl ester III into the organic phase with the zinc salts
remaining in the aqueous phase.
[0149] Scheme A illustrates the preparation of the
ZnCl.sub.2/oxazole adduct. The scheme discloses the use of solid
ZnCl.sub.2. Solutions of ZnCl.sub.2 can be used, but solid
ZnCl.sub.2 is preferred. The alkyllithium base used can be
n-butyllithium t-butyllithium, sec-butyllithium, or methyllithium.
N-butyl lithium is preferred. The lithiation of oxazoles has been
described in Hodges, et al., J. Org. Chem. 1991, 56, 449; and
Whitney, S. E., et al., J. Org. Chem. 1991, 56, 3058 and in
references cited therein.
[0150] Scheme B illustrates a reaction between a compound of
formula I (wherein R.sub.6 is di-n-propylamine, X is Br, and R, is
alkoxy) and a zinc chloride/oxazole adduct of formula II to form a
coupled product of formula III. The ester is then hydrolyzed or
otherwise cleaved to form the carboxylic acid.
[0151] Scheme C illustrates the conversion of a carboxylic acid of
formula IV into an acid halide or an imidazolide (compound of
formula V wherein X.sub.1 is Cl or imidazolyl, respectively), or an
acid anhydride (compound of formula VI). Scheme C further
illustrates the coupling of the acid (IV), acid chloride (or
bromide) (V), acid anhydride(VI) or imidazolide (V) with the amine
of formula VIII to generate a compound of formula X. The amine
and/or alcohol in compounds of formula VIII may be protected before
the coupling reaction is performed. One of skill in the art can
determine the need for the use of protecting groups. See for
example, "Protective Groups in Organic Synthesis, third edition" by
Wuts and Green. These couplings are also known to those of skill in
the art. The coupled compounds of formula X are generally disclosed
in International Publication WO 02/02512 based on
PCT/13S01/21012
[0152] International Publication WO02/02512 further discloses that
the substituted amines of formula X are prepared by reacting the RN
acid, acid halide, anhydride or carbonyl imidazole compound with
the corresponding amine of formula VIII.
[0153] Schemes D and E disclose a method for preparing one possible
amine of formula VIII.
[0154] Scheme F illustrates a coupling of a compound of formula I
with an amine of formula VIII to form the amide of formula XI. In
this scheme, it should be noted that the compound of formula I has
not been coupled to the zinc chloride/oxazole adduct before being
coupled to the amine of formula VIII. Compound XI can then be
coupled to the zinc chloride/oxazole adduct to form compound XII.
The protecting group can then be removed to form the compound of
formula X.
[0155] All temperatures are in degrees Celsius.
[0156] CDI refers to 1,1'-carbonyldiimidazole.
[0157] MTBE refers to methyl t-butyl ether.
[0158] TLC refers to thin-layer chromatography.
[0159] HPLC refers to high pressure liquid chromatography.
[0160] Chromatography (column and flash chromatography) refers to
purification/separation of compounds expressed as (support, 10
eluent). It is understood that the appropriate fractions are pooled
and concentrated to give the desired compound(s).
[0161] NMR refers to nuclear (proton) magnetic resonance
spectroscopy, chemical shifts are reported in ppm (d) downfield
from TMS.
[0162] CMR refers to C 13 magnetic resonance spectroscopy, chemical
shifts are reported in ppm (.delta.) downfield from TMS.
[0163] MS refers to mass spectrometry expressed as m/e, m/z or
mass/charge unit. [M+H].sup.+ refers to the positive ion of a
parent plus a hydrogen atom. EI refers to electron impact. CI
refers to chemical ionization. FAB refers to fast atom
bombardment.
[0164] ESMS refers to electrospray mass spectrometry.
[0165] THF refers to tetrahydrofuran.
[0166] Ether refers to diethyl ether.
[0167] Saline refers to an aqueous saturated solution of sodium
chloride.
[0168] Tetrakis(triphenylphosphine) Palladium refers to
Pd(PPh.sub.3).sub.4.
[0169] Pharmaceutically acceptable refers to those properties
and/or substances which are acceptable to the manufacturing
pharmaceutical chemist from a physical/chemical point of view
regarding composition, formulation and stability.
[0170] When solvent pairs are used, the ratios of solvents used are
volume/volume (v/v).
[0171] When the solubility of a solid in a solvent is used the
ratio of the solid to the solvent is weight/volume (wt/v).
[0172] Dichlorobis(triphenyl-phosphine)palladium (II) refers to
(PdCl.sub.2(PPh.sub.3).sub.2). Triphenylphosphine oxide refers to
Ph.sub.3PO.
[0173] Prot refers to a protecting group or hydrogen. Protecting
groups are well known to those skilled in the art. Further
information on protecting groups can be found in, "Protective
Groups in Organic Synthesis, third edition" by Wuts and Green.
[0174] Palladium(O) catalysts are those catalysts containing
palladium with an oxidation state of zero. Palladium(O) catalysts
include, but are not limited to: Pd(PPh.sub.3).sub.4,
PdCl.sub.2(PPh.sub.3).sub.2, PdCl.sub.2, PdCl.sub.2 and PPh.sub.3,
Pd(OCOCH.sub.3).sub.2, and ((o-Tol).sub.3P).sub.2PdCl.sub.2. One
skilled in the art will recognize that some of the fore-mentioned
palladium(O) catalysts contain palladium in an oxidized state, for
example, Pd(II)Cl.sub.2. One skilled in the art readily recognizes
that the palladium(0) species can be generated in situ through the
use of butyllithium, DIBAL-H or other reagents known in the art of
organic synthesis. See for example, Negishi, et al., J. Chem. Soc.,
Chem Commun. 1986, 1338. The preferred palladium(O) catalyst is Pd
(PPh.sub.3).sub.4.
EXAMPLES
[0175] Starting materials are generally readily available from
commercial sources, such as Sigma-Aldrich Corp. (St. Louis, Mo.),
or may be prepared as described herein. The processes shown in the
above schemes and set forth below in the Examples are not to be
construed as limiting the invention in scope or spirit to the
specific reagents and conditions shown in them. Those having skill
in the art will recognize that the starting materials, reagents and
conditions may be varied and additional steps employed in the
processes of the invention and to produce compounds encompassed by
the invention. In some cases, protection of reactive
functionalities may be necessary to achieve the desired
transformations. In general, such need for protecting groups, as
well as the conditions necessary to attach and remove such groups,
will be apparent to those skilled in the art of organic synthesis.
Unless otherwise stated in the schemes below, the variables are as
defined above.
[0176] All references mentioned in this application are
incorporated by reference, in their entirety.
[0177] All reagents are of commercial grade unless otherwise noted.
All reactions are stirred or otherwise agitated. Unless otherwise
stated, none of the solvents were degassed.
Preparation
1t-Butyl(1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethynylphenyl)cyclopropyl-
]amino}-2-hydroxypropylcarbamate
Part (A)--Preparation of bromophenylcyclopropylnitrile (2)
[0178] A mixture of 1-bromo-2-chloroethane (120 ml), 3-bromobenzyl
cyanide (1, 25 g) and benzyl-triethylammonium chloride (1.1 g) is
stirred at 400 while aqueous sodium hydroxide (50%, 120 g) is added
dropwise over approximately 20 min. The reaction temperature rises
to about 800 during the addition of the aqueous base. The reaction
mixture is stirred very vigorous while the temperature slowly drops
to 50.degree. (over about 3 hr). After 3 hours, the reaction
mixture is cooled down to 20-250, water (100 ml) is added and the
mixture stirred for 5 min. The organic phase is separated and the
aqueous phase is extracted with dichloromethane (3.times.). The
combined organic phases are washed with water and dilute
hydrochloric acid. The organic phase is then dried over magnesium
sulfate, filtered and concentrated. The concentrate is purified by
a high vacuum fractionation using short-path set-up and single
receiver. The fractions with bp=108-115.degree./0.1-0.05 mm Hg are
collected; after cooling to 20-25.degree. this liquid
solidified.
Part (B)--Preparation of bromoamide (3)
[0179] The bromophenylcyclopropylnitrile, ((2), part (A), 5.9 g;
26.6 mmol), is dissolved in methanol (150 ml). Potassium hydroxide
(25% aqueous solution, 0.68 ml) and hydrogen peroxide (30%, 35 ml)
are added and the reaction mixture is heated at 550 for 5 hr. The
mixture is concentrated to give the chide bromoamide.
Part (C)--Preparation of bromoacid (4)
[0180] The crude bromoamide ((3), part (B)) is slurried in methanol
(10 ml) and sodium hydroxide (10% aqueous, 150 ml) is added. The
reaction mixture is refluxed for 4.5 hr. The reaction mixture is
then cooled to 20-25.degree., acidified to pH=2 with hydrochloric
acid (15%) and concentrated. The resulting precipitated (6.8 g) is
collected by filtration.
Part (D)--Preparation of acid chloride (5)
[0181] Thionyl chloride (2.73 ml) and benzotriazole (4.47 g) are
dissolved in dry dichloromethane (25 ml.) 22.2 ml (1.25
equivalents) are then added portionwise over several minutes to the
crude bromoacid ((4), part (C), 6.8 g) in dichloromethane (120 ml.)
Before the addition is complete, benzotriazole hydrochloride
started separating out as a white solid. The reaction mixture is
stirred for an additional 15 min and then the solids are filtered
off. The filtrate is stirred with anhydrous magnesium sulfate (2 g)
to destroy an excess reagent. The solids are filtered off and the
filtrate is concentrated under reduced pressure and dried under
high vacuum for approximately 1 hr to afford the desired product
(6.6 g.)
Part (E)--Preparation of bromoamine (6)
[0182] The crude acid chloride ((5), part (D)), is dissolved in dry
acetone (40 ml), cooled to -10.degree. and treated with sodium
azide (4 g in 15 ml of water). After stirring for 1 hr at
-10.degree. the mixture is allowed to warm to 0.degree. and is
poured into cold water (300 ml). The azide is extracted into
smallest possible amount of toluene (about 40 ml). The toluene
phase is separated and washed with water and dried over
Na.sub.2SO.sub.4. The solids are filtered off and the filtrate is
heated cautiously at 100.degree. for 1 hr. Concentrated
hydrochloric acid (about 25 ml) is added through the condenser and
the mixture is refluxed for 15 min. On cooling a precipitate forms
and is filtered off. The filtrate is slightly concentrated, cooled
down and an additional portion of precipitate is collected. The
combined solids are dried to give the desired product (4.1 g) as
the hydrochloride salt.
Part (F)--Preparation of the 3,5-difluorobenzyl-bromo compound
(7)
[0183] The crude bromoamine ((6), part (E), 2 g; 8 mmol) is
dissolved in saturated sodium carbonate (20 ml) and extracted with
dichloromethane (5.times.10 ml). The combined extracts are dried,
and concentrated. The extract containing the bromoamine (1.68 g,
7.92 mmol) is dissolved in isopropanol (20 ml) and BOC
protected-3,5-difluorobenzylepoxide (ii, International Publication
WO02/02512, EXAMPLE 3, 2.36 g, 7.92 mmol) is added. The mixture is
heated to 80.degree. in a sealed tube for 16 hours. The reaction
mixture is concentrated to afford the crude
3,5-difluorobenzyl-bromo compound (3.9 g).
Part (G)--Preparation of silyl compound (8)
[0184] Crude 3,5-difluorobenzyl-bromo compound ((7), part (F), 3.9
g; 7.0 mmol; 1 equivalent) is dissolved in triethylamine (20 ml.)
Dichlorobis(triphenyl-phosphine)palladium (II) (0.196 g, 0.28 mmol;
0.04 equivalents) and CuI (b.068 g; 0.36 mmol; 0.05 equivalents)
are then added. The reaction mixture is heated to reflux and
trimethylsilyl acetylene (0.82 g, 1.2 ml, 8.2 mmol, 1.2 equivalent)
is added in one portion. The reaction mixture is refluxed for 3 hr
under nitrogen, then it is cooled to 20-250 before paxtitioning
between aqueous saturated sodium carbonate and ethyl acetate. The
organic phase is separated and the aqueous phase is extracted with
ethyl acetate (3.times.25 ml,). The combined organic extracts are
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated to give the desired silyl compound.
Part (H)--Preparation of BOC protected-acetylene compound (8a)
[0185] Tetrabutylammonium fluoride (1M in THF, 8 ml) is added to a
solution of the crude silyl compound ((8), part (G)) in THF (5 ml).
The reaction mixture is stirred for 1 hr at 20-25.degree. and then
concentrated. The concentrate is dissolved in ether (30 ml), washed
with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The crude product is purified by flash chromatography
(silica gel; ethyl acetate/hexane, 2/3 mixture) to give the title
compound.
Example 1
Methyl
1-[3-[(Dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)]benzoate
[0186] ##STR20##
[0187] Compound 13 may be prepared as follows. n-Butyl lithium (1.4
equivalents) is added drop wise over 30 min to a stirred,
--78.degree. mixture of 1,3-oxazole (1.3 equivalents) in THF, while
maintaining the mixture at a temperature below about -55.degree. C.
15 The mixture is stirred for 30 min and then solid zinc chloride
(3 equivalents ) is added in 3-10 portions over about 10-15
minutes. The cooling bath is then removed, the reaction mixture is
allowed to warm to 20-25.degree. and then the reaction is stirred
for an additional 10 min. Next, the zinc chloride-oxazole adduct,
12, is added over a period of 2 hr to a mixture of methyl
3-bromo-5-[(dipropylamino)carbonyl]benzoate (10, WO02/0251.2,
PREPARATION 3) and tetrakis(triphenylphosphine) palladium (5 mole
%) in THF at 50.degree.. Once the addition is complete, the
reaction is stirred at 50.degree. until no methyl
3-bromo-5-[(dipropylamino)carbonyl]benzoate 10 is observed by HPLC
(usually about 1 hour.)
[0188] HPLC retention time=3.9 min (column: 15 cm luna phenylhexyl;
acetonitrile/water, 0.2M ammonium formate; 65/35, .lamda.=210 nm;
1.0 mL/min).
[0189] The reaction mixture is cooled to 20-25 .degree. and methyl
t-butyl ether and hydrochloric acid (1N) are added. The phases are
separated and the aqueous phase is extracted three times with
methyl L-butyl ether. The combined organic phases are concentrated
under reduced pressure to give a solid. The product is purified
using silica gel chromatography (ethyl acetate/octane, 25/75 to
ethyl acetate/octane 50/50) to give the title compound in 84%
yield; NMR (d.sub.6-DMSO) 8.50, 8.28, 8.10, 7.94, 7.44, 3.90,
3.38-3.14, 1.62-1.49 and 0.99-0.67 .delta.; CMR (d.sub.6-DMSO)
168.56, 164.99, 159.29, 140.98, 138.77, 130.95, 128.41, 127.69,
126.53, 54.91, 52.67, 50.14, 45.93, 21.46, 20.27, 11.30 and 10.80
.delta..
Example 2
Methyl
1-[3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)]benzoate
[0190] ##STR21##
[0191] In a preferred aspect, 13 may be prepared as follows.
n-Butyllithium (405 mL, 1.0 moles, 1.4 equivalents) is added
dropwise over approximately 30 min. to oxazole (50.32 g, 0.73
moles, 1.3 equivalents) in -78.degree. THF, while maintaining the
mixture at a temperature below about -55.degree. C. Zinc chloride
solid (300 g, 2.2 moles, 3 equivalents) is added in 3-10 portions
over about 10-15 minutes and the reaction mixture is warmed to
20-25.degree. by removing the cold bath.
[0192] Once at 20-25.degree., the reaction is stirred for an
additional 10 min. and then methyl
3-bromo-5-[(dipropylamino)carbonyl]benzoate (10, 155 g, 0.45 moles,
1 equivalents) and tetrakis(triphenylphosphine) Palladium (5 mole
%) are added. The reaction mixture is then heated to reflux and
stirred until the starting material has been consumed. Once judged
complete by HPLC, the reaction mixture is cooled to 20-25.degree.
and the crude reaction mixture is concentrated to dryness. To the
resulting solid material is added NH.sub.4Cl and EtOAc. The phases
are separated and the aqueous phase is extracted with ethyl
acetate. The organic layers are combined and washed with saturated
aqueous ammonium chloride. The solvent is removed under reduced
pressure to give the title compound.
[0193] HPLC retention time=3.5 min (column: 15 cm luna phenylhexyl;
acetonitrile/water, 60/40; .lamda.=210 nm; 1.0 mL/min).
[0194] This material may be purified using silica gel
chromatography (ethyl acetate/octane, 25/75 to ethyl acetate/octane
50/50) or be used without purification in the next step.
[0195] An alternative work up for the above reaction is as
follows.
[0196] Once the reaction is complete, the reaction mixture is
cooled to 20-25.degree. C. and concentrated to afford a solid.
EtOAc (1 L) and sat NH.sub.4Cl (1 L) were added to the solid. The
layers were separated and the aqueous layer was extracted with
EtOAc (2.times.100 mL.) The combined organic layers were then
washed with sat NH.sub.4Cl (2.times.100 mL), and concentrated to
afford the desired product.
Example 3
1-[3-[(Dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)]benzoic acid
(14)
[0197] ##STR22##
[0198] Aqueous sodium hydroxide (2N, 120 mL, 4 equivalents) is
added portionwise to a mixture of methyl
1-[3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)]benzoate (13,
EXAMPLE 2) in methanol (300 mL) at 20-25.degree.. The resultant
slurry is stirred at 20-25.degree. for 1 hr at which time the
reaction is judged to be complete by HPLC. Water is then added (3
volumes based on methanol), the layers are separated and the
aqueous layer is extracted with MTBE until no triphenylphosphine
oxide could be detected in the aqueous layer by HPLC. The pH of the
aqueous layer is adjusted to less than one with concentrated
hydrochloric acid and the product is extracted into ethyl acetate
(200 mL). The ethyl acetate phase is separated and is subsequently
distilled under reduced pressure while adding octane, which causes
precipitation of the acid. The resulting solids are collected by
filtration and dried under reduced pressure to give the title
compound.
[0199] HPLC retention time=1.1 min (column: 15 cm luna phenylhexyl;
acetonitrile/water; 60/40; .lamda.=210 nm; 1.0 mL/min).
Example 4
(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethynylphenyl)cyclopropyl]-
amino]butan-2-ol (17)
[0200] ##STR23##
[0201] Acetyl chloride (84 mL, 1.18 moles, 15 equivalents based on
the protected 3,5-difluorobenzyl compound) is added slowly to
stirred methanol (250 mL). (Alternatively, HCl or TFA may be
utilized.) The mixture is stirred for at least 15 min at which time
t-butyl(1S,2R)-1-(3,5-difluorobenzyl)-3-{[l-(3-ethynylphenyl)cyclopropyl]-
amino}-2-hydroxypropylcarbamate (WO02/02512, PREPARATION 1, 37.8 g,
0.08 moles, 1 equivalent) dissolved in methanol (100 mL) is added
slowly. The mixture is then stirred at 20-25.degree. until the
reaction is judged to be complete by HPLC. Once complete, the
methanol is removed under reduced pressure and the resulting
residue is dissolved in water (500 ml,). This mixture is washed
with MTBE (2.times.200 mL) and the combined organic phases are
washed with hydrochloric acid (1N, 100 mL). The pH of the combined
aqueous phases is adjusted to greater than 10 with base and then
extracted with MTBE (2.times.200 mL). The combined organic phases
are then concentrated to dryness under reduced pressure to give the
title compound.
[0202] HPLC retention time=3.9 min (column: 15 cm luna phenylhexyl;
acetonitrile/water, 0.2M ammonium formate; 65/35, .lamda.=210 nm;
1.0 mL/min).
[0203] This product can then be dissolved in THF and used without
purification in the coupling reaction.
Example 5
N.sup.1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxy-
propyl}-5-(1,3-oxazol-2-yl)-N.sup.3,N.sup.3-dipropylisophthalamide
(19)
[0204] ##STR24##
[0205] Solid
1-[3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)]benzoic acid
(14, EXAMPLE 3,1.0 equivalents) is added slowly to CDI (1.3
equivalents) in room temperature THF. The resulting mixture is
stirred for at least 1 hr at which time it is added slowly over 1
hr to a -35.degree. mixture of
(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol
(18, International Publication WO02/02512, 1.0 equivalent) in THF.
After this addition, the reaction is warmed to 0.degree. and
stirred until complete by HPLC. Once judged complete, the contents
are poured into hydrochloric acid (1N) and the aqueous phase is
separated and extracted with ethyl acetate. The combined organic
phases are washed with saturated sodium bicarbonate and the solvent
removed under reduced pressure. The crude product is purified using
silica gel chromatography to afford the title compound.
Example 6
N1-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethynylphenyl)cyclopropyl]amin-
o}-2-hydroxypropyl)-5-(1,3-oxazol-2-yl)-N.sup.3,N.sup.3-dipropylisophthala-
mide (20)
[0206] ##STR25##
[0207] Solid
1-[3-[(Dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)]benzoic acid
(14, EXAMPLE 3, 23 g, 0.08 moles, 1.0 equivalent is added slowly to
a mixture of CDI (14. 6 g, 0.09 moles, 1.3 equivalents) in THF (150
mL). The resultant mixture is stirred at 20-25.degree. for at least
1 hr at which time it is added slowly over 1 hr to a -35.degree.
mixture of
(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethynylphenyl)cyclopropyl-
]aminobutan-2-ol (17, EXAMPLE 4, 28 g, 0.08 moles, 1.0 equivalent)
in THF (300 mL). After this addition is complete, the reaction is
allowed to warm to 0.degree.. Once judged complete, the reaction
mixture is poured into hydrochloric acid (1N, 500 mL.) The aqueous
phase is then separated and extracted with ethyl acetate
(2.times.500 mL). The combined organic extracts are washed with
saturated sodium bicarbonate (250 mL) and then concentrated. The
crude product is purified using silica gel chromatography to afford
the title compound.
HPLC retention time=4.7 min (column: 15 cm luna phenylhexyl,
acetonitrile/water, 0.2 ammonium formate, 65/35, .lamda.=210 nm,
1.0 mL/min).
[0208] The invention and the manner and process of making and using
it, are now described in such full, clear, concise and exact terms
as to enable any person skilled in the art to which it pertains, to
make and use the same. It is to be understood that the foregoing
describes preferred embodiments of the present invention and that
modifications may be made therein without departing from the spirit
or scope of the present invention as set forth in the claims. To
particularly point out and distinctly claim the subject matter
regarded as invention, the following claims conclude this
specification.
* * * * *