Process for the preparation of saroglitazar pharmaceutical salts

Patent metadata

Field	Value
Publication number	US-10112898-B2
Application number	US-201414916402-A
Country	US
Kind code	B2
Filing date	Sep 5, 2014
Priority date	Sep 6, 2013
Publication date	Oct 30, 2018
Grant date	Oct 30, 2018

Abstract

The present invention relates to an improved process for the preparation of pyrroles derivatives having hypolipidemic and hypocholesteremic activities. In particular, the invention relates to an improved process for the preparation of 2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethoxy)phenyl)propanoate and its pharmaceutically acceptable salts, hydrates, solvates, polymorphs or intermediates thereof. The invention also relates to an improved process for the preparation of mesylate compound (A1).

First claim

We claim:

1. A process for the preparation of a saroglitazar pharmaceutically acceptable salt of Formula (IB),

wherein M is a pharmaceutically acceptable cation,
the process comprising:
(a) reacting a hydroxy compound (A) with a mesylate compound (A1), in a mixture of cyclohexane and tetrahydrofuran in the presence of a base, to obtain alkoxy ester compound of Formula (II);

(b) hydrolyzing the alkoxy ester compound of Formula (II) using a base to obtain a compound of Formula (IB-1);

wherein M is a pharmaceutically acceptable cation selected from sodium, potassium, lithium, calcium, barium, strontium, and zinc;
(c) neutralizing the compound of Formula (IB-1) with an acid to obtain a compound of Formula (IB-2):

wherein M′ is hydrogen; and
(d) converting the compound of Formula (IB-2) to a compound of Formula (IB).

2. The process as claimed in claim 1 , wherein the reaction of hydroxy compound (A) with mesylate compound (A1) is performed in the presence of a phase transfer catalyst.

3. The process as claimed in claim 1 , wherein the acid in step (c) comprises one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, and formic acid.

4. The process as claimed in claim 1 , wherein the base in step (b) comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, strontium hydroxide, zinc hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, potassium tert-butoxide, and sodium pentoxide.

5. The process as claimed in claim 1 , wherein in step (d) the pharmaceutically acceptable cation of Formula (IB) is selected from sodium, potassium, lithium, calcium, barium, magnesium, strontium, and zinc.

6. A process for the preparation of saroglitazar magnesium Formula (I),

the process comprising:
(a) reacting a hydroxy compound (A) with a mesylate compound (A1), in a mixture of cyclohexane and tetrahydrofuran in the presence of a base, to obtain alkoxy ester compound of Formula (II);

(b) hydrolyzing the alkoxy ester compound of Formula (II) using a base to obtain a compound of Formula (IB);

wherein M is a pharmaceutically acceptable cation selected from sodium, potassium, lithium, calcium, barium, strontium, and zinc;
(c) neutralizing the compound of Formula (IB) with an acid to obtain a compound of Formula (IB-1):

wherein M′ is hydrogen; and
(d) reacting the compound of Formula (IB-1) with a magnesium source to obtain the saroglitazar magnesium of Formula (I).

7. The process as claimed in claim 6 , wherein the base in step (b) comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, strontium hydroxide, zinc hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, potassium tert-butoxide, and sodium pentoxide.

8. The process as claimed in claim 6 , wherein the magnesium source in step (d) comprises one or more of magnesium hydroxide, magnesium methoxide, magnesium acetate, magnesium chloride, and magnesium metal.

9. The process as claimed in claim 6 , further comprising:
extracting the saroglitazar magnesium in step (d) with one or more organic solvents;
removing the organic solvent to obtain a residue;
treating the residue with one or more organic solvents to obtain a solution;
adding the solution into an anti-solvent to obtain saroglitazar magnesium; and
filtering and drying the saroglitazar magnesium, and thereafter milling the saroglitazar magnesium.

10. The process as claimed in claim 9 , wherein the organic solvent comprises one or more of: methylene dichloride, ethylene dichloride, chlorobenzene, toluene, xylene, and ethylbenzene.

11. The process as claimed in claim 9 , wherein the anti-solvent comprises one or more of: pentane, hexane, heptane, cyclohexane, tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tertbutyl ether.

12. The process as claimed in claim 9 , wherein the anti-solvent is diluted with one or more solvents comprising an ester selected from ethyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate, and isobutyl acetate.

13. A process for the preparation of saroglitazar magnesium of Formula (I),

the process comprising:
(a) reacting a hydroxy compound (A) with a mesylate compound (A1), in a mixture of cyclohexane and tetrahydrofuran in the presence of a base, to obtain alkoxy ester compound of Formula (II);

(b) hydrolyzing the alkoxy ester compound of Formula (II) with a base to obtain a compound of Formula (IB);

wherein M is a pharmaceutically acceptable cation selected from sodium, potassium, lithium, calcium, barium, strontium, and zinc;
(c) neutralizing the compound of Formula (IB) with an acid to obtain a compound of Formula (IB-1)

wherein M′ is hydrogen; and
(d) reacting the compound of Formula (IB-1) with an organic amine to obtain a compound of Formula (IC);

(e) converting the compound of Formula (IC) to a compound of Formula (IB-2):

 and
(f) reacting the compound of Formula (IB-2) with a magnesium source to obtain the saroglitazar magnesium of Formula (I).

14. The process as claimed in claim 13 , wherein the organic amine in step (d) comprises one or more of ammonia, methylamine, dimethylamine, ethylamine, diethylamine, 1,2-ethanediamine, n-propyl amine, isopropylamine, diisopropylamine, N-methyl isopropylamine, butylamine, t-butyl amine, 2-butamine, 1,2-ethanediamine, N-methylglucamine, N,N,N-trimethylethanol- amine hydroxide (choline), tromethamine, cyclohexylamine, N-methylcyclohexylamine, guanidine, N-(4-aminobutyl)guanidine dicyclohexylamine, benzenemethanamine, ethanolamine, diethanolamine, tris(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, (R,S)-1

Assignees

• Cadila Healthcare Ltd
• Cadila Healthcare Ltd

Inventors

• Dwivedi Shri Prakash Dhar
• Singh Ramesh Chandra
• Patel Jagdish Maganlal
• Patel Vikas
• Tripathi Vishwadeepak Rama Pati
• Gangwar Pranav Jitendra
• Raval Jigar Mukundbhai

Classifications

• C07D207/333 Primary

  Radicals substituted by oxygen or sulfur atoms · CPC title

• C07D207/32

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title