Process for the preparation of Enzalutamide

Patent metadata

Field	Value
Publication number	US-10131636-B2
Application number	US-201515516206-A
Country	US
Kind code	B2
Filing date	Oct 1, 2015
Priority date	Oct 1, 2014
Publication date	Nov 20, 2018
Grant date	Nov 20, 2018

Abstract

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.

First claim

We claim:

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.

Assignees

• Laurus Labs Ltd
• Laurus Labs Ltd

Inventors

• Chivukula Kameswar R
• Karuturi Veera Venkateswara Rao
• Benda Srinivas
• Anke Ramachandra
• Gajula Dharmapuri
• Moturu Venkata Rama Krishna Murthy
• Indukuri Venkata S
• Gorantla Seeta Ram Anjaneyulu
• Chava Satyanarayana

Classifications

• C07D233/86 Primary

  Oxygen and sulfur atoms, e.g. thiohydantoin · CPC title

• C07C335/26

  Y being a hydrogen or a carbon atom, e.g. benzoylthioureas · CPC title

• C07C335/22

  being further substituted by carboxyl groups · CPC title

• C07C333/08

  having nitrogen atoms of thiocarbamic groups bound to carbon atoms of six-membered aromatic rings · CPC title

• C07C331/28

  having isothiocyanate groups bound to carbon atoms of six-membered aromatic rings · CPC title