Methods of asymmetrically synthesizing enantiomers of casodex, its derivatives and intermediates thereof

• US 20040030130A1
• Filed: 05/23/2003
• Published: 02/12/2004
• Est. Priority Date: 10/19/1999
• Status: Active Grant

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Biocon Limited (Biocon Incorporated)
• Inventors: Ekwuribe, Nnochiri Nkem
• Granted Patent: US 7,022,869 B2
• Time in Patent Office: Days
• US Class Current: 544/59
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 315/02 by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
• CPC Class Codes: C07C 317/46 the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 319/14 of sulfides
• CPC Class Codes: C07C 319/20 by reactions not involving the formation of sulfide groups
• CPC Class Codes: C07C 323/52 the carbon skeleton being acyclic and saturated
• CPC Class Codes: C07C 323/60 with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• CPC Class Codes: C07D 317/34 Oxygen atoms

Abstract

A method of synthesizing pure enantiomers of acylanalides such as Casodex® (bicalutamide) and its derivatives includes contacting a compound having a ring structure that, when opened, provides a substituent having the structure of Formula I:

wherein

R¹ is alkyl or haloalkyl having up to 4 carbons;

R² is alkyl having up to 6 carbon atoms; and

R³ is CH₂OR⁴ where R⁴ is hydrogen or benzyl, C(O)CH₃, or C(O)OR⁵ where R⁵ is hydrogen or alkyl;

with a compound having a structure of Formula II:

R⁷—R⁶—X¹H   Formula II

wherein

R⁶ is a direct link or alkyl having up to 6 carbon atoms;

R⁷ is alkyl, alkenyl, hydroxyalkyl or cycloalkyl each of up to 6 carbons; or R⁷ is phenyl which bears one, two or three substituents independently selected from hydrogen, halogen, nitro, carboxy, carbamoyl and cyano, and alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl, perfluoroalkylsulphonyl, alkoxycarbonyl and N-alkylcarbamoyl each of up to 4 carbon atoms, and phenyl, phenylthio, phenylsulphinyl and phenylsulphonyl; or R⁷ is naphthyl; or R⁷ is a 5- or 6-membered saturated or unsaturated heterocyclic which contains one, two or three heteroatoms selected from oxygen, nitrogen and sulfur, which heterocyclic may be a single ring or may be fused to a benzo-ring, and which heterocyclic is unsubstituted or bears one or two halogen, cyano or amino, or alkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl each of up to 4 carbon atoms, or oxy or hydroxy substituents, or which if sufficiently saturated may bear one or two oxo substituents; and

X¹ is oxygen, sulfur, sulphinyl (—SO—), sulphonyl (—SO₂—), imino (—NH—) or alkylimino (—NR⁸—) where R⁸ is alkyl having up to 6 carbon atoms;

under conditions sufficient to provide a compound having the structure of Formula III:

wherein X² is oxygen, sulfur, sulphinyl (—SO—), sulphonyl (—SO₂—), imino (—NH—), oxidized imino alkylimino (—NR⁸—) where R⁸ is alkyl having up to 6 carbon atoms, or oxidized alkylimino. The method further includes treating the compound of Formula III under conditions sufficient to provide a pure enantiomer of acylanalides such as Casodex® (bicalutamide) and/or derivatives thereof. In preferred embodiments, R¹ is methyl, R² is methylene, R⁶ is a direct link, R⁷ is 4-fluorophenyl, X¹ is sulfur, the compound of Formula II is 4-fluorobenzenethiol, and X² is sulphonyl. Methods of synthesizing acylanalides such as Casodex® (bicalutamide) and/or derivatives thereof from a starting material of citramalic acid are also provided.

Claims

1. A method of asymmetrically synthesizing an enantiomer of an acylanilide or a derivative thereof comprising:

(a) contacting a compound having a ring structure that, when opened, provides a substituent having the structure of Formula I;

wherein

R¹ is alkyl or haloalkyl having up to 4 carbons;

R² is alkyl having up to 6 carbon atoms; and

R³ is CH₂OR⁴ where R⁴ is hydrogen or benzyl, C(O)CH₃, or C(O)OR⁵ where R⁵ is hydrogen or alkyl;

with a compound having a structure of Formula II;

R⁷—

R⁶—

X¹H  

 

Formula II

wherein

R⁶ is a direct link or alkyl having up to 6 carbon atoms;

R⁷ is alkyl, alkenyl, hydroxyalkyl or cycloalkyl each of up to 6 carbons;

or R⁷ is phenyl which bears one, two or three substituents independently selected from hydrogen, halogen, nitro, carboxy, carbamoyl and cyano, and alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl, perfluoroalkylsulphonyl, alkoxycarbonyl and N-alkylcarbamoyl each of up to 4 carbon atoms, and phenyl, phenylthio, phenylsulphinyl and phenylsulphonyl;

or R⁷ is naphthyl;

or R⁷ is a 5- or 6-membered saturated or unsaturated heterocyclic which contains one, two or three heteroatoms selected from oxygen, nitrogen and sulfur, which heterocyclic may be a single ring or may be fused to a benzo-ring, and which heterocyclic is unsubstituted or bears one or two halogen, cyano or amino, or alkyl, alkoxy, alkylthio, alkylsulphinyl or alkylsulphonyl each of up to 4 carbon atoms, or oxy or hydroxy substituents, or which if sufficiently saturated may bear one or two oxo substituents; and

X¹ is oxygen, sulfur, sulphinyl (—

SO—

), sulphonyl (—

SO₂—

), imino (—

NH—

) or alkylimino (—

NR⁸—

) where R⁸ is alkyl having up to 6 carbon atoms;

under conditions sufficient to provide a compound having the structure of Formula III;

wherein X² is oxygen, sulfur, sulphinyl (—

SO—

), sulphonyl (—

SO₂—

), imino (—

NH—

), oxidized imino alkylimino (—

NR⁸—

) where R⁸ is alkyl having up to 6 carbon atoms, or oxidized alkylimino; and

(b) treating the compound of Formula III under conditions sufficient to provide a pure enantiomer of an acylanilide or a derivative thereof.

2. The method according to claim 1, wherein the compound having a ring structure is a compound of Formula IV:

3. The method according to claim 2, wherein R¹ is methyl and R² is methylene.

4. The method according to claim 2, further comprising treating a starting compound of citramalic acid under conditions sufficient to provide a compound having the structure of Formula IV.

5. The method according to claim 4, wherein the citramalic acid is (S)-citramalic acid, and wherein the pure enantiomer of an acylanilide is (R)-Casodex®

(bicalutamide) or a derivative there.

6. The method according to claim 1, wherein the compound having a ring structure is a compound of Formula VIII:

7. The method according to claim 1, wherein the compound having a ring structure is a compound of Formula XI:

8. The method according to claim 1, wherein X¹ is sulfur, R⁶ is a direct link, and R⁷ is 4-fluorophenyl, and the compound of Formula II is 4-fluorobenzenethiol.

9. The method according to claim 1, wherein step (b) comprises:

treating the compound of Formula III with a compound having the structure of Formula XIII;

wherein

R¹³ is cyano, carbamoyl, nitro, fluoro, chloro, bromo, iodo, or hydrogen, or alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each having up to 4 carbon atoms, or phenylthio, phenylsulphinyl or phenylsulphonyl;

R¹⁴ is cyano, cabamoyl, nitro, fluoro, chloro, bromo or iodo, or alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, perfluoroalkyl, perfluoroalkylthio, perfluoroalkylsulphinyl or perfluoroalkylsulphonyl each of having up to 4 carbon atoms;

or phenylthio, phenylsulphinyl or phenylsulphonyl; and

R¹⁵ is hydrogen or halogen;

under conditions sufficient to provide a compound of Formula XIV;

wherein X² is oxygen, sulfur, sulphinyl (—

SO—

), sulphonyl (—

SO₂—

), imino (—

NH—

), oxidized imino alkylimino (—

NR⁸—

) where R⁸ is alkyl having up to 6 carbon atoms, or oxidized alkylimino.

10. A method of forming an optically active compound having the structure of Formula III:

11. The method according to claim 10, wherein the compound of Formula II is 4-fluorobenzenethiol.

12. The method according to claim 10, wherein step (b) comprises contacting the compound of Formula IV with a hydrolyzing agent to open the heterocyclic ring of Formula IV.

13. The method according to claim 10, wherein X¹ is sulfur or sulphinyl and X² is sulphonyl.

14. The method according to claim 13, wherein step (b) comprises the steps of:

contacting the compound of Formula V with an oxidizing agent to convert X¹ to X²; and

then

contacting the oxidized compound with a hydrolyzing agent to open the heterocyclic ring of Formula V and provide the compound of Formula III.

15. The method according to claim 13, wherein step (b) comprises the steps of:

contacting the compound of Formula V with a hydrolyzing agent to open the heterocyclic ring of Formula V; and

then

contacting the hydrolyzed compound with an oxidizing agent to convert X¹ to X² and provide the compound of Formula III.

16. The method according to claim 10, further comprising the step of:

treating a starting compound of citramalic acid under conditions sufficient to provide a compound having the structure of Formula IV wherein R¹ is methyl and R² is methylene.

17. A method of forming an optically active compound having the structure of Formula III:

18. The method according to claim 17, wherein the compound of Formula II is 4-fluorobenzenethiol.

19. The method according to claim 17, wherein step (b) comprises contacting the compound of Formula IX with a hydrolyzing agent to open the 6-membered heterocyclic ring of Formula IX.

20. The method according to claim 17, wherein X¹ is sulfur or sulphinyl and X² is sulphonyl.

21. The method according to claim 20, further comprising the steps of:

contacting the compound of Formula IX with an oxidizing agent to convert X¹ to X²; and

then

contacting the oxidized compound with a hydrolyzing agent to open the 6-membered heterocyclic ring of Formula IX to provide a compound having the structure of Formula III.

22. The method according to claim 20, further comprising the steps of:

contacting the compound of Formula IX with a hydrolyzing agent to open the 6-membered heterocyclic ring of Formula IX and form an acid; and

then

contacting the hydrolyzed compound with an oxidizing agent to convert X¹ to X² to provide a compound having the structure of Formula III.

23. The method according to claim 17, wherein the chiral carbon at the 3 position of the 6-membered heterocyclic ring of Formula IX has an R configuration.

24. The method according to claim 17, wherein the chiral carbon at the 3 position of the 6-membered heterocyclic ring of Formula IX has an S configuration.

25. A method of forming an optically active compound having the structure of Formula III:

26. The method according to claim 25, wherein the compound of Formula II is 4-fluorobenzenethiol.

27. The method according to claim 25, wherein X¹ is sulfur or sulphinyl and X² is sulphonyl.

28. The method according to claim 25, wherein step (b) comprises contacting the compound of Formula XI with an oxidizing agent to convert X¹ to X².

29. The method according to claim 25, wherein the chiral carbon at the 2 position of the heterocyclic ring of Formula XI has an R configuration.

30. The method according to claim 25, wherein the chiral carbon at the 2 position of the heterocyclic ring of Formula XI has an S configuration.

31. A method of synthesizing an optically active compound having the structure of Formula XVI:

32. The method according to claim 31, wherein the treating step comprises the step of aldol condensation reacting citramalic acid with a compound capable of undergoing an aldol condensation reaction to provide a compound having the structure of Formula XV:

33. The method according to claim 32, wherein R⁹ is hydrogen, R¹⁰ is CBr₃ and the compound is tribromoacetaldehyde.

34. The method according to claim 32, wherein the treating step further comprises the step of decarboxylation reacting the compound of Formula XV to provide a compound having the structure of Formula XVI.

35. The method according to claim 34, wherein the decarboxylation reacting step comprises decarboxylatively brominating the compound of Formula XV with 2-mercaptopyridine N-oxide and dicyclohexylcarbodiamide in the presence of CBrCl₃ to provide a compound having the structure of Formula XVI.

37. The compound according to claim 35, wherein R¹ is methyl, R² is methylene, R⁹ is hydrogen, R¹⁰ is benzyl or CX₃⁴ where X⁵ is CH₃, Cl, Br, or phenyl, and X³ is Br.

38. The compound according to claim 35, wherein the compound is 5-bromomethyl-5-methyl-2-tribromomethyl-[1,3]dioxolan-4-one.

36. A compound having a chemical structure of Formula IV: