Process for the preparation of pazopanib or a pharmaceutically acceptable salt thereof

Patent metadata

Field	Value
Publication number	US-10730859-B2
Application number	US-201415034797-A
Country	US
Kind code	B2
Filing date	Nov 5, 2014
Priority date	Nov 5, 2013
Publication date	Aug 4, 2020
Grant date	Aug 4, 2020

Abstract

The present invention is relates to an improved process for the preparation of pazopanib or a pharmaceutically acceptable salts thereof. The present invention also relates to novel polymorphic Forms of pazopanib hydrochloride, and its intermediates thereof.

First claim

We claim:

1. An improved process for preparation of pazopanib or a pharmaceutically acceptable salt thereof of Formula I,

comprising:
a) reacting a compound of Formula A with a compound of Formula B in a solvent (S1) in presence of a base (B1) to obtain a compound of Formula II,

b) purifying the compound of Formula II to a chemical purity of at least about 95% as measured by HPLC using an organic solvent, wherein the organic solvent is selected form the group consisting of methyl ethyl ether, methyl tertiary butyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, water and mixtures thereof;
c) reacting the purified compound of Formula II with a methylating agent in a solvent (S2) in presence of a base (B2) to obtain a compound of Formula III,

and
d) condensing the compound of Formula III with a compound of Formula C in a solvent (S3) to obtain pazopanib or a pharmaceutically acceptable salts thereof,

wherein the base (B1) is triethylamine, wherein the solvent (S1) is dimethylsulfoxide, water, or a mixture thereof, and wherein the base (B2) is selected from the group consisting of ammonia, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate and mixtures thereof.

2. The process of claim 1 , wherein the methylating agent is methyl iodide or dimethylsulfate.

3. The process of claim 1 , wherein the solvent (S2) is selected from the group consisting of alcohols, ethers, amides, ketones, nitriles, water, and mixtures thereof.

4. The process of claim 3 , wherein the solvent (S2) is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, methyl tertiary butyl ether, diethyl ether, dimethyl formamide, dimethylsulfoxide, dimethyl acetamide, acetone, methyl isobutyl ketone, methyl ethyl ketone, acetonitrile, propionitrile, water and mixtures thereof.

5. The process of claim 1 , wherein the base (B2) is sodium hydroxide and the solvent (S2) is acetone.

6. The process of claim 1 , wherein the solvent (S3) is selected from the group consisting of alcohols, ethers, amides, ketones, nitriles, and mixtures thereof.

7. The process of claim 6 , wherein the solvent (S3) is selected from the group consisting of methanol, tetrahydrofuran, acetonitrile, and mixtures thereof.

8. An improved process for preparation of pazopanib or a pharmaceutically acceptable salt thereof of Formula I, comprising:
a) reacting a compound of Formula A with a compound of Formula B in a solvent (S1) in the presence of a base (B1) to obtain a compound of Formula II;
b) purifying the compound of Formula II to a chemical purity of at least about 95% as measured by HPLC; and
c) converting the purified compound of Formula II into pazopanib or a pharmaceutically acceptable salt thereof;
wherein the base (B1) is triethylamine, and wherein the solvent (S1) is dimethylsulfoxide, water, or a mixture thereof.

9. An improved process for preparation of pazopanib or a pharmaceutically acceptable salt thereof of Formula I, comprising:
a) reacting a compound of Formula A with a compound of Formula B in a solvent (S1) in presence of a base (B1) to obtain a compound of Formula II;
b) reacting a compound of Formula II having a chemical purity of at least about 95% as measured by HPLC with a methylating agent in a solvent (S2) in presence of a base (B2) to obtain a compound of Formula III; and
c) converting the compound of Formula III into pazopanib or a pharmaceutically acceptable salt thereof;
wherein the base (B1) is triethylamine, wherein the solvent (S1) is dimethylsulfoxide, water, or a mixture thereof, wherein the base (B2) is an inorganic base or an organic base, wherein the organic base is ammonia, an alkali or alkaline earth metal hydroxide, an alkali or alkaline earth metal alkoxide, an alkali or alkaline earth metal carbonate, an alkali or alkaline earth metal bicarbonate except potassium carbonate or cesium carbonate, and wherein the organic base is an alkyl or an aryl amine.

10. The process of claim 9 , wherein the base (B2) is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethyl amine, N-methyl morpholine and diisopropylethylamine.

11. The process of claim 9 , wherein the solvent (S2) is selected from the group consisting of alcohols, ethers, amides, ketones, nitriles, water, and mixtures thereof.

12. The process of claim 11 , wherein the solvent (S2) is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, methyl tertiary butyl ether, diethyl ether, dimethyl formamide, dimethylsulfoxide, dimethyl acetamide, acetone, methyl isobutyl ketone, methyl ethyl ketone, acetonitrile, propionitrile, water and mixtures thereof.

13. The process of claim 9 , wherein the base (B2) is sodium hydroxide, and the solvent (S2) is acetone.

14. The process of claim 1 , further comprising:
d) condensing the compound of Formula III with the compound of Formula C in a solvent (S3) in the presence of catalytic amount of hydrochloric acid to obtain the pharmaceutically acceptable salt of pazopanib,
e) cooling the solution to precipitation, and
f) isolating a pazopanib hydrochloride form of Form I,
wherein the solvent (S3) is selected from the group consisting of n-propanol, n-butanol and 2-butanol.

15. The process of claim 14 , wherein the step d) is carried out at a temperature of about 25° C. to about reflux temperature.

16. The process of claim 14 , wherein the step e) is carried out at a temperature about 25° C. to about 30° C.

17. The process of claim 1 , further comprising:
d) preparing a pharmaceutical composition using the pharmaceutically acceptable salt of pazopanib obtained in step d) with at least one pharmaceutically acceptable excipient.

Assignees

• Laurus Labs Private Ltd
• Laurus Labs Ltd

Inventors

• Chava Satyanarayana
• Gorantla Seeta Rama Anjaneyulu
• Indukuri Venkata Sunil Kumar
• Dehury Sanjay Kumar
• Mekala Nagaraju
• Shaik Jahangeer Baba
• Kuchipudi Durga Prasad

Classifications

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title