U.S. patent application number 09/813546 was filed with the patent office on 2002-04-11 for processesand intermediatesfor preparing substitutedchromanol derivatives.
Invention is credited to Caron, Stephanie, Castaldi, Michael J., Dugger, Robert W., Hawkins, Joel M., Kelly, Sarah E., Piscopio, Anthony, Raggon, Jeffrey W., Ruggeri, Sally G..
Application Number | 20020042526 09/813546 |
Document ID | / |
Family ID | 21831429 |
Filed Date | 2002-04-11 |
United States Patent
Application |
20020042526 |
Kind Code |
A1 |
Piscopio, Anthony ; et
al. |
April 11, 2002 |
Processesand intermediatesfor preparing substitutedchromanol
derivatives
Abstract
The invention relates to processes for preparing a compound of
the formula 1 and the enantiomer of said compound, wherein the
benzoic acid moiety is attached at position 6 or 7 of the chroman
ring, and R.sup.1, R.sup.2, and R.sup.3 are as defined herein. The
invention further relates to intermediates that are useful in the
preparation of the compound of formula X above.
Inventors: |
Piscopio, Anthony;
(Longmount, CO) ; Hawkins, Joel M.; (Old Lyme,
CT) ; Caron, Stephanie; (Groton, CT) ; Kelly,
Sarah E.; (Mystic, CT) ; Raggon, Jeffrey W.;
(Uncasville, CT) ; Castaldi, Michael J.;
(Pawcatuck, CT) ; Dugger, Robert W.; (Stonington,
CT) ; Ruggeri, Sally G.; (Waterford, CT) |
Correspondence
Address: |
Paul H. Ginsburg
Pfizer Inc
20th Floor
235 East 42nd Street
New York
NY
10017-5755
US
|
Family ID: |
21831429 |
Appl. No.: |
09/813546 |
Filed: |
March 21, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09813546 |
Mar 21, 2001 |
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09511475 |
Feb 23, 2000 |
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09511475 |
Feb 23, 2000 |
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09367235 |
Mar 5, 1999 |
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6096906 |
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09367235 |
Mar 5, 1999 |
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PCT/IB97/01024 |
Aug 25, 1997 |
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60026372 |
Sep 16, 1996 |
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Current U.S.
Class: |
549/401 |
Current CPC
Class: |
C07F 5/025 20130101;
C07D 311/22 20130101; C07C 33/50 20130101 |
Class at
Publication: |
549/401 |
International
Class: |
C07D 311/22 |
Claims
What is claimed is:
1. A process of preparing a compound of the formula 54or the
enantiomer of said compound, wherein in said compound of formula X
the R.sup.3-substituted benzoic acid moiety is attached at carbon 6
or 7 of the chroman ring; R.sup.1 is
--(CH.sub.2).sub.qCHR.sup.5R.sup.6 wherein q is 0 to 4; each
R.sup.2 and R.sup.3 is independently selected from the group
consisting of H, fluoro, chloro, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, phenylsulfinyl, phenylsulfonyl, and
--S(O).sub.n(C.sub.1-C.sub.6alkyl) wherein n is 0 to 2, and wherein
said alkyl group, the alkyl moiety of said alkoxy and
--S(O).sub.n(C.sub.1-C.s- ub.6 alkyl) groups, and the phenyl moiety
of said phenylsulfinyl and phenylsulfonyl groups are optionally
substituted by 1 to 3 fluoro groups; R.sup.5 is H, C.sub.1-C.sub.6
alkyl, or phenyl substituted by R.sup.2; R.sup.6 is H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10
aryl, or 5-10 membered heteroaryl, wherein said aryl and heteroaryl
groups are optionally substituted by 1 or 2 substituents
independently selected from phenyl, R.sup.2, and phenyl substituted
by 1 or 2 R.sup.2; which comprises treating a compound of the
formula 55or the enantiomer of said compound of formula IX in the
preparation of the enantiomer of said compound of formula X,
wherein R.sup.1, R.sup.2, and R.sup.3 are as defined above, R.sup.4
is C.sub.1-C.sub.6 alkyl, and the benzoate moiety is attached to
position 6 or 7 of the chroman ring, with a base.
2. The process of claim 1 wherein the compound of formula IX, or
the enantiomer of said compound, is prepared by treating a compound
of the formula 56or the enantiomer of said compound of formula VII
in the preparation of the enantiomer of said compound of formula
IX, wherein R.sup.3 and R.sup.2 are as defined in claim 1 and the
boronic acid moiety is attached at position 6 or 7 of the chroman
ring, with a compound of the formula 57wherein R.sup.3 and R.sup.4
are as defined in claim 1 and Z is halo or C.sub.1-C.sub.4
perfluoroalkylsulfonate, in the presence of a base or fluoride salt
and a palladium catalyst.
3. The process of claim 2 wherein the compound of formula VII, or
the enantiomer of said compound, wherein R.sup.3 and R.sup.2 are as
defined in claim 2, is prepared by treating a compound of the
formula 58or the enantiomer of said compound of formula VI in the
preparation of the enantiomer of said compound of formula VII,
wherein R.sup.1 and R.sup.2 are as defined in claim 2 and X is a
halide and is attached at position 6 or 7 of the chroman ring, with
(1) C.sub.1-C.sub.4 alkyl lithium, and (2) a borating agent.
4. The process of claim 3 wherein the compound of formula VI, or
the enantiomer of said compound, wherein R.sup.1, R.sup.2 and X are
as defined in claim 3, is prepared by treating a compound of the
formula 59or the enantiomer of said compound of formula V in the
preparation of the enantiomer of said compound of formula VI,
wherein R.sup.1, R.sup.2 and X are as defined in claim 3 and X is
attached at position 4 or 5 of the phenyl ring, and Y is halo or
nitro, with a base, optionally in the presence of added copper
salts.
5. The process of claim 4 wherein the compound of formula V, or the
enantiomer of said compound, wherein R.sup.1, R.sup.2, X and Y are
as defined in claim 4, is prepared by treating a compound of the
formula 60or the enantiomer of said compound of formula IV in the
preparation of the enantiomer of said compound of formula V,
wherein R.sup.3, R.sup.2, X and Y are as defined in claim 4 and X
is attached at position 4 or 5 of the phenyl ring, and X.sub.c is a
chiral auxiliary, with a hydride reducing agent.
6. The process of claim 5 wherein the compound of formula IV, or
the enantiomer of said compound, wherein R.sup.1, R.sup.2, X,
X.sub.c and Y are as defined in claim 5, is prepared by treating a
compound of the formula R.sup.1--CH.sub.2C(O)--X.sub.c, wherein
R.sup.1 and X.sub.c are as defined above, with (1) a Lewis acid,
(2) a base, and (3) a compound of formula 61wherein R.sup.2, X and
Y are as defined in claim 5 and X is attached at position 4 or 5 of
the phenyl ring.
7. The process of claim 5 wherein the compound of formula IV, or
the enantiomer of said compound of formula IV, wherein R.sup.1,
R.sup.2, X, X.sub.c and Y are as defined in claim 5, is prepared by
treating a compound of the formula R.sup.1--CH.sub.2C(O)--X.sub.c,
wherein R.sup.1 and X.sub.c are as defined in claim 5, with (1) a
titanium(IV) halide, (2) a base optionally followed by treatment
with a donor ligand, and (3) a compound of formula 62wherein
R.sup.2, X and Y are as defined in claim 5 and X is attached at
position 4 or 5 of the phenyl ring.
8. The process of claim 1 wherein the compound of formula IX, or
the enantiomer of said compound, wherein R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are as defined in claim 1, is prepared by coupling a
compound of the formula 63or the enantiomer of said compound of
formula VI in the preparation of the enantiomer of said compound of
formula IX, wherein R.sup.1 and R.sup.2 are as defined in claim 1
and X', which is attached at position 6 or 7 of the chroman ring,
is halo or C.sub.1-C.sub.4 perfluoroalkylsulfonate, with a compound
of the formula 64wherein R.sup.3 and R.sup.4 are as defined in
claim 1, in the presence of a base or fluoride salt and a palladium
catalyst.
9. The process of claim 8 wherein the compound of formula XIV
wherein R.sup.3 and R.sup.4 are as defined in claim 8, is prepared
by hydrolyzing a compound of the formula 65wherein R.sup.3 and
R.sup.4 are as defined in claim 8, the dashed line indicates a bond
or no bond between the B and N atoms, n and m are independently 2
to 5, and R.sup.8 is H or C.sub.1-C.sub.6 alkyl.
10. The process of claim 9 wherein the compound of formula XVI,
wherein R.sup.3, R.sup.4 and R.sup.8 are as defined in claim 9,
prepared by reacting a compound of formula 66wherein R.sup.3 and
R.sup.4 are as defined in claim 9, with a compound of formula
HO(CH.sub.2).sub.m--N(R.su- p.8)--(CH.sub.2).sub.nOH, wherein n, m,
and R.sup.8 are as defined in claim 9.
11. The process of claim 8 wherein the compound of formula XIV,
wherein R.sup.4 and R.sup.3 are as defined in claim 8, is prepared
by hydrolyzing a compound of the formula 67wherein R.sup.3 and
R.sup.4 are as defined in claim 8 and R.sup.7 is C.sub.1-C.sub.6
alkyl.
12. The process of claim 11 wherein the compound of formula XIII,
wherein R.sup.3, R.sup.4 and R.sup.7 are as defined in claim 11, is
prepared by treating a compound of the formula 68wherein R.sup.3
and R.sup.4 are as defined in claim 11, with a metal amide base in
the presence of tri-(C.sub.1-C.sub.6 alkyl)borate.
13. The process of claim 1 and further comprising reacting the
compound of formula X, or the enantiomer of said compound, wherein
R.sup.1, R.sup.2, and R.sup.3 are as defined in claim 1, with a
secondary amine of the formula NHR.sup.5R.sup.6, wherein R.sup.5
and R.sup.6 are as defined in claim 1, to form an ammonium
carboxylate of the formula 69or the enantiomer of said compound of
formula XVII when prepared from the enantiomer of said compound of
the formula X, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5 and
R.sup.6 are as defined in claim 1.
14. A process of preparing a compound of the formula 70or the
enantiomer of said compound, wherein R.sup.1 is
--(CH.sub.2).sub.qCHR.sup.5R.sup.6 wherein q is 0 to 4; each
R.sup.2 is independently selected from the group consisting of H,
fluoro, chloro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
phenylsulfinyl, phenylsulfonyl, and --S(O).sub.n(C.sub.1-C.sub.6
alkyl) wherein n is 0 to 2, and wherein said alkyl group, the alkyl
moiety of said alkoxy and --S(O).sub.n(C.sub.1-C.s- ub.6 alkyl)
groups, and the phenyl moiety of said phenylsulfinyl and
phenylsulfonyl groups are optionally substituted by 1 to 3 fluoro
groups; R.sup.5 is H, C.sub.1-C.sub.6 alkyl, or phenyl substituted
by R.sup.2; R.sup.6 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.6-C.sub.10 aryl, or 5-10 membered heteroaryl,
wherein said aryl and heteroaryl groups are optionally substituted
by 1 or 2 substituents independently selected from phenyl, R.sup.2,
and phenyl substituted by 1 or 2 R.sup.2; X.sub.c is a chiral
auxiliary; and, R.sup.11 is C.sub.1-C.sub.9 alkyl, C.sub.2-C.sub.9
alkenyl or phenyl substituted by Y in the 2 position, X in the 4 or
5 position, and R.sup.2 in one of the remaining positions of the
phenyl moiety, wherein Y is halo, nitro or C.sub.1-C.sub.4 alkoxy,
and X is a halide, which comprises treating a compound of the
formula R.sup.1--CH.sub.2C(O)--X.sub.c, wherein R.sup.1 and X.sub.c
are as defined above, with (1) a titanium(IV) halide, (2) a base
optionally followed by treatment with a donor ligand, and (3) less
than 2 equivalents of a compound of the formula R.sup.11C(O)H,
wherein R.sup.11 is as defined above, relative to the amount of
said compound of formula R.sup.1--CH.sub.2C(O)--X.sub.c.
15. A compound of the formula 71or the enantiomer of said compound,
wherein R.sup.1 is --(CH.sub.2).sub.qCHR.sup.5R.sup.6 wherein q is
0 to 4; each R.sup.2 is independently selected from the group
consisting of H, fluoro, chloro, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, phenylsulfinyl, phenylsulfonyl, and
--S(O).sub.n(C.sub.1-C.sub.6 alkyl) wherein n is 0 to 2, and
wherein said alkyl group, the alkyl moiety of said alkoxy and
--S(O).sub.n(C.sub.1-C.sub.6 alkyl) groups, and the phenyl moiety
of said phenylsulfinyl and phenylsulfonyl groups are optionally
substituted by 1 to 3 fluoro groups; R.sup.5 is H, C.sub.1-C.sub.6
alkyl, or phenyl substituted by R.sup.2; R.sup.6 is H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10
aryl, or 5-10 membered heteroary, wherein said aryl and heteroaryl
groups are optionally substituted by 1 or 2 substituents
independently selected from phenyl, R.sup.2, and phenyl substituted
by 1 or 2 R.sup.2; X is a halo group and is attached at position 4
or 5 of the phenyl ring; and, Y is halo or nitro.
16. A compound of the formula 72or the enantiomer of said compound,
wherein R.sup.1 is --(CH.sub.2).sub.qCHR.sup.5R.sup.6 wherein q is
0 to 4; each R.sup.2 is independently selected from the group
consisting of H, fluoro, chloro, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, phenylsulfinyl, phenylsulfonyl, and
--S(O).sub.n(C.sub.1-C.sub.6alkyl) wherein n is 0 to 2, and wherein
said alkyl group, the alkyl moiety of said alkoxy and
--S(O).sub.n(C.sub.1C.sub.6 alkyl) groups, and the phenyl moiety of
said phenylsulfinyl and phenylsulfonyl groups are optionally
substituted by 1 to 3 fluoro groups; R.sup.5 is H, C.sub.1-C.sub.6
alkyl, or phenyl substituted by R.sup.2; R.sup.6 is H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10
aryl, or 5-10 membered heteroaryl, wherein said aryl and heteroaryl
groups are optionally substituted by 1 or 2 substituents
independently selected from phenyl, R.sup.2, and phenyl substituted
by 1 or 2 R.sup.2; X' is halo or C.sub.1-C.sub.4
perfluoroalkylsulfonate and is attached at position 6 or 7 of the
chroman ring.
17. A compound of the formula 73or the enantiomer of said compound,
wherein R.sup.1 is --(CH.sub.2).sub.qCHR.sup.5R.sup.8 wherein q is
0 to 4; each R.sup.2 is independently selected from the group
consisting of H, fluoro, chloro, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, phenylsulfinyl, phenylsulfonyl, and
--S(O).sub.n(C.sub.1-C.sub.6 alkyl) wherein n is 0 to 2, and
wherein said alkyl group, the alkyl moiety of said alkoxy and
--S(O).sub.n(C.sub.1-C.sub.6 alkyl) groups, and the phenyl moiety
of said phenylsulfinyl and phenylsulfonyl groups are optionally
substituted by 1 to 3 fluoro groups; R.sup.5 is H, C.sub.1-C.sub.6
alkyl, or phenyl substituted by R.sup.2; R.sup.6 is H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10
aryl, or 5-10 membered heteroaryl, wherein said aryl and heteroaryl
groups are optionally substituted by 1 or 2 substituents
independently selected from phenyl, R.sup.2, and phenyl substituted
by 1 or 2 R.sup.2; and, the boronic acid moiety is attached at
position 6 or 7 of the chroman ring.
18. A compound of the formula 74or the enantiomer of said compound,
wherein the benzoate moiety is attached at carbon 6 or 7 of the
chroman ring; R.sup.1 is --(CH.sub.2).sub.qCHR.sup.5R.sup.6wherein
q is 0 to 4; each R.sup.2 and R.sup.3 is independently selected
from the group consisting of H, fluoro, chloro, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, phenylsulfinyl, phenylsulfonyl, and
--S(O).sub.n(C.sub.1-C.sub.6 alkyl) wherein n is 0 to 2, and
wherein said alkyl group, the alkyl moiety of said alkoxy and
--S(O).sub.n(C.sub.1-C.sub.6 alkyl) groups, and the phenyl moiety
of said phenylsulfinyl and phenylsulfonyl groups are optionally
substituted by 1 to 3 fluoro groups; R.sup.4is C.sub.1-C.sub.6
alkyl; R.sup.5 is H, C.sub.1-C.sub.6 alkyl, or phenyl substituted
by R.sup.2; R.sup.6is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.6-C.sub.10aryl, or 5-10membered heteroaryl,
wherein said aryl and heteroaryl groups are optionally substituted
by 1 or 2 substituents independently selected from phenyl, R.sup.2,
and phenyl substituted by 1 or 2 R.sup.2.
19. A compound of the formula 75wherein R.sup.3 is selected from
the group consisting of H, fluoro, chloro, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, phenylsulfinyl, phenylsulfonyl, and
--S(O).sub.n(C.sub.1-C.sub.6 alkyl) wherein n is 0 to 2, and
wherein said alkyl group, the alkyl moiety of said alkoxy and
--S(O).sub.n(C.sub.1-C.s- ub.6 alkyl) groups, and the phenyl moiety
of said phenylsulfinyl and phenylsulfonyl groups are optionally
substituted by 1 to 3 fluoro groups; R.sup.4 is C.sub.1-C.sub.6
alkyl; and, R.sup.7 is C.sub.1-C.sub.6 alkyl.
20. A compound of the formula 76wherein R.sup.3 is selected from
the group consisting of H, fluoro, chloro, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, phenylsulfinyl, phenylsulfonyl, and
--S(O).sub.n(C.sub.1-C.sub.6 alkyl) wherein n is 0 to 2, and
wherein said alkyl group, the alkyl moiety of said alkoxy and
--S(O).sub.n(C.sub.1-C.s- ub.6 alkyl) groups, and the phenyl moiety
of said phenylsulfinyl and phenylsulfonyl groups are optionally
substituted by 1 to 3 fluoro groups; and, R.sup.4 is
C.sub.1-C.sub.6 alkyl.
21. A compound of the formula 77wherein the dashed line indicates a
bond or no bond between the B and N atoms; n and m are
independently 2 to 5; R.sup.3 is selected from the group consisting
of H, fluoro, chloro, C.sub.1-C.sub.6 alkyl, C.sub.1C.sub.6 alkoxy,
phenylsulfinyl, phenylsulfonyl, and --S(O).sub.n(C.sub.1-C.sub.6
alkyl) wherein n is 0 to 2, and wherein said alkyl group, the alkyl
moiety of said alkoxy and --S(O).sub.n(C.sub.1-C.sub.6 alkyl)
groups, and the phenyl moiety of said phenylsulfinyl and
phenylsulfonyl groups are optionally substituted by 1 to 3 fluoro
groups; R.sup.4 is C.sub.1-C.sub.6 alkyl; and, R.sup.8 is H or
C.sub.1-C.sub.6 alkyl.
22. An ammonium carboxylate of the formula 78or the enantiomer of
said compound, wherein in said carboxylate of formula XVII the
R.sup.3-substituted phenyl moiety is attached at carbon 6 or 7 of
the chroman ring; R.sup.1 is
--(CH.sub.2).sub.qCHR.sup.5R.sup.6wherein q is 0 to 4; each R.sup.2
and R.sup.3 is independently selected from the group consisting of
H, fluoro, chloro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
phenylsulfinyl, phenylsulfonyl, and --S(O).sub.n(C.sub.1-C.sub.6
alkyl) wherein n is 0 to 2, and wherein said alkyl group, the alkyl
moiety of said alkoxy and --S(O).sub.n(C.sub.1-C.sub.6 alkyl)
groups, and the phenyl moiety of said phenylsulfinyl and
phenylsulfonyl groups are optionally substituted by 1 to 3 fluoro
groups; each R.sup.5 is independently H, C.sub.1-C.sub.6 alkyl, or
phenyl substituted by R.sup.2; each R.sup.6 is independently H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10
aryl, or 5-10 membered heteroaryl, wherein said aryl and heteroaryl
groups are optionally substituted by 1 or 2 substituents
independently selected from phenyl, R.sup.2, and phenyl substituted
by 1 or 2 R.sup.2.
23. A compound of the formula 79or the enantiomer of said compound,
wherein X is attached at position 4 or 5 of the phenyl moiety;
R.sup.1 is --(CH.sub.2).sub.qCHR.sup.5R.sup.6 wherein q is 0 to 4;
each R.sup.2 is independently selected from the group consisting of
H, fluoro, chloro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
phenylsulfinyl, phenylsulfonyl, and --S(O).sub.n(C.sub.1-C.sub.6
alkyl) wherein n is 0 to 2, and wherein said alkyl group, the alkyl
moiety of said alkoxy and --S(O).sub.n(C.sub.1-C.sub.6 alkyl)
groups, and the phenyl moiety of said phenylsulfinyl and
phenylsulfonyl groups are optionally substituted by 1 to 3 fluoro
groups; R.sup.3 is H, C.sub.1-C.sub.6 alkyl, or phenyl substituted
by R.sup.2; R.sup.6 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.6-C.sub.6 aryl, or 5-10 membered heteroaryl,
wherein said aryl and heteroaryl groups are optionally substituted
by 1 or 2 substituents independently selected from phenyl, R.sup.2,
and phenyl substituted by 1 or 2 R.sup.2; X is halo; Y is halo or
nitro; and, X.sub.c is a chiral auxiliary.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to the preparation of substituted
chromanol derivatives and to intermediates useful in said
preparation. The substituted chromanol derivatives that are
prepared in accord with the present invention are disclosed in U.S.
patent application Ser. No. 08/295,827, filed Jan. 9, 1995,
entitled "Benzopyran And Related LTB.sub.4 Antagonists," PCT
international application publication number WO 96/11925 (published
Apr. 25, 1996), PCT international application publication number WO
96/11920 (published Apr. 25, 1996), PCT international application
publication number WO 93/15066 (published Aug. 5, 1993). Each of
the foregoing United States and PCT internation patent applications
are incorporated herein by reference in their entirety.
[0002] The substituted chromanol derivatives that are prepared in
accord with the present invention inhibit the action of LTB.sub.4,
as disclosed in U.S. patent application Ser. No. 08/295,827,
referred to above. As LTB.sub.4 antagonists, the substituted
chromanol derivatives that are prepared according to the present
invention are useful in the treatment of LTB.sub.4-induced
illnesses such as inflammatory disorders including rheumatoid
arthritis, osteoarthritis, inflammatory bowel disease, psoriasis,
eczema, erythma, pruritis, acne, stroke, graft rejection,
autoimmune diseases, and asthma.
SUMMARY OF THE INVENTION
[0003] The present invention relates to a process of preparing a
compound of the formula 2
[0004] or the enantiomer of said compound, wherein in said compound
of formula X the R.sup.3-substituted benzoic acid moiety is
attached at carbon 6 or 7 of the chroman ring;
[0005] R.sup.1 is --(CH.sub.2).sub.qCHR.sup.5R.sup.6 wherein q is 0
to 4;
[0006] each R.sup.2 and R.sup.3 is independently selected from the
group consisting of H, fluoro, chloro, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, phenylsulfinyl, phenylsulfonyl, and
--S(O).sub.n(C.sub.1-C.sub.6 alkyl) wherein n is 0 to 2, and
wherein said alkyl group, the alkyl moiety of said alkoxy and
--S(O).sub.n(C.sub.1-C.sub.6 alkyl) groups, and the phenyl moiety
of said phehylsulfinyl and phenylsulfonyl groups are optionally
substituted by 1 to 3 fluoro groups;
[0007] R.sup.5 is H, C.sub.1-C.sub.6 alkyl, or phenyl substituted
by R.sup.2;
[0008] R.sup.6 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.6-C.sub.10 aryl, or 5-10 membered heteroaryl,
wherein said aryl and heteroaryl groups are optionally substituted
by 1 or 2 substituents independently selected from phenyl, R.sup.2,
and phenyl substituted by 1 or 2 R.sup.2;
[0009] which comprises treating a compound of the formula 3
[0010] or the enantiomer of said compound of formula IX in the
preparation of the enantiomer of said compound of formula X,
wherein R.sup.1, R.sup.2, and R.sup.3 are as defined above, R.sup.4
is C.sub.1-C.sub.6 alkyl, and the benzoate moiety is attached to
position 6 or 7 of the chroman ring, with a base.
[0011] In said process of preparing the compound of formula X, the
compound of formula IX is preferably treated with an aqueous
hydroxide base, R.sup.1 is preferably benzyl, 4-fluorobenzyl,
4-phenylbenzyl, 4-(4-fluorophenyl)benzyl, or phenethyl, R.sup.2 is
preferably hydrogen or fluoro, R.sup.3 is preferably fluoro,
chloro, or methyl optionally substituted by 1 to 3 fluorines, and
R.sup.4 is preferably ethyl or 2,2-dimethylpropyl. Most preferably,
said compound of formula IX is treated with a base comprising
aqueous sodium hydroxide, said compound of formula IX is
(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluorometh-
yl-benzoic acid ethyl ester, and said compound of formula X is
(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid-
.
[0012] In a further aspect of the present invention, said compound
of formula IX, or the enantiomer of said compound, wherein R.sup.1,
R.sup.2, R.sup.3, and R.sup.4 are as defined above, is prepared by
treating a compound of the formula 4
[0013] or the enantiomer of said compound of formula VII in the
preparation of the enantiomer of the compound of formula IX,
wherein R.sup.1 and R.sup.2 are as defined above and the boronic
acid moiety is attached at position 6 or 7 of the chroman ring,
with a compound of the formula 5
[0014] wherein R.sup.3 and R.sup.4 are as defined above and Z is
halo or C.sub.1-C.sub.4 perfluoroalkylsulfonate, in the presence of
a base or fluoride salt and a palladium catalyst.
[0015] In said process of making the compound of formula IX, or the
enantiomer of said compound, preferred substituents for R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are as stated above for said process
of making the compound of formula X. In another preferred
embodiment, Z is halo, the base or fluoride salt is selected from
sodium carbonate, triethylamine, sodium bicarbonate, cesium
carbonate, tripotassium phosphate, potassium fluoride, cesium
fluoride, sodium hydroxide, barium hydroxide, and
tetrabutylammonium fluoride, the palladium catalyst is selected
from tetrakis(triphenylphosphine)palladium(0),
dichlorobis(triphenylphosphine)- palladium(II), palladium(II)
acetate, allylpalladium chloride dimer,
tris(dibenzylideneacetone)dipalladium(0), and 10% palladium on
carbon. Most preferably, the base or fluoride salt is potassium
fluoride, the palladium catalyst is 10% palladium on carbon, the
compound of formula VII is
(3S,4R)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronic acid, and the
compound of formula VIII is ethyl
2-iodo-4-trifluoromethyl-benzoate.
[0016] In a further aspect of the invention, the compound of
formula VII, or the enantiomer of said compound, wherein R.sup.1
and R.sup.2 are as defined above, is prepared by treating a
compound of the formula 6
[0017] or the enantiomer of said compound of formula VI in the
preparation of the enantiomer of the compound of formula VII,
wherein R.sup.1 and R.sup.2 are as defined above and X is a halide
and is attached at position 6 or 7 of the chroman ring, with (1)
C.sub.1-C.sub.4 alkyl lithium, and (2) a borating agent.
[0018] In said process of making the compound of formula VII, or
the enantiomer of said compound, preferred substituents for R.sup.1
and R.sup.2 are as stated above for said process of making the
compound of formula X. In another preferred embodiment, X is bromo
or iodo, and said compound of formula VI is treated with (1) methyl
lithium, (2) butyl lithium, and (3) said borating agent which is
selected from borane-tetrahydrofuran complex, triisopropyl borate,
and trimethyl borate. Most preferably, the compound of formula VI
is (3S,4R)-3-benzyl-7-bromo-chroman-4-oland said borating agent is
borane-tetrahydrofuran complex.
[0019] In a further aspect of the invention, the compound of
formula VI, or the enantiomer of said compound, wherein R.sup.1,
R.sup.2 and X are as defined above, is prepared by treating a
compound of the formula 7
[0020] or the enantiomer of said compound of formula V in the
preparation of the enantiomer of the compound of formula VI,
wherein R.sup.1, R.sup.2 and X are as defined above and X is
attached at position 4 or 5 of the phenyl ring, and Y is halo or
nitro, with a base, optionally in the presence of added copper
salts.
[0021] In said process of making the compound of formula VI, or the
enantiomer of said compound, preferred substituents for R.sup.1,
R.sup.2 and X are as stated above for said process of making the
compound of formula VII. In another preferred embodiment, Y is
halo, and said base is potassium tert-butoxide, sodium
bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide,
cesium carbonate, or sodium hydride. Most preferably, said base is
potassium tert-butoxide and the compound of formula V is
(1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-dio-
l.
[0022] In a further aspect of the invention, the compound of
formula V, or the enantiomer of said compound, wherein R.sup.1,
R.sup.2, X and Y are as defined above, is prepared by treating a
compound of the formula 8
[0023] or the enantiomer of said compound of formula IV in the
preparation of the enantiomer of the compound of formula V, wherein
R.sup.1, R.sup.2, X and Y are as defined above and X is attached at
position 4 or 5 of the phenyl ring, and X.sub.c is a chiral
auxiliary, with a hydride reducing agent.
[0024] In said process of making the compound of formula V, or the
enantiomer of said compound, preferred substituents for R.sup.1,
R.sup.2, X and Y are as stated above for said process of making the
compound of formula VI. In another preferred embodiment, X.sub.c is
(R)-4-benzyl-2-oxazolidinone, (S)-4-benzyl-2-oxazolidinone,
(4R,5S)-4-methyl-5-phenyl-oxazolidin-2-one, or
(4S,5R)-4-methyl-5-phenyl-- oxazolidin-2-one,wherein said X.sub.c
is attached at the nitrogen of the oxazolidin-2-one ring, and said
reducing agent is lithium borohydride, lithium aluminum hydride,
sodium borohydride, or calcium borohydride. Most preferably, the
compound of formula IV is [4R-[3(2R,3R)]]-4-benzyl-3-
-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-o-
ne, 1-methyl-2-pyrrolidinone solvate or
[4R-[3(2R,3R)]]-4-benzyl-3-[2-benz-
yl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one,
and said reducing agent is lithium borohydride.
[0025] In a further aspect of the invention, the compound of
formula IV, or the enantiomer of said compound, wherein R.sup.1,
R.sup.2, X, X.sub.c and Y are as defined above, is prepared by
treating a compound of the formula R.sup.1--CH.sub.2C(O)--X.sub.c,
wherein R.sup.1 and X.sub.c are as defined above, with (1) a Lewis
acid, (2) a base, and (3) a compound of formula 9
[0026] wherein R.sup.2, X and Y are as defined above and X is
attached at position 4 or 5 of the phenyl ring.
[0027] In said process of making the compound of formula IV, or the
enantiomer of said compound, preferred substituents for R.sup.1,
R.sup.2, X, X.sub.c and Y are as stated above for said process of
making the compound of formula V. In another preferred embodiment,
said Lewis acid is a boron halide or sulfonate, and said base is
triethylamine or diisopropylethylamine. Most preferably, said
compound of formula R.sup.1--CH.sub.2C(O)--X.sub.c is
(R)-4-benzyl-3-(3-phenyl-propionyl)-oxa- zolidin-2-one,said
compound of formula III is 4-bromo-2-fluoro-benzaldehyd- e, said
Lewis acid is dibutylboron triflate, and said base is
triethylamine.
[0028] In a further aspect of the invention, the compound of
formula IV, or the enantiomer of said compound, wherein R.sup.1,
R.sup.2, X, X.sub.c and Y are as defined above, is prepared by
treating a compound of the formula R.sup.1--CH.sub.2C(O)--X.sub.c,
wherein R.sup.1 and X.sub.c are as defined above, with (1) a
titanium(IV) halide, (2) a base optionally followed by treatment
with a donor ligand, and (3) a compound of formula 10
[0029] wherein R.sup.2, X and Y are as defined above and X is
attached at position 4 or 5 of the phenyl ring.
[0030] In said process of making the compound of formula IV, or the
enantiomer of said compound, preferred substituents for R.sup.1,
R.sup.2, X, X.sub.c and Y are as stated above for said process of
making the compound of formula V. In another preferred embodiment,
said titanium(IV) halide is titanium tetrachloride, and said base
is a tertiary amine or tertiary diamine base. In another preferred
embodiment, said base is triethylamine or
N,N,N',N'-tetramethylethylenediamine,and said treatment with said
base is followed by treatment with a donor ligand selected from
1-methyl-2-pyrrolidinone, dimethylformamide,
1,3-dimethyl-3,4,5,6-tetrahy- dro-2(1H)-pyrimidinone,
triethylphosphate, and 2,2'-dipyridyl. Most preferably, said
compound of formula R.sup.1--CH.sub.2C(O)--X.sub.c is
(R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one,said compound
of formula III is 4-bromo-2-fluoro-benzaldehyde, said base is
N,N,N',N'-tetramethylethylenediamine, and said donor ligand is
1-methyl-2-pyrrolidinone.
[0031] In a further aspect of the invention, said compound of
formula IX, or the enantiomer of said compound, wherein R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are as defined above, is prepared by
coupling a compound of the formula 11
[0032] or the enantiomer of said compound in the preparation of the
enantiomer of the compound of formula IX, wherein R.sup.1 and
R.sup.2 are as defined above and X', which is attached at position
6 or 7 of the chroman ring, is halo or C.sub.1-C.sub.4
perfluoroalkylsulfonate, with a compound of the formula 12
[0033] wherein R.sup.3 and R.sup.4 are as defined above, in the
presence of a base or fluoride salt and a palladium catalyst.
[0034] In the process of preparing the compound of formula IX, or
the enantiomer of said compound, as recited directly above,
preferred substituents for R.sup.1, R.sup.2, R.sup.3 and R.sup.4
are as stated above for the process of making the compound of
formula X. In another preferred embodiment, X' is preferably bromo,
iodo, or trifluoromethanesulfonate, the palladium catalyst is
preferably selected from tetrakis(triphenylphosphine)palladium(0),
dichlorobis(triphenylphosp- hine)palladium(II), palladium(II)
acetate, allylpalladium chloride dimer,
tris(dibenzylideneacetone)dipalladium(0), and 10% palladium on
carbon, and the base or fluoride salt is selected from sodium
carbonate, triethylamine, sodium bicarbonate, cesium carbonate,
tripotassium phosphate, pottasium fluoride, cesium fluoride, sodium
hydroxide, barium hydroxide, and tetrabutylammonium fluoride. Most
preferably, the compound of formula VI is
(3S,4R)-3-benzyl-7-bromo-chroman-4-ol,the compound of formula XIV
is 2-(2,2-dimethyl-propoxycarbonyl-5-trifluoromethyl-benzeneb-
oronic acid, the base or fluoride salt is sodium carbonate, and the
palladium catalyst is tetrakis(triphenylphosphine)palladium(0).
[0035] In a further aspect of the invention, the compound of
formula XIV, wherein R.sup.3 and R.sup.4 are as defined above, is
prepared by hydrolyzing a compound of the formula 13
[0036] wherein R.sup.3 and R.sup.4 are as define above, the dashed
line indicates a bond or no bond between the B and N atoms, n and m
are independently 2 to 5, and R.sup.8 is H or C.sub.1-C.sub.6
alkyl. R.sup.8 is preferably H and preferred substituents for
R.sup.3 and R.sup.4 are as stated above for said process of making
a compound of formula X. Preferably, said hydrolysis is effected
with an acid, such as hydrochloric acid, and n and m are each 2.
Most preferably, said compound of formula XVI is
2-[1,3,6,2]dioxazaborocan-2-yl-4-trifluoromethyl-benzoi- c acid
2,2-dimethyl-propyl ester.
[0037] In a further aspect of the invention, the compound of
formula XVI, wherein R.sup.3, R.sup.4 and R.sup.8 are as defined
above, is prepared by reacting a compound of formula XIV, wherein
R.sup.3 and R.sup.4 are as defined above, with a compound of
formula HO(CH.sub.2).sub.m--N(R.sup.3)-- -(CH.sub.2).sub.nOH
(formula XV), wherein n, m and R.sup.8 are as defined above. In
said process of preparing the compound of formula XVI, preferred
substituents for R.sup.3 and R.sup.4 are as stated above for said
process of preparing a compound of formula X. Most preferably, said
compound of formula XIV is
2-(2,2-dimethyl-propoxycarbonyl)-5-trifluorome- thyl-benzeneboronic
acid and said compound of formula XV is diethanolamine.
[0038] In a further aspect of the invention, the compound of
formula XIV, wherein R.sup.4 and R.sup.3 are as defined above, is
prepared by hydrolyzing a compound of the formula 14
[0039] wherein R.sup.3 and R.sup.4 are as defined above and R.sup.7
is C.sub.1-C.sub.6 alkyl. Said hydrolysis is preferably effected
with an acid, such as hydrochloric acid. Preferred substituents for
R.sup.3 and R.sup.4 are as stated above for said process of making
a compound of formula X.
[0040] In a further aspect of the invention, the compound of
formula XIII, wherein R.sup.3, R.sup.4 and R.sup.7 are as defined
above, is prepared by treating a compound of the formula 15
[0041] wherein R.sup.3 and R.sup.4 are as defined above, with a
metal amide base in the presence of a tri-(C.sub.1-C.sub.6
alkyl)borate.
[0042] In said process of making the compound of formula XIII,
preferred substituents for R.sup.3 and R.sup.4 are as stated above
for said process of making the compound of formula X. In another
preferred embodiment, said metal amide base is selected from
lithium diisopropylamide, lithium diethylamide, lithium
2,2,6,6-tetramethylpiperidine, and
bis(2,2,6,6-tetramethylpiperidino)magnesium, and said
tri-(C.sub.1-C.sub.4alkyl)borate is selected from
triisopropylborate, triethylborate, and trimethylborate. Most
preferably, the compound of formula XII is
4-trifluoromethyl-benzoic acid 2,2-dimethyl-propyl ester, said
metal amide base is lithium diisopropylamide, and said
tri-(C.sub.1-C.sub.6 alkyl)borate is triisopropylborate.
[0043] In a further aspect of the invention, the compound of
formula X, or the enantiomer of said compound, wherein R.sup.1,
R.sup.2, and R.sup.3 are as defined above, is reacted with a
secondary amine of the formula NHR.sup.5R.sup.6, wherein R.sup.5
and R.sup.6 are as defined above, to form an ammonium carboxylate
of the formula 16
[0044] or the enantiomer of said compound of formula XVII, wherein
R.sup.1, R.sup.2, R.sup.3, R.sup.5 and R.sup.6 are as defined
above. Preferred substituents for R.sup.1, R.sup.2, and R.sup.3 are
as stated above for said process of making a compound of formula X.
In said secondary amine, R.sup.5 and R.sup.6 are each preferably
cyclohexyl. Most preferably, said compound of formula XVII is
(3S,4R)-dicyclohexylammonium-
-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl
benzoate.
[0045] The invention also relates to a process of preparing a
compound of the formula 17
[0046] or the enantiomer of said compound, wherein R.sup.1 and
X.sub.c are as defined above for said process of preparing a
compound of formula V, and R.sup.11 is C.sub.1-C.sub.9 alkyl,
C.sub.2-C.sub.9 alkenyl or phenyl substituted by Y in the 2
position, X in the 4 or 5 position, and R.sup.2 in one of the
remaining positions of the phenyl moiety, wherein Y, X and R.sup.2
are as defined above for said process of preparing a compound of
formula V, by treating a compound of the formula
R.sup.1--CH.sub.2C(O)--X- .sub.c, wherein R.sup.1 and X.sub.c are
as defined above, with (1) a titanium(IV) halide, (2) a base
optionally followed by treatment with a donor ligand, and (3) less
than 2 equivalents, preferably about 1 equivalent, of a compound of
the formula R.sup.11--C(O)H, wherein R.sup.11 is as defined above,
relative to the amount of said compound of formula
R.sup.1--CH.sub.2C(O)--X.sub.c. Preferred substituents and reagents
for said process of preparing said compound of formula XIX, or the
enantiomer of said compound, are as stated above for said process
of preparing a compound of formula IV using said titanium(IV)
halide.
[0047] The invention also relates to a compound of the formula
18
[0048] and to the enantiomer of said compound, wherein R.sup.1,
R.sup.2, X and Y are as stated above for said process of preparing
a compound of the formula VI.
[0049] In said compound of formula V, and the enantiomer of said
compound, preferred substituents for R.sup.1, R.sup.2, X and Y are
as stated above for said process of preparing a compound of the
formula VI. Most preferably, said compound of formula V is
(1R,2S)-2-benzyl-1-(4-bromo-2-f-
luoro-phenyl)-propane-1,3-diol.
[0050] The invention also relates to a compound of the formula
19
[0051] and to the enantiomer of said compound, wherein R.sup.1 and
R.sup.2 are as stated above for said compound of formula V and X'
is halo or C.sub.1-C.sub.4 perfluoroalkylsulfonate and is attached
at position 6 or 7 of the chroman ring.
[0052] In said compound of formula VI, and the enantiomer of said
compound, preferred substituents for R.sup.1 and R.sup.2 are as
stated above for said compound of formula V, and X' is preferably
bromo, iodo, or trifluoromethanesulfonate. Most preferably, said
compound of the formula VI is
(3S,4R)-3-benzyl-7-bromo-chroman-4-ol.
[0053] The invention also relates to a compound of the formula
20
[0054] and to the enantiomer of said compound, wherein R.sup.1 and
R.sup.2 are as stated above for said compound of formula VI.
[0055] In said compound of formula VII, and the enantiomer of said
compound, preferred substituents for R.sup.1 and R.sup.2 are as
stated above for said compound of formula VI. Most preferably, said
compound of the formula VII is
(3S,4R)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronic acid.
[0056] The invention also relates to a compound of the formula
21
[0057] and to the enantiomer of said compound, wherein R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are as stated above for said process
of preparing a compound of the formula X and the benzoate moiety is
attached to position 6 or 7 of the chroman ring.
[0058] In said compound of formula IX, and the enantiomer of said
compound, preferred substituents for R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are as stated above for said process of preparing a
compound of the formula X. Most preferably, the compound of formula
IX is
(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoiacid
ethylester.
[0059] The invention also relates to a compound of the formula
22
[0060] wherein R.sup.3, R.sup.4 and R.sup.7 are as stated above for
said process of preparing a compound of the formula XIV using a
compound of formula XIII.
[0061] In said compound of formula XII, preferred substituents for
R.sup.7, R.sup.3 and R.sup.4 are as stated above for said process
of preparing a compound of the formula XIV using a compound of
formula XIII.
[0062] The invention also relates to a compound of the formula
23
[0063] wherein R.sup.3 and R.sup.4 are as stated above for said
compound of formula XIII.
[0064] In said compound of formula XIV, preferred substituents for
R.sup.3 and R.sup.4 are as stated above for said compound of
formula XIII. Most preferably, said compound of the formula XIV is
2-(2,2-dimethyl-propoxyca- rbonyl)-5-trifluoromethyl-benzeneboronic
acid.
[0065] The invention also relates to compounds of the formula
24
[0066] wherein the dashed line indicates a bond or no bond between
the B and N atoms, n and m are independently 2 to 5, R.sup.3 and
R.sup.4 are as defined above for said compound of formula XIV, and
R.sup.8 is H or C.sub.1-C.sub.6 alkyl.
[0067] In said compound of formula XVI, n and m are each preferably
2, preferred substituents for R.sup.3 and R.sup.4 are as defined
above for said compound of formula XIV, and R.sup.8 is preferably
H. Most preferably, the compound of formula XVI is
2-[1,3,6,2]dioxazaborocan-2-yl- -4-trifluoromethyl-benzoicacid
2,2-dimethyl-propyl ester.
[0068] The invention also relates to an ammonium carboxylate
compound of the formula 25
[0069] and to the enantiomer of said compound, wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.5 and R.sup.6 are as defined above for said
process of preparing a compound of the formula X. Preferred
substituents for R.sup.1, R.sup.2, and R.sup.3 are as stated above
for said process of making a compound of formula X. In the ammonium
moiety, R.sup.5 and R.sup.6 are each preferably cyclohexyl. Most
preferably, said compound of formula XVII is
(3S,4R)-dicyclohexylammonium-2-(3-benzyl-4-hydroxy-chroma-
n-7-yl)-4-trifluoromethyl benzoate.
[0070] The present invention also relates to a compound of the
formula 26
[0071] and to the enantiomer of said compound, wherein R.sup.1,
R.sup.2, X, Y and X.sub.c are as defined above for said process of
preparing a compound of formula V. The present invention also
relates to solvates of said compound of formula IV and the
enantiomer of said compound of formula IV. Preferred solvates of
said compound of formula IV, and the enantiomer of said compound,
are those formed with a donor ligand selected from
1-methyl-2-pyrrolidinone, dimethylformamide,
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,
triethylphosphate, and 2,2'-dipyridyl. The preferred compound of
formula IV is
[4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-propio-
nyl]-oxazolidin-2-one, and the preferred solvate of said compound
is
[4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydrox-
y-propionyl]-oxazolidin-2-one, 1-methyl-2-pyrrolidinone
solvate.
[0072] The term "halo", as used herein, unless otherwise indicated,
means fluoro, chloro, bromo or iodo.
[0073] The term "alkyl", as used herein, unless otherwise
indicated, includes saturated monovalent hydrocarbon radicals
having straight, branched or cyclic moieties or combinations
thereof.
[0074] The term "alkoxy", as used herein, includes O-alkyl groups
wherein "alkyl" is defined above.
[0075] The term "aryl", as used herein, unless otherwise indicated,
includes an organic radical derived form an aromatic hydrocarbon by
removal of one hydrogen, such as phenyl or naphthyl.
[0076] The term "heteroaryl", as used herein, unless otherwise
indicated, includes an organic radical derived from an aromatic
heterocyclic compound by removal of one hydrogen, such as pyridyl,
furyl, thienyl, isoquinolyl, pyrimidinyl, and pyrazinyl.
[0077] The term "enantiomer" as used herein in reference to the
compound of formula X 27
[0078] means a compound of the formula 28
[0079] The term "enantiomer" as used herein in reference to the
compound of formula IX 29
[0080] means a compound of the formula 30
[0081] The term "enantiomer" as used herein in reference to a
compound of formula VII 31
[0082] means a compound of the formula 32
[0083] The term "enantiomer" as used herein in reference to a
compound of the formula VI 33
[0084] means a compound of the formula 34
[0085] The term "enantiomer" as used herein in reference to a
compound of the formula V 35
[0086] means a compound of the formula 36
[0087] The term "enantiomer" as used herein in reference to a
compound of the formula IV 37
[0088] means a compound of the formula 38
[0089] The term "enantiomer" as used herein in reference to a
compound of the formula XVII 39
[0090] means a compound of the formula 40
[0091] The term "enantiomer" as used herein in reference to a
compound of the formula XIX 41
[0092] means a compound of the formula 42
DETAILED DESCRIPTION OF THE INVENTION
[0093] The process of the present invention and the preparation of
the compounds of the present invention are illustrated in the
following Schemes. In the following Schemes and discussion that
follows, unless otherwise indicated, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.11, Y, Z, X,
X.sub.c, and X' are as defined above. The following Schemes and the
discussion that follows describe the preparation of the compounds
of formulas I-XIX. The following Schemes and description that
follows also applies to the enantiomers of the compounds of
formulas I-XIX, wherein the term "enantiomer" is as defined above.
43 44 45 46
[0094] Overall, the synthetic sequence in Scheme I involves
attaching chiral auxiliary X.sub.c to R.sup.1-containing compound I
(step 1), asymmetric aldol condensation with aldehyde III (step 2
or 2'), reductive removal of the chiral auxiliary from aldol IV
(step 3), base-mediated cyclization of diol V (step 4), lithiation
and boration of halochromanol VI (step 5), coupling boronic acid
VII with aryl halide or sulfonate VIII (step 6), and hydrolysis of
ester IX (step 7).
[0095] In step 1 of Scheme 1, chiral auxiliary HX.sub.c is
converted to the corresponding anion by treatment with a suitably
strong base, such as an alkyllithium base, preferably butyllithium,
in an aprotic solvent, such as an ethereal solvent, preferably
tetrahydrofuran (THF), at a temperature of approximately -80 to
0.degree. C., preferably -78 to -55.degree. C., over a period of
about 20 minutes to one hour. Substituent X.sub.c is a chiral
auxiliary that is suitable to control relative and absolute
stereochemistry in asymmetric aldol reactions. Examples of HX.sub.c
include (R)-4-benzyl-2-oxazolidinone,(S)-4-benzyl-2--
oxazolidinone, (4R,5S)-4-methyl-5-phenyl-oxazolidin-2-one, and
(4S,5R)-4-methyl-5-phenyl-oxazolidin-2-one. The resulting anion is
treated with acylating agent 1, wherein group W is a halide,
preferably chloride, and R.sup.1 is as defined above, in the same
solvent at a temperature of approximately -80 to 0.degree. C.,
preferably about -75.degree. C., over a period of about one hour,
and then warmed to approximately --20 to 20.degree. C., preferably
about 0.degree. C., before aqueous workup, which is preferably done
by treatment with aqueous sodium bicarbonate, to yield acylated
chiral auxiliary II.
[0096] Step 2 of Scheme 1 is an "Evans aldol" reaction that is
performed under conditions that are analogous to those described in
Evans, D. A.; Bartroli, J.; Shih, T. L., J. Am. Chem. Soc. 1981,
103, 2127 and Gage, J. R.; Evans, D. A., Org. Syn. 1989, 68, 83,
both of which references are incorporated herein by reference. In
particular, in step 2 of Scheme 1, the acylated chiral auxiliary II
is treated with a Lewis acid, a base, and substituted benzaldehyde
III to yield alcohol IV with a high degree of stereoselectivity.
Benzaldehyde III is substituted with ortho substituent Y which
serves as a leaving group during cyclization step 4, group X (or X'
for Scheme 2, in particular coupling step 4 of Scheme 2) which is
substituted by the aryl sidechain during coupling step 6, and
substituent R.sup.2 which is as defined above. Substituent X (or X'
for Scheme 2) is attached at position 4 or 5 of the phenyl moiety
of benzaldehyde III. The leaving group Y is typically a halo or
nitro group and X is a halide (and, for Scheme 2, X' is a halide or
C.sub.1-C.sub.4 perfluoroalkylsulfonate). To prepare aldol product
IV, acylated chiral auxiliary II is treated with a boron halide or
sulfonate, such as a dialkylboron sulfonate, preferably
dibutylboron triflate, in an aprotic solvent, such as
dichloromethane, 1,2-dichloroethane, toluene, or diethyl ether,
preferably dichloromethane, at a temperature of about -78 to
40.degree. C., preferably -5.degree. C., over a period of about 20
minutes, followed by treatment with a tertiary amine base, such as
triethylamine or diisopropylethylamine, preferably triethylamine,
at a temperature of about -78 to 40.degree. C., preferably -5 to
5.degree. C., over a period of about one hour. This mixture is
treated with substituted benzaldehyde III at a temperature of about
-100 to 0.degree. C., preferably about -70.degree. C., over a
period of about 30 minutes. This mixture is allowed to warm to a
temperature of about -20 to 25.degree. C., preferably about
-10.degree. C., over a period of about one hour, and then treated
with a protic oxidative quench, preferably by the successive
addition of a pH 7 buffer solution, methanol, and aqueous hydrogen
peroxide, at a temperature of less than about 15.degree. C., to
yield alcohol IV.
[0097] Step 2' of Scheme 1 is an alternative, and preferable,
method of providing alcohol IV using a titanium-containing Lewis
acid. In step 2' of Scheme 1, acylated chiral auxiliary II is
treated with a titanium(IV) halide, preferably titanium
tetrachloride, in an aprotic solvent such as dichloromethane,
1,2-dichloroethane, or toluene, preferably dichloromethane, at a
temperature of about -80 to 0.degree. C., preferably -80 to
-70.degree. C., over a period of about 30 minutes with additional
stirring for about 30 minutes, followed by treatment with a
tertiary amine or tertiary diamine base, such as triethylamine or
N,N,N',N'-tetramethylethylenediamine, preferably
N,N,N',N'-tetramethyleth- ylenediamine, at a temperature of about
'80 to 0.degree. C., preferably -80 to -65.degree. C., over a
period of about 30 minutes. This is optionally, and preferably,
followed by treatment with a donor ligand, such as
1-methyl-2-pyrrolidinone, dimethylformamide,
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,triethylphosphate,
or 2,2'-dipyridyl, preferably 1-methyl-2-pyrrolidinone, at a
temperature of about -80 to 0.degree. C., preferably -80 to
-65.degree. C., followed by stirring for a period of about 30
minutes. This mixture is treated with substituted benzaldehyde III
at a temperature of about -100 to 0.degree. C., preferably -80 to
-65.degree. C., over a period of about 30 minutes, and allowed to
warm to a temperature of -30 to 30.degree. C., preferably 0 to
25.degree. C., over a period of about one to 24 hours, preferably
about 4 hours. This mixture is treated with a protic quench,
preferably aqueous ammonium chloride, at a temperature of -30 to
30.degree. C., preferably 0 to 25.degree. C., to yield alcohol IV.
Where treatment with a donor ligand is done, the alcohol IV is, in
some cases, provided as a crystalline solvate with the donor
ligand. Stirring the quenched reaction mixture with a solid support
such as Celite.RTM. for a period of about 12 hours at a temperature
of about 20.degree. C. improves the filtration of the reaction
mixture for removal of titanium byproducts.
[0098] The titanium aldol conditions of step 2' of Scheme 1 are
preferable and operationally more simple than the boron aldol
conditions of step 2 of Scheme 1 in that they avoid the pyrophoric
reagent tributylborane, the corrosive reagent triflic acid, and
their exothermic combination in the preparation of the Lewis acid
dibutylboron triflate. Further, in contrast to titanium aldol
reactions described in the literature, such as in Evans, D. A.;
Rieger, D. L.; Bilodeau, M. T.; Urpi, F., J. Am. Chem. Soc. 1991,
113, 1047, the titanium aldol conditions of step 2' of Scheme 1
provide high selectivity with less than two equivalents of the
aldehyde III. Preferably, about one equivalent of aldehyde III is
used in this step. The phrase "about one equivalent" as used herein
in reference to aldehyde III or a compound of the formula
R.sup.11C(O)H (as recited in the claims) means less than 1.5
equivalents of said compound. In the foregoing article by Evans et
al., it is reported that two equivalents of aldehyde would be
required for a titanium aldol reaction analogous to step 2' of
Scheme 1.
[0099] In addition to having utility in the preparation of the
therapeutic agents of formula X, the titanium aldol conditions of
step 2' of Scheme 1 are useful in the preparation of HIV protease
inhibitor compounds that are described in United Kingdom patent
application number 2,270,914 (published Mar. 30, 1994) and in B. D.
Dorsey et al., Tetrahedron Letters, 1993, 34(12), 1851. Scheme 4
illustrates the application of titanium aldol reaction to aldehyde
XVIII in which R.sup.11 is C.sub.1-C.sub.9 alkyl, C.sub.2-C.sub.9
alkenyl, or phenyl substituted by Y in the 2 position, X in the 4
or 5 position, and R.sup.2 in one of the remaining positions of the
phenyl moiety, wherein Y, X and R.sup.2 are as defined above. The
reaction conditions for Scheme 4 are the same as those described
above for step 2' of Scheme 1. Aldehyde XVIII encompasses aldehyde
III from Scheme 1, and alcohol XIX encompasses alcohol IV from
Scheme 1. The reaction of Scheme 4 can be used to prepare the HIV
protease inhibitor compounds that are described in United Kingdom
patent application number 2,270,914, referred to above, where
R.sup.11 is C.sub.1-C.sub.9 alkyl or C.sub.2-C.sub.9 alkenyl,
preferably 3-cyclohexylpropenyl.
[0100] Table 1 below illustrates how the product of Scheme 4 or
step 2' of Scheme 1 can vary depending on the reaction conditions
that are used, and, in particular, how the diastereoselectivity
increases by increasing the amount TMEDA from 1.2 to 3 equivalents
and by the addition of 2 equivalents of NMP. In Table 1, 1.0
equivalent of aldehyde RCHO was used for each reaction, x and y
represent equivalents of base and NMP, respectively, NMP means
1-methyl-2-pyrrolidinone, TMEDA means
N,N,N',N'-tetramethylethylenediamine, NEtiPr.sub.2 means
diisopropylethylamine, and the ratio of diastereomers was
determined by HPLC. The aldol isomers were identified by separation
and conversion to known carboxylic acid isomers by hydrolysis with
LiOH/H.sub.2O.sub.2 according to procedures analogous to those
described in Van Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.;
Heathcock, C. H., J. Org. Chem. 1991, 56, 2499 and Gage, J. R.;
Evans, D. A., Org. Syn. 1989, 68, 83. The desired isomer is
indicated in bold.
1TABLE 1 SCHEME FOR TABLE 1 47 48 enolization ratio of aldol RCHO x
base y NMP temperature diastereomers 49 1.2 NEtiPr.sub.2 0 NMP
0.degree. C. 33:--:2:65 (syn:anti:syn:anti) " 1.2 TMEDA 0 NMP
0.degree. C. 22:--:55:23 " 1.2 NEtiPr.sub.2 0 NMP -78.degree. C.
29:--:10:62 " 1.2 TMEDA 0 NMP -78.degree. C. 16:--:57:28 " 2 TMEDA
0 NMP -78.degree. C. 2:--:86:11 " 3 TMEDA 0 NMP -78.degree. C.
2:--:94:5 " 3 TMEDA 2 NMP -78.degree. C. 1:--:99:-- 50 1.2 TMEDA 0
NMP -78.degree. C. --:--:11:89 (anti:anhI:syn:syn) " 3 TMEDA 2 NMP
-78.degree. C. --:--:--:100 51 1.2 TMEDA 0 NMP -78.degree. C.
28:39:33:-- " 3 TMEDA 2 NMP -78.degree. C. 4:92:3:2 52 1.2 TMEDA 0
NMP -78.degree. C. 18:40:42:-- " 3 TMEDA 2 NMP -78.degree. C.
2:96:2:--
[0101] In step 3 of Scheme 1, chiral auxiliary X.sub.c is removed
(and optionally recovered for reuse in step 1), and the oxidation
state of compound IV (acid level) is reduced to the desired alcohol
V according to a procedure analogous to the procedure described in
Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.;
Miyashiro, J. M.; Rowell, B. W.; Yu, S. S., Syn. Commun. 1990, 20,
307, which is incorporated herein by reference. In this process,
alcohol IV is treated with a hydride reducing agent, such as
lithium borohydride, lithium aluminum hydride, sodium borohydride,
or calcium borohydride, preferably lithium borohydride, in an
ethereal solvent such as THF, diisopropyl ether, or methyl
tert-butyl ether, preferably THF, typically containing a protic
solvent, such as water, ethanol, or isopropanol, at a temperature
of about -78.degree. C. to reflux temperature, preferably 0.degree.
C. to ambient temperature (20-25.degree. C.). After a period of one
to 24 hours, typically 12 hours, the reaction is quenched with
water with the optional subsequent addition of hydrogen peroxide.
Chiral auxiliary HX.sub.c can be recovered for reuse in step 1 by
selective precipitation, or by extraction of HX.sub.c into aqueous
acid, preferably hydrochloric acid, from a solution of diol V in an
organic solvent such as diisopropyl ethyl or a mixture of ethyl
acetate and hexane, followed by neutralization of the aqueous
acidic extracts with base, and extraction of HX.sub.c into an
organic solvent.
[0102] Step 4 of Scheme 1 is an intramolecular aromatic
substitution whereby the primary hydroxyl in diol V displaces ortho
leaving group Y to generate the chromanol ring system of VI. In
particular, diol V, in which leaving group Y is a halo or nitro
group, preferably a fluoro group, is treated with a base, such as
potassium tert-butoxide, sodium bis(trimethylsilyl)amide, potassium
bis(trimethylsilyl)amide, cesium carbonate, or sodium hydride,
preferably potassium tert-butoxide, in an aprotic solvent such as
THF, dimethyl sulfoxide, or 1-methyl-2-pyrrolidinone, preferably
THF, optionally in the presence of added copper salts, at a
temperature of between ambient temperature and 130.degree. C.,
preferably about 70.degree. C., for a period of one to 24 hours,
typically about four hours, giving chromanol VI. In chromanol VI,
the substituent X (or X' for Scheme 2) is attached at position 6 or
7 of the chroman ring.
[0103] In step 5 of Scheme 1, substituent X in chromanol VI is
converted to lithium and then a boronic acid group. For lithiation,
chromanol VI is preferably treated first with methyl lithium to
form the lithium alkoxide followed by butyl lithium to form the
aryl lithium. In this process, chromanol VI, in which X is a
halide, preferably bromide or iodide, is treated with two
equivalents of alkyllithium, preferably first with one equivalent
of methyllithium followed by one equivalent of butyl lithium, in an
ethereal solvent, preferably THF, at a temperature of -78 to
0.degree. C., preferably -70 to -65.degree. C., for a period of
about one hour, followed by treatment with a borating agent, such
as borane-tetrahydrofuran complex, triisopropyl borate, ortrimethyl
borate, preferably borane-THF complex, at a temperature of -78 to
0.degree. C., preferably -70 to -65.degree. C., over a period of
about 30 minutes, followed by quenching with water or optionally
aqueous acid at a temperature of about -65.degree. C. to ambient
temperature, preferably at about 0.degree. C., giving boronic acid
VII in which the boronic acid moiety is attached at position 6 or 7
of the chroman ring.
[0104] Step 6 of Scheme 1 is a Suzuki coupling between boronic acid
VII and compound VIII to form the biaryl bond of compound IX. In
compound VIII, Z is a halide or sulfonate, preferably bromide,
iodide, or trifluoromethanesulfonate, R.sup.4 is C.sub.1-C.sub.6
alkyl and R.sup.3 is as defined above. This procedure is analogous
to the procedure described in Miyaura, N.; Suzuki, A., Chem. Rev.
1995, 95, 2457, which is incorporated herein by reference. This
procedure is preferable to the coupling of zinc or tin species due
to the difficulty of preparing organozincs on a large scale and the
toxicity of organotin compounds. In this process, a mixture of
boronic acid VII, arene VIII, a palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(0),
dichlorobis(triphenylphosphine)palladium(II), palladium(II)
acetate, allylpalladium chloride dimer,
tris(dibenzylideneacetone)dipalladium(0), or 10% palladium on
carbon, preferably 10% palladium on carbon, and a base or fluoride
salt, such as sodium carbonate, triethylamine, sodium bicarbonate,
cesium carbonate, tripotassium phosphate, potassium fluoride,
cesium fluoride, or tetrabutylammonium fluoride, preferably
potassium fluoride, in a solvent such as ethanol, dimethoxyethane,
or toluene, optionally containing water, preferably ethanol, are
stirred at a temperature of between ambient temperature and
130.degree. C., preferably reflux temperature, for a period of
about one to about 24 hours, preferably about three hours, giving
biaryl IX in which the benzyl ester moiety is attached at position
6 or 7 of the chroman ring.
[0105] In step 7 of Scheme 1, ester IX is treated with aqueous
hydroxide base, such as aqueous sodium hydroxide, in an alcoholic
solvent, such as isopropyl alcohol, at a temperature of between
40.degree. C. and reflux temperature, preferably reflux
temperature, for a period of about one to about 24 hours,
preferably about six hours. The reaction mixture is cooled to
ambient temperature and partitioned between aqueous base and an
organic solvent, such as a mixture of hexane and isopropyl ether.
The aqueous solution is acidified, and the final compound X is
extracted into an organic solvent such as ethyl acetate. This
method of extracting the compound X with organic solvents removes
neutral impurities which is particularly advantageous in the last
step of this synthesis.
[0106] To facilitate the handling of carboxylic acid X, this
compound can be treated with a secondary amine of the formula
NHR.sup.5R.sup.6, wherein R.sup.5 and R.sup.6 are as defined above,
in a solvent such as toluene, to form an ammonium carboxylate of
the formula 53
[0107] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5 and R.sup.6 are
as defined above. Ammonium carboxylate XVII can be treated with an
aqueous acid such a hydrochloric acid or sulphuric acid, preferably
hydrochloric acid, in a solvent such as ethyl acetate, toluene, or
methylene chloride, preferably ethyl acetate, at a temperature
ranging from 0.degree. C. to ambient temperature for a period of 30
minutes to 3 hours, preferably 1 hour, to provide carboxylic acid
X.
[0108] Scheme 2 illustrates an alternative to the coupling sequence
of steps 5 and 6 of Scheme 1. The process of Scheme 2 is preferred.
Step 1 of Scheme 2 is an esterification of carboxylic acid XI with
alcohol R.sup.4OH, in which R.sup.3 and R.sup.4 are as defined
above, to generate ester XII. In this process, carboxylic acid XI
is treated with alcohol R.sup.4OH, preferably a primary or
secondary alcohol such as 2,2-dimethyl-propyl alcohol, and an acid
such as sulfuric acid, hydrochloric acid, methanesulfonic acid,
toluenesulfonic acid, or camphor sulfonic acid, preferably sulfuric
acid, in a solvent such as toluene, dichloromethane, or
dichloroethane, preferably toluene, at a temperature of 0.degree.
C. to reflux temperature, preferably reflux temperature, for a
period of one to 24 hours, typically 4 hours, to provide ester
XII.
[0109] In step 2 of Scheme 2, ester XII is treated with a base and
the resulting ortho metallated species is trapped with a
trialkylborate to give boronate ester XII. In step 3 of Scheme 2,
the boronate ester XIII is hydrolyzed to the corresponding boronic
acid XIV which is performed by methods known to those skilled in
the art. In steps 2 and 3 of Scheme 2, ester XII is treated with a
metal amide base such as lithium diisopropylamide, lithium
diethylamide, lithium 2,2,6,6-tetramethylpiperi- dine, or
bis(2,2,6,6-tetramethylpiperidino)magnesium, preferably lithium
diisopropylamide, in the presence of a tri-(C.sub.1-C.sub.4
alkyl)borate, such as triisopropylborate, triethylborate, or
trimethylborate, preferably triisopropylborate, in an ethereal
solvent, such as THF, diisopropyl ether, dioxane, or methyl
tert-butyl ether, preferably THF, over a temperature range of about
-78.degree. C. to ambient temperature (20-25.degree. C.),
preferably about 0.degree. C. After a period of 10 minutes to 5
hours, typically 1 hour, the reaction is quenched with aqueous acid
to provide boronic acid XIV.
[0110] To facilite the handling of boronic acid XIV before
proceeding to step 4 of Scheme 2, the boronic acid XIV can be
reacted with an aminodiol as illustrated in Scheme 3. In Scheme 3,
boronic acid XIV is reacted with aminodiol XV, wherein R.sup.8, m
and n are as defined above, in a solvent such as isopropanol,
ethanol, methanol, hexanes, toluene, or a combination of the
foregoing solvents, preferably isopropanol, at a temperature within
the range of 0.degree. C. to reflux temperature, preferably ambient
temperature, for a period of 15 minutes to 10 hours, preferably 10
hours, to provide the amine complex XVI. To proceed with step 4 of
Scheme 2, amine complex XV is hydrolyzed to boronic acid XIV
according to methods known to those skilled in the art. Such
methods include the use of aqueous acid, such as hydrochloric
acid.
[0111] Step 4 of Scheme 2 is a Suzuki coupling between boronic acid
XIV and chromanol VI to form the biaryl bound of IX. In this
process, a mixture is prepared containing boronic acid XIV,
chromanol VI, a palladium catalyst, such as
tetrakis(triphenylphosphine)palladium(0),
dichlorobis(triphenylphosphine)palladium(II), palladium(II)
acetate, allylpalladium chloride dimer,
tris(dibenzylideneacetone)dipalladium(0), or 10% palladium on
carbon, preferably tetrakis(triphenylphosphine)pallad- ium(0), a
base or fluoride salt, such as sodium carbonate, triethylamine,
sodium bicarbonate, cesium carbonate, tripotassium phosphate,
pottasium fluoride, cesium fluoride, sodium hydroxide, barium
hydroxide, or tetrabutylammonium fluoride, preferably sodium
carbonate, and a solvent such as toluene, ethanol, dimethoxyethane,
optionally containing water, preferably toluene containing water.
In chromanol VI, which is prepared according to Scheme 1, X', which
is attached at position 6 or 7 of the chroman ring, represents a
halide or C.sub.1-C.sub.4 perfluoroalkylsulfonate, preferably
bromide, iodide, or trifluoromethanesulfonate. The mixture is
stirred at a temperature of between ambient temperature and reflux
temperature, preferably reflux temperature, for a period of about
10 minutes to about 6 hours, preferably 1 hour, to provide biaryl
IX.
[0112] In step 5 of Scheme 2, ester IX is hydrolyzed to provide the
carboxylic acid X as described above for step 7 of Scheme 1.
[0113] The present invention is illustrated by the following
examples, but it is not limited to the details thereof. In the
following examples, the term "ambient temperature" means a
temperature within the range of about 20.degree. C. to about
25.degree. C.
EXAMPLE 1
(R)-4-Benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one
[0114] To a solution of (R)-(+)-4-benzyl-2-oxazolidinone (910 g,
5.14 mol) and 500 mg of 2,2'-dipyridyl as an indicator in
tetrahydrofuran (9 L) at -78.degree. C. was added over 30 minutes a
2.5 M solution of BuLi in hexanes (2.03 L, 5.14 mol). The
temperature of the reaction mixture was maintained at less than
-55.degree. C. during the addition. The reaction mixture was cooled
to -75.degree. C. and hydrocinnamoyl chloride (950 g, 5.63 mol) was
added over 5 minutes. The reaction mixture was allowed to warm to
0.degree. C., at which point the reaction mixture was judged to be
complete by thin layer chromatography (hexanes/ethyl acetate, 2:1).
The reaction was quenched by adding 10% aqueous sodium bicarbonate
(3.6 L) and water (3.6 L). The aqueous phase was separated and
extracted with ethyl acetate (3 L). The combined organic layers
were washed with 5% aqueous sodium carbonate (3.6 L) and saturated
aqueous sodium chloride (2 L), dried over magnesium sulfate, and
concentrated in vacuo to approximately 2 L of a viscous yellow
suspension. This slurry was dissolved in ethyl acetate (3 L),
concentrated to a solid, and dissolved in ethyl acetate at
50.degree. C. Hexanes (10.7 L) was added, and the mixture was
slowly cooled to 10.degree. C. resulting in the precipitation of
solids which were stirred at 10.degree. C. for 30 minutes. The
solids were collected by filtration, washed with hexanes, and
air-dried at ambient temperature yielding 1.4 kg (88% ) of
(R)-4-benzyl-3-(3-phenyl-pr- opionyl)-oxazolidin-2-one as pale
yellow needles: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.14-7.33
(m, 10H), 4.66 (m, 1H), 4.17 (t, J=3.4 Hz, 2H), 3.26 (m, 3H),3.03
(t, J=7 Hz, 2H), 2.75 (dd, J=9.5, 13.4 Hz, 1H); IR 1787, 1761,
1699, 1390, 1375, 1308, 1208, 1203, 746, 699 cm.sup.-1; mp
102-104.degree. C.
EXAMPLE 2
[4R-[3(2R
,3R)]]-4-Benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydrox-
y-propionyl]-oxazolidin-2-one
[0115] To a solution of
(R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-o- ne(1064 g, 3.44
mol) in dichloromethane (5.6 L) at -5.degree. C. was added
dibutylboron triflate (1133 g, 4.13 mol) over 20 minutes, followed
by the addition of triethylamine (719 mL, 5.16 mol) while
maintaining a reaction temperature of less than 5.degree. C. This
mixture was cooled to -70.degree. C., and a solution of
4-bromo-2-fluoro-benzaldehyde (699 g, 3.44 mol) in dichloromethane
(2 L) was added over 30 minutes. The mixture was allowed to warm to
-10.degree. C. over 1 hour, at which point it was judged to be
complete by thin layer chromatography (hexanes/ethyl acetate, 2:1).
The reaction was quenched by adding potassium phosphate
monobasic-sodium hydroxide pH 7 buffer (3.5 L) over 30 minutes
followed by methanol (1.8 L) and 35% aqueous hydrogen peroxide (1.8
L) over 1.5 hours while maintaining a reaction temperature of less
than 15.degree. C. The organic layer was separated, washed with
saturated aqueous sodium bicarbonate (6.7 L), and diluted with
anhydrous ethanol (4 L) and 25% aqueous sodium bisulfite. The
organic layer was separated, washed with water (4 L), dried over
magnesium sulfate, and concentrated in vacuo giving 1818 g (103%
-crude weight) of [4R-[3(2R,3R)]]-4-benzyl-3-[2-benzy-
l-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one
as a very viscous amber-colored oil: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.7.46 (t, J=8.0 Hz, 1H), 7.16-7.32(m, 10H),
6.94-6.96 (m, 2H), 5.35 (d, J=4.7 Hz, 1H), 4.92-5.29 (m, 1H),
4.45-4.51 (m, 1H), 3.92 (m, 2H), 3.01-3.14 (m, 3H), 2.83 (dd,
J=3.1, 13.6 Hz, 1H), 2.05 (dd, J=10.0, 13.5 Hz,1H); IR 3460 (br),
1780, 1696, 1483, 1388, 1350, 1209, 1106, 1068, 877, 760, 747, 701,
583, 512, 486 cm.sup.-1.
EXAMPLE 3
[4R-[3(2R,3R)]]-4-Benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-
-propionyl]-oxazolidin-2-one, 1-Methyl-2-pyrrolidinone Solvate
[0116] To a solution of
(R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-o- ne(12.0 kg,
38.8 mol) in dichloromethane (180 L) at -70.degree. C. to -800C was
added titanium tetrachloride (8.8 kg, 46.6 mol) over 30 minutes
giving a thick suspension which was stirred for an additional 30
minutes at -70.degree. C. to -80.degree. C.
N,N,N'N'-Tetramethylethylenediamine (17.6 L, 116.4 mol) was added
over 30 minutes giving a more fluid reaction mixture.
1-Methyl-2-pyrrolidinone (7.6 kg, 77.6 mol) was added, and the
reaction mixture was stirred for 30 minutes, all while maintaining
a reaction temperature of less than -65.degree. C. A solution of
4-bromo-2-fluoro-benzaldehyde (7.9 kg, 38.8 mol) in dichloromethane
(38 L) was added over 30 minutes while maintaining a reaction
temperature of less than or equal to -68.degree. C. The reaction
mixture was allowed to warm to 20.degree. C. over 8 hours at which
point it was cooled to 10.degree. C. and quenched with a solution
of 5.0 kg of ammonium chloride in 11 L of water inducing a white
precipitate and an exotherm to 28.degree. C. Celite.RTM. (12 kg)
was added and the reaction mixture was stirred for 12 hours at
20.degree. C. The reaction mixture was filtered, concentrated
atmospherically to an oil, treated with hexanes (120 L),
concentrated to approximately 50 L, slowly cooled to 0.degree. C.
and granulated for 24 hours. The crude product, 24.3 kg, was
isolated by filtration, combined with the crude products from two
similar reactions in 110 L of dichloromethane, treated with 320 L
of hexanes, concentrated atmospherically to a final volume of
approximately 250 L (distillate temperature 65.degree. C.), seeded
with authentic product, and slowly cooled with granulation over 18
hours at 20.degree. C. Filtration yielded 67.4 kg (94% ) of
[4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluor-
o-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one,
1-methyl-2-pyrrolidinone solvate as a light tan granular solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.46 (t, J=8.0 Hz, 1H),
7.15-7.29(m, 10H), 6.94 (dd, J=1.9, 7.2 Hz, 2H), 5.34 (d, J=4.8 Hz,
1H), 4.91-4.96 (m, 1H), 4.44-4.49 (m, 1H), 3.90-3.95 (m, 2H), 3.55
(bs, 1H), 3.37 (dd, J=7.2, 7.2 Hz, 2H), 3.00-3.13 (m, 2H), 2.83 (s,
3H), 2.82 (dd, J=3.3, 13.3 Hz, 1H), 2.36 (dd, J=8.2, 8.2 Hz, 2H),
1.97-2.06 (m, 3H); IR 3150 (br), 1776, 1695, 1652, 1600, 1221,
1050, 996, 953, 875 cm.sup.-1; mp 80-83.degree. C.
EXAMPLE 4
(1R,2S)-2-Benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol
[0117] A 2 M solution of lithium borohydride in tetrahydrofuran
(1.7 L, 3.4 mol) was diluted with tetrahydrofuran (1.7 L) and
cautiously treated with water (61 mL, 3.4 mol) over 15 minutes.
This mixture was stirred at ambient temperature until hydrogen
evolution ceased (0.5 to 1 hour), and then added to a solution of
[4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bro-
mo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one (1.75 kg,
3.4 mol) in tetrahydrofuran (8.75 L) at 0.degree. C. over 30
minutes. The resulting milky-white suspension was allowed to warm
to ambient temperature over 12 hours at which point it was judged
to be complete by thin layer chromatography (hexanes/ethyl acetate,
2:1). The reaction mixture was cooled to 15.degree. C. and quenched
with water (5.25 L) over 15 minutes and stirred an additional 10
minutes before adding 35% aqueous hydrogen peroxide (2.6 L) over 20
minutes. The reaction mixture was stirred for 15 minutes and then
diluted with ethyl acetate (5.3 L) and water (4 L). The organic
layer was separated and washed with water (5.3 L), 5% aqueous
sodium bisulfite (5.25 L), and 50% saturated aqueous sodium
chloride (7.5 L). Peroxides were detected in the organic layer, so
it was further washed with 5% aqueous sodium bisulfite (5 L) and
50% saturated aqueous sodium chloride (6 L). The organic layer was
concentrated in vacuo to an oil, diluted with ethyl acetate (4 L)
and hexanes (13 L), and washed with 1 N aqueous hydrochloric acid
(6 times 17 L) to remove the (R)-(+)-4-benzyl-2-oxazolidinone. The
organic layer was washed with saturated aqueous sodium bicarbonate
(5.3 L), diluted with toluene (2 L), and concentrated in vacuo
yielding 1138 g (98% ) of
(1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol as an
oil: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.47-7.51 (m, 1H),
7.33 (dd, J=1.9, 8.3 Hz, 1H), 7.15-7.25 (m, 4H), 7.04-7.06(m, 2H),
5.39 (d, J=2.6 Hz, 1H), 3.77 (dd, J=3.0, 10.7 Hz, 1H), 3.64 (dd,
J=5.0, 10.8 Hz, 1H), 3.44 (bs, 1H), 2.68 (dd, J=11.0, 13.8 Hz, 1H),
2.59 (dd, J=4.1, 13.9 Hz, 1H), 2.15-2.20(m, 1H), 2.01 (bs, 1H); IR
3370 (br), 3269 (br), 1485, 1406, 1213, 1033, 1021, 870, 700
cm.sup.-1.
EXAMPLES
(3S ,4R)-3-Benzyl-7-bromo-chroman-4-ol
[0118] A 1 M solution of sodium bis(trimethylsilyl)amide in
tetrahydrofuran (6.55 L, 6.55 mol) was added over 20 minutes to a
solution of
(1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol (1975
g, 5.82 mol) in dimethyl sulfoxide (9.88 L) at ambient temperature.
The mixture was slowly heated to 60.degree. C. under aspirator
vacuum to displace the tetrahydrofuran from the reaction mixture,
and then heated at 60 to 65.degree. C. for 5 hours under aspirator
vacuum at which point the reaction was judged to be complete
according to thin layer chromatography (hexanes/ethyl acetate,
2:1). The reaction mixture was cooled to ambient temperature and
quenched by adding water (10 L) followed by 1 N aqueous
hydrochloric acid (10 L). The resulting tan suspension was
filtered, washed with water (2 L), and dissolved in ethyl acetate
(12 L). This solution was washed with water (two times 12 L),
concentrated to a low volume, dissolved in isopropyl ether (4 L),
and concentrated under atmospheric pressure at 50 to 60.degree. C.
to 1.0 L, at which point solids began to precipitate. The resulting
suspension was cooled to ambient temperature, stirred for 12 hours,
concentrated to one-half its volume, cooled to 0 to 5.degree. C.,
and filtered giving 916 g (49% ) of
(3S,4R)-3-benzyl-7-bromo-chroman-4-ol as a white solid. The
filtrate was concentrated to a dark oil (906 g), dissolved in
isopropyl ether (1.5 L) at reflux, cooled to ambient temperature,
stirred, and filtered yielding an additional 82 g of solid. The
filtrate was concentrated and chromatographed on silica gel (60-230
mesh) eluting with 3:1 hexanes/ethyl acetate. Product-rich
fractions were concentrated and recrystallized from isopropyl ether
yielding an additional 82 g of solid. The total yield of
(3S,4R)-3-benzyl-7-bromo-chroman-4-ol was 1080 g (58% ): .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.7.29-7.33 (m, 2H), 7.21-7.25 (m,
1H), 7.15-7.19 (m, 3H), 7.06-7.09 (m, 2H), 4.44 (bs, 1H), 4.21 (dd,
J=2.6, 11.3 Hz, 1H), 3.97 (dd, J=4.5, 11.3 Hz, 1H), 2.68 (dd,
J=6.5, 13.8 Hz, 1H), 2.51 (dd, J=9.1, 13.8 Hz, 1H), 2.18-2.23 (m,
1H), 1.85 (d, J=4.3 Hz, 1H); IR 3274 (br), 3181 (br), 1598, 1573,
1493, 1480, 1410, 1219, 1070, 1052, 1023, 859, 700 cm.sup.-1; mp
143.5-144.0.degree. C.
EXAMPLE 6
(3S,4R)-3-Benzyl-7-bromo-chroman-4-ol
[0119] To a solution of
(1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propa- ne-1,3-diol
(prepared from 33.5 kg (54.8 moles) of [4R-[3(2R,3R)]]-4-benzy-
l-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin--
2-one, 1-methyl-2-pyrrolidinone solvate without isolation) in 185 L
of tetrahydrofuran was added 12.9 kg (115 mol) of potassium
tert-butoxide. The reaction mixture was heated at reflux for 4
hours at which point the reaction was found to be complete by thin
layer chromatography (hexanes/ethyl acetate, 3:1). The reaction
mixture was cooled to ambient temperature, quenched with 170 L of
water, diluted with 83 L of ethyl acetate, and acidified to pH 5.3
(aqueous layer) with 7.5 L of concentrated hydrochloric acid. The
organic layer was concentrated under vacuum to approximately 38 L
of a slurry, diluted with 76 L of isopropyl ether, warmed to
dissolve the solids, slowly cooled to 0.degree. C., and granulated
at 0.degree. C. for 12 hours. (3S,4R)-3-Benzyl-7-bromo-chroman-
-4-ol,5.1 kg of white solid, was isolated by filtration. The mother
liquor was washed with 4 L of saturated aqueous sodium chloride,
concentrated to a final volume of 57 L, and granulated at 0.degree.
C. for 12 hours affording a 4.3 kg second crop of
(3S,4R)-3-benzyl-7-bromo-chroman-4-ol.
[0120] A second identical reaction mixture was quenched, diluted
with ethyl acetate, and acidified as described above. The organic
layer was dried over 10 kg of magnesium sulfate, concentrated
atmospherically to approximately 30 L of a slurry, diluted with 38
L of isopropyl ether, concentrated to approximately 57 L, slowly
cooled, and granulated at 0 to 10.degree. C. for 12 hours.
(3S,4R)-3-Benzyl-7-bromo-chroman-4-ol,8.7 kg, was isolated by
filtration. The mother liquor was combined with the mother liquor
from the second crop from the first reaction, concentrated to an
oil, solidified by cooling, granulated in 6 L of isopropyl ether at
20.degree. C. for 12 hours and 0.degree. C. for 2 hours, and
filtered giving 6.3 kg of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol
after washing with cold isopropyl ether. The combined crops from
both reactions were dried giving 20.8 kg (59% ) of
(3S,4R)-3-benzyl-7-bromo-chroman-4-ol.
EXAMPLE 7
(3S,4 R)-(3-Benzyl-4-hydroxy-chroman-7-yl)-boronic Acid
[0121] To a solution of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol (377
g, 1.18 mol) in tetrahydrofuran (5.6 L) at -75.degree. C. was added
a 1.48 M solution of methyllithium in ether (1.6 L, 2.37 mol) over
45 minutes while maintaining a temperature of less than -65.degree.
C. The reaction mixture was stirred at less than -65.degree. C. for
1 hour, followed by the addition of a 2.5 M solution of
butyllithium in hexanes (440 mL, 1.3 mol) over 15 minutes. The
reaction mixture was stirred at less than -65.degree. C. for 1
hour, followed by the addition of a 1.0 M solution of
borane-tetrahydrofuran complex in tetrahydrofuran (5.9 L, 5.9 mol)
over 30 minutes. The reaction mixture was warmed to 0.degree. C.,
quenched by adding water (4.4 L), adjusted to pH 2 with 1 N aqueous
hydrochloric acid (4 L), and extracted with isopropyl ether (4 L).
The aqueous layer was extracted with isopropyl ether (4 L), and the
combined organic layers were washed with 0.5 N aqueous sodium
hydroxide (7.2 L). The aqueous layer was adjusted to pH 3 with 1 N
aqueous hydrochloric acid (5.5 L) and extracted with ethyl acetate
(5.4 L and 2.7 L). The combined ethyl acetate layers were dried
over magnesium sulfate, and concentrated in vacuo yielding 304.5 g
(91% ) of (3S,4R)-(3-benzyl-4-hydroxy-chroman-7- -yl)-boronic acid
as a yellow foam: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.7.35-7.00 (m, 8H), 4.42 (d, J=4.1 Hz, 1H), 4.19 (d, J=11 Hz,
1H), 3.90 (m, 1H), 2.68 (dd, J=6.2, 13.8 Hz, 1H), 2.47 (m, 1H),
2.15 (m, 1H); IR 3330 (br), 1413, 1348, 1320, 1211, 1025, 749, 730,
700 cm.sup.-1.
EXAMPLE 8
(3S,4R)-2-(3-Benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic
Acid Ethyl Ester
[0122] A mixture of ethyl 2-iodo-4-trifluoromethyl-benzoate (723 g,
2.1 mol), (3S,4R)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronic acid
(627 g, 2.2 mol), potassium fluoride (366 g, 6.3 mol), 10%
palladium on carbon (157 g, 50% water wet), and anhydrous ethanol
(6.27 L) was heated at reflux for 3 hours at which point thin layer
chromatography (toluene/acetic acid, 5:1) indicated the reaction to
be complete. The reaction mixture was diluted with isopropyl ether
(8 L), filtered through Celite.RTM. and washed with 10% aqueous
sodium bicarbonate (1.5 L). The aqueous layer was separated and
extracted with isopropyl ether (3 L). The combined organic layers
were washed with water (6 L), dried over magnesium sulfate, and
treated with Darco.RTM. G-60 (1.0 kg) and silica gel (1 kg, 70-230
mesh) at ambient temperature. This mixture was filtered through a
pad of silica gel (70-230 mesh) and concentrated in vacuo to 922 g
of dark oil. This oil was diluted with ethyl acetate (1 L) and
filtered through a column of silica gel (2 kg) eluting with ethyl
acetate giving a light amber solution which was concentrated to
afford 897 g (92% ) of
(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic
acid ethyl ester as a light amber oil: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.7.89 (d, J=8.1 Hz, 1H), 7.63-7.67 (m, 2H),
7.18-7.38 (m, 6H), 6.91 (dd, J=1.8, 7.8 Hz, 1H), 6.86 (d, J=1.7 Hz,
1H), 4.55 (bs, 1H), 4.25 (dd, J=2.7, 11.2 Hz, 1H), 4.17 (q, J=7.1
Hz, 2H), 4.00 (ddd, J=1.0, 4.5, 11.2 Hz, 1H), 2.75 (dd, J=6.4, 13.9
Hz, 1H), 2.56 (dd, J=9.3, 13.8 Hz, 1H), 2.26 (m, 1H), 1.93 (d,
J=4.3 Hz,1H), 1.09 (t, J=7.2 Hz, 3H); IR 3307 (br), 3216 (br),
1734, 1339, 1298, 1247, 1191, 1175, 1118, 1097, 1050 cm.sup.-1.
EXAMPLE 9
(3S,4R)-2-(3-Benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic
Acid
[0123] A mixture of
(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluor-
omethyl-benzoic acid ethyl ester (897 g, 1.93 mol) and 10% aqueous
sodium hydroxide (980 mL, 2.72 mol) in isopropyl alcohol (9 L) was
heated at reflux for 6 hours, cooled to ambient temperature, and
stirred for 12 hours. The reaction mixture was diluted with water
(13.5 L), hexanes (9 L), and isopropyl ether (4.5 L). The aqueous
layer was separated and extracted with hexanes (9 L) and isopropyl
ether (4.5 L), adjusted to pH 2 with 2 N aqueous hydrochloric acid,
and extracted with ethyl acetate (8 L and 4 L). The combined ethyl
acetate extracts were washed with water (6 L), dried over magnesium
sulfate, and concentrated in vacuo to a dark amber oil which was
diluted with toluene (2 L) and concentrated again to an oil. The
oil was dissolved in toluene (4.2 L) at 60.degree. C., and hexanes
(8.8 L) were added at a rate to maintain a temperature of greater
than 50.degree. C. The tan solids which precipitated upon slowly
cooling to ambient temperature over several hours were filtered and
washed with 2:1 hexane/toluene (2 L). These solids were dissolved
in toluene (5 L) at 60.degree. C., treated with Darco.RTM. DG-60,
filtered, washed with toluene, and concentrated in vacuo to
approximately 4.0 L. This mixture was heated to 50-60.degree. C.,
treated drop-wise with hexanes(8.6 L), cooled, and granulated at
5.degree. C. for 1 to 2 hours. The resulting solids were filtered,
washed with 2:1 hexanes/toluene (2 L), and the wet cake was stirred
with hexanes (4 L) at reflux for 30 minutes. This mixture was
cooled to ambient temperature, granulated for 1 hour, filtered, and
the resulting solids were dried under vacuum overnight to provide
450 g (55% ) of (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-tri-
fluoromethyl-benzoic acid as an off white solid: .sup.1H NMR (400
MHz, CDCl.sub.3) .delta.7.99 (d, J=8.1 Hz, 1H), 7.66 (dd, J=1.1,
8.1 Hz, 1H), 7.63 (s, 1H), 7.15-7.32 (m, 6H), 6.89 (dd, J=1.7, 7.9
Hz, 1H), 6.85 (d, J=1.7 Hz, 1H), 6.1 (bs, 2H), 4.50 (d, J=4.3 Hz,
1H), 4.18 (dd, J=2.7, 11.2 Hz, 1H), 3.94 (dd, J=4.6, 11.0 Hz, 1H),
2.74 (dd, J=6.1, 13.8 Hz, 1H), 2.51 (dd, J=9.4, 13.9 Hz, 1H),2.22
(m,1H); IR 3454, 3218 (br),1699, 1431, 1337, 1299, 1275, 1258,
1191, 1178, 1135, 1123, 700 cm.sup.-1; mp 142.degree. C.
EXAMPLE 10
4-Trifluoromethyl-benzoic Acid 2,2-Dimethyl-propyl Ester
[0124] To a suspension of 4-trifluoromethylbenzoic acid (75.0 g,
394 mmol) and 2,2-dimethyl-propyl alcohol (70.5 g, 800 mmol) in
toluene (500 mL) was added concentrated sulfuric acid (3.0 mL). The
mixture was stirred at reflux for 4 hours, cooled to room
temperature, poured into saturated aqueous sodium carbonate (250
mL) and the layers were separated. The organic layer was washed
with saturated aqueous sodium carbonate (250 mL), and brine (100
mL), and was concentrated to give 4-trifluoromethyl-benzoic acid,
2,2-dimethyl-propyl ester (102 g, 99% yield) as a yellow liquid:
R.sub.f: 0.66 (ethyl acetate/hexanes25/75); IR 2932, 1727, 1327,
1280, 1133, 1066, 862, 775, 704 cm.sup.-1; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.8.16 (d, J=7.9 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H),
4.04 (s, 2H), 1.04 (s, 9); .sup.13C NMR (100 MHz, CDCl.sub.3)
.delta.26.51, 31.61, 74.72, 123.63 (q, J=272.7 HZ), 125.4, 129.9,
133.7, 134.35 (q, J =31.7 Hz), 165.35.
EXAMPLE 11
2-(2,2-Dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic
Acid
[0125] To a solution of 4-trifluoromethyl-benzoic acid
2,2-dimethyl-propyl ester (4.225 g, 16.23 mmol) in tetrahydrofuran
(40 mL) was added triisopropylborate (9.00 mL, 39.0 mmol). The
solution was cooled to -78.degree. C. and lithium diisopropylamide
(12.0 mL of a 2.0 M solution in tetrahydrofuran/heptane, 24.0 mmol)
was added dropwise over 5 minutes. The red solution was stirred for
30 minutes, warmed to 0.degree. C., and quenched by the slow
addition of 1 N hydrochloric acid (50 mL). The mixture was allowed
to warm to room temperature, stirred for 30 minutes and added to
hexanes (200 mL). The layers were separated and the organic layer
was washed successively with 2N hydrochloric acid (two limes with
100 mL), water (100 mL), and brine (50 mL). The organic extracts
were dried over magnesium sulfate, filtered, and concentrated to an
oil. The crude product was crystallized from heptane (40 mL) to
provide
2-(2,2-dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic
acid (3.037 g, 62% yield) as a white solid: mp=159-160.degree. C.;
IR 3377 (br), 2963, 1703, 1371, 1308, 1171, 1131, 794, 709
cm.sup.-1; .sup.1H NMR (400 MHz, DMSO/D.sub.2O) .delta.8.05 (d,
J=8.1 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.66 (s, 1H), 3.94 (s, 2H),
0.95 (s, 9H); .sup.13C NMR (100 MHz, DMSO/D.sub.2O) .delta.26.69,
31.69, 74.91, 125.29, 125.75, 128.30, 129.62, 131.98 (q, J=31.8
Hz), 136.28, 142.68, 166.90.
EXAMPLE 12
(3S,4R)-2-(3-Benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic
acid 2,2-Dimethyl-propyl Ester
[0126] A bi-phasic solution of
2-(2,2-dimethyl-propoxycarbonyl)-5-trifluor- omethyl-benzeneboronic
acid (1.72 g, 5.66 mmol), (3S,4R)-3-benzyl-7-bromo--
chroman-4-ol(1.80 g, 5.63 mmol), sodium carbonate (1.82 g, 17.2
mmol), and tretrakis(triphenyl-phosphine)palladium(0) (12 mg, 0.19
mol % ) in toluene (15 mL) and water (9 mL) was stirred at reflux
for 100 minutes. The reaction mixture was cooled to room
temperature, poured into water (40 mL) and extracted with
diisopropylether (75 mL). The organic extracts were washed with
brine (50 mL), treated with Darco.RTM. G-60, dried over magnesium
sulfate, filtered through Celite.RTM., and concentrated. The crude
product was purified by chromatography on silica gel (ethyl
acetate/hexanes20/80) to provide (3S,
4R)-2-(3-benzyl-4-hydroxy-chroman-7- -yl)-4-trifluoromethyl-benzoic
acid 2,2-dimethylpropyl ester as a white foam (2.35 g, 84% yield):
R.sub.f: 0.32 (ethyl acetate/hexanes25/75); IR 3407 (br), 2961,
1721, 1336, 1292, 1252, 1172, 1134, 1110, 1022, 848, 749 cm.sup.-1;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.90 (d, J=8.1 Hz, 1H),
7.66 (d, J=8.1 Hz, 1H), 7.63 (s, 1H), 7.19-7.37 (m, 6H), 6.88-6.93
(m, 2H), 4.53 (t, J=4.4 Hz, 1H),4.22 (dd, J=11.2, 2.5 Hz,1H),3.99
(dd, J=11.2, 3.3 Hz, 1H), 3.78 (s, 2H),2.73 (dd, J=13.8, 6.3 Hz,
1H), 2.54 (dd, J=13.6, 9.4 Hz, 1H), 2.20-2.80 (m, 1H), 1.81 (d,
J=5.2 Hz, 1H), 0.74 (s, 9H); .sup.13C NMR (100 MHz, CDCl.sub.3)
.delta.26.64, 30.96, 34.62, 41.53, 64.76, 67.42, 75.33, 116.77,
121.07, 122.97, 124.13, 126.44, 127.50, 127.54, 128.45, 128.60,
128.92, 129.11, 130.25, 130.31, 139.08, 141.69, 142.03, 154.44,
168.14.
EXAMPLE 13
(3S,4R)-2-(3-Benzyl-4-hydroxy-chroman-7yl)-4-trifluoromethyl-benzoic
Acid
[0127] A solution of
(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluo-
romethyl-benzoic acid 2,2-dimethyl-propyl ester (2.34 g, 4.69 mmol)
in isopropyl alcohol (23 mL) was treated with 10% aqueous sodium
hydroxide (2.3 mL, 6.4 mmol) and heated at reflux for 3 hours. The
reaction mixture was cooled to ambient temperature, poured into
water (34 mL), and extracted with hexanes (23 mL) and isopropyl
ether (13 mL). The aqueous layer was separated and extracted with
hexanes (23 mL) and isopropyl ether (13 mL), adjusted to pH 2 with
6N aqueous hydrochloric acid, and extracted with ethyl acetate (two
times 40 mL). The combined ethyl acetate extracts were washed with
brine (40 mL), dried over magnesium sulfate, filtered and
concentrated to a white foam which was recrystallized from
toluene/hexanes. The resulting solids were filtered and washed with
hexanes, and the wet cake was stirred with hexanes (20 mL) for 1
hour. The mixture was filtered, and the resulting solids were dried
under vacuum to provide 1.01 g (50% yield) of
(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic
acid as a white solid: .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.8.00 (d, J=8.1 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.64 (s,
1H), 7.1 8-7.36(m, 6H), 6.91 (dd, J=7.9, 1.7 Hz, 1H), 6.86 (d,
J=1.7 Hz, 1H), 4.53 (d, J=4.2 Hz, 1H), 4.24 (dd, J=11.2, 2.7 Hz,
1H), 3.97 (dd, J=11.0, 4.0 HZ, 1H), 2.76 (dd, J=13.9, 6.4 Hz, 1H),
2.53 (dd, J=13.7, 9.3 Hz, 1H), 2.24-2.26 (m, 1H).
EXAMPLE 14
2-[1,3,6,2]Dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid
2,2-dimethyl-propyl Ester
[0128] To a solution of 4-trifluoromethyl-benzoic acid
2,2-dimethyl-propyl ester (35.8 g, 138 mmol) in tetrahydrofuran
(250 mL) was added triisopropylborate (73.0 mL, 316 mmol). The
solution was cooled to 0.degree. C., lithium diisopropylamide (73.0
mL of a 2.0 M solution in tetrahydrofuran/heptane, 146.0 mmol) was
added dropwise over 20 minutes, and the red solution was stirred
for an additional 30 minutes. Hexanes (200 mL) was added followed
by 1N hydrochloric acid (200 mL). The mixture was stirred for 10
minutes and poured into hexanes (200 mL). The organic layer was
washed with 1 N hydrochloric acid (two times 150 mL), and brine
(100 mL). The organic extracts were dried over magnesium sulfate,
filtered, and concentrated to about 200 mL. Isopropyl alcohol (100
mL), and diethanolamine (15.95 g, 151.7 mmol) were added, and the
mixture was stirred at room temperature for 10 hours. The solids
were filtered and washed with a mixture of isopropyl alcohol (15
mL) and hexanes (30 mL) to provide
2-[1,3,6,2]dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid
2,2-dimethyl-propyl ester (37.83 g, 74% yield) as a white solid.
mp=233-234.degree. C.; IR 3077, 2963, 2862, 1722, 1480, 1467, 1371,
1331, 1298, 1290, 1279, 1254, 1161, 1117, 1108, 1087, 1074, 995,
952, 862, cm.sup.-1; .sup.1H NMR (400 MHz, CDCl.sub.3) d 8.23 (s,
1H), 7.72 (d, J=7.9 Hz, 1H), 7.52 (dd, J=7.9, 1.3 Hz, 1H), 6.33
(brs, 1H), 4.08-4.14 (m, 2H), 3.98 (s, 2H), 3.93.398
(m,2H),3.42-3.50(m,2H),2.88-2.94(m, 2H), 1.02 (s,9H); .sup.13C NMR
(100 MHz, CDCl.sub.3) 26.51, 31.69, 50.92, 63.33, 74.72, 123.94,
128.59, 132.06, 139.61, 171.56.
EXAMPLE 15
(3S,4R)-Dicyclohexylammonium-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluo-
romethyl-benzoate
[0129] A mixture of
2-[1,3,6,2]dioxazaborocan-2-yl-4-trifluoromethyl-benzo- ic acid
2,2-dimethyl-propyl ester (7.04 g,18.9 mmol) in toluene (45 mL) and
1.5 N hydrochloric acid (45 mL) was stirred at room temperature for
45 minutes. The aqueous layer was removed and sodium carbonate
(2.73 g, 25.8 mmol), (3S,4R)-3-benzyl-7-bromo-chroman-4-ol (5.47 g,
1 7.1 mmol), tetrakis(triphenylphosphine)palladium(0) (24.0 mg,
20.8 .mu.mol), and water (20 mL) were added. The bi-phasic solution
was stirred at reflux for 100 minutes, cooled to room temperature,
and poured into water (50 mL). The layers were separated, and the
organic layer was treated with Darco.RTM. G-60, filtered, and
concentrated. The crude ester was dissolved in isopropyl alcohol
(80 mL) and 10% aqueous sodium hydroxide (8.0 mL) was added. The
solution was heated at reflux for 3 hours, cooled to room
temperature, poured into water (120 mL), and extracted with hexanes
(80 mL) and isopropyl ether (40 mL). The aqueous layer was washed
with hexanes (80 mL) and isopropyl ether (40 mL), adjusted to pH 2
with 6 N hydrochloric acid, and extracted with methyl tert-butyl
ether (two times 75 mL). The organic extracts were dried over
magnesium sulfate, filtered, and concentrated. The crude product
was dissolved in methyl tert-butyl ether (40 mL), and
dicyclohexylamine (4.10 mL, 20.6 mmol) was added. The mixture as
stirred overnight, and the solid was filtered and washed with
methyl tert-butyl ether (20 mL) to afford
(3S,4R)-dicyclohexylammonium-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-triflu-
oromethyl-benzoate (7.32 g, 70% yield): mp=209-210.degree. C.; IR
3307, 3025, 2939, 2858, 1626, 1564, 1429, 1398, 1388, 1333, 1168,
1119, 903, 875, 846, 838 cm.sup.-1; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.7.62 (d, J=7.7 Hz, 1H), 7.55 (s, 1 H), 7.52 (d,
J=7.9 Hz, 1H), 7.17-7.31 (m, 6H), 7.08 (dd, J=7.9, 1.7 Hz, 1H),
7.00 (d, J=1.7 Hz, 1H), 4.48 (d, J=4.4 Hz, 1H), 4.17 (dd, J=11.0,
2.6 Hz, 1H), 3.90 (dd, J=11.0, 5.0 Hz 1H), 2.74-2.79 (m, 3H), 2.50
(dd, J=13.8, 9.4 Hz, 1H), 1.80-1.82 (m, 4h), 2.20 (brs, 1H),
1.68-1.70(m, 4H), 1.56 (d, J=12.2 Hz, 2H), 1.00-1.26(m, 10H),
.sup.13C NMR (100 MHz, CDCl.sub.3) .delta.24.70, 24.73, 25.03,
28.94, 29.09, 34.75, 41.75, 52.64, 65.00, 67.57, 116.50, 121.42,
122.59, 123.77, 126.38, 126.73, 128.03, 128.55, 129.06, 129.45,
138.95, 139.16, 142.51, 144.20, 154.04, 173.85.
EXAMPLE 16
(3S,4R)-2-(3-Benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic
acid
[0130] A mixture of
(34S4R)-dicyclohexylammonium-2-(3-benzyl4-hydroxy-chro-
man-7-yl)-4-trifluoromethyl-benzoate (2.37 g, 3.89 mmol) in ethyl
acetate (25 mL), and 1 N hydrochloric acid (25 mL) was stirred at
room temperature for 1 hour. The mixture was poured into ethyl
acetate (20 mL) and the aqueous layer was removed. The organic
layer was washed with water (six times 50 mL), dried over magnesium
sulfate, filtered, and concentrated to provide
(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-tri-
fluoromethyl-benzoic acid (1.66 g, 100% yield): .sup.1H NMR (400
MHz, CDCl.sub.3) .delta.8.00 (d, J=8.1 Hz, 1H), 7.67 (d, J=8.1 Hz,
1H), 7.64 (s, 1H), 7.18-7.36 (m, 6H), 6.91 (dd, J=7.9,1.7 Hz, 1H),
6.86 (d, J=1.7 Hz, 1H), 4.53 (d, J=4.2 Hz, 1H), 4.24 (dd, J=11.2,
2.7 Hz, 1H), 3.97 (dd, J=11.0, 4.0 Hz, I H), 2.76 (dd, J=13.9, 6.4
Hz, 1H), 2.53 (dd, J=13.7, 9.3 Hz, 1H), 2.24-2.26 (m, 1H).
EXAMPLE 17
[[3(2R,3R)]-4R,5S]-3-[2-Benzyl-3-(4-bromo-2-fluro-phenyl)-3-hydroxy-propio-
nyl]-4-methyl-5-phenyl-oxazolidin-2-one
[0131] To a solution of
(4R,5S)-4-methyl-5-phenyl-3-(3-phenyl-propionyl)-o- xazolidin-2-one
(1.50 g, 4.8 mmol) in dichloromethane (23 mL) at -70.degree. C. was
added titanium tetrachloride (0.6 mL, 5.3 mmol) giving a
yellow-orange solution which was stirred for 15 minutes at
-70.degree. C. N,N,N',N'-Tetramethylethylenediamine(2.2 mL, 15
mmol) was added over 10 minutes giving a dark red reaction mixture
which was stirred for 70 minutes at -78.degree. C.
1-Methyl-2-pyrrolidinone (0.90 mL, 9.7 mmol) was added dropwise,
and the reaction mixture was stirred for 30 minutes at -70.degree.
C. A solution of 4-bromo-2-fluoro-benzaldehyde (0.990 g, 4.9 mmol)
in dichloromethane (5 mL) was added dropwise while maintaining a
reaction temperature of less than or equal to -68.degree.0 C. The
reaction mixture was stirred at -70.degree. C. for 60 minutes and
then allowed to warm to 0.degree. C. over 90 minutes, at which
point it was quenched with 15 mL of saturated aqueous ammonium
chloride and 1.2 g. of Celite.RTM.. This mixture was stirred
overnight at room temperature and filtered. The phases were
separated and the organic phase was washed three times with water
and once with brine, dried over magnesium sulfate, and concentrated
under vacuum to 2.76 g of an oil containing the title compound and
1.2 equivalents of 1-methyl-2-pyrrolidinone: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.7.48 (t, J=8.1 Hz, 1H), 7.09-7.34 (m, 12H), 5.35
(d, J=7.3 Hz, 1 H), 5.32 (d, J=4.9 Hz, 1H), 4.89-4.92 (m, 1H),
4.51-4.55 (m, 1H), 3.65 (bs, 1H), 3.35 (dd, J=7.1, 7.1 Hz, 2H),
3.03-3.06 (m, 2H), 2.81 (s, 3H), 2.34 (dd, J=8.1, 8.1 Hz, 2H),
1.95-2.03 (m, 2H), 0.40 (d, J=6.6 Hz, 3H).
* * * * *