Process for preparation of optically active sulfonamides and intermediates for their synthesis
View Patent ↗A method including resolution of a diastereomeric mixture represented by the formula wherein R 1 and R 2 are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, only one of R 1 and R 2 contains one asymmetric carbon, and R a is an optically active and optionally substituted hydrocarbon group or an optically active and optionally substituted heterocyclic group, or a salt thereof, to produce the diastereomer having a steric configuration of the asymmetric carbon for R 1 or R 2 of an R configuration or an S configuration, or a salt thereof.
1. A method comprising
reacting a racemate represented by the formula
R 1 —SO 2 —NH—R 2 (II)
wherein
R 1 and R 2 are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and only one of R 1 and R 2 contains one asymmetric carbon,
or a salt thereof
with an optically active compound represented by the formula
R a —COOH (III)
wherein
R a is an optically active and optionally substituted hydrocarbon group or an optically active and optionally substituted heterocyclic group, a salt thereof or a reactive derivative thereof
to give a diastereomeric mixture represented by the formula
wherein each symbol is as defined above,
or a salt thereof, and
resolving the diastereomeric mixture or a salt thereof
wherein resolution is carried out by solvent extraction, liquid exchange, phase transfer, salting out, crystallization, recrystallization or chromatography,
to produce the diastereomer having a steric configuration of the asymmetric carbon for R 1 or R 2 of an R configuration or an S configuration,
or a salt thereof.
2. The method of claim 1 , wherein R a is an optically active and optionally substituted hydrocarbon group containing an asymmetric carbon or an optically active and optionally substituted heterocyclic group containing an asymmetric carbon.
3. The method of claim 1 , wherein the resolution is free of hydrolase.
4. A production method of a diastereomeric mixture represented by the formula
wherein R 1 and R 2 are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and only one of R 1 and R 2 contains one asymmetric carbon, and R a is an optically active and optionally substituted hydrocarbon group or an optically active and optionally substituted heterocyclic group, or a salt thereof, which comprises reacting a racemate represented by the formula
R 1 —SO 2 —NH—R 2 (II)
wherein each symbol is as defined above, or a salt thereof with an optically active compound represented by the formula
R a —COOH (III)
wherein R a is as defined above, or a salt thereof or a reactive derivative thereof.
5. A production method of an optically active compound represented by the formula
R 1a —SO 2 —NH—R 2a (V)
wherein R 1a and R 2a are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, only one of R 1a and R 2a contains one asymmetric carbon, and a steric configuration of the asymmetric carbon is an R configuration or an S configuration, or a salt thereof,
which comprises reacting a racemate represented by the formula
R 1 —SO 2 —NH—R 2 (II)
wherein R 1 and R 2 are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group and only one of R 1 and R 2 contains one asymmetric carbon, or a salt thereof
with an optically active compound represented by the formula
R a —COOH (III)
wherein R a is an optically active and optionally substituted hydrocarbon group or an optically active and optionally substituted heterocyclic group, a salt thereof or a reactive derivative thereof
to give a diastereomeric mixture represented by the formula
wherein each symbol is as defined above, or a salt thereof,
resolving the diastereomeric mixture or a salt thereof, wherein said resolution is carried out by solvent extraction, liquid exchange, phase transfer, salting out, crystallization, recrystallization or chromatography,
to give the diastereomer wherein the asymmetric carbon for R 1 or R 2 has a steric configuration of an R configuration or an S configuration or a salt thereof,
then deacylating said diastereomer or a salt thereof.
6. The method of claim 1 , wherein the group represented by the formula
is a group represented by the formula
wherein R 3 and R 4 are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
R 3 and R 4 may form an optionally substituted cyclic group together with the adjacent carbon atom,
Ar is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and
the symbol
indicates a racemate,
and the diastereomer comprises a group represented by the formula
wherein * shows the position of the asymmetric carbon and other symbols are as defined above,
which has a steric configuration of the asymmetric carbon of an R configuration or an S configuration.
7. The method of claim 1 , wherein the group represented by the formula
is a group represented by the formula
wherein R 5 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, the formula —OR 6 (R 6 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group) or the formula —NR 7 R 8 (R 7 and R 8 are the same or different and each is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group),
Ar 1 is an optionally substituted aromatic hydrocarbon group,
ring A may be further substituted,
n is an integer of 1-4 and
the symbol
indicates a racernate,
and the diastereomer comprises a group represented by the formula
wherein * shows the position of the asymmetric carbon and other symbols are as defined above,
which has a steric configuration of the asymmetric carbon of an R configuration or an S configuration.
8. The method of claim 1 , wherein the group represented by the formula
is a group represented by the formula
wherein R 9 is a C 1-6 alkyl group, Ar 2 is a C 6-14 aryl group optionally having a halogen atom, and the symbol
indicates a racemate, and the diastereomer comprises a group represented by the formula
wherein * shows the position of the asymmetric carbon and other symbols are as defined above, which has a steric configuration of the asymmetric carbon of an R configuration or an S configuration.
9. The method of claim 4 , wherein the compound represented by the formula
R a —COOH (III)
wherein R a is an optically active and optionally substituted hydrocarbon group or an optically active and optionally substituted heterocyclic group, is a compound containing an asymmetric carbon at the α-position of the carboxyl group.
10. The method of claim 9 , wherein the compound represented by the formula
R a —COOH (III)
wherein R a is an optically active and optionally substituted hydrocarbon group or an optically active and optionally substituted heterocyclic group is
(1) an optically active compound represented by the formula
wherein R b is a C 6-14 aryl group and R c is a C 1-6 alkanoyl group or a C 1-4 alkyl group, or a salt thereof, or
(2) an optically active compound represented by the formula
wherein R d and R e are the same or different and each is a C 1-4 alkyl group, or a salt thereof.
11. A compound represented by the formula
wherein
R a is an optically active and optionally substituted hydrocarbon group or an optically active and optionally substituted heterocyclic group,
R 5 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, a group represented by the formula —OR 6 (R 6 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group) or a group represented by the formula —NR 7 R 8 (R 7 and R 8 are the same or different and each is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group),
Ar 1 is an optionally substituted aromatic hydrocarbon group,
ring A may be further substituted,
n is an integer of 1-4, and
* shows the position of an asymmetric carbon,
or a salt thereof.
12. The compound of claim 11 , wherein R a CO— is a group represented by the formula
wherein R b is a C 6-14 aryl group and R c is a C 1-6 alkanoyl group or a C 1-4 alkyl group.
13. The compound of claim 11 , wherein R a CO— is a group represented by the formula
wherein R d and R e are the same or different and each is a C 1-4 alkyl group.
14. (6R)-6-({[(2S)-2-(Acetyloxy)-2-phenylethanoyl]-2-chloro-4-fluoroanilino}sulfonyl)-1-cyclohexene-1-carboxylic acid ethyl ester.
15. (6R)-6-({2-Chloro-4-fluoro[(2R)-4-methoxy-2-methyl-4-oxobutanoyl]anilino}sulfonyl)-1-cyclohexene-1-carboxylic acid ethyl ester.
16. (6S)-6-({[(2R)-2-(Acetyloxy)-2-phenylethanoyl]-2-chloro-4-fluoroanilino}sulfonyl)-1-cyclohexene-1-carboxylic acid ethyl ester.
17. (6S)-6-({2-Chloro-4-fluoro[(2S)-4-methoxy-2-methyl-4-oxobutanoyl]anilmo}sulfonyl)-1-cyclohexene-1-carboxylic acid ethyl ester.
18. The method of claim 2 , wherein the group represented by the formula
is a group represented by the formula
wherein R 3 and R 4 are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R 3 and R 4 may form an optionally substituted cyclic group together with the adjacent carbon atom, Ar is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and the symbol
indicates a racemate, and the diastereomer comprises a group represented by the formula
wherein * shows the position of the asymmetric carbon and other symbols are as defined above, which has a steric configuration of the asymmetric carbon of an R configuration or an S configuration.
19. The method of claim 3 , wherein the group represented by the formula
is a group represented by the formula
wherein R 3 and R 4 are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R 3 and R 4 may form an optionally substituted cyclic group together with the adjacent carbon atom, Ar is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and the symbol
indicates a racemate, and the diastereomer comprises a group represented by the formula
wherein * shows the position of the asymmetric carbon and other symbols are as defined above, which has a steric configuration of the asymmetric carbon of an R configuration or an S configuration.
20. The method of claim 4 , wherein the group represented by the formula
is a group represented by the formula
wherein R 3 and R 4 are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R 3 and R 4 may form an optionally substituted cyclic group together with the adjacent carbon atom, Ar is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and the symbol
indicates a racemate, and the diastereomer comprises a group represented by the formula
wherein * shows the position of the asymmetric carbon and other symbols are as defined above, which has a steric configuration of the asymmetric carbon of an R configuration or an S configuration.
21. The method of claim 5 , wherein the group represented by the formula
in the formulas (I) and (II) is a group represented by the formula
wherein R 3 and R 4 are the same or different and each is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, R 3 and R 4 may form an optionally substituted cyclic group together with the adjacent carbon atom, Ar is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and the symbol
indicates a racemate, and the diastereomer comprises a group represented by the formula
wherein * shows the position of the asymmetric carbon and other symbols are as defined above, which has a steric configuration of the asymmetric carbon of an R configuration or an S configuration.
22. The method of claim 2 , wherein the group represented by the formula
is a group represented by the formula
wherein R 5 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, the formula —OR 6 (R 6 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group) or the formula —NR 7 R 8 (R 7 and R 8 are the same or different and each is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group), Ar 1 is an optionally substituted aromatic hydrocarbon group, ring A may be further substituted, n is an integer of 1-4 and the symbol
indicates a racemate, and the diastereomer comprises a group represented by the formula
wherein * shows the position of the asymmetric carbon and other symbols are as defined above, which has a steric configuration of the asymmetric carbon of an R configuration or an S configuration.
23. The method of claim 3 , wherein the group represented by the formula
is a group represented by the formula
wherein R 5 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, the formula —OR 6 (R 6 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group) or the formula —NR 7 R 8 (R 7 and R 8 are the same or different and each is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group), Ar 1 is an optionally substituted aromatic hydrocarbon group, ring A may be further substituted, n is an integer of 1-4 and the symbol
indicates a racemate, and the diastereomer comprises a group represented by the formula
wherein * shows the position of the asymmetric carbon and other symbols are as defined above, which has a steric configuration of the asymmetric carbon of an R configuration or an S configuration.
24. The method of claim 4 , wherein the group represented by the formula
is a group represented by the formula
wherein R 5 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, the formula —OR 6 (R 6 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group) or the formula —NR 7 R 8 (R 7 and R 8 are the same or different and each is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group), Ar 1 is an optionally substituted aromatic hydrocarbon group, ring A may be further substituted, n is an integer of 1-4 and the symbol
indicates a racemate, and the diastereomer comprises a group represented by the formula
wherein * shows the position of the asymmetric carbon and other symbols are as defined above, which has a steric configuration of the asymmetric carbon of an R configuration or an S configuration.
25. The method of claim 5 , wherein the group represented by the formula
in the formulas (I) and (II) is a group represented by the formula
wherein R 5 is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, the formula —OR 6 (R 6 is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group) or the formula —NR 7 R 8 (R 7 and R 8 are the same or different and each is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group), Ar 1 is an optionally substituted aromatic hydrocarbon group, ring A may be further substituted, n is an integer of 1-4 and the symbol
indicates a racemate, and the diastereomer comprises a group represented by the formula
wherein * shows the position of the asymmetric carbon and other symbols are as defined above, which has a steric configuration of the asymmetric carbon of an R configuration or an S configuration.
26. The method of claim 2 , wherein the group represented by the formula
is a group represented by the formula
wherein R 9 is a C 1-6 alkyl group, Ar 2 is a C 6-14 aryl group optionally having a halogen atom, and the symbol
indicates a racemate, and the diastereomer comprises a group represented by the formula
wherein * shows the position of the asymmetric carbon and other symbols are as defined above, which has a steric configuration of the asymmetric carbon of an R configuration or an S configuration.
27. The method of claim 3 , wherein the group represented by the formula
is a group represented by the formula
wherein R 9 is a C 1-6 alkyl group. Ar 2 is a C 6-14 aryl group optionally having a halogen atom, and the symbol
indicates a racemate, and the diastereomer comprises a group represented by the formula
wherein * shows the position of the asymmetric carbon and other symbols are as defined above, which has a steric configuration of the asymmetric carbon of an R configuration or an S configuration.
28. The method of claim 4 , wherein the group represented by the formula
is a group represented by the formula
wherein R 9 is a C 1-6 alkyl group, Ar 2 is a C 6-14 aryl group optionally having a halogen atom, and the symbol
indicates a racemate, and the diastereomer comprises a group represented by the formula
wherein * shows the position of die asymmetric carbon and other symbols are as defined above, which has a steric configuration of the asymmetric carbon of an R configuration or an S configuration.
29. The method of claim 5 , wherein the group represented by the formula
in the formulas (I) and (II) is a group represented by the formula
wherein R 9 is a C 1-6 alkyl group, A 2 is a C 6-14 aryl group optionally having a halogen atom, and the symbol
indicates a racemate, and the diastereomer comprises a group represented by the formula
wherein * shows the position of the asymmetric carbon and other symbols are as defined above, which has a steric configuration of the asymmetric carbon of an R configuration or an S configuration.
30. The method of claim 5 , wherein the group represented by the formula
R a —COOH (III)
wherein R a is an optically active and optionally substituted hydrocarbon group or an optically active and optionally substituted heterocyclic group, is a compound containing an asymmetric carbon at the α-position of the carboxyl group.