Process for making bicalutamide and intermediates thereof
Bicalutamide and/or its intermediates are made by the use of p-fluorobenzenesulfinic acid salt as a reagent.
1. A process for making bicalutamide, which comprises reacting a compound of formula (2)
wherein Z represents a cation, with a suitable reaction partner to form a bicalutamide of formula (1):
or a non-bicalutamide product and, if said reacting step produces said non-bicalutamide product, then converting said non-bicalutamide product to a bicalutamide of formula (1);
wherein said suitable reaction partner is a compound of the formula (3), formula (3.1) or Formula (3.2):
wherein A represents OR, in which R is a hydrogen, a C 1 –C 6 alkyl, a C 3 –C 6 cycloalkyl, a phenyl, or a benzyl group; or an aniline derivative of the formula:
Y represents a leaving group and X represents hydrogen or X and Y join together to form a 3- to 6-membered heterocyclic ring or X and A join together to form a 5- to 10-membered fused or unfused heterocyclic ring with the proviso that if a ring nitrogen is present, it may be substituted by a 3-trifluoromethyl-4-cyano-phenyl group:
wherein Y is as defined for formula (3);
wherein Y is as defined for formula (3).
2. The process according to claim 1 , wherein Z is a cation selected from the group consisting of alkali metals, magnesium halides, and ammoniums.
3. The process according to claim 2 , wherein Z is a sodium cation.
4. The process according to claim 1 , wherein said reacting step is carried out in a bi-phasic reaction system or in a lower alcohol.
5. A process, which comprises reacting a compound of formula (2)
wherein Z represents a cation; with a compound of formula (3)
wherein A represents OR, in which R is a hydrogen, a C 1 –C 6 alkyl, a C 3 –C 6 cycloalkyl, a phenyl, or a benzyl group; or A represents an aniline derivative of the formula:
Y represents a leaving group and X represents hydrogen or X and Y join together to form a 3- to 6-membered heterocyclic ring or X and A join together to form a 5- to 10-membered fused or unfused heterocyclic ring with the proviso that if a ring nitrogen is present, it may be substituted by a 3-trifluoromethyl-4-cyano-phenyl group; to form a compound of the formula (4):
wherein A and X have the same meaning as in formula (3).
6. The process according to claim 5 , wherein Z is a cation selected from the group consisting of alkali metals, magnesium halide, and ammonium.
7. The process according to claim 5 , wherein Y represents a halogen or a group of the formula —OS(O) 2 —R 2 , wherein R 2 represents a hydroxyl group, a C 1 –C 4 alkyl group, a phenyl group, or an alkyl-substituted phenyl group.
8. The process according to claim 7 , wherein Y represents a group selected from the group consisting of iodine, chlorine, bromine, methanesulfonyloxy, and toluenesulfonyloxy.
9. The process according to claim 5 , wherein Y and X join together to complete an oxiran ring.
10. The process according to claim 5 , wherein A is said aniline derivative and said compound of formula (4) is a bicalutamide of formula (1):
11. The process according to claim 10 , wherein said compound of formula (3) is optically active and said bicalutamide is enriched R-bicalutamide.
12. The process according to claim 10 , wherein said produced bicalutamide is racemic bicalutamide and which further comprises isolating the R-bicalutamide isomer therefrom.
13. The process according to claim 10 , wherein Y represents a group selected from the group consisting of iodine, bromine, chlorine, methanesulfonyloxy, and toluenesulfonyloxy.
14. The process according to claim 13 , wherein Y is bromine or iodine.
15. The process according to claim 10 , wherein Y and X together complete an oxiran ring.
16. The process according to claim 14 , wherein Z is a sodium cation.
17. The process according to claim 15 , wherein Z is a sodium cation.
18. The process according to claim 5 , wherein A is OR.
19. The process according to claim 18 , which further comprises converting said compound of formula (4) to a compound of formula (4.1)
wherein L represents a leaving group for an amidation reaction.
20. The process according to claim 19 , wherein L represents a halogen; a group of the formula OS(O) 2 —R 2 , wherein R 2 represents a hydroxyl group, a C 1 –C 4 alkyl group, a phenyl group, or an alkyl-substituted phenyl group; a mixed anhydride group of formula —O—C(O)—R 3 , wherein R 3 is a C 1 –C 4 alkyl group or a phenyl group, each optionally substituted by one or more halogens; or an activated ester group.
21. The process according to claim 20 , wherein R 3 represents a group selected from the group consisting of trifluoromethyl, tert-butyl, isobutyl and o-dichlorophenyl group.
22. The process according to claim 20 , wherein L represents a halogen or a group of the formula —OS(O) 2 —R 2 , wherein R 2 represents a hydroxyl group, a C 1 –C 4 alkyl group, a phenyl group, or an alkyl-substituted phenyl group.
23. The process according to claim 22 , wherein L represents a group selected from the group consisting of bromine, chlorine, methanesulfonyloxy, and toluenesulfonyloxy.
24. The process according to claim 19 , which further comprises reacting said compound of formula (4.1) with an amine of the formula (11):
to form a bicalutamide of formula (1):
25. The process according to claim 24 , wherein said compound of formula (3) is optically active and said bicalutamide is enriched R-bicalutamide.
26. The process according to claim 24 , wherein said produced bicalutamide is racemic bicalutamide and which further comprises isolating the R-bicalutamide isomer therefrom.
27. The process according to claim 18 , which further comprises reacting said compound of formula (4) with an amine of the formula (11):
to form a bicalutamide of formula (1):
28. The process according to claim 27 , wherein A represents hydrogen.
29. The process according to claim 5 , wherein X and A together complete a ring to form a compound selected from the following formulae 3A–3C:
wherein R 8 represents a hydrogen, an C 1 –C 6 alkyl or a C 3 –C 6 cyclcoalkyl; R 9 represents a C 1 –C 6 halogenated alkyl; and Y is as defined for formula (3).
30. The process according to claim 29 , which further comprises hydrolyzing said compound of formula (4) and forming a bicalutamide of formula (1):