Processes for the preparation of ivacaftor

Patent metadata

Field	Value
Publication number	US-10501419-B2
Application number	US-201615755436-A
Country	US
Kind code	B2
Filing date	Sep 2, 2016
Priority date	Sep 2, 2015
Publication date	Dec 10, 2019
Grant date	Dec 10, 2019

Abstract

The present invention provides processes for the preparation of ivacaftor using novel intermediates and a process for its preparation.

First claim

We claim:

1. A process for the preparation of ivacaftor of Formula I or a pharmaceutically acceptable salt thereof,

comprising:
a1) reacting a compound of Formula VI with a dimethyl formamide-dimethyl amine complex to obtain a compound of Formula VII,

wherein ‘X’ represents a halo and ‘R1’ represents either hydrogen or a protecting group;
b1) reacting the compound of Formula VII with a source of ammonia to obtain a compound of Formula VIII,

c1) cyclizing the compound of Formula VIII to obtain the ivacaftor of Formula I, when R1 is hydrogen, or to obtain a compound of Formula IX, when R1 represents a protecting group and deprotecting the Formula IX in a deprotecting agent to obtain the ivacaftor,

2. The process of claim 1 , wherein when ‘R1’ represents a protecting group, ‘R1’ is selected from the group consisting of methoxycarbonyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, benzyl, benzoyl, p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl, p-nitrobenzoyl, and trimethylsilyl.

3. The process of claim 1 , wherein ‘X’ represents one of a fluoro, chloro, bromo, or iodo.

4. The process of claim 1 , wherein ‘X’ is fluoro and ‘R1’ represents one of hydrogen and methoxycarbonyl.

5. The process of claim 1 , wherein the step a1) is carried out in presence of an organic solvent.

6. The process of claim 5 , wherein the organic solvent is selected from the group consisting of acetonitrile, propionitrile, tetrahydrofuran, dimethyl ether, methyl tertiary butyl ether, dimethoxyethane, toluene, xylene, and mixtures thereof.

7. The process of claim 1 , wherein the source of ammonia is selected from the group consisting of ammonia gas, ammonium hydroxide, ammonium acetate, and ammonium formate.

8. The process of claim 1 , wherein the step b1) is carried out in presence of a solvent selected from the group consisting of methanol, ethanol, isopropanol, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone, toluene, xylene, water, and mixtures thereof.

9. The process of claim 1 , wherein the cyclization is carried out in presence of a solvent at a temperature of about 25-45° C.

10. The process of claim 9 , wherein the solvent is selected from the group consisting of tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl ether, methyl tertiary butyl ether, methanol, ethanol, isopropanol, toluene, xylene, dimethylformamide, dimethyl acetamide, N-methyl pyrrolidinone, dimethylsulfoxide, sulfolane, acetonitrile, propionitrile, and mixtures thereof.

11. The process of claim 1 , wherein the step of deprotection is carried out with a deprotecting agent in presence of a solvent.

12. The process of claim 11 , wherein the deprotecting agent is selected from the group consisting of hydrochloric acid, hydrobromic acid, trifluoro acetic acid, sodium hydroxide, sodium ethoxide, and mixtures thereof.

13. The process of claim 11 , wherein the solvent is selected from the group consisting of ethanol, ethanol, isopropanol, acetone, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tertiary butyl ether, dimethyl formamide, dimethylsulfoxide, dimethyl acetamide, N-methyl pyrrolidinone, and mixtures thereof.

14. The process of claim 11 , wherein the deprotecting agent is sodium ethoxide and the solvent is dimethyl formamide.

Assignees

• Laurus Labs Private Ltd
• Laurus Labs Ltd

Inventors

• Thatipally Suresh
• Reddy Venkata Krishna
• Dammalapati Venkata Lakshmi Narasimha Rao
• Chava Satyanarayana

Classifications

• C07C237/20

  the carbon skeleton containing six-membered aromatic rings · CPC title

• C07D215/56 Primary

  with oxygen atoms in position 4 · CPC title

• C07C235/80

  having carbon atoms of carboxamide groups and keto groups bound to the same carbon atom, e.g. acetoacetamides · CPC title

• A61K31/47

  Quinolines; Isoquinolines · CPC title