Polymorphic form of pyrrole derivative and intermediate thereof

Patent metadata

Field	Value
Publication number	US-2016207884-A1
Application number	US-201414915457-A
Country	US
Kind code	A1
Filing date	Aug 28, 2014
Priority date	Aug 29, 2013
Publication date	Jul 21, 2016
Grant date	—

Abstract

The present invention relates to Saroglitazar free acid of Formula (IA) or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable esters, stereoisomers, tautomers, analogs and derivatives thereof. The present invention also provides an amorphous form of saroglitazar free acid and processes of preparation thereof. The present invention also provides pharmaceutical composition comprising an amorphous form saroglitazar magnesium.

First claim

We claim:

1 . Saroglitazar free acid of Formula (IA) or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable esters, stereoisomers, tautomers, analogs and derivatives thereof.

2 . The pharmaceutically acceptable salts according to claim 1 comprises of alkali or alkaline earth metal selected from lithium, barium, strontium, and zinc; or ammonium salt; or organic amines salts selected from methylamine, dimethylamine, ethylamine, diethylamine, 1,2-ethanediamine, n-propylamine, isopropylamine, diisopropylamine, N-methyl isopropylamine, n-butylamine, t-butylamine, 2-butamine, 1,2-ethanediamine, N-methylglucamine, N,N,N-trimethyl ethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methyl cyclohexylamine, guanidine, N-(4-aminobutyl) guanidine, dicyclohexylamine, benzene-methanamine, ethanolamine, diethanolamine, tris-(hydroxymethyl)methylamine, hydroxylamine, methanaminium, benzylamine, N-methylbenzylamine, N-ethyl benzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, L-alanine, L-lysine, D-lysine, L-arginine, L-histidine, L-threonine, 2-thiopheneethanamine, (2S)-3,3-dimethyl-2-butanamine, cyclopentanamine, and cycloheptanamine.

3 . An amorphous form of saroglitazar free acid of Formula (IA).

4 . The amorphous form of saroglitazar free acid according to claim 3 having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 5 .

5 . An amorphous form of saroglitazar magnesium of Formula (I).

6 . The amorphous form of saroglitazar magnesium according to claim 5 having a purity of at least about 98% by area percentage of HPLC and less than about 0.5% residual solvent.

7 . The amorphous form of saroglitazar magnesium according to claim 5 having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 2 .

8 . A process for the preparation of an amorphous form of saroglitazar magnesium of Formula (I),

the process comprising:
(a) dissolving saroglitazar magnesium of Formula (I) in one or more organic solvents to obtain a solution,
(b) adding the solution in one or more of anti-solvent at temperature from about −80° C. to about 150° C. to obtain saroglitazar magnesium of Formula (I); and
(c) obtaining the amorphous saroglitazar magnesium by removal of anti-solvent.

9 . The process according to claim 8 , wherein the organic solvent comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; or mixtures thereof.

10 . The process according to claim 8 , wherein the anti-solvent comprises one or more of hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tertbutyl ether.

11 . The process according to claim 8 , wherein the solution is added to one or more of anti-solvent at the temperature of about −40° C. or at about 90° C.

12 . A process for the preparation of an amorphous form of saroglitazar magnesium of Formula (I),

the process comprising:
(a) reacting a hydroxy compound (A) with a mesylate compound (A1) in one or more organic solvents in the presence of a base to obtain an alkoxy ester compound of Formula (II),

(b) hydrolyzing the alkoxy ester compound of Formula (II) with a base in one or more organic solvents to obtain a reaction mixture,
(c) washing the reaction mixture with one or more organic solvents to obtain aqueous layer,
(d) treating the aqueous layer with magnesium source to obtain saroglitazar magnesium solution,
(e) removal of solvent from the solution to obtain saroglitazar magnesium residue;
and;
(f) addition of one or more of anti-solvent to the residue followed by removal of anti-solvent to obtain the amorphous form of saroglitazar magnesium of Formula (I).

13 . The process according to claim 12 , wherein the organic solvent comprises one or more of alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, and t-butyl alcohol; ketones selected from acetone, butanone, and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, and chlorobenzene; hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tert-butyl ether; or mixture thereof.

14 . The process according to claim 12 , wherein the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydride, potassium tert-butoxide, and sodium pentoxide.

15 . The process according to claim 12 , wherein the organic solvent for washing comprises one or more of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, acetone, butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate, n-butyl acetate, methylene dichloride, ethylene dichloride, and chlorobenzene, or mixture thereof.

16 . The process according to claim 12 , wherein the magnesium source comprises one or more of magnesium hydroxide, magnesium methoxide, magnesium acetate, magnesium chloride, and magnesium metal.

17 . The process according to claim 12 , wherein the anti-solvent comprises one or more hydrocarbons selected from pentane, hexane, heptane, and cyclohexane; ethers selected from tetrahydrofuran, 1,4-dioxane, diisopropyl ether, diethyl ether, and methyl tertbutyl ether.

18 . The amorphous form of saroglitazar magnesium according to claim 12 having particle size distributions having D(10) of about 20 μm or less, (D50) of about 100 μm or less, and D(90) of about 200 μm or less, or any combination thereof.

19 . A process for the preparation of saroglitazar free acid of Formula (IA) or its pharmaceutically acceptable salts thereof,

the process comprising:
(a) reacting a hydroxy compound (A) with a mesylate compound (A1) in one or more of suitable organic solvent 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 in one or more organic solvent to obtain reaction mixture,
(c) a

Assignees

• Cadila Healthcare Ltd

Inventors

• Dwivedi Shri Prakash Dhar
• Singh Ramesh Chandra
• Patel Vikas
• Desai Amar Rajendra

Classifications

• C07D207/325

  with substituted hydrocarbon radicals directly attached to the ring nitrogen atom · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• C07D207/333 Primary

  Radicals substituted by oxygen or sulfur atoms · CPC title