Process for the preparation of Enzalutamide
The present invention relates to an improved process for the preparation of enzalutamide by conventional synthesis, which avoids utilization of microwave irradiation and noxious reagents. The present invention also relates to an improved process for preparation of 4-isothiocyanato-2-(trifluoromethyl) benzonitrile, which is an intermediate in the synthesis of Enzalutamide.
1. A process for the preparation of enzalutamide of Formula I,
comprising:
a) reacting 4-amino-2-trifluoromethyl benzonitrile of Formula 2 with a source of isothiocyanate of Formula P-NCS, to obtain a compound of Formula 8, wherein ‘P’ represents hydrogen or a protective group,
b) optionally deprotecting the compound of Formula 8 to obtain a compound of Formula 9,
c) heating the compound of Formula 9 to obtain a compound of Formula 3,
d) reacting the compound of Formula 3 with a compound of Formula 4 in a solvent system to obtain a compound of Formula 5,
and
e) reacting the compound of Formula 5 with an acid in an organic solvent to obtain enzalutamide.
2. The process of claim 1 , wherein the protective group is selected from one of R—CO—, R—CO—O—, and R—SO 2 —, and wherein ‘R’ is selected from one of an alkyl, an alkoxy, a haloalkyl, an aryl, an aralkyl and an aryloxy.
3. The process of claim 1 , wherein ‘P’ is the protective group benzoyl.
4. The process of claim 1 , wherein the source of isothiocyanate is benzoyl isothiocyanate.
5. The process of claim 1 , wherein the step a) is carried out in the presence of a solvent.
6. The process of claim 5 , wherein the solvent of the step a) is selected from one of acetone, methyl tertiary butyl ether, and tetrahydrofuran.
7. The process of claim 1 , wherein the deprotection is carried out in the presence of a base.
8. The process of claim 7 , wherein the base is selected from one of sodium hydroxide and potassium hydroxide.
9. The process of claim 1 , wherein the step c) is carried out in a solvent selected from one of toluene, chlorobenzene, bromo benzene, ethyl benzene, xylenes, cumene, trimethylbenzene and mixtures thereof.
10. The process of claim 1 , wherein the step c) of heating is carried out at a temperature of about 100° C. to 150° C.
11. The process of claim 1 , wherein the step c) is carried out at a temperature of about 130-135° C. in chlorobenzene.
12. The process of claim 1 , wherein the solvent of step d) is selected from one of an amide, a nitrile, an ether, an ester, a sulfone, and mixtures thereof.
13. The process of claim 1 , wherein the solvent of the step d) is selected from one of dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, and mixtures thereof.
14. The process of claim 1 , wherein the step d) is carried out under stirring at a temperature of about 50° C. to 90° C.
15. The process of claim 1 , wherein the acid is selected from one of hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, acetic acid, trifluoro acetic acid, trichloro acetic acid, methane sulfonic acid, and mixtures thereof.
16. The process of claim 1 , wherein the organic solvent is selected from one of an alcohol, a halogenated hydrocarbon, an aromatic hydrocarbon, and mixtures thereof.
17. The process of claim 1 , wherein the acid is hydrochloric acid and the organic solvent is methanol.
18. The process according to claim 1 , further comprising:
f) combining the enzalutamide with at least one pharmaceutically acceptable excipient.