Process for the preparation of dolutegravir and pharmaceutically acceptable salts thereof

Patent metadata

Field	Value
Publication number	US-10301321-B2
Application number	US-201715809151-A
Country	US
Kind code	B2
Filing date	Nov 10, 2017
Priority date	Jan 21, 2014
Publication date	May 28, 2019
Grant date	May 28, 2019

Abstract

The present invention relates to a novel process for the preparation of dolutegravir and pharmaceutically acceptable salts thereof using novel intermediates.

First claim

We claim:

1. A compound of Formula III, wherein R is one of an alkyl, an aryl and an aralkyl, and each of P 1 and P 2 is, independently, a ketal protecting group or together form a cyclic ring

2. A compound of Formula IV, wherein R is one of an alkyl, an aryl and an aralkyl

3. A compound of Formula V, wherein R is one of an alkyl, an aryl and an aralkyl

4. A compound of Formula VII, wherein R is one of an alkyl, an aryl and an aralkyl, and each of R 1 and R 2 is, independently, an alkyl

5. The compound according to claim 1 , wherein R is one of a methyl, an ethyl, an isoamyl, and a benzyl, and wherein when P 1 and P 2 together form a cyclic ring the cyclic ring comprising one of ethylene glycol and propane diol.

6. A method of preparing a compound of Formula III,

comprising reacting 2,4-difluoro benzylamine with a compound of Formula II or a reactive derivative thereof,

to produce the compound of Formula III, wherein R is one of an alkyl, an aryl and an aralkyl group, and wherein each of P 1 and P 2 is, independently, a ketal protecting group or together form a cyclic ring.

7. The method of claim 6 , wherein the reaction of the compound of Formula II with 2,4-difluorobenzylamine is carried out in the presence of a base, an acid chloride forming agent or coupling agent, and optionally a solvent.

8. The method of claim 7 , wherein,
the acid chloride forming agent is selected from one of ethyl chloroformate, isobutyl chloroformate, isopropenyl chloroformate and thionylchloride;
the coupling agent is selected from one of cabonyldiimidazole, carbonyl-di(1,2,4-triazole),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N′-diisopropyl carbodiimide, and dicyclohexyl carbodiimide;
the base is selected from one of N-methylmorpholine, triethylamine, trimethylamine and diisopropylethylamine; and
the optional solvent is selected from one of a nitrile, an ether, a chloro solvent, a hydrocarbon, an ester, an amide, and mixtures thereof.

9. The compound according to claim 2 , wherein R is one of a methyl, an ethyl, an isoamyl, and a benzyl.

10. A method of preparing a compound of Formula IV,

comprising deprotecting a compound of Formula III,

to produce a compound of Formula IV, wherein R is one of an alkyl, an aryl and an aralkyl group, and each of P 1 and P 2 is, independently, a ketal protecting group or together form a cyclic ring.

11. The method of claim 10 , wherein the deprotection step is carried out in the presence of an acid, a solvent, and optionally a phase transfer catalyst.

12. The method of claim 11 , wherein,
the acid is selected from one of hydrochloric acid, hydrobromic acid, acetic acid, sulfuric acid, p-toluene sulfonic acid, methane sulfonic acid, and mixtures thereof;
the solvent is selected from one of an ether, a ketone, a hydrocarbon, an ester, and mixtures thereof, and
the optional phase transfer catalyst is selected from one of tetra butyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium chloride, tetra butyl ammonium tribromide, tetra butyl phosphonium bromide, triethylbenzyl ammonium chloride, tetra methyl ammonium iodide, tetra butyl ammonium acetate, Aliquat-336, or tetra butyl ammonium fluoride.

13. The method of claim 11 , wherein the acid is hydrochloric acid, the solvent is one or toluene or acetone, and the optional phase transfer catalyst is tetra butyl ammonium bromide.

14. The compound according to claim 3 , wherein R is one of a methyl, an ethyl, an isoamyl, and a benzyl.

15. A method of preparing a compound of Formula V,

comprising treating the compound of Formula IV,

with N,N-dimethyl-1,1-bis(methyloxy) methanamine to produce the compound of Formula V, wherein R is one of an alkyl, an aryl and an aralkyl group.

16. The method of claim 15 , wherein the reaction of compound of Formula IV with N,N-dimethyl-1,1-bis(methyloxy) methanamine is carried out in the presence of a solvent selected from one of an alcohol, an ether, a hydrocarbon, an amide, and mixtures thereof.

17. The method of claim 16 , wherein the solvent is one of toluene and dimethyl formamide.

18. The compound according to claim 4 , wherein R is one of a methyl, an ethyl, an isoamyl, and a benzyl, and wherein each of R 1 and R 2 is, independently, a methyl.

19. A method of preparing a compound of Formula VII,

comprising reacting a compound of Formula V with a compound of Formula VI,

to produce the compound of Formula VII, wherein each of R 1 and R 2 is, independently, an alkyl.

20. The method of claim 19 , wherein the reaction of the compound of Formula V with the compound of Formula VI carried out in the presence of a solvent selected from one of an alcohol, an ether, a hydrocarbon, an amide, and mixtures thereof.

21. The method of claim 20 , wherein the solvent is one of toluene and dimethyl formamide.

Assignees

• Laurus Labs Ltd

Inventors

• Chava Satyanarayana
• Gorantla Seeta Rama Anjaneyulu
• Dammalapati Venkata Lakshmi Narasimha
• Kotala Mani Bushan
• Aduri Ravindra

Classifications

• C07D319/06

  not condensed with other rings · CPC title

• C07D498/14 Primary

  Ortho-condensed systems · CPC title

• C07D317/30

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D213/82

  in position 3 · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title