U.S. patent application number 09/967368 was filed with the patent office on 2002-10-24 for preparation of cyclohexene carboxylate derivatives.
This patent application is currently assigned to GILEAD SCIENCES, INC.. Invention is credited to Kelly, Daphne E., Kent, Kenneth M., Kim, Choung U., McGee, Lawrence R., Munger, John D., Postich, Michael J., Prisbe, Ernest J., Rohloff, John C., Williams, Matthew A., Zhang, Lijun.
Application Number | 20020156300 09/967368 |
Document ID | / |
Family ID | 27362267 |
Filed Date | 2002-10-24 |
United States Patent
Application |
20020156300 |
Kind Code |
A1 |
Kent, Kenneth M. ; et
al. |
October 24, 2002 |
Preparation of cyclohexene carboxylate derivatives
Abstract
The present invention provides new synthetic methods and
compositions. In particular, new methods of preparing intermediates
useful in the synthesis of neuraminidase inhibitors and
compositions useful as intermediates that are themselves useful in
the synthesis of neuraminidase inhibitors are provided.
Inventors: |
Kent, Kenneth M.;
(Sunnyvale, CA) ; Kim, Choung U.; (San Carlos,
CA) ; McGee, Lawrence R.; (Pacifica, CA) ;
Munger, John D.; (Alviso, CA) ; Prisbe, Ernest
J.; (Los Altos, CA) ; Postich, Michael J.;
(Walnut Creek, CA) ; Rohloff, John C.; (Mountain
View, CA) ; Kelly, Daphne E.; (San Francisco, CA)
; Williams, Matthew A.; (Foster City, CA) ; Zhang,
Lijun; (Foster City, CA) |
Correspondence
Address: |
Mark L. Bosse
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City
CA
94404
US
|
Assignee: |
GILEAD SCIENCES, INC.
|
Family ID: |
27362267 |
Appl. No.: |
09/967368 |
Filed: |
September 27, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09967368 |
Sep 27, 2001 |
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09740504 |
Dec 19, 2000 |
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09740504 |
Dec 19, 2000 |
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09242119 |
Apr 28, 1999 |
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6204398 |
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09242119 |
Apr 28, 1999 |
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PCT/US97/14813 |
Aug 22, 1997 |
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Current U.S.
Class: |
549/436 |
Current CPC
Class: |
C07C 227/08 20130101;
C07C 2601/16 20170501; C07D 317/46 20130101; C07D 203/26 20130101;
C07D 303/40 20130101 |
Class at
Publication: |
549/436 |
International
Class: |
C07D 317/62 |
Claims
What is claimed is:
1. A process for preparation of compounds of the formula:
51wherein: R.sup.1 is a cyclic hydroxy protecting group; R.sup.2 is
a carboxylic acid protecting group; R.sup.3 is a hydroxy protecting
group; and each R.sup.20 is independently H or an alkyl of 1 to 12
carbon atoms; which process comprises reaction of a compound of the
formula: 52with a dehydrating reagent.
2. The process of claim 1 which further comprises separating
compound 5 by treatment with a noble metal complex.
3. The process of claim 1 wherein compoud 4 is of the formula:
53
4. A process for preparation of compounds of the formula:
54wherein: R.sup.2 is a carboxylic acid protecting group; R.sup.3
is a hydroxy protecting group; R.sup.4 is C(R.sup.30).sub.3;
R.sup.5 is H or R.sup.3; R.sup.7 is H or an amino protecting group;
R.sup.8 is H or R.sup.2; R.sup.9 is H or a thiol protecting group;
each R.sup.20 is independently H or an alkyl of 1 to 12 carbon
atoms; each R.sup.21 is independently R.sup.20, Br, Cl, F, I, CN,
NO.sub.2 or N.sub.3; each R.sup.22 is independently F, Cl, Br, I,
--CN, N.sub.3, --NO.sub.2, OR.sup.5, CR.sup.20,
--N(R.sup.20).sub.2, --N(R.sup.20)(R.sup.7), --N(R.sup.7).sub.2,
--SR.sup.20, SR.sup.9, --S(O)R.sup.20, --S(O).sub.2R.sup.20,
--S(O)OR.sup.20, --S(O)OR.sup.8, --S(O).sub.2OR.sup.20
--S(O).sub.2OR.sup.8, C(O)OR.sup.20, --C(O)OR.sup.8,
--S(O)R.sup.20, --N(R.sup.20)(C(O)R.sub.2O),
--N(R.sup.7)(C(O)R.sup.20), --N(R.sup.20)(C(O)OR.sup.2)),
--N(R.sup.7)(C(O)OR.sup.20), --C(O)N(R.sup.20).sub.2,
--C(O)N(R.sup.7)(R.sup.20) ,--C(O)N(R.sup.7).sub.2,
--C(NR.sup.20)(N(R.sup.20).sub.2),
--C(N(R.sup.7))(N(R.sup.20)).sub.2),
--C(N(R.sub.2O))(N(R.sup.20)(R.sup.7)),
--C(N(R.sup.7))(N(R.sup.20)(R.sup- .7)),
--C(N(R.sup.20))(N(R.sup.7).sub.2),
--C(N(R.sup.7))(N(R.sup.7).sub.2- ),
--N(R.sup.2()C(N(R.sup.20)(N(R.sup.20).sub.2),
--N(R.sup.20)C(N(R.sup.2- 0))(N(R.sup.20)(R.sup.7)),
--N(R.sup.20)C(N(R.sup.7))(N(R.sup.20).sub.2),
--N(R.sup.7)C(N(R.sub.2O)) (N(R.sup.20).sub.2), --N(R.sup.7)C(N(
R.sup.7))(N(R.sub.2O)).sub.2),
--N(R.sup.7)C(N(R.sup.20))(N(R.sup.20)(R.s- up.7)),
--N(R.sup.20)C(N(R.sup.7))(N(R.sup.20)(R.sup.7)),
--N(R.sup.20)C(N(R.sup.20))(N(R.sup.7).sub.2),
--N(R.sup.7)C(N(R.sup.7))(- N(R.sup.20) (R.sup.7)),
--N(R.sup.7)C(N(R.sup.20))(N(R.sup.7).sub.2),
--N(R.sup.20)C(N(R.sup.7))(N(R.sup.7).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N- (R.sup.7).sub.2), .dbd.O, .dbd.S,
.dbd.N(R.sup.20), .dbd.N(R.sup.7) or W; R.sup.23 is independently
alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbon atoms, or
alkynyl of 2 to 11 carbon atoms; R.sup.24 is independently R.sup.23
wherein each R.sup.23 is substituted with 0 to 3 R.sup.22 groups;
R.sup.24a is independently alkylene of 1 to 11 carbon atoms,
alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon
atoms any one of which alkylene, alkenylene or alkynylene is
substituted with 0-3 R.sup.22 groups; R.sup.28 is independently
alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or
alkynyl of 2 to 12 carbon atoms; R.sup.29 is independently R.sup.22
or R.sup.28 wherein each R.sup.28 is substituted with 0 to 3
R.sup.22 groups; each R.sup.30 is independently H, R.sup.24, W or
--R.sup.24a W; and W is carbocycle or heterocycle wherein any one
of which carbocycle or heterocycle is substituted with 0 to 3
R.sup.29 groups; which process comprises reaction of a compound of
the formula: 55wherein R.sup.31 is a ketal or acetal, with a lewis
acid reagent; provided that R.sup.4, taken as a whole, contains: 0
to 3 W groups substituted with 0 to 3 R.sup.29 groups; and, in
addition, 1 to 12 carbon atoms substituted with 0 to 3 R.sup.22
groups.
5. The process of claim 4 which further comprises treating compound
10 with a reducing reagent.
6. The process of claim 4 wherein compound 11 is of the formula:
56
7. A process for preparation of compounds of the formula:
57wherein: R.sup.2 is a carboxylic acid protecting group; R.sup.3
is a hydroxy protecting group; R.sup.4 is C(R.sup.30).sub.3;
R.sup.5 is H or R.sup.3; R.sup.7 is H or an amino protecting group;
R.sup.8 is H or R.sup.2; R.sup.9 is H or a thiol protecting group;
each R.sup.20 is independently H or an alkyl of 1 to 12 carbon
atoms; each R.sup.21 is independently R.sup.20, Br, Cl, F, I, CN,
NO.sub.2 or N.sub.3; each R.sup.22 is independently F, Cl, Br, I,
--CN, N.sub.3, --N.sub.0.sub.2, --OR.sup.5.sub.1, CR.sup.20,
--N(R.sup.20).sub.2, --N(R.sup.20)(R.sup.7), --N(R.sup.7).sub.2,
--SR.sup.20, --SR.sup.9, --S(O)R.sup.20, --S(O).sub.2R.sup.20,
--S(O)OR.sup.20, --S(O)OR.sup.8, --S(O).sub.20R.sup.20,
--S(O).sub.2OR.sup.8, --C(O)OR.sup.20, --C(O)OR.sup.8,
OC(O)R.sup.20, --N(R.sup.20)(C(O)R.sup.20),
--N(R.sup.7)(C(O)R.sup.20), --N(R.sup.20)(C(O)OR.sup.20),
--N(R.sup.7)(C(O)OR.sup.20), --C(O)N(R.sup.20).sub.2,
--C(O)N(R.sup.7)(R.sup.20), --C(O)N(R.sup.7).sub.2,
--C(NR.sup.20)(N(R.sup.20).sub.2),
--C(N(R.sup.7))(N(R.sup.20).sub.2), --C(N(R.sup.20))(N(R.sup.20)
(R.sup.7)), --C(N(R.sup.7))(N(R.sup.20) (R.sup.7)),
--C(N(R.sup.20))(N(R.sup.7).sub.2), --C(N(R.sup.7))(N(R.sup.7-
).sub.2), --N(R.sup.20)C(N(R.sup.20))(N(R.sup.20).sub.2),
--N(R.sup.20)C(N(R.sup.20)) (N(R.sup.20)(R.sup.7)),
--N(R.sup.20)C(N(R.sup.7))(N(R.sup.20).sub.2),
--N(R.sup.7)C(N(R.sup.20))- (N(R.sup.20).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N(R.sup.20).sub.2),
--N(R.sup.7)C(N(R.sup.20))(N(R.sup.20) (R.sup.7)),
--N(R.sup.20)C(N(R.sup.7))(N(R.sup.20)(R.sup.7)),
--N(R.sup.20)C(N(R.sup.- 20))(N(R.sup.7).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N(R.sup.20) (R.sup.7)),
--N(R.sup.7)C(N(R.sup.20))(N(R.sup.7).sub.2),
--N(R.sup.20)C(N(R.sup.7))(- N(R.sup.7).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N(R.sup.7).sub.2), .dbd.O, .dbd.S,
.dbd.N(R.sup.20), .dbd.N(R.sup.7) or W; R.sup.23 is independently
alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbon atoms, or
alkynyl of 2 to 11 carbon atoms; R.sup.24 is independently R.sup.23
wherein each R.sup.23 is substituted with 0 to 3 R.sup.22 groups;
R.sup.2.sup.4a is independently alkylene of 1 to 11 carbon atoms,
alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon
atoms any one of which alkylene, alkenylene or alkynylene is
substituted with 0-3 R.sup.22 groups; R.sup.28 is independently
alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or
alkynyl of 2 to 12 carbon atoms; R.sup.29 is independently R.sup.22
or R.sup.28 wherein each R.sup.28 is substituted with 0 to 3
R.sup.22 groups; each R.sup.30 is independently H, R.sup.24, W or
--R.sup.24a W; W is carbocycle or heterocycle wherein any one of
which carbocycle or heterocycle is substituted with 0 to 3 R.sup.29
groups; which process comprises reaction of a compound of the
formula: 58with a reducing reagent; provided that R.sup.4, taken as
a whole, contains: 0 to 3 W groups substituted with 0 to 3 R.sup.29
groups; and, in addition, 1 to 12 carbon atoms substituted with 0
to 3 R.sup.22 groups.
8. The process of claim 7 wherein the reducing reagent is a
trisubstituted phosphine reducing reagent.
9. The process of claim 7 wherein compound 31 is of the formula:
59.
10. A process for preparation of compounds of the formula:
60wherein: R.sup.2 is a carboxylic acid protecting group; R.sup.3
is a hydroxy protecting group; R.sup.4 is--C(R.sup.30).sub.3;
R.sup.5 is H or R.sup.3; R.sup.7 is H or an amino protecting group;
R.sup.8 is H or R.sup.2; R.sup.9 is H or a thiol protecting group;
each R.sup.20 is independently H or an alkyl of 1 to 12 carbon
atoms; each R.sup.21 is independently R.sup.20, Br, Cl, F, I, --CN,
NO.sub.2 or N.sub.3; each R.sup.22 is independently F, Cl, Br, I,
--CN, N.sub.3, --NO.sub.2, --OR.sup.5, --OR.sup.20, --N(
R.sup.20).sub.2, --N(R.sup.20)(R.sup.7), --N(R.sup.7).sub.2,
--SR.sup.20, --SR.sup.9, --S(O)R.sup.20, --S(O).sub.2R.sup.20,
--S(O)OR.sup.20, --S(O).sub.0R.sup.8, --S(O).sub.2OR.sup.20,
--S(O).sub.2OR.sup.8, ((O).sub.0R.sup.20, --C(O)OR.sup.8,
EC(O)R.sup.20, --N(R.sup.20) (C(O)R.sup.20), --N(R.sup.7)
(C(O)R.sup.20), --N(R.sup.20)(C(O).sub.0R.sup.20), --N(R.sup.7)
(C(O)OR.sup.20, --C(O)N(R.sup.20).sub.2,
--C(O)N(R.sup.7)(R.sup.20), --C(O)N(R.sup.7).sub.2, --C
(NA.sup.20)(N(R.sup.20).sub.2), --C(N(R.sup.7)) (N(R.sup.20).sub.2,
--C(N(R.sup.20)) (N(R.sup.2G)(R.sup.7)),
--C(N(R.sup.7)(N(R.sup.20)) (1R.sup.7)),
--C(N(R.sup.20))(N(R.sup.7).sub.2), --C
(N(R.sup.7))(N(R.sup.7).sub.2), --N(R.sup.20)(N(R.sup.20))
(N(R.sup.20).sub.2), --N(R.sup.20)C(N(R.sup.20- ) )(N(R.sup.20)
(R.sup.7)), --N(R.sup.20)C(N(R.sup.7) )(N(R.sup.20).sub.2),
--N(R.sup.7)C (N(R.sup.20)) (N(R.sup.20).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N(R.sup.20).sub.2),
--N(R.sup.7)C(N(R.sup.20))(- N(R.sup.20)(R.sup.7)),
--N(R.sup.20)C(N(R.sup.7))(N(R.sup.20)(R.sup.7)),
--N(R.sup.20)C(N(R.sup.20))(N(R.sup.7).sub.2),
--N(R.sup.7)C(N(R.sup.7))(- N(R.sup.20)(R.sup.7)),
--N(R.sup.7)C(N(R.sup.20)) (N(R.sup.7).sub.2),
--N(R.sup.20)C(N(R.sup.7))(N(R.sup.7).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N- (R.sup.7).sub.2), .dbd.O, S,
.dbd.N(R.sup.20), .dbd.N(R.sup.7) or W; R.sup.23 is independently
alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbon atoms, or
alkynyl of 2 to 11 carbon atoms; R.sup.24 is independently R.sup.23
wherein each R.sup.23 is substituted with 0 to 3 R.sup.22 groups;
R.sup.24a is independently alkylene of 1 to 11 carbon atoms,
alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon
atoms any one of which alkylene, alkenylene or alkynylene is
substituted with 0-3 R.sup.22 groups; R.sup.28 is independently
alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or
alkynyl of 2 to 12 carbon atoms; R.sup.29 is independently R.sup.22
or R.sup.28 wherein each R.sup.28 is substituted with 0 to 3
R.sup.22 groups; each R.sup.30 is independently H, R.sup.24, W or
--R.sup.24a W; W is carbocycle or heterocycle wherein any one of
which carbocycle or heterocycle is substituted with 0 to 3 R.sup.29
groups; and Y.sup.1 is a mono--, di- or unsubstituted amino group;
which process comprises reaction of a compound of the formula:
61with an amine reagent; provided that R.sup.4, taken as a whole,
contains: 0 to 3 W groups substituted with 0 to 3 R.sup.29 groups;
and, in addition, 1 to 12 carbon atoms substituted with 0 to 3
R.sup.22 groups.
11. The process of claim 10 wherein the amine reagent is a
phthalimide reagent.
12. The process of claim 10 wherein compound 41 is of the formula:
62.
13. A process for preparation of compounds of the formula:
63wherein: R.sup.2 is a carboxylic acid protecting group; R.sup.3
is a hydroxy protecting group; R.sup.4 is C(R.sup.30).sub.3;
R.sup.5 is H or R.sup.3; R.sup.7 is H or an amino protecting group;
R.sup.8 is H or R.sup.2; R.sup.9 is H or a thiol protecting group;
each R.sup.20 is independently H or an alkyl of 1 to 12 carbon
atoms; each R.sup.21 is independently R.sup.20, Br, Cl, F, I CN,
NO.sub.2 or N.sub.3; each R.sup.22 is independently F, Cl, Br, I,
--CN, N.sub.3, --NO.sub.2,--OR.sup.5, OR.sup.20,
--N(R.sup.20).sub.2, --N(R.sup.20)(R.sup.7), --N(R.sup.7).sub.2,
--SR.sup.20, --SR.sup.9, --S(O)R.sup.20, --S(O).sub.2R.sup.20,
--S(O)OR.sup.2O, --S(O)OR.sup.8, --S(O).sub.2OR.sup.20,
--S(O).sub.2OR.sup.8, C(O)OR.sup.20, --C(O)OR.sup.8, OC(O)R.sup.20,
--N(R.sup.20)(C(O)R.sup.20), --N(R.sup.7)(C(O)R.sup.20),
--N(R.sup.20)(C(O)OR.sup.20), --N(R.sup.7)(C(O)OR.sup.20),
--C(O)N(R.sup.20).sub.2, --C(O)N(R.sup.7)(R.sup.20),
--C(O)N(R.sup.7).sub.2, --C(NR.sup.20)(N(R.sup.20).sub.2),
--C(N(R.sup.7)) (N(R.sup.20).sub.2), --C
(N(R.sup.20))(N(R.sup.20)(R.sup.20)), --C(N(R.sup.7))(N(R.sup.20)
(R.sup.7)), --C(N(R.sup.20))(N(R.sup.7).sub.2),
--C(N(R.sup.7))(N(R.sup.7- ).sub.2),
--N(R.sup.20)C(N(R.sup.20))(N(R.sup.20).sub.2),
--N(R.sup.20)C(N(R.sup.20))(N(R.sup.20)(R.sup.7)),
--N(R.sup.20)C(N(R.sup.7))(N(R.sup.20).sub.2), --N(R.sup.7)C
(N(R.sup.20))(N(R.sup.20).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N(R.sup.20).s- ub.2),
--N(R.sup.7)C(N(R.sup.20))(N(R.sup.20) (R.sup.7)),
--N(R.sup.20)C(N(R.sup.7))(N(R.sup.20) (R.sup.7))
--N(R.sup.20)C(N(R.sup.- 20))(N(R.sup.7).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N(R.sup.20) (R.sup.7)),
--N(R.sup.7)C(N(R.sup.20)) (N(R.sup.7).sub.2),
--N(R.sup.20)C(N(R.sup.7))- (N(R.sup.7).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N(R.sup.7).sub.2), .dbd.O, .dbd.S,
.dbd.N(R.sup.20), .dbd.N(R.sup.7) or W; R.sup.23 is independently
alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbon atoms, or
alkynyl of 2 to 11 carbon atoms; R.sup.24 is independently R.sup.23
wherein each R.sup.23 is substituted with 0 to 3 R.sup.22 groups;
R.sup.24a is independently alkylene of 1 to 11 carbon atoms,
alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon
atoms any one of which alkylene, alkenylene or alkynylene is
substituted with 0-3 R.sup.22 groups; R.sup.28 is independently
alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or
alkynyl of 2 to 12 carbon atoms; R.sup.29 is independently R.sup.22
or R.sup.28 wherein each R.sup.28 is substituted with 0 to 3
R.sup.22 groups; each R.sup.30 is independently H, R.sup.24, W or
--R.sup.24a W; W is carbocycle or heterocycle wherein any one of
which carbocycle or heterocycle is substituted with 0 to 3 R.sup.29
groups; and Y.sup.1 is a mono--, di- or unsubstituted amino group;
which process comprises reaction of a compound of the formula:
64with an oxidizing reagent; provided that R.sup.4, taken as a
whole, contains: 0 to 3 W groups substituted with 0 to 3 R.sup.29
groups; and, in addition, 1 to 12 carbon atoms substituted with 0
to 3 R.sup.22 groups.
14. The process of claim 13 wherein compound 51 is of the formula:
65.
15. A process for preparation of a compound of the formula:
66wherein: R.sup.2 is a carboxylic acid protecting group; R.sup.3
is a hydroxy protecting group; R.sup.4 is --C(R.sup.30).sub.3;
R.sup.5 is H or R.sup.3; R.sup.7 is H or an amino protecting group;
R.sup.8 is H or R.sup.2; R.sup.9 is H or a thiol protecting group;
each R.sup.20 is independently H or an alkyl of 1 to 12 carbon
atoms; each R.sup.22 is independently F, Cl, Br, I, --CN, N.sub.31
--NO.sub.2, --OR.sup.5, CR.sup.20, --N(R.sup.20).sub.2,
--N(R.sup.20)(R.sup.7), --N(R.sup.7).sub.2, --SR.sup.20,
--SR.sup.9, --S(O)R.sup.20, --S(O).sub.2R.sup.20, --S(O)R.sup.20,
--S(O).sub.0R.sup.8, --S(O).sub.2OR.sup.20, S(O).sub.2OR.sup.8,
((O)R.sup.20, --C(O)OR.sup.8, EC(O)R.sup.20, --N(R.sup.20)
(C(O)R.sup.20), --N(R.sup.7)(C(O)R.sup.20), --N(R.sup.20) (C
(O).sub.0R.sup.20), --N(R.sup.7) (C(O)R.sup.20),
--C(O)N(R.sup.20).sub.2, --C(O)N(R.sup.7) (R.sup.20),
--C(O)N(R.sup.7).sub.2, --C(NR.sup.20) (N(R.sup.20).sub.2),
--C(N(R.sup.7))(N(R.sup.20).sub.2), --C(N(R.sup.20))
(N(R.sup.20)(R.sup.7)), --C(N(R.sup.7))(N(R.sup.20)(R.sup.7)), --C
(N(R.sup.20))(N(R.sup.7).sub.2), --C
(N(R.sup.7))(N(R.sup.7).sub.2),
--N(R.sup.20)C(N(R.sup.20)(N(R.sup.20).sub.2),
--N(R.sup.20)C(N(R.sup.20)- )(N(R.sup.20)(R.sup.7)),
--N(R.sup.20)C(N(R.sup.7)(N(R.sup.20).sub.2),
--N(R.sup.7)C(N(R.sup.20))(N(R.sup.20).sub.2),
--N(R.sup.7)C(N(R.sup.7))(- N(R.sup.20).sub.2),
--N(R.sup.7)C(N(R.sup.20))(N(R.sup.20)(R.sup.7)),
--N(R.sup.20)C(N(R.sup.7))(N(R.sup.20)(R.sup.7)),
--N(R.sup.20)C(N(R.sup.- 20))(N(R.sup.7).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N(R.sup.20)(R.sup.7)),
--N(R.sup.7)C(N(R.sup.20))(N(R.sup.7).sub.2),
--N(R.sup.20)C(N(R.sup.7))(- N(R.sup.7).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N(R.sup.7).sub.2), .dbd.O, .dbd.S,
.dbd.N(R.sup.20), .dbd.N(R.sup.7) or W; R.sup.23 is independently
alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbon atoms, or
alkynyl of 2 to 11 carbon atoms; R.sup.24 is independently R.sup.23
wherein each R.sup.23 is substituted with 0 to 3 R.sup.22 groups;
R.sup.24a is independently alkylene of 1 to 11 carbon atoms,
alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon
atoms any one of which alkylene, alkenylene or alkynylene is
substituted with 0-3 R.sup.22 groups; R.sup.28 is independently
alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or
alkynyl of 2 to 12 carbon atoms; R.sup.29 is independently R.sup.22
or R.sup.28 wherein each R.sup.28 is substituted with 0 to 3
R.sup.22 groups; each R.sup.30 is independently H, R.sup.24, W or
--R.sup.24a W; W is carbocycle or heterocycle wherein any one of
which carbocycle or heterocycle is substituted with 0 to 3 R.sup.29
groups; and Y.sup.1 is a mono- , di- or unsubstituted amino group;
which process comprises reaction of a compound of the formula:
67with a base; provided that R.sup.4, taken as a whole, contains: 0
to 3 W groups substituted with 0 to 3 R.sup.29 groups; and, in
addition, 1 to 12 carbon atoms substituted with 0 to 3 R.sup.22
groups.
16. The process of claim 15 wherein compound 61 is of the formula:
68.
17. A process for preparation of compounds of the formula:
69wherein: R.sup.2 is a carboxylic acid protecting group; R.sup.3
is a hydroxy protecting group; R.sup.4 is C(R.sup.30).sub.3;
R.sup.5 is H or R.sup.3; R.sup.7 is H or an amino protecting group;
R.sup.8 is H or R.sup.2; R.sup.9 is H or a thiol protecting group;
each R.sup.20 is independently H or an alkyl of 1 to 12 carbon
atoms; each R.sup.21 is independently R.sup.20, Br, Cl, F, I, CN,
NO.sub.2 or N.sub.3; each R.sup.22 is independently F, Cl, Br, I,
--CN, N.sub.3, --NO.sub.2, --OR.sup.5, CR.sup.20,
--N(R.sup.20).sub.2, --N(R.sup.20)(R.sup.7), --N(R.sup.7).sub.2,
--SR.sup.20, --SR.sup.9, --S(O)R.sup.20, --S(O).sub.2R.sup.20,
--S(O)OR.sup.20, --S(O)OR.sup.8, --S(O).sub.2OR.sup.20,
--S(O).sub.2OR.sup.8, C(O)OR.sup.20, --C(O)oR.sup.8, OC(O)R.sup.20,
--N(R.sup.20)(C(O)R.sub.2O), --N(R.sup.7)(C(O)R.sup.20),
--N(R.sup.20)(C(O)OR.sup.20), --N(R.sup.7)(C(O)OR.sup.20),
--C(O)N(R.sup.20).sub.2, --C(O)N(R.sup.7)(R.sup.20),
--C(O)N(R.sup.7).sub.2, --C(NR.sup.20)(N(R.sup.20).sub.2),
--C(N(R.sup.7))(N(R.sup.20).sub.2), --C(N(R.sup.20))
(N(R.sup.20)(R.sup.7)), --C(N(R.sup.7))(N(R.sup.20)(R.su- p.7)),
--C(N(R.sup.20))(N(R.sup.7).sub.2),
--C(N(R.sup.7))(N(R.sup.7).sub.- 2),
--N(R.sup.20)C(N(R.sup.20))(N(R.sup.20).sub.2),
--N(R.sup.20)C(N(R.sup.20))(N(R.sup.20)(R.sup.7)),
--N(R.sup.20)C(N(R.sup.7))(N(R.sup.20).sub.2), --N(R.sup.7)C
(N(R.sup.20))(N(R.sup.20).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N(R.sup.20).s- ub.2),
--N(R.sup.7)C(N(R.sup.20))(N(R.sup.20)(R.sup.7)),
--N(R.sup.20)C(N(R.sup.7))(N(R.sup.20)(R.sup.7)),
--N(R.sup.20)C(N(R.sup.- 20))(N(R.sup.7).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N(R.sup.20)(R.sup.7)),
--N(R.sup.7)C(N(R.sup.20))(N(R.sup.7).sub.2),
--N(R.sup.20)C(N(R.sup.7))(- N(R.sup.7).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N(R.sup.7).sub.2), .dbd.O, .dbd.S,
.dbd.N(R.sup.20), .dbd.N(R.sup.7) or W; R.sup.23 is independently
alkyl of 1 to 11 carbon atoms, alkenyl of 2 to 11 carbon atoms, or
alkynyl of 2 to 11 carbon atoms; R.sup.24 is independently R.sup.23
wherein each R.sup.23 is substituted with 0 to 3 R.sup.22 groups;
R.sup.24a is independently alkylene of 1 to 11 carbon atoms,
alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon
atoms any one of which alkylene, alkenylene or alkynylene is
substituted with 0-3 R.sup.22 groups; R.sup.28 is independently
alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or
alkynyl of 2 to 12 carbon atoms; R.sup.29 is independently R.sup.22
or R.sup.28 wherein each R.sup.28 is substituted with 0 to 3
R.sup.22 groups; each R.sup.30 is independently H, R.sup.24, W or
--R.sup.24a W; W is carbocycle or heterocycle wherein any one of
which carbocycle or heterocycle is substituted with 0 to 3 R.sup.29
groups; and Y.sup.1 is a mono--, di- or unsubstituted amino group;
which process comprises reaction of a compound of the formula:
70with a reductive amination reagent; provided that R.sup.4, taken
as a whole, contains: 0 to 3 W groups substituted with 0 to 3
R.sup.29 groups; and, in addition, 1 to 12 carbon atoms substituted
with 0 to 3 R.sup.22 groups.
18. The process of claim 17 wherein compound 71 is of the formula:
71.
19. A process according to any one or sequential combination of
processes AA, AB, AC, AD, AE, AF, AG, AH, Al, AJ, or AK of Schemes
1 and 2.
20. A process according to any one or sequential combination of the
processes of Example 1, Example 2, Example 3, Example 4, Example 5,
Example 6, Example 7, Example 8, Example 9, Example 10, Example 11,
Example 12 or Example 13.
21. A process according to any one or sequential combination of
processes AL, AM, AN, AO, or AP of Scheme 3.
22. A process for preparation of compounds of the formula:
72wherein: R.sup.1 is a cyclic hydroxy protecting group; R.sup.2 is
a carboxylic acid protecting group; R.sup.3 is a hydroxy protecting
group; and each R.sup.20 is independently H or an alkyl of 1 to 12
carbon atoms; which process comprises reaction of a compound of the
formula: 73with a dehydrating reagent; provided that excluded is
the process of converting a compound of the formula: 74to a
compound of the formula: 75by reaction with POCl.sub.3 in
pyridine.
23. The process of claim 22 wherein compound 4 is of the formula:
76
24. A process for the preparation of a compound of the formula:
77which process comprises reaction of a compound of the formula:
78with a dehydrating reagent and a noble metal complex.
25. A process for the preparation of a compound of the formula:
79which process comprises reaction of a compound of the formula:
80with a Lewis acid reagent.
26. A process for the preparation of a compound of the formula:
81wherein R is a mono, di- or unsubstituted amino group, which
process comprises reaction of a compound of the formula: 82with an
anine reagent.
27. A compound of the formula: 83.
28. A compound of the formula: 84.
29. A compound of the formula: 85.
30. A compound of the formula: 86.
31. A compound of the formula: 87.
32. A compound of the formula: 88.
33. A compound of the formula: 89.
34. A compound of the formula: 90.
35. A compound of the formula: 91.
36. A process for preparing the compound of the formula 116 92which
comprises a) converting the compound of formula 110 93to compound
of formula 111: 94b) converting the compound of formula 111 to the
compound of formula 113: 95c) converting the compound of formula
113 to the compound of formula 114: 96d) convert the compound of
formula 114 to the compound of formula 115: 97e) converting the
compound of formula 115 to the compound of formula 116.
37. The process of claim 36 wherein a) in step a) compound 110 is
treated with sodium azide; b) in step b) compound 111 is treated
with a reducing reagent, in particular triphenylphosphine; c) in
step c) compound 113 is treated with sodium azide; in step d)
compound 114 is treated with an acetylating reagent; and e) in step
e) compound 115 is subjected to catalytic hydrogenation.
38. A process for preparing the compound of formula 116: 98which
comprises a) converting the compound of formula 201 99to the
compound of formula 202 100b) converting the compound of formula
202 to 4 compound of formula 203 101c) converting the compound of
formula 203 to the compound of formula 204 102d) converting the
compound of formula 204 to the compound of formula 205 103and e)
converting the compound of formula 205 to the compound of formula
116.
39. The process of claim 38 wherein a) in step a) compound 201 is
treated with an amine reagent; b) in step b) compound 202 is
treated with an oxidizing reagent; c) in step c) compound 203 is
treated with a base: d) in step d) compound 204 is treated with a
reductive amination reagent; and e) in step e) compound 205 is
treated with an acetylating reagent.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention is directed to methods of preparing
carbocyclic compounds and intermediates therefore.
[0003] 2. Brief Description of Related Art
[0004] U.S. patent application (having Attorney Docket No. 205.6)
Ser. No. 08/702,308, filed Aug. 23, 1996, which was a
continuation-in-part application of U.S. patent application Ser.
No. 08/653,034, filed Mar. 24, 1996, which was a
continuation-in-part application of U.S. patent application Ser.
No. 08/606,624, filed Feb. 26, 1996, which was a
continuation-in-part application of U.S. patent application Ser.
No. 08/580,567, filed Dec. 29, 1995, which was a
continuation-in-part application of U.S. patent application Ser.
No. 08/476,946, filed Jun. 6, 1995, which was a
continuation-in-part application of U.S. patent application Ser.
No. 08/395,245, filed Feb. 27, 1995, all of which are incorporated
herein by reference in their entirety, describe, inter alia,
neuraminadase inhibitors and intermediates in the synthesis of
neuraminidase inhibitor. The present invention provides processes
useful in the preparation of these compositions.
OBJECTS OF THE INVENTION
[0005] Selected embodiments of the invention are directed to one or
more of the following objects:
[0006] A principal object of the invention is to provide new
synthetic methods and compositions.
[0007] An additional object of the invention is to provide new
methods of preparing intermediates useful in the synthesis of
neuraminidase inhibitors.
[0008] An additional object of the invention is to provide
compositions useful as intermediates that are themselves useful in
the synthesis of neuraminidase inhibitors.
[0009] An additional object of the invention is to provide
compositions useful as neuraminidase inhibitors.
SUMMARY OF THE INVENTION
[0010] One aspect of the present invention is directed to processes
for the preparation of compounds of the formula: 1
[0011] wherein:
[0012] R.sup.1 is a cyclic hydroxy protecting group;
[0013] R.sup.2 is a carboxylic acid protecting group;
[0014] R.sup.3 is a hydroxy protecting group; and each R.sup.20 is
independently H or an alkyl of 1 to 12 carbon atoms;
[0015] which process comprises reaction of a compound of the
formula: 2
[0016] with a dehydrating reagent.
[0017] Another aspect of the present invention is directed to
processes for the preparation of compounds of the formula: 3
[0018] wherein:
[0019] each of R.sup.2, R.sup.3 and R.sup.20 are as defined
above;
[0020] R.sup.4 is C(R.sup.30).sub.3;
[0021] each R.sup.5 is independently H or R.sup.3;
[0022] each R.sup.7 is independently H or an amino protecting
group;
[0023] each R.sup.8 is independently H or R.sup.2;
[0024] each R.sup.9 is independently H or a thiol protecting
group;
[0025] each R.sup.21 is independently R.sup.20, Br, Cl, F, I, CN,
NO.sub.2 or N.sub.3;
[0026] each R.sup.22 is independently F, Cl, Br, I, --CN, N.sub.3,
--NO.sub.2,--OR.sup.5, OR.sup.20, --N(R.sup.20).sub.2,
--N(R.sup.20)(R.sup.7), --N(R.sup.7).sub.2, --SR.sup.20,
--SR.sup.9, --S(O)R.sup.20, --S(O).sub.2R.sup.20, --S(O)OR.sup.20,
--S(O)OR.sup.8, --S(O).sub.2OR.sup.20, --S(O).sub.2OR.sup.8, C
(O)OR.sup.20, --C(O)OR.sup.8, OC(O)R.sup.20,
--N(R.sup.20)(C(O)R.sup.20), --N(R.sup.7)(C(O)R.sup.20),
--N(R.sup.20)(C(O)OR.sup.20), --N(R.sup.7)(C(O)OR.sup.20), --C
(O)N(R.sup.20).sub.2, --C(O)N(R.sup.7) (R.sup.20),
--C(O)N(R.sup.7).sub.2, --C(NR.sup.20)(N(R.sup.20).sub.2),
--C(N(R.sup.7))(N(R.sup.20).sub.2),
--C(N(R.sup.20))(N(R.sup.20)(R.sup.7)- ),
--C(N(R.sup.7))(N(R.sup.20)(R.sup.7)),
--C(N(R.sup.20)))(N(R.sup.7).sub- .2),
--C(N(R.sup.7))(N(R.sup.7).sub.2),
--N(R.sup.20)C(N(R.sup.20))(N(R.su- p.20).sub.2),
--N(R.sup.20)C(N(R.sup.20))(N(R.sup.20)(R.sup.7)),
--N(R.sup.2O)C(N(R.sup.7))(N(R.sup.20).sub.2), --N(R.sup.7)C
(N(R.sup.20))(N(R.sup.20).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N(R.sup.20).s- ub.2),
--N(R.sup.7)C(N(R.sup.20))(N(R.sup.20)(R.sup.7)),
--N(R.sup.20)C(N(R.sup.7))(N(R.sup.20)(R.sup.7)),
--N(R.sup.20)C(N(R.sup.- 20))(N(R.sup.7).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N(R.sup.20) (R.sup.7)),
--N(R.sup.7)C(N(R.sup.20))(N(R.sup.7).sub.2),
--N(R.sup.20)C(N(R.sup.7))(- N(R.sup.7).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N(R.sup.7).sub.2), .dbd.O, .dbd.S,
.dbd.N(R.sup.20), .dbd.N(R.sup.7) or W;
[0027] each R.sup.23 is independently alkyl of 1 to 11 carbon
atoms, alkenyl of 2 to 11 carbon atoms, or alkynyl of 2 to 11
carbon atoms;
[0028] each R.sup.24 is independently R.sup.23 wherein each
R.sup.23 is substituted with 0 to 3 R.sup.22 groups;
[0029] each R.sup.24a is independently alkylene of 1 to 11 carbon
atoms, alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11
carbon atoms any one of which alkylene, alkenylene or alkynylene is
substituted with 0-3 R.sup.22 groups;
[0030] each R.sup.28 is independently alkyl of 1 to 12 carbon
atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12
carbon atoms;
[0031] each R.sup.29 is independently R.sup.22 or R.sup.28 wherein
each R.sup.28 is substituted with 0 to 3 R.sup.22 groups;
[0032] each R.sup.30 is independently H, R.sup.24, W or --R.sup.24a
W; and
[0033] each W is independently carbocycle or heterocycle wherein
any one of which carbocycle or heterocycle is substituted with 0 to
3 R.sup.29 groups; which process comprises reaction of a compound
of the formula: 4
[0034] wherein R.sup.31 is a ketal or acetal, with a lewis acid
reagent; provided that R.sup.4, taken as a whole, contains:
[0035] 0 to 3 W groups substituted with 0 to 3 R.sup.29 groups;
and, in addition,
[0036] 1 to 12 carbon atoms substituted with 0 to 3 R.sup.22
groups.
[0037] Another aspect of the present invention is directed to
processes for the preparation of compounds of the formula: 5
[0038] wherein:
[0039] R.sup.2, R.sup.4, R.sup.7, R.sup.20 and R.sup.21 are as
defined above. which process comprises reaction of a compound of
the formula: 6
[0040] with a reducing reagent.
[0041] Another aspect of the present invention is directed to
processes for the preparation of compounds of the formula: 7
[0042] wherein:
[0043] R.sup.2, R.sup.4, R.sup.5, R.sup.20 and R.sup.21 are as
described above; and
[0044] Y.sup.1 is a mono-, di- or unsubstituted amino group; which
process comprises reaction of a compound of the formula: 8
[0045] with an amine reagent.
[0046] Another aspect of the present invention is directed to
processes for the preparation of compounds of the formula: 9
[0047] wherein:
[0048] R.sup.2, R.sup.4, R.sup.20, R.sup.21 and Y.sup.1 are as
described above; which process comprises reaction of a compound of
the formula: 10
[0049] with an oxidizing reagent.
[0050] Another aspect of the present invention is directed to
processes for wthe preparation of compounds of the formula: 11
[0051] wherein:
[0052] R.sup.2, R.sup.4, R.sup.20, R.sup.21 and Y.sup.1 are as
described above; which process comprises reaction of a compound of
the formula: 12
[0053] with a base.
[0054] Another aspect of the present invention is directed to
processes for the preparation of compounds of the formula: 13
[0055] wherein:
[0056] R.sup.2, R.sup.4, R.sup.7, R.sup.20, R.sup.21 and Y.sup.1
are as described above; which process comprises reaction of a
compound of the formula: 14
[0057] with a reductive amination reagent.
DETAILED DESCRIPTION
General
[0058] The present invention is directed to methods of making the
compositions described herein. Even though the compositions of the
invention are prepared by any of the applicable techniques of
organic synthesis, the present invention provides advantageous
methods for accomplishing the preparations.
[0059] Many conventional techniques are well known in the art and
will not be elaborated here. However, many of the known techniques
are elaborated in "Compendium of Organic Synthetic Methods" John
Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen
Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974;
Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G.
Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6,
Michael B. Smith; as well as March, J., "Advanced Organic
Chemistry, Third Edition", (John Wiley & Sons, New York, 1985),
"Comprehensive Organic Synthesis. Selectivity, Strategy &
Efficiency in Modern Organic Chemistry. In 9 Volumes", Barry M.
Trost, Editor-in--Chief (Pergamon Press, New York, 1993
printing).
[0060] Generally, the reaction conditions such as temperature,
reaction time, solvents, workup procedures, and the like, will be
those common in the art for the particular reaction to be
performed. The cited reference material, together with material
cited therein, contains detailed descriptions of such
conditions.
[0061] The terms "treated", "treating", "treatment", and the like,
mean contacting, mixing, reacting, allowing to react, bringing into
contact, and other terms common in the art for indicating that one
or more chemical entities is treated in such a manner as to convert
it to one or more other chemical entities. This means that
"treating compound one with compound two" is synonymous with
"allowing compound one to react with compound two", "contacting
compound one with compound two", "reacting compound one with
compound two", and other expressions common in the art of organic
synthesis for reasonably indicating that compound one was
"treated", "reacted", "allowed to react", etc., with compound two.
"Treating" indicates the reasonable and usual manner in which
organic chemicals are allowed to react. Normal concentrations
(0.01M to 10M, typically 0.1M to 1M), temperatures (-100.degree. C.
to 250.degree. C., typically -78.degree. C. to 150.degree. C., more
typically -78.degree. C. to 100.degree. C., still more typically
0.degree. C. to 100.degree. C.), solvents (aprotic or protic),
reaction times (typically 10 seconds to 10 days, more typically 1
min. to 10 hours, still more typically 10 min. to 6 hours),
reaction vessels (typically glass, plastic, metal), pressures,
atmospheres (typically air for oxygen and water insensitive
reactions or nitrogen or argon for oxygen or water sensitive),
etc., are intended unless otherwise indicated. The knowledge of
similar reactions known in the art of organic synthesis are used in
selecting the conditions and apparatus for "treating" in a given
process. In particular, one of ordinary skill in the art of organic
sysnthesis selects conditions and apparatus reasonably expected to
successfully carry out the chemical reactions of the described
processes based on the knowledge in the art.
[0062] Oxidation and reduction reactions are typically carried out
at temperatures near room temperature (about 20.degree. C.),
although for metal hydride reductions frequently the temperature is
reduced to 0.degree. C. to -100.degree. C., solvents are typically
aprotic for reductions and may be either protic or aprotic for
oxidations. Reaction times are adjusted to achieve desired
conversions.
[0063] Condensation reactions are typically carried out at
temperatures near room temperature, although for non-equilibrating,
kinetically controlled condensations reduced temperatures
(0.degree. C. to -100.degree. C.) are also common. Solvents can be
either protic (common in equilibrating reactions) or aprotic
(common in kinetically controlled reactions).
[0064] Standard synthetic techniques such as azeotropic removal of
reaction by-products and use of anhydrous reaction conditions (e.g.
inert gas environments) are common in the art and will be applied
when applicable. Workup typically consists of quenching any
unreacted reagents followed by partition between a water/organic
layer system (extraction) and separating the layer containing the
product. Each of the products of the following processes is
optionally separated, isolated, and/or purified prior to its use in
subsecquent processes.
Embodiments
[0065] One aspect of the present invention is directed to processes
for the preparation of compounds of the formula: 15
[0066] R.sup.1 is a cyclic hydroxy protecting group. A very large
number of common protecting groups (including cyclic hydroxy
protecting groups) and corresponding chemical cleavage reactions
are described in "Protective Groups in Organic Chemistry", Theodora
W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN
0-471-62301-6) ("Greene"). See also Kocienski, Philip J.;
"Protecting Groups" (Georg Thieme Verlag Stuttgart, New York,
1994). In particular Chapter 1, Protecting Groups: An Overview,
pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94,
Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4,
Carboxyl Protecting Groups, pages 118-154, Chapter 5, Carbonyl
Protecting Groups, pages 155-184, and Chapter 6, Amino Protecting
Groups, pages 185-243. Typically, the cyclic hydroxyprotecting
groups are those commonly useful as 1,2-diol protecting groups.
[0067] Typical 1,2-diol protecting groups (thus, generally where
two OH groups are taken together with the R.sup.1 protecting
functionality) are described in Greene at pages 118-142 and include
Cyclic Acetals and Ketals (Methylene, Ethylidene,
1-t-Butylethylidene, 1-Phenylethylidene,
(4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide
(Isopropylidene), Cyclopentylidene, Cyclohexylidene,
Cycloheptylidene, Benzylidene, p-Methoxybenzylidene,
2,4-Dimethoxybenzylidene, 3,4-Dimethoxybenzylidene,
2--Nitrobenzylidene); Cyclic Ortho Esters (Methoxymethylene,
Ethoxymethylene, Dimethoxymethylene, 1-Methoxyethylidene,
1-Ethoxyethylidine, 1,2-Dimethoxyethylidene, o-Methoxybenzylidene,
1-(N.sub.1N-Dimethylamino)ethylidene Derivative,
C-(N,N-Dimethylamino)benzylidene Derivative,
2-Oxacyclopentylidene); Silyl Derivatives (Di-t-butylsilylene
Group, 1,3-(1,1,3,3-Tetraisopropyld- isiloxanylidene), and
Tetra-t-butoxydisiloxane-1,3-diylidene), Cyclic Carbonates, Cyclic
Boronates, Ethyl Boronate and Phenyl Boronate.
[0068] More typically, 1,2-diol protecting groups include those
shown in Table A, or ayalic ketals or acetals. Still more
typically, cyclic ketals and acetals.
1TABLE A 16 17 18 19 20 21 22 23 24 25 26
[0069] wherein R.sup.1a is C.sub.1-C.sub.6 alkyl (as defined
immediately below).
[0070] "Alkyl" as used herein, unless stated to the contrary, is
C.sub.1-C.sub.6 hydrocarbon containing normal, secondary, tertiary
or cyclic carbon atoms. Examples are methyl (Me, --CH.sub.3), ethyl
(Et, --CH.sub.2CH.sub.3), 1-propyl (n-Pr, n-propyl,
--CH.sub.2CH.sub.2CH.sub.3- ), 2-propyl (i-Pr, i-propyl,
--CH(CH.sub.3).sub.2), 1-butyl (n-Bu, n-butyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-methyl-1-propyl (i-Bu,
i-butyl, CH.sub.2CH(CH.sub.3).sub.2), 2-butyl (s-Bu, -butyl,
--CH(CH.sub.3)CH.sub.2CH.sub.3), 2-methyl-2-propyl (t-Bu, t-butyl,
--C(CH.sub.3).sub.3), 1-pentyl (n-pentyl,
CH.sub.2CH.sub.2CH.sub.2CH.sub.- 2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.s- ub.2CH.sub.3), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 3-methyl-1-butyl
(--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-1-butyl
(CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), 1-hexyl
(--CH.sub.2CH.sub.2CH.sub- .2CH.sub.2CH.sub.2CH.sub.3), 2-hexyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub- .2CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)),
2-methyl-2-pentyl (--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3),
3-methyl-2-pentyl (H(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3),
4-methyl-2-pentyl (--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2),
3-methyl-3-pentyl (--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2),
2-methyl-3-pentyl (H(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2),
2,3-dimethyl-2-butyl (--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2),
3,3-dimethyl-2-butyl (--CH(CH.sub.3)C(CH.sub.3).sub.3). Typical
alkyls are methyl, ethyl, 1-propyl, and 2-propyl.
[0071] R.sup.2 is a carboxylic acid protecting group. Typical
carboxylic acid protecting groups are R.sup.25 (described
immediately below) or those described in Greene at pages 224-276.
Those described in Greene include Esters (Methyl); Substituted
Methyl Esters (9-Fluorenylmethyl, Methoxymethyl, Methylthiomethyl,
Tetrahydropyranyl, Tetrahydrofuranyl, Methoxyethoxymethyl,
2-(Trimethylsilyl)ethoxymethyl, Benzyloxymethyl, Phenacyl,
p-Bromophenacyl, .alpha.-Methylphenacyl, p-Methoxyphenacyl,
Carboxamidomethyl, N-Phthalimidomethyl); 2-Substituted Ethyl Esters
(2,2,2-Trichloroethyl, 2-Haloethyl, .omega.-Chloroalkyl,
2-(Trimethylsilyl)ethyl, 2-Methylthioethyl, 1,3-Dithianyl-2-methyl,
2-(p-Nitrophenylsulfenyl)ethyl, 2-(p-Toluenesulfonyl)ethyl,
2-(2'-Pyridyl)ethyl, 2-(Diphenylphosphino)ethyl,
1-Methyl-1-phenylethyl, t-Butyl, Cyclopentyl, Cyclohexyl, Allyl,
3-Buten-1-yl, 4-(Trimethylsilyl)-2-buten-1-yl, Cinnamyl,
.alpha.-Methylcinnamyl, Phenyl, p-(Methylmercapto)phenyl, Benzyl);
Substituted Benzyl Esters (Triphenylmethyl, Diphenylmethyl,
Bis(o-nitrophenyl)methyl, 9-Anthrylmethyl,
2-(9,10-Dioxo)anthrylmethyl, 5-Dibenzosuberyl, 1-Pyrenylmethyl,
2-(Trifluoromethyl)-6-chromylmethyl, 2,4,6-Trimethylbenzyl,
p-Bromobenzyl, o-Nitrobenzyl, p-Nitrobenzyl, p-Methoxybenzyl,
2,6-Dimethoxybenzyl, 4-(Methylsulfinyl)benzyl, 4-Sulfobenzyl,
Piperonyl, 4-Picolyl, p-poly-Benzyl); Silyl Esters (Trimethylsilyl,
Triethylsilyl, t-Butyldimethylsilyl, 1-Propyldimethylsilyl,
Phenyldimethylsilyl, Di-t-butylmethylsilyl); Activated Esters
(Thiols); Miscellaneous Derivatives (Oxazoles,
2-Alkyl-1,3-oxazolines, 4-Alkyl-5-oxo-1,3-oxazolidines,
5-Alkyl-4-oxo-1,3-dioxolanes, Ortho Esters, Phenyl Group,
Pentaaminocobalt(III) Complex); Stannyl Esters (Triethylstannyl,
Tri-n-butylstannyl); Amnides (N,N-Dimethyl, Pyrrolidinyl,
Piperidinyl, 5,6-Dihydrophenanthridinyl, o-Nitroanilides,
N-7-Nitroindolyl, N-8-Nitro-1,2,3,4-tetrahydroquinolyl,
p-poly-Benzenesulfonamides); and Hydrazides (Hydrazides, N-Phenyl,
N,N'-Diisopropyl).
[0072] R.sup.25 is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to
12 carbon atoms, or alkynyl of 2 to 12 carbon atoms, any one of
which alkyl, alkenyl, or alkynyl is substituted with 0-3 R.sup.22
groups (R.sup.22 is described below). More typically R.sup.25 is
alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or
alkynyl of 2 to 6 carbon atoms, any one of which alkyl, alkenyl, or
alkynyl is substituted with 0-3 R.sup.22 groups. Still more
typically, R.sup.25 is alkyl of 1 to 8 carbon atoms substituted
with 0-2 R.sup.22 groups. Even more typically, R.sup.25 is alkyl of
1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Most typically R.sup.25 is
methyl, ethyl, 1-propyl or 2-propyl.
[0073] "Alkenyl" as used herein, unless stated to the contrary, is
C.sub.1-C.sub.6 hydrocarbon containing normal, secondary, tertiary
or cyclic carbon atoms. Examples are ethenyl (--CH.dbd.CH.sub.2),
1-prop-1-enyl (--CH.dbd.CHCH.sub.3), 1-prop-2-enyl
(CH.sub.2CH.dbd.CH.sub.2), 2-prop-1-enyl
(--C.dbd.CH.sub.2)(CH.sub.3)), 1-but-1-enyl
(CH.dbd.CHCH.sub.2CH.sub.3), 1-but-2-enyl
(--CH.sub.2CH.dbd.CHCH.sub.3), 1-but-3-enyl
(--CH.sub.2CH.sub.2CH.dbd.CH.- sub.2), 2-methyl-1-prop-1-enyl
(--CH.dbd.C(CH.sub.3).sub.2), 2-methyl-1-prop-2-enyl
(--CH.sub.2C(.dbd.CH.sub.2)(CH.sub.3)), 2-but-1-enyl
(C(.dbd.CH.sub.2)CH.sub.2CH.sub.3), 2-but-2-enyl
(C(CH).dbd.CHCH.sub.3), 2-but-3-enyl
(--CH(CH.sub.3)CH.dbd.CH.sub.2), 1-pent-1-enyl
(C.dbd.CHCH.sub.2CH.sub.2CH.sub.3), 1-pent-2-enyl
(CHCH.dbd.CHCH.sub.2CH.sub.3), 1-pent-3-enyl
(CHCH.sub.2CH.dbd.CHCH.sub.3- ), 1-pent-4-enyl
(--CHCH.sub.2CH.sub.2CH.dbd.CH.sub.2), 2-pent-1-enyl
((.dbd.CH.sub.2)CH.sub.2CH.sub.2CH.sub.3), 2-pent-2-enyl
(--C(CH.sub.3).dbd.CH.sub.2CH.sub.2CH.sub.2), 2-pent-3-enyl
(CH(CH.sub.3)CH.dbd.CHCH), 2-pent-4-enyl
(CH(CI3)CH.sub.2CH.dbd.CH.sub.2) or 3-methyl-1-but-2-enyl
(--CH.sub.2CH.dbd.C(CI13).sub.2). More typically, alkenyl groups
are of 2, 3 or 4 carbon atoms.
[0074] "Alkynyl" as used herein, unless stated to the contrary, is
C.sub.1-C.sub.6 hydrocarbon containing normal, secondary, tertiary
or cyclic carbon atoms. Examples are ethynyl (.dbd.CH),
1-prop-1-ynyl (--C--CC.dbd.3), 1-prop-2-ynyl (--CH.sub.2CCH),
1-but-1-ynyl (--C.ident.CH.sub.2CH.sub.3), 1-but-2-ynyl
(CH.sub.2C.dbd.CCH.sub.3), 1-but-3-ynyl
(--CH.sub.2CH.sub.2C.ident.CH), 2-but-3-ynyl
(CH(CH.sub.3)C.dbd.--CH), 1-pent-1-ynyl
(C.dbd.CCH.sub.2CH.sub.2CH.sub.3)- , 1-pent-2-ynyl
(CH.sub.2C-.dbd.CCH.sub.2CH.sub.3), 1-pent-3-ynyl
(CH.sub.2CH.sub.2CCCH.sub.3) or 1-pent-4-ynyl
(CH.sub.2CH.sub.2CH.sub.2C.- dbd.CH). More typically, alkynyl
groups are of 2, 3 or 4 carbon atoms.
[0075] R.sup.3 is a hydroxy protecting group. Typical R.sup.3
hydroxy protecting groups described in Greene (pages 14-118)
include Ethers (Methyl); Substituted Methyl Ethers (Methoxymethyl,
Methylthiomethyl, t-Butylthiomethyl,
(Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl,
p-Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl,
t-Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl,
2-Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl,
Bis(2-chloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl,
Tetrahydropyranyl, 3-Bromotetrahydropyranyl,
Tetrahydropthiopyranyl, 1-Methoxycyclohexyl, 4-Me
thoxytetrahydropyranyl, 4-Me thoxyte trahydrothiopyranyl,
4-Methoxytetrahydropthiopyranyl S,S-Dioxido,
1-[(2-Chloro-4-methyl)phenyl- ]-4-methoxypiperidin-4-yl, 35,
1,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl,
2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-me-
thanobenzofuran-2-yl)); Substituted Ethyl Ethers (1-Ethoxyethyl,
1-(2-Chloroethoxy)ethyl, 1-Methyl-l-methoxyethyl,
1-Methyl-1-benzyloxyeth- yl, 1-Methyl-1-benzyloxy-2-fluoroethyl,
2,2,2-Trichloroethyl, 2-Trimethylsilylethyl,
2-(Phenylselenyl)ethyl, t-Butyl, Allyl, p-Chlorophenyl,
p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl); Substituted Benzyl
Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl,
p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl, p-Cyanobenzyl,
p-Phenylbenzyl, 2- and 4-Picolyl, 3-Methyl-2-picolyl N-Oxido,
Diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-Dibenzosuberyl,
Triphenylmethyl, cc--Naphthyldiphenylmethyl,
p-methoxyphenyldiphenylmethy- l, Di(p-methoxyphenyl)phenylmethyl,
Tri(p-methoxyphenyl)methyl,
4-(4'-Bromophenacyloxy)phenyldiphenylmethyl, 4,4',
4"-Tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',
4"-Tris(levulinoyloxyphenyl)methyl, 4,4',
4"-Tris(benzoyloxyphenyl)methyl- , 3-(Imidazol-1-ylmethyl)bis(4',
4"-dimethoxyphenyl)methyl,
1,1-Bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-Anthryl,
9-(9-Phenyl)xanthenyl, 9-(9-Phenyl-10-oxo)anthryl,
1,3-Benzodithiolan-2-yl, Benzisothiazolyl s,s-Dioxido); Silyl
Ethers (Trimethylsilyl, Triethylsilyl, Triisopropylsilyl,
Dimethylisopropylsilyl, Diethylisopropylsily, Dimethylthexylsilyl,
t-Butyldimethylsilyl, t-Butyldiphenylsilyl, Tribenzylsilyl,
Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl,
t-Butylmethoxyphenylsilyl); Esters (Formate, Benzoylformate,
Acetate, Choroacetate, Dichloroacetate, Trichloroacetate,
Trifluoroacetate, Methoxyacetate, Triphenylmethoxyacetate,
Phenoxyacetate, p-Chlorophenoxyacetate, p-poly-Phenylacetate,
3-Phenylpropionate, 4-Oxopentanoate (Levulinate),
4,4-(Ethylenedithio)pentanoate, Pivaloate, Adamantoate, Crotonate,
4-Methoxycrotonate, Benzoate, p-Phenylbenzoate,
2,4,6-Trimethylbenzoate (Mesitoate)); Carbonates (Methyl,
9-Fluorenylmethyl, Ethyl, 2,2,2-Trichloroethyl,
2-(Trimethylsilyl)ethyl, 2-(Phenylsulfonyl)ethyl,
2-(Triphenylphosphonio)ethyl, Isobutyl, Vinyl, Allyl,
p-Nitrophenyl, Benzyl, p-Methoxybenzyl, 3,4-Dimethoxybenzyl,
o-Nitrobenzyl, p-Nitrobenzyl, S-Benzyl Thiocarbonate,
4-Ethoxy-1-naphthyl, Methyl Dithiocarbonate); Groups With Assisted
Cleavage (2-Iodobenzoate, 4-Azidobutyrate,
4-Niotro-4-methylpentanoate, o-(Dibromomethyl)benzoate,
2-Formylbenzenesulfonate, 2-(Methylthiomethoxy)ethyl Carbonate,
4-(Methylthiomethoxy)butyrate,
2-(Methylthiomethoxymethyl)benzoate); Miscellaneous Esters
(2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro-4-(1,1,3,3
tetramethylbutyl)phenoxyacetate,
2,4-Bis(1,1-dimethylpropyl)phenoxyacetat- e, Chorodiphenylacetate,
Isobutyrate, Monosuccinoate, (E)-2-Methyl-2-butenoate (Tigloate),
o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, .alpha.-Naphthoate,
Nitrate, Alkyl N,N,N ',N '-Tetramethylphosphorodiamidate,
N-Phenylcarb amate, Borate, Dimethylphosphinothioyl,
2,4-Dinitrophenylsulfenate); and Sulfonates (Sulfate,
Methanesulfonate (Mesylate), Benzylsulfonate, Tosylate).
[0076] More typically, R.sup.3 hydroxy protecting groups include
substituted methyl ethers, substituted benzyl ethers, silyl ethers,
and esters including sulfonic acid esters, still more typically,
trialkylsilyl ethers, tosylates, mesylates and acetates.
[0077] Each R.sup.20 is independently H or an alkyl of 1 to 12
carbon atoms. Typically R.sup.20 is H or alkyl of 1 to 6 carbon as
described above. Still more typically, R.sup.20 is H or methyl.
More typically yet, R.sup.20 is H.
[0078] This process embodiment comprises reaction of a compound of
the formula: 27
[0079] with a dehydrating reagent. Typically the hydroxy group at
position 1 is eliminated without removing the cis-4,5-diol
protecting group. The hydroxy group at position 1 is eliminated to
form an olefinic bond between positions 1 and 6.
[0080] Typically the process comprises treating compound 4 with a
suitable dehydrating agent, such as a mineral acid (HCl,
H.sub.2SO.sub.4) or SO.sub.2C.sub.12. More typically, compound 4 is
treated with SO.sub.2C.sub.12, followed by an alkanol. Still more
typically, compound 4 is treated with SO.sub.2C.sub.12 in a
suitable polar, aprotic solvent, such as an amine to form an
olefin. More typically yet, compound 4 is treated with
SO.sub.2C.sub.12 in pyridine/CH.sub.2Cl.sub.2 at a temperature
between -100.degree. C. and 0.degree. C., typically -100.degree. C.
and -10.degree. C., more typically -78.degree. C., to form compound
5.
[0081] In a typical embodiment, a solution of compound 4 and
pyridine in dichioromethane is cooled to 20.degree. to -30.degree.
C. and treated portionwise with sulfuryl chloride. After the
exothermic reation subsided, the resulting slurry is quenched with
ethanol, warmed to 0.degree. C., and washed successively with 16%
sulfuric acid, water and 5% aqueous sodium bicarbonate. A detailed
example of this embodiment is provided as Example 4 below.
[0082] Optionally, the process of this embodiment further comprises
purifying or separating compound 5 from any other reaction products
or other contaminents such as other double bond isomers,
halogenated side products or starting materials and reagents by
treatment with a noble metal complex. Noble metals include gold,
silver, platinum, palladium, iridium, rhenium, mercury, ruthenium
and osmium. Typically, the noble metal complex of this embodiment
is a complex of platinum or palladium. More typically the complex
is a palladium (O) complex, still more typically, the complex is a
tetrakis(triarylphosphine)palladium (O) complex.
[0083] In a typical embodiment the organic layer of the reaction
contains a mixture of olefin and halogenated products as well as
starting material. It is concentrated in vacuo and ethyl acetate is
added. The solution is treated with pyrrolidine and
tetrakis(triphenylphosphine)pall- adium(O) at ambient temperature,
followed by washing with 16% sulfuric acid. The organic layer is
filtered through a pad of silica gel and eluted with ethyl acetate.
The filtrate is concentrated in vacuo. The residue is dissolved in
ethyl acetate at reflux and hexane is added. Upon cooling, the
product crystallizes and is separated by filtration and washed with
14% ethyl acetate in hexane. After drying in vacuo, 5 was obtained.
A detailed example of this embodiment is provided as Example 4
below.
[0084] In another example of this embodiment compound 5 is of the
formula: 28
[0085] Another aspect of the present invention is directed to
processes for the preparation of compounds of the formula: 29
[0086] wherein:
[0087] R.sup.2, R.sup.3 and R.sup.20 are as defined above.
[0088] R.sup.4 is described below.
[0089] W is carbocycle or heterocycle wherein any one of which
carbocycle or heterocycle is substituted with 0 to 3 R.sup.29
groups (R.sup.29 is described below).
[0090] W is a carbocycle or heterocycle, with the proviso that each
W is independently substituted with 0 to 3 R.sup.29 groups
(R.sup.29 is described below). W carbocycles and heterocycles are
stable chemical structures. Such structures are isolatable in
measurable yield, with measurable purity, from reaction mixtures at
temperatures from -78.degree. C. to 200.degree. C. Each W is
independently substituted with 0 to 3 R.sup.29 groups. Typically, W
is a saturated, unsaturated or aromatic ring comprising a mono- or
bicyclic carbocycle or heterocycle. More typically, W has 3 to 10
ring atoms, still more typically, 3 to 7 ring atoms, and ordinarily
3 to 6 ring atoms. The W rings are saturated when containing 3 ring
atoms, saturated or monounsaturated when containing 4 ring atoms,
saturated, or mono- or diunsaturated when containing 5 ring atoms,
and saturated, mono- or diunsaturated, or aromatic when containing
6 ring atoms.
[0091] When W is carbocyclic, it is typically a 3 to 7 carbon
monocycle or a 7 to 12 carbon atom bicycle. More typically, W
monocyclic carbocycles have 3 to 6 ring atoms, still more typically
5 or 6 ring atoms. W bicyclic carbocycles typically have 7 to 12
ring atoms arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6]
system, still more typically, 9 or 10 ring atoms arranged as a
bicyclo [5,6] or [6,6] system. Examples include cyclopropyl,
cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,
1-cyclopent-3-enyl, cydohexyl, 1-cyclohex-1-enyl,
1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and
naphthyl.
[0092] A W heterocycle is typically a monocycle having 3 to 7 ring
members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from
N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9
carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S).
More typically, W heterocyclic monocycles have 3 to 6 ring atoms (2
to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and
S), still more typically, 5 or 6 ring atoms (3 to 5 carbon atoms
and 1 to 2 heteroatoms selected from N and S). W heterocyclic
bicycles typically have 7 to 10 ring atoms (6 to 9 carbon atoms and
1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo
[4,5], [5,5], [5,6], or [6,6] system, still more typically, 9 to 10
ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected
from N and S) arranged as a bicyclo [5,6] or [6,6] system.
[0093] "Heterocycle" as used herein includes by way of example and
not limitation these heterocycles described in Paquette, Leo A.;
"Principles of Modern Heterocyclic Chemistry" (W. A. Benjamin, New
York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The
Chemistry of Heterocyclic Compounds, A series of Monographs" (John
Wiley & Sons, New York, 1950 to present), in particular Volumes
13, 14, 16, 19, and 28; and "J. Am. Chem. Soc.", 82:5566
(1960).
[0094] Examples of heterocycles include by way of example and not
limitation pyridyl, thiazolyl, tetrahydrothiophenyl, sulfur
oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl,
pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl,
thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl,
benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,
2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,
octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl,
2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl,
isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl,
isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl,
isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl,
phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,
cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,
.beta.-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl,
phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl,
imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl,
isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl,
benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and
isatinoyl.
[0095] By way of example and not limitation, carbon bonded
heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine,
position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a
pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4,
or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or
tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or
thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or
isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4
of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or
position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more
typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl,
4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl,
5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,
5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or
5-thiazolyl.
[0096] By way of example and not limitation, nitrogen bonded
heterocycles are bonded at position 1 of an aziridine, azetidine,
pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,
imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,
2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole,
indoline, 1H-indazole, position 2 of a isoindole, or isoindoline,
position 4 of a morpholine, and position 9 of a carbazole, or
.beta.-carboline. Still more typically, nitrogen bonded
heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl,
1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
[0097] Typically W heterocycles are selected from pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl,
imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,
furanyl, thiofuranyl, thienyl, or pyrrolyl.
[0098] More typically, the heterocycle of W is bonded through a
carbon atom or nitrogen atom thereof. Still more typically W
heterocycles are bonded by a stable covalent bond through a carbon
or nitrogen atom thereof. Stable covalent bonds are chemically
stable structures as described above.
[0099] W optionally is selected from the group consisting of:
30
[0100] R.sup.5 is H or R.sup.3.
[0101] R.sup.7 is H or an amino protecting group. R.sup.7 amino
protecting groups are described by Greene at pages 315-385. They
include Carbamates (methyl and ethyl, 9-fluorenylmethyl,
9(2-sulfo)fluoroenylmethyl, 9-(2,7-dibromo)fluorenylmethyl,
2,7-di-t-buthyl-[9-(10,10-dioxo-10,10,10,-
10-tetrahydrothioxanthyl)]methyl, 4-methoxyphenacyl); Substituted
Ethyl (2,2,2-trichoroethyl, 2-trimethylsilylethyl, 2-phenylethyl,
1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl,
1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl,
1-methyl-1-(4-biphenylyl)ethyl,
1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2'- and
4'-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl,
1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl,
4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio,
benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl,
p-chorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl,
9-anthrylmethyl, diphenylmethyl); Groups With Assisted Cleavage
(2-methylthioethyl, 2-methylsulfonylethyl,
2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl,
4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl,
2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl,
m-choro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl,
5-benzisoxazolylmethyl, 2-(trifluoromethyl)-6-c- hromonylmethyl);
Groups Capable of Photolytic Cleavage (m-nitrophenyl,
3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl,
phenyl(o-nitrophenyl)methyl); Urea-Type Derivatives
(phenothiazinyl-(10)-carbonyl, N'-p-toluenesulfonylaminocarbonyl,
N'-phenylaminothiocarbonyl); Miscellaneous Carbamates (t-amyl,
S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl,
cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl,
diisopropylmethyl, 2,2-dimethoxycarbonylvinyl,
o-(N,N-dimethylcarboxamido)benzyl,
1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl,
1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl,
2-Iodoethyl, Isobornyl, Isobutyl, Isonicotinyl,
p-(p'-Methoxyphenylazo)benzyl, 1-methylcyclobutyl,
1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,
1-methyl-1-(3,5-dimetho- xyphenyl)ethyl,
1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,
1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,
2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl- ,
2,4,6-trimethylbenzyl); Amides (N-formyl, N-acetyl, N-choroacetyl,
N-trichoroacetyl, N-trifluoroacetyl, N-phenylacetyl,
N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarboxamide,
N-benzoylphenylalanyl, N-benzoyl, N-p-phenylbenzoyl); Amides With
Assisted Cleavage (N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl,
N-acetoacetyl, (N'-dithiobenzyloxycarbonylamino)a- cetyl,
N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl,
N-2-methyl-2-(o-nitrophenoxy)propionyl,
N-2-methyl-2-(o-phenylazophenoxy)- propionyl, N-4-chlorobutyryl,
N-3-methyl-3-nitrobutyryl, N'-o-nitrocinnamoyl, N-acetylmethionine,
N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl,
4,5-diphenyl-3-oxazolin-2-one); Cyclic Imide Derivatives
(N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl,
N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisil-
ylazacyclopentane adduct, 5-substituted
1,3-dimethyl-l,3,5-triazacyclohexa- n-2-one, 5-substituted
1,3-dibenzyl-1,3-5-triazacyclohexan-2-one, 1-substituted
3,5-dinitro-4-pyridonyl); N-Alkyl and N-Aryl Amines (N-methyl,
N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl,
N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), Quaternary Ammonium
Salts, N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl,
N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl,
N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene,
N-ferrocenylmethyl, N-2-picolylamine N'-oxide), Imine Derivatives
(N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenylidene,
N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene,
N,(N',N'-dimethylaminomethylene, N,N'-isopropylidene,
N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene,
N-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylidene);
Enamine Derivatives (N-(5,5-dimethyl-3-oxo-1-cyclohexenyl));
N-Metal Derivatives (N-borane derivatives, N-diphenylborinic acid
derivatives, N-[phenyl(pentacarbonylchromium- or
-tungsten)]carbenyl, N-copper or N-zinc chelate); N-Derivatives
(N-nitro, N-nitroso, N-oxide); N-P Derivatives
(N-diphenylphosphinyl, N-dimethylthiophosphinyl,
N-diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl
phosphoryl, N-diphenyl phosphoryl); N--Si Derivatives; N--S
Derivatives; N--Sulfenyl Derivatives (N-benzenesulfenyl,
N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl,
N-pentachlorobenzenesulfenyl, N-2-nitro-4-methoxybenzenesulfenyl,
N-triphenylmethylsulfenyl, N-3-nitropyridinesulfenyl); and
N-sulfonyl Derivatives (N-p-toluenesulfonyl, N-benzenesulfonyl,
N-2,3,6-trimethyl-4-methoxybenze- nesulfonyl,
N-2,4,6-trimethoxybenzenesulfonyl, N-2,6-dimethyl-4-methoxyben-
zenesulfonyl, N-pentamethylbenzenesulfonyl,
N-2,3,5,6,-tetramethyl-4-metho- xybenzenesulfonyl,
N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesul- fonyl,
N-2,6-dimethoxy-4-methylbenzenesulfonyl,
N-2,2,5,7,8-pentamethylchr- oman-6-sulfonyl, N-methanesulfonyl,
N-p-trimethylsilyethanesulfonyl, N-9-anthracenesulfonyl, N-4-(4',
8'-dimethoxynaphthylmethyl)benzenesulfon- yl, N-benzylsulfonyl,
N-trifluoromethylsulfonyl, N-phenacylsulfonyl). Typically, R.sup.7
is H or a --C(O)R.sup.25 (R.sup.25 is described above).
[0102] R.sup.8 is H or R.sup.2. Typically R.sup.8 is H.
[0103] R.sup.9 is H or a thiol protecting group. R.sup.9 amino
protecting groups are described by Greene at pages 277-308. They
include Thioethers (S-Benzyl, S-p-Methoxybenzyl, S-o- or p-Hydroxy-
or Acetoxybenzyl, S-p-Nitrobenzyl, S-4-Picolyl, S-2-Picolyl
N-Oxide, S-9-Anthrylmethyl, S-9-Fluorenylmethyl,
S-Ferrocenylmethyl); S-Diphenylmethyl, Substituted
S-Diphenylmethyl, and S-Triphenylmethyl Thioethers
(S-Diphenylmethyl, S-Bis(4-methoxyphenyl)methyl,
S-5-Dibenzosuberyl, S-Triphenylmethyl, S-Diphenyl-4-pyridylmethyl,
S-Phenyl, S-2,4-Dinitrophenyl, S-t-Butyl, S-1-Adamantyl);
Substituted S-Methyl Derivatives Monothio, Dithio, and Aminothio
Acetals (S-Methoxymethyl, S-Isobutoxymethyl, S-2-Tetrahydropyranyl,
S-Benzylthiomethyl, S-Phenylthiomethyl, Thiazolidines,
S-Acetamidomethyl, S-Trimethylacetamidomethyl, S-Benzamidomethyl,
S-Acetyl-, 5-Carboxy-, and S--Cyanomethyl); Substituted S-Ethyl
Derivatives (S-2-Nitro-1-phenylethyl, S-2-(4'-Pyridyl)ethyl,
S-2-Cyanoethyl, 5-2,2-Bis(carboethoxy)ethyl, S-1-m
-Nitrophenyl-2-benzoylethyl, S-2-Phenylsulfonylethyl,
S-1-(4-Methylphenylsulfonyl)-2-methylprop-2-yl); Silyl Thioethers,
Thioesters, (S-Acetyl Derivative, S-Benzoyl Derivative,
S--N-[[(p-Biphenylyl)isopropoxy]
carbonyl]--N-methyl-r-aminobutyrate,
S--N-(t-Butoxycarbonyl)--N-methyl-y-aminobutyrate); Thiocarbonate
Derivatives (S-2,2,2-Trichloroethoxycarbonyl, S-t-Butoxycarbonyl,
S-Benzyloxycarbonyl, S-p-Methoxybenzyloxycarbonyl); Thiocarbamate
Derivatives (S-(N-Ethyl), S-(N-Methoxymethyl); Miscellaneous
Derivatives, Unsymmetrical Disulfides (S-Ethyl, S-t-Butyl,
Substituted S-Phenyl); Sulfenyl Derivatives (S--Sulfonate,
S-Sulfenylthiocarbonate, S-3-Nitro-2-pyridinesulfenyl Sulfide);
Protection for Dithiols, Dithio Acetals and Ketals (S,S'-Methylene,
S,S'-Isopropylidene, and S,S'-Benzylidene,
S,S'-p-Methoxybenzylidene); Protection for Sulfides
(S-Methylsulfonium Salt, S-Benzyl- and S-4-Methoxybenzylsulfonium
Salt, S-1-(4-Phthalimidobutyl)sulfonium Salt); S-P Derivatives
(S-(Dimethylphosphino)thioyl, S-(Diphenylphosphino)thioyl);
[0104] Each R.sup.21 is independently R.sup.20, Br, Cl, F, I CN,
NO.sub.2 or N.sub.3. Typically, R.sup.21 is Cl, F or R.sup.20, more
typically, R.sup.20, still more typically, H.
[0105] Each R.sup.22 is independently F, Cl, Br, I, CN, N.sub.3,
--NO.sub.2, --OR.sup.5, --OR.sup.20, --N(R.sup.20).sub.2,
--N(R.sup.20)(R.sup.7), --N(R.sup.7).sub.2, --SR.sup.20,
--SR.sup.9, --S(O)R.sup.20, --S(O).sub.2R.sup.20,
--S(O).sub.0R.sup.20, --S(O)OR.sup.8, --S(O).sub.2OR.sup.20,
--S(O).sub.20R.sup.8, C(O)OR.sup.2O, --C(O)OR.sup.8, OC(O)R.sup.20,
--N(R.sup.20)(C(O)R.sup.20)- , --N(R.sup.7)(C(O)R.sup.20),
--N(R.sup.20)(C(O)OR.sup.20), --N(R.sup.7)(C(O)OR.sup.20),
--C(O)N(R.sup.20).sub.2, --C(O)N(R.sup.7)(R.sup.20),
--C(O)N(R.sup.7).sub.2, --C(NR.sup.20)(N(R.sup.20).sub.2),
--C(N(R.sup.7))(N(R.sup.20).sub.2),
--C(N(R.sup.20))(N(R.sup.20)(R.sup.7)),
--C(N(R.sup.7))(N(R.sup.20)(R.sup- .7)),
--C(N(R.sup.20))(N(R.sup.7).sub.2),
--C(N(R.sup.7))(N(R.sup.7).sub.2- ),
--N(R.sup.20)C(N(R.sup.20))(N(R.sup.20).sub.2),
--N(R.sup.20)C(N(R.sup.- 20))(N(R.sup.20)(R.sup.7)),
--N(R.sup.20)C(N(R.sup.7))(N(R.sup.20).sub.2),
--N(R.sup.7)C(N(R.sup.20)) (N(R.sup.20).sub.2),
--N(R.sup.7)C(N(R.sup.7)) (N(R.sup.20).sub.2),
--N(R.sup.7)C(N(R.sup.20))(N(R.sup.20)(R.sup.7)),
--N(R.sup.20)C(N(R.sup.7))(N(R.sup.20)(R.sup.7)), --N(R.sup.20)C
(N(R.sup.20))(N(R.sup.7).sub.2), --N(R.sup.7)C(N(R.sup.7))
(N(R.sup.20)(R.sup.7)), --N(R.sup.7)C(N(R.sup.20))
(N(R.sup.7).sub.2), --N(R.sup.20)C(N(R.sup.7))(N(R.sup.7).sub.2),
--N(R.sup.7)C(N(R.sup.7))(N- (R.sup.7).sub.2), .dbd.O, .dbd.S,
.dbd.N(R.sup.20), .dbd.N(R.sup.7) or W.
[0106] Typically R.sup.22 is F, Cl, Br, I, CN, N.sub.3, --N0.sub.2,
--OR.sup.5, --OR.sup.20, --N(R.sup.20).sub.2,
--N(R.sup.20)(R.sup.7), --N(R.sup.7).sub.2, --SR.sup.20,
--SR.sup.9, --S(O)R.sup.20, --S(O).sub.2R.sup.20, --S(O)OR.sup.20,
--S(O)OR.sup.8, --S(O).sub.2OR.sup.20, --S(O).sub.2OR.sup.8,
--C(O)OR.sup.20, --C(O)OR.sup.8, .dbd.O, .dbd.S, .dbd.N(R.sup.20)
or .dbd.N(R.sup.7). More typically R.sup.22 is F, Cl, Br, --CN,
N.sub.3, --NO.sub.2, --OR.sup.5, --OR.sup.20, --N(R.sup.20).sub.2,
--N(R.sup.20)(R.sup.7), --N(R.sup.7).sub.2, --C(O)OR.sup.20,
--C(O)OR.sup.8,or .dbd.O. Still more typically R.sup.22 is F, Cl,
Br, --CN, N.sub.3, --NO.sub.2, --OR.sup.20, --N(R.sup.20).sub.2,
--C(O)OR.sup.20 or .dbd.O. More typically yet R.sup.22 is F, Cl,
Br, --CN, --OH, --N(H).sub.2, C(O)OR.sup.20 or .dbd.O.
[0107] Each R.sup.23 is independently alkyl of 1 to 11 carbon
atoms, alkenyl of 2 to 11 carbon atoms, or alkynyl of 2 to 11
carbon atoms. More typically R.sup.23 is alkyl of 1 to 8 carbon
atoms, alkenyl of 2 to 8 carbon atoms, or alkynyl of 2 to 8 carbon
atoms, still more typically, R.sup.23 is alkyl of 1 to 6 carbon
atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon
atoms. More typically yet, R.sup.23 is R.sup.25.
[0108] Each R.sup.24 is independently R.sup.23 wherein each
R.sup.23 is substituted with 0 to 3 R.sup.22 groups. Each of the
typical embodiments of R.sup.23 and R.sup.22 are typical of
R.sup.24. More typically R.sup.24 is substituted with 0, 1, 2, or 3
R.sup.22 groups.
[0109] R.sup.24a is independently alkylene of 1 to 11 carbon atoms,
alkenylene of 2 to 11 carbon atoms, or alkynylene of 2-11 carbon
atoms any one of which alkylene, alkenylene or alkynylene is
substituted with 0-3 R.sup.22 groups. More typically R.sup.24a is
alkylene of 1 to 8 carbon atoms, alkenylene of 2 to 8 carbon atoms,
or alkynylene of 2 to 8 carbon atoms, still more typically,
R.sup.24a is alkylene of 1 to 6 carbon atoms, alkenylene of 2 to 6
carbon atoms, or alkynylene of 2 to 6 carbon atoms. More typically
yet, R.sup.24a is --CH.sub.2--, CH.sub.2CH.sub.2--,
CH.sub.2CH.sub.2CH.sub.2-- or --C(H)(CH.sub.3)--.
[0110] Each R.sup.28 is independently alkyl of 1 to 12 carbon
atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12
carbon atoms. More typically R.sup.28 is alkyl of 1 to 8 carbon
atoms, alkenyl of 2 to 8 carbon atoms, or alkynyl of 2 to 8 carbon
atoms, still more typically, R.sup.28 is alkyl of 1 to 6 carbon
atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon
atoms. More typically yet, R.sup.28 is R.sup.25.
[0111] Each R.sup.29 is independently R.sup.22 or R.sup.28 wherein
each R.sup.28 is substituted with 0 to 3 R.sup.22 groups. Each of
the typical embodiments of R.sup.28 and R.sup.22 are typical of
R.sup.29. More typically R.sup.29 is substituted with 0, 1, 2, or 3
R.sup.22 groups.
[0112] Each R.sup.30 is independently H, R.sup.24, W or
R.sup.24AW.
[0113] R.sup.4 is --C(R.sup.30).sub.3, provided that R.sup.4, taken
as a whole, contains 0 to 1 W groups (W is described above)
substituted with 0 to 3 R.sup.29 groups (R.sup.29 is described
above); and, in addition, 1 to 12 carbon atoms substituted with 0
to 3 R.sup.22 groups (R.sup.22 is described above). Exemplary
embodiments of R.sup.4 are provided as Ul embodiments in the
documents cited in the "Brief Description of Related Art"
above.
[0114] Typically one R.sup.30 is H. More typically, one R.sup.30 is
H and the remaining two R.sup.30's are independently R.sup.24, W or
--R.sup.24a W. More typically yet, one R.sup.30 is H, one R.sup.30
is R.sup.24 and the remaining R.sup.30 is independently R.sup.24, W
or --R.sup.24a W.
[0115] In one embodiment of R.sup.4, one R.sup.30 is H, one
R.sup.30 is R.sup.25 and one R.sup.30 is R.sup.24, W or --R.sup.24a
W. Typically, one R.sup.30 is H and two R.sup.30's are R.sup.25. In
another embodiment of R.sup.4, one R.sup.30 is H, one R.sup.30 is
--R.sup.24a W and one R.sup.30 is R.sup.24, W or --R.sup.24a W.
Typically, one R.sup.30 is H, one R.sup.30 is --R.sup.24a W and one
R.sup.30 is R.sup.24. In another embodiment, one R.sup.30 is H and
two R.sup.30's are alkyl of 1 to 6 carbon atoms.
[0116] In another embodiment, R.sup.4 is: 31
[0117] wherein R.sup.26 is H, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, OCH.sub.3, --OAc (--O--C(O)CH.sub.3),
OH, --NH2, or --SH, typically H, --CH.sub.3 or
--CH.sub.2CH.sub.3.
[0118] Typically each R.sup.4 (taken as a whole) contains 0-3 W
groups each of which is independently substituted with 0-3 R.sup.29
groups; and each R.sup.4 (taken as a whole) in addition contains
1-12 carbon atoms, each carbon atom of which is independently
substituted with 0-3 R.sup.22 groups. More typically each R.sup.4
contains 0, 1 or 2 such W groups, more typically yet, 0 or 1 such W
group.
[0119] In another embodiment, each R.sup.30 group (taken as whole)
of R.sup.4 is not so electron withdrawing as to prevent the
formation of compound 11. Lowry, T. H. and Richardson, K. S.
"Mechanism and Theory in Organic Chemistry" (Harper & Row,
1976) at section 2.2, pages 60-71, and March, J. "Advanced Organic
Chemistry" (McGraw-Hill, 1977) at Chapter 9, Quantitative
Treatments of the Effect of Structure on Reactivity", pages
251-259, provide details of the electron withdrawing properties of
substitutent groups. In another embodiment, each R.sup.30 group
(taken as whole) of R.sup.4 has a Hammett (para value of less than
about 1, typically less than about 0.75, more typically less than
about 0.5. In another embodiment, each R.sup.30 group (taken as
whole) of R.sup.4 has a Hammett cpara value of -1.0 to 1.0, more
typically -0.75 to 0.75, more typically yet -0.5 to 0.5.
[0120] This process embodiment comprises reaction of a compound of
the formula: 32
[0121] wherein R.sup.31 is a ketal or acetal, with a lewis acid
reagent. Typically R.sup.31 is --C(R.sup.30).sub.2-- wherein
R.sup.30 is as described above, Typically, compound 10 is reacted
with a Lewis acid catalyst common in the art, such as
BF.sub.3.circle-solid.Et.sub.2O, TiCl.sub.3, TMSOTf,
SmI.sub.2(THF).sub.2, LiCIO.sub.4, Mg(ClO.sub.4).sub.2,
Ln(OTf).sub.3 (where Ln.dbd.Yb, Gd, Nd), Ti(Oi--Pr).sub.4,
AlCl.sub.3, AlBr.sub.3, BeCI.sub.2, CdCl.sub.2, ZnCl.sub.2,
BF.sub.3, BC.sub.13, BBr.sub.3, GaCl.sub.3, GaBr.sub.3,TiCl.sub.4,
TiBr.sub.4, ZrCI.sub.4, SnCI.sub.4, SnBr.sub.4, SbCI.sub.5,
SbCl.sub.3, BiCl.sub.3, FeCI.sub.3, UCl.sub.4, ScCl.sub.3,
YCl.sub.3, LaCl.sub.3, CeCl.sub.3, PrCI.sub.3, NdCl.sub.3,
SmCl.sub.3, EuCl.sub.3, GdCl.sub.3, TbC.sub.13, LuCl.sub.3,
DYCl.sub.3, HoCl.sub.3, ErCl.sub.3, TmCl.sub.3, YbCl.sub.3,
Znl.sub.2, Al(OPrl).sub.3, Al(acac).sub.3, ZnBr2, or SnC.sub.4.
Optionally, compound 10 is also treated with a reducing reagent.
Typical reducing reagents are of the form B(R.sup.30).sub.3 such as
BH.sub.3. Optionally reducing reagents of the form
B(R.sup.30).sub.3 are complexed with common solvents such as
diethylether and dimethylsulfide. A wide range of borane reducing
reagents are known and will not be described in detail here. For
example Brown, H.C. "Boranes in Organic Chemistry", (Cornell Univ.
Press, Ithaca, N.Y., 1972) (Brown) provides a very large number of
examples such as is found in Part Four, Selective Reductions, pages
209-251, Part Five, Hydroboration, pages 255-297, and Part Six,
Organoboranes, pages 301-446.
[0122] In a typical embodiment, compound 10 is treated with a lewis
acid in a nonprotic solvent. More typically, compound 10 is treated
with a lewis acid and a reducing reagent in a nonprotic
solvent.
[0123] In a typical embodiment, a solution of 10 in
dichlorormethane is cooled and treated with borane-methyl sulfide
complex and trimethylsilyl trifluoromethanesulfonate. 10% Aqueous
sodium bicarbonate solution is slowly added. The mixture is warmed
to ambient temperature and stirred. The organic layer is filtered
and concentrated in vacuo to leave compound 11. A detailed example
of this embodiment is provided as Example 6 below.
[0124] In another example process of this embodiment compound 11 is
of the formula: 33
[0125] Another aspect of the present invention is directed to
processes for the preparation of compounds of the formula: 34
[0126] wherein:
[0127] R.sup.2, R.sup.4, R.sup.7, R.sup.20 and R.sup.21 are as
defined above.
[0128] This process embodiment comprises reaction of a compound of
the formula: 35
[0129] with a reducing reagent.
[0130] The azide of compound 30 is reduced to form compound 31.
[0131] Typically the process comprises treating compound 30 with a
reducing agent to form compound 31. More typically the process
comprises treating compound 30 with hydrogen gas and a catalyst
(such as platinum on carbon or Lindlar's catalyst), or reducing
reagents (typically a trisubstituted phosphine such as trialkyl
(P(R.sup.25).sub.3) or triaryl phosphine (PW.sub.3, e.g.
triphenylphosphine). More typically still, the process comprises
treating compound 30 with triphenylphosphine and a base to form
compound 31.
[0132] Typically, compound 30 is disolved in a suitable polar,
aprotic solvent such as anhydrous acetonitrile. A solution of
anhydrous triphenylphosphine in a suitable solvent such as
anhydrous tetrahydrofuran or a mixture of solvents is added
dropwise. The mixture is heated at reflux then concentrated in
vacuo to leave compound 5. A detailed example of this embodiment is
provided as Example 9 below.
[0133] In another embodiment of this process compound 31 is of the
formula: 36
[0134] Another aspect of the present invention is directed to
processes for. the preparation of compounds of the formula: 37
[0135] wherein:
[0136] R.sup.2, R.sup.4, R.sup.5, R.sup.20 and R.sup.21 are as
described above.
[0137] Y.sup.1 is a mono--, di- or unsubstituted amino group.
Typically Y.sup.1 is of the formula --N(R.sup.30).sub.2, a
phthalimide or is a nitrogen containing heterocycle (defined above
under W), more typically, Y.sup.1 is a phthalimide, more typically
yet, a phthalimide salt.
[0138] This process embodiment comprises reaction of a compound of
the formula: 38
[0139] with an amine reagent. Typically, the amine reagent is of
the formula HY.sup.1 or a salt of HY.sup.1, such as, by way of
example, NH.sub.3 (McManns, et al., "Bull Soc. Chim. France" 850
(1947)), HY.sup.1 generally (Moussevon, M., et al., "Synth.
Commun." 3:177 (1973)) or phthalimide. (Gabriel, et al., "Ber."
20:2224 (1887) or Gibson, et al., "Angew. Chem. Int.", 7:919-930
(1968)).
[0140] The process comprises treating compound 40 with the amine
reagent to produce compound 32. More typically, compound 40 is
treated with the amine reagent in a suitable polar a protic solvent
(e.g. CH.sub.3CN, DMF or THF). Optionally compound 40 is treated
with the amine reagent and a base. Typical details of this process
embodiment can be found in March, "Advanced Organic Chemistry" 4th.
ed., pp 425-427.
[0141] In another embodiment of this process compound 41 is of the
formula: 39
[0142] Another aspect of the present invention is directed to
processes for the preparation of compounds of the formula: 40
[0143] wherein:
[0144] R.sup.2, R.sup.4, R.sup.20, R.sup.21 and Y.sup.1 are as
described above;
[0145] This process embodiment comprises reaction of a compound of
the formula: 41
[0146] with an oxidizing reagent. A wide range of suitable
oxidation reagents are common in the art and will not be detailed
here. For example House, H. O. "Modern Synthetic Reactions, Second
Edition", Chapter .sub.5, pages 259-273, describes the selective
oxidation of alcohols. Typical reagents include CrO.sub.3,
Na.sub.2Cr.sub.2O.sub.7, KMnO.sub.4, PDC and PCC. Typical details
of this process embodiment can be found in Larock, "Comprehensive
Organic Transformations", pp. 604-614; Corey et al., "Tetrahedron
Lett." 31:2647-50 (1975); Ley et al., "Chem. Common" 1625 (1987);
Sweon, et al., "J. Org. Chem." 43:2480-2 (1978); and Martin, et
al., "J. Org. Chem." 48:4155-56 (1983). Solvents typically include
inert polar solvents (e.g. CH.sub.2Cl.sub.2, toluene or
CH.sub.3CN).
[0147] In another embodiment of this process compound 51 is of the
formula: 42
[0148] Another aspect of the present invention is directed to
processes for the preparation of compounds of the formula: 43
[0149] wherein:
[0150] R.sup.2, R.sup.4, R.sup.20, R.sup.21 and Y.sup.1 are as
described above;
[0151] This process embodiment comprises reaction of a compound of
the formula: 44
[0152] with a base. Typically the base is a hindered amine or
hindred alkoxide or the salts of either. More typically the base is
of the formula NaOR.sup.25, KOR.sup.25 or NR.sup.25.sub.3, more
typically yet, DBN, DBU or diisopropyl ethyl amine.
[0153] In another embodiment of this process compound 61 is of the
formula: 45
[0154] Another aspect of the present invention is directed to
processes for the preparation of compounds of the formula: 46
[0155] wherein:
[0156] R.sup.2, R.sup.4, R.sup.7, R.sup.20, R.sup.21 and Y.sup.1
are as described above;
[0157] This process embodiment comprises reaction of a compound of
the formula: 47
[0158] with a reductive amination reagent. Typical details of and
references to this process embodiment can be found in Larock, op.
cit., pp. 421-425. Another typical description (NaCNBH.sub.3
method) is Borch, "J. Am. Chem. Soc." 93:2897-2904 (1971).
[0159] Schemes I and 2 depict embodiments of the invention.
Detailed descriptions of the processes of Schemes 1 and 2 are
provided in the Examples (below).
[0160] Additional individual process embodiments of the invention
include any one or sequential combination of processes AA, AB, AC,
AD, AE, AF, AG, AH, AI, AJ, or AK of Schemes 1 and 2. "Sequential
combination" as used herein means more than one process wherein the
individual processes are performed one after the other in the order
shown. Isolation, separation, purification is optionally performed
prior to any of the individual processes.
[0161] Additional individual process embodiments of the invention
include any one or sequential combination of the processes of
Example 1, Example 2, Example .sub.3, Example .sub.4, Example
.sub.5, Example 6, Example 7, Example 8, Example 9, Example 10,
Example 11, Example 12 or Example 13. 48 49
[0162] Scheme 3 depicts the synthesis of the neuraminidase
inhibitor 206 (R.dbd.H.sub.2) by use of alternative nitrogen
nucleophiles (March, "Advanced Organic Chemistry" 4th. ed., pp
425-427) to open the epoxide 201. Oxidation of azidoalcohol 202
gives ketone 203 (Larock, "Comprehensive Organic Transformations",
pp. 604-614) in which the .beta.-axial NR group isomerizes to the
.alpha.-equatorial configuration 204. Reductive amination of the
ketone 204 (Larock, op. cit., pp. 421-425) gives the
.beta.-equatorial amine 205 which is acetylated to afford 206.
Cleavage of the R moiety (Greene, "Protective Groups in Organic
Synthesis", pp. 218-287) gives the neuramridase inhibitor 206
(R.dbd.H.sub.2).
[0163] Additional individual process embodiments of the invention
include any one or sequential combination of processes AL, AM, AN,
AO, or AP of Scheme 3. 50
[0164] Modifications of each of the above schemes leads to various
analogs of the specific exemplary materials produced above. The
above cited citations describing suitable methods of organic
synthesis are applicable to such modifications.
[0165] In each of the above exemplary schemes it may be
advantageous to separate reaction products from one another and/or
from starting materials. The desired products of each step or
series of steps is separated and/or purified (hereinafter
separated) to the desired degree of homogeneity by the techniques
common in the art. Typically such separations involve multiphase
extraction, crystallization from a solvent or solvent mixture,
distillation, sublimation, or chromatography. Chromatography can
involve any number of methods including, for example, size
exclusion or ion exchange chromatography, high, medium, or low
pressure liquid chromatography, small scale and preparative thin or
thick layer chromatography, as well as techniques of small scale
thin layer and flash chromatography.
[0166] Another class of separation methods involves treatment of a
mixture with a reagent selected to bind to or render otherwise
separable a desired product, unreacted starting material, reaction
by product, or the like. Such reagents include adsorbents or
absorbents such as activated carbon, molecular sieves, ion exchange
media, or the like. Alternatively, the reagents can be acids in the
case of a basic material, bases in the case of an acidic material,
binding reagents such as antibodies, binding proteins, selective
chelators such as crown ethers, liquid/liquid ion extraction
reagents (LIX), or the like.
[0167] Selection of appropriate methods of separation depends on
the nature of the materials involved. For example, boiling point,
and molecular weight in distillation and sublimation, presence or
absence of polar functional groups in chromatography, stability of
materials in acidic and basic media in multiphase extraction, and
the like. One skilled in the art will apply techniques most likely
to achieve the desired separation.
Stereoisomers
[0168] The compounds of the invention are enriched or resolved
optical isomers at any or all asymmetric atoms. For example, the
chiral centers apparent from the depictions are provided as the
chiral isomers or racemic mixtures. Both racemic and diasteromeric
mixtures, as well as the individual optical isomers isolated or
synthesized, substantially free of their enantiomeric or
diastereomeric partners, are all within the scope of the
invention.
[0169] One or more of the following enumerated methods are used to
prepare the enantiomerically enriched or pure isomers herein. The
methods are listed in approximately their order of preference,
i.e., one ordinarily should employ stereospecific synthesis from
chiral precursors before chromatographic resolution before
spontaneous crystallization.
[0170] Stereospecific synthesis is described in the examples.
Methods of this type conveniently are used when the appropriate
chiral starting material is available and reaction steps are chosen
do not result in undesired racemization at chiral sites. One
advantage of stereospecific synthesis is that it does not produce
undesired enantiomers that must be removed from the final product,
thereby lowering overall synthetic yield. In general, those skilled
in the art would understand what starting materials and reaction
conditions should be used to obtain the desired enantiomerically
enriched or pure isomers by stereospecific synthesis. If an
unexpected racernization occurs in a method thought to be
stereospecific then one needs only to use one of the following
separation methods to obtain the desired product.
[0171] If a suitable stereospecific synthesis cannot be empirically
designed or determined with routine experimentation then those
skilled in the art would turn to other methods. One method of
general utility is chromotographic resolution of enantiomers on
chiral chromatography resins. These resins are packed in columns,
commonly called Pirkle columns, and are commercially available. The
columns contain a chiral stationary phase. The racemate is placed
in solution and loaded onto the column, and thereafter separated by
HPLC. See for example, Proceedings Chromatographic
Society--International Symposium on Chiral Separations, Sep. 3-4,
1987. Examples of chiral columns that could be used to screen for
the optimal separation technique would include Diacel Chriacel OD,
Regis Pirkle Covalent Dphenylglycine, Regis Pirkle Type 1A, Astec
Cyclobond II, Astec Cyclobond III, Serva Chiral D-DL-Daltosil 100,
Bakerbond DNBLeu, Sumipax OA-1000, Merck Cellulose Triacetate
column, Astec Cyclobond I-Beta, or Regis Pirkle Covalent
D-Naphthylalanine. Not all of these columns are likely to be
effective with every racemic mixture. However, those skilled in the
art understand that a certain amount of routine screening may be
required to identify the most effective stationary phase. When
using such columns it is desireable to employ embodiments of the
compounds of this invention in which the charges are not
neutralized, e.g., where acidic functionalities such as carboxyl
are not esterified or amidated.
[0172] Another method entails converting the enantiomers in the
mixture to diasteriomers with chiral auxiliaries and then separting
the conjugates by ordinary column chromatography. This is a very
suitable method, particularly when the embodiment contains free
carboxyl, amino or hydroxyl that will form a salt or covalent bond
to a chiral auxiliary. Chirally pure amino acids, organic acids or
organosulfonic acids are all worthwhile exploring as chiral
auxiliaries, all of which are well known in the art. Salts with
such auxiliaries can be formed, or they can be covalently (but
reversibly) bonded to the functional group. For example, pure D or
L amino acids can be used to amidate the carboxyl group of
embodiments of this invention and then separated by
chromatography.
[0173] Enzymatic resolution is another method of potential value.
In such methods one prepares covalent derivatives of the
enantiomers in the racemic mixture, generally lower alkyl esters
(for example of carboxyl), and then exposes the derivative to
enzymatic cleavage, generally hydrolysis. For this method to be
successful an enzyme must be chosen that is capable of
stereospecific cleavage, so it is frequently necessary to routinely
screen several enzymes. If esters are to be cleaved, then one
selects a group of esterases, phosphatases, and lipases and
determines their activity on the derivative. Typical esterases are
from liver, pancreas or other animal organs, and include porcine
liver esterase.
[0174] If the enatiomeric mixture separates from solution or a melt
as a conglomerate, i.e., a mixture of enantiomerically-pure
crystals, then the crystals can be mechanically separated, thereby
producing the enantiomerically enriched preparation. This method,
however, is not practical for large scale preparations and is of no
value for true racemic compounds.
[0175] Asymmetric synthesis is another technique for achieving
enantiomeric enrichment. For example, a chiral protecting group is
reacted with the group to be protected and the reaction mixture
allowed to equilibrate. If the reaction is enantiomerically
specific then the product will be enriched in that enantiomer.
[0176] Further guidance in the separation of enantiomeric mixtures
can be found, by way of example and not limitation, in
"Enantiomers, Raceinates, and resolutions", Jean Jacques, Andre
Collet, and Samuel H. Wilen (Krieger Publishing Company, Malabar,
Fla., 1991, ISBN 0-89464-618-4). In particular, Part 2, "Resolution
of Enantiomer Mixture", pages 217-435; more particularly, section
4, "Resolution by Direct Crystallization", pages 217-251, section
5, "Formation and Separation of Diastereomers", pages 251-369,
section 6, "Crystallization-Induced Asymmetric Transformations",
pages 369-378, and section 7, "Experimental Aspects and Art of
Resolutions", pages 378-435; still more particularly, section
5.1.4, "Resolution of Alcohols, Transformation of Alcohols into
Salt-Forming Derivatives", pages 263-266, section 5.2.3, "Covalent
Derivatives of Alcohols, Thiols, and Phenols", pages 332-335,
section 5.1.1, "Resolution of Acids", pages 257-259, section 5.1.2,
"Resolution of Bases", pages 259-260, section 5.1.3, "Resolution of
Amino Acids", page 261-263, section 5.2.1, "Covalent Derivatives of
Acids", page 329, section 5.2.2, "Covalent Derivatives of Amines",
pages 330-331, section 5.2.4, "Covalent Derivatives of Aldehydes,
Ketones, and Sulfoxides", pages 335-339, and section 5.2.7,
"Chromatographic Behavior of Covalent Diastereomers", pages
348-354, are cited as examples of the skill of the art.
Salts and Hydrates
[0177] The compositions of this invention optionally comprise salts
of the compounds herein, for example, Na+, Li+, K+, Ca++ and Mg++.
Such salts may include those derived by combination of appropriate
cations such as alkali and alkaline earth metal ions or ammonium
and quaternary amino ions with an acid anion moiety. Monovalent
salts are preferred if a water soluble salt is desired.
[0178] Metal salts typically are prepared by reacting the metal
hydroxide with a compound of this invention. Examples of metal
salts which are prepared in this way are salts containing Li+, Na+,
and K+. A less soluble metal salt can be precipitated from the
solution of a more soluble salt by addition of the suitable metal
compound.
[0179] In addition, salts may be formed from acid addition of
certain organic and inorganic acids, e.g., HCl, HBr,
H.sub.2SO.sub.4, H.sub.3PO.sub.4 or organic sulfonic acids, to
basic centers, typically amines. Finally, it is to be understood
that the compositions herein comprise compounds of the invention in
their un-ionized, as well as zwitterionic form, and combinations
with stoiochimetric amounts of water as in hydrates.
[0180] Also included within the scope of this invention are the
salts of the parental compounds with one or more amino acids. Any
of the amino acids described above are suitable, especially the
naturally-occuring amino acids found as protein components,
although the amino acid typically is one bearing a side chain with
a basic or acidic group, e.g., lysine, arginine or glutamic acid,
or a neutral group such as glycine, serine, threonine, alanine,
isoleucine, or leucine.
Additional Uses for the Compounds of This Invention
[0181] The compounds of the invention are polyfunctional. As such
they represent a unique class of monomers for the synthesis of
polymers. By way of example and not limitation, the polymers
prepared from the compounds of this invention include polyamides,
polyesters and mixed polyester-polyamides.
[0182] The present compounds are used as monomers to provide access
to polymers having unique pendent functionalities. The compounds of
this invention are useful as comonomers with monomers which do not
fall within the scope of the invention. Polymers of the compounds
of this invention will have utility as cation exchange agents
(polyesters or polyamides) in the preparation of molecular sieves
(polyamides), textiles, fibers, films, formed articles and the
like. Polymers are prepared by any conventional method, for
example, by cross-linking an --OH or --NH.sub.2 group of the
compounds of the invention with a diacid comonomer. The preparation
of these polymers from the compounds of the invention is
conventional per se.
[0183] The compounds of the invention are also useful as a unique
class of polyfunctional surfactants. Particularly when R.sup.4 or
R.sup.2 do not contain hydrophilic substituents and are, for
example, alkyl, the compounds have the properties of bi-functional
surfactants. As such they have useful surfactant, surface coating,
emulsion modifying, rheology modifying and surface wetting
properties.
[0184] As polyfunctional compounds with defined geometry and
carrying simultaneously polar and non-polar moieties, the compounds
of the invention are useful as a unique class of phase transfer
agents. By way of example and not limitation, the compounds of the
invention are useful in phase transfer catalysis and liquid/liquid
ion extraction (LIX).
[0185] The compounds of the invention optionally contain asymmetric
carbon atoms. As such, they are a unique class of chiral
auxiliaries for use in the synthesis or resolution of other
optically active materials. For example, a racemic mixture of
carboxylic acids can be resolved into its component enantiomers by:
1) forming a mixture of diastereomeric esters or amides with a
compound of the invention containing an --OH or --MH.sub.2 group;
2) separating the diastereomers; and 3) hydrolyzing the ester
structure. Further, such a method can be used to resolve the
compounds of the invention themselves if optically active acids are
used instead of racemic starting materials.
[0186] The compounds of this invention are useful as linkers or
spacers in preparing affinity absorption matrices, immobilized
enzymes for process control, or irrmunoassay reagents. The
compounds herein contain a multiplicity of functional groups that
are suitable as sites for cross-linking desired substances. For
example, it is conventional to link affinity reagents such as
hormones, peptides, antibodies, drugs, and the like to insoluble
substrates. These insolublized reagents are employed in known
fashion to absorb binding partners for the affinity reagents from
manufactured preparations, diagnostic samples and other impure
mixtures. Similarly, immobilized enzymes are used to perform
catalytic conversions with facile recovery of enzyme. Bifunctional
compounds are commonly used to link analytes to detectable groups
in preparing diagnostic reagents.
[0187] Many functional groups in the compounds of this invention
are suitable for use in cross-linking. For example, --OH and
--NH.sub.2 groups. Suitable protection of reactive groups will be
used where necessary while assembling the cross-linked reagent to
prevent polymerization of the bifunctional compound of this
invention: In general, the compounds here are used by linking them
through hydroxyl or amino groups to carboxylic or phosphonic acid
groups of the first linked partner, then covalently bonding to the
other binding partner through another OHI or --NH.sub.2 group. For
example a first binding partner such as a steroid hormone is
reacted to form an amide bond with the --NH.sub.2 group of a
compound of this invention and then this conjugate is cross-linked
through a hydroxyl to cyanogen bromide activated Sepaharose,
whereby immobilized steroid is obtained. Other chemistries for
conjugation are well known. See for example Maggio,
"Enzyme-Immunoassay" (CRC, 1988, pp 71-135) and references cited
therein.
[0188] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how to make the compounds and compositions of the
invention and are not intended to limit the scope of what the
inventors regard as their invention. Efforts have been made to
insure accuracy with respect to numbers used (e.g., amounts,
temperatures, etc.), but some experimental errors and deviations
should be taken into account. Unless indicated otherwise, parts are
parts by weight, temperature is in degrees Centigrade, and pressure
is at or near atmospheric.
EXAMPLES
EXAMPLE 1
[0189] Lactone 100: A solution of quinic acid (20 kg, 104 mol;
[a].sub.D-43.7.degree. (c=1.12, water); "Merck Index 11th ed".,
8071: [.alpha.].sub.D-42.degree. to -44.degree. (water)),
2,2-dimethoxypropane (38.0 kg, 365 mol) and p-toluenesulfonic acid
monohydrate (0.200 kg, 1.05 mol) in acetone (80 kg) was heated at
reflux for two hours. The reaction was quenched by addition of 21%
sodium ethoxide in ethanol (0.340 kg, 1.05 mol) and most of the
solvent was distilled in vacuo. The residue was partitioned between
ethyl acetate (108 kg) and water (30 kg). The aqueous layer was
back-extracted with ethyl acetate (13 kg) and the combined organic
layers were washed with 5% aqueous sodium bicarbonate (14 kg). Most
of the ethyl acetate was distilled in vacuo to leave a pale yellow
solid residue of 100 which was used directly in the next step.
EXAMPLE 2
[0190] Hydroxy ester 101: A solution of the crude lactone 100 (from
104 mol. (-)-quinic acid) in absolute ethanol (70 kg) was treated
with.20% sodium ethoxide in ethanol (0.340kg, 1.05 mol). After two
hours at room temperature, acetic acid (0.072 kg, 1.2 mol) was
added and the solvent was distilled in vacuo. Ethyl acetate (36 kg)
was added and the distillation continued to near dryness. The tan
solid residue composed of a ca. 5:1 mixture of 101:100 was
dissolved in ethyl acetate (9 kg) at reflux and hexane (9 kg) was
added. Upon cooling, a white crystalline solid formed which was
isolated by filtration to afford a ca. 6.5:1 mixture of 101:100
(19.0 kg, 70% yield).
EXAMPLE 3
[0191] Mesyl ester 102: A solution of a ca. 6.5:1 mixture (18.7 kg,
ca. 72 mol) of hydroxy ester 101 and lactone 100 in dichloromethane
(77 kg) was cooled to 0-10.degree. C. and treated with
methanesulfonyl chloride (8.23 kg, 71.8 mol), followed by slow
addition of triethylamine (10.1 kg, 100 mol). An additional portion
of methanesulfonyl chloride (0.84 kg, 7.3 mol) was added. After one
hour, water (10 kg) and 3% hydrochloric acid (11 kg) were added.
The layers were separated and the organic layer was washed with
water (9 kg), then distilled in vacuo to leave a semi-solid residue
composed of a ca. 6.5:1 mixture of mesyl ester 102 and mesyl
lactone 103. The residue was dissolved in ethyl acetate (11 kg) and
cooled to-10.degree. to -20.degree. C. for two hours. Mesyl lactone
103 crystallized and was separated by filtration and washed with
cold ethyl acetate (11 kg). The filtrate was concentrated to afford
mesyl ester 102 as an orange resin (20.5 kg, .sup.84..sup.3%
yield).
EXAMPLE 4
[0192] Mesyl acetonide 104: A solution of mesyl ester 102 (10.3 kg,
30.4 mol) and pyridine (10.4 kg, 183 mol) in dichloromethane (63
kg) was cooled to -20.degree. to -30.degree. C. and treated
portionwise with sulfuryl chloride (6.22 kg, 46 mol). After the
exothermic reaction subsided, the resulting slurry was quenched
with ethanol (2.4 kg), warmed to 0.degree. C., and washed
successively with 16% sulfuric acid (35 kg), water (15 kg) and 5%
aqueous sodium bicarbonate (1 kg). The organic layer containing a
ca. 4:1:1 mixture of 104:105:106 was concentrated in vacuo and
ethyl acetate (14 kg) was added. The allylic mesylate 105 was
selectively removed by treatment of the ethyl acetate solution with
pyrrolidine (2.27 kg, 31.9 mol) and
tetrakis(triphenylphosphine)palladiun- (O) (0.0704 kg, 0.061mol) at
ambient temperature for five hours, followed by washing with 16%
sulfuric acid (48 kg). The organic layer was filtered through a pad
of silica gel (11 kg) and eluted with ethyl acetate (42 kg). The
filtrate was concentrated in vacuo to leave a thick orange oil
composed of a ca. 4:1 mixture of 104:106. The residue was dissolved
in ethyl acetate (5.3 kg) at reflux and hexane (5.3 kg) was added.
Upon cooling, mesyl acetonide 104 crystallized and was separated by
filtration and washed with 14% ethyl acetate in hexane (2.1 kg).
After drying in vacuo, 104 was obtained as pale yellow needles
(4.28 kg, 43.4% yield), mp 102-3.degree. C.
EXAMPLE 5
[0193] Pentyl ketal 107: A solution of acetonide 104 (8.9 kg, 27.8
mol), 3-pentanone (24 kg, 279 mol) and 70% perchloric acid (0.056
kg, 0.39 mol) was stirred for 18 hours. The volatiles were
distilled in vacuo at ambient temperature and fresh 3-pentanone (30
kg, 348 mol) was added gradually as the distillation progressed.
The reaction mixture was filtered, toluene (18 kg) was added, and
the resulting solution was washed successively with 6% aqueous
sodium bicarbonate (19 kg), water (18 kg) and brine (24 kg). The
organic layer was concentrated in vacuo and toluene (28 kg) was
added gradually as the distillation progressed. When no more
distilled, the residual orange oil was composed of pentyl ketal 107
(9.7 kg, 100% yield) and toluene (ca. 2 kg).
EXAMPLE 6
[0194] Pentyl ether 108: A solution of ketal 107 (8.6 kg, 25 mol)
in dichloromethane (90 kg) was cooled to -30.degree. to -20.degree.
C. and treated with borane-methyl sulfide complex (2.1 kg, 27.5
mol) and trimethylsilyl trifluoromethanesulfonate (7.2 kg, 32.5
mol). After one hour, 10% aqueous sodium bicarbonate solution (40
kg) was slowly added. The mixture was warmed to ambient temperature
and stirred for 12 hours. The organic layer was filtered and
concentrated in vacuo to leave a ca. 8:1 mixture of 108:109 as a
gray waxy solid (7.8 kg, 90% yield).
EXAMPLE 7
[0195] Epoxide 110: A ca. 8:1 mixture of isomeric pentyl ethers
108:109 (7.8 kg, 22.3 mol) in ethanol (26 kg) was treated with a
solution of potassium hydrogen carbonate (3.52 kg, 35 mol) in water
(22 kg). After heating at 55.degree.-65.degree. C. for two hours,
the solution was cooled and twice extracted with hexanes (31 kg,
then 22 kg). Unreacted 109 remained in the aqueous ethanol layer.
The combined hexane extracts were filtered and concentrated in
vacuo to leave epoxide110 as a flocculent white crystalline solid
(3.8 kg, 60% yield), mp=54.6.degree. C.
EXAMPLE 8
[0196] Hydroxy azide 111: A mixture of epoxide 110 (548 g, 2.0
mol), sodium azide (156 g, 2.4 mol) and ammonium chloride (128.4 g,
2.4 mol) in water (0.265 L) and ethanol (1.065 L) was heated at
70.degree.-75.degree. C. for eight hours. Aqueous sodium
bicarbonate (0.42 L of 8% solution) was added and the ethanol was
distilled in vacuo. The aqueous residue was extracted with ethyl
acetate (1 L) and the extract was washed with water (0.5 L). The
water wash was back-extracted with ethyl acetate (0.5 L). The
combined organic extracts were washed with brine (0.5 L), dried
over anhydrous sodium sulfate, filtered and concentrated in vacuo
to leave a ca. 10:1 mixture of isomeric hydroxy azides 111:112 (608
g, 102% yield) as a dark brown oil.
EXAMPLE 9
[0197] Aziridine 113: A ca. 10:1 mixture of hydroxy azides 111:112
(608 g, 2.0 mol) was three times co-evaporated in vacuo from
anhydrous acetonitrile (3.times.0.3 L) and then dissolved in
anhydrous acetonitrile (1 L). A solution of anhydrous
triphenylphosphine (483 g, 1.84 mol) in anhydrous tetrahydrofuran
(0.1 L) and anhydrous acetonitrile (0.92 L) was added dropwise over
two hours. The mixture was heated at reflux for six hours then
concentrated in vacuo to leave a golden paste composed of aziridine
113, triphenylphosphine oxide and traces of triphenylphosphine. The
paste was triturated with diethyl ether (0.35 L). Most of the
insoluble triphenylphosphine oxide was removed by filtration and
washed with diethyl ether (1.5 L). The filtrate was concentrated in
vacuo to leave a dark brown oil which was dissolved in 20% aqueous
methanol and extracted three times with hexanes (3.times.1 L) to
remove triphenylphosphine. The hexane extracts were back-extracted
with 20% aqueous methanol (0.5 L) and the combined aqueous methanol
layers were concentrated in vacuao. The residue was twice
co-evaporated in bacuo from anhydrous acetonitrile (2.times.0.5 L)
to leave a dark brown oil composed of aziridene 113 (490 g, 96.8%
yield) and triphenylphosphine oxide (ca. 108 g) which was used
directly in the next step.
EXAMPLE 10
[0198] Acetamido azide 115: A mixture of aziridine 113 (490 g, 1.93
mol) and triphenylphosphine oxide (ca. 108 g), sodium azide (151 g,
2.33 mol) and ammonium chloride (125 g, 2.33 mol) in
dimethylformamide (1.3 L) was heated at 80.degree.-85.degree. C.
for five hours. Sodium bicarbonate (32.8 g, 0.39 mol) and water
(0.66 L) were added. The amino azide 114 was isolated from the
reaction mixture by six extractions with hexanes (6.times.1 L). The
combined hexane extracts were concentrated in vacuo to ca. 4.5 L
total volume and dichioromethane (1.04 L) was added. Aqueous sodium
bicarbonate (4.2 L of 8% solution, 3.88 mol) was added, followed by
acetic anhydride (198 g, 1.94 mol). After stirring for one hour at
ambient temperature, the aqueous layer was discarded. The organic
phases were concentrated in vacuao to 1.74 kg total weight and
dissolved with ethyl acetate (0.209 L) at reflux. Upon cooling,
acetamido azide 115 crystallized and was isolated by filtration.
After washing with cold 15% ethyl acetate in hexane (1 L) and
drying in vacuo at ambient temperature, pure 115 was obtained as
off-white crystals (361 g, 55% yield), mp 126-132.degree. C.
EXAMPLE 11
[0199] Acetamido amine 116: A mixture of azide 115 (549 g, 1.62
mol) and Lindlar catalyst (50 g) in abs. ethanol (3.25 L) was
stirred for eighteen hours while hydrogen (1 atm.) was bubbled
through the mixture. Filtration through Celite and concentration of
the filtratein vacuao afforded 116 as a foam which solidified on
standing (496 g, 98% yield).
EXAMPLE 12
[0200] Phosphate salt of 116: A solution of acetamido amine 116
(5.02 g, 16.1 mmol) in acetone (75 mL) at reflux was treated with
85% phosphoric acid (1.85 g, 16.1 mmol) in abs. ethanol (25 mL).
Crystallization commenced immediately and after cooling to
0.degree. C. for 12 hours the precipitate was collected by
filtration to afford 116.circle-solid.H.sub.- 3PO.sub.4 as long
colorless needles (4.94 g, 75% yield; [.alpha.].sub.D-39.9.degree.
(c=1, water)), mp 203-4.degree. C.
EXAMPLE 13
[0201] Hydrochloride salt of 116: A solution of acetamido amine 116
(2.8 g, 8.96 mmol) in abs. ethanol (9 mL) was treated with 2.08 M
hydrogen chloride in ethanol (8.6 mL, 17.9 mmol). Most of the
ethanol was evaporated in vacuo and the oily residue was stirred
with ethyl acetate (20 mL) until solid formed. Hexanes (20 mL) were
gradually added to the stirred mixture. After one hour at ambient
temperature, the solid was collected by filtration, washed with
diethyl ether and dried in vacuo. This afforded 116oHCl as an
off-white solid (2.54 g, 81% yield; [a].sub.D -43.degree. (c=0.4,
water)), mp206.degree. C.
[0202] All literature and patent citations above are hereby
expressly incorporated by reference in their entirety at the
locations of their citation. Specifically cited sections or pages
of the above cited works are incorporated by reference with
specificity.
[0203] Whenever a compound described herein is substituted with
more than one of the same designated group, such as, by was of
example andc not limitation, "R.sup.7", "R.sup.8", "R.sup.9,"
"R.sup.20", or "R.sup.22", then it will be understood that each of
the groups may be the same or different, i.e., each group is
independently selected. So for example, the phrase "R.sup.22 is" is
synonymous with the phrase "each R.sup.22 is independently".
[0204] The invention has been described in detail sufficient to
allow one of ordinary skill in the art to make and use the subject
matter of the following claims. It is apparent that certain
modifications of the methods and compositions of the following
claims can be made within the scope and spirit of the
invention.
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