A process for preparation of pyrroles having hypolipidemic hypocholesteremic activities

Patent metadata

Field	Value
Publication number	US-2016107989-A1
Application number	US-201414894744-A
Country	US
Kind code	A1
Filing date	May 30, 2014
Priority date	May 30, 2013
Publication date	Apr 21, 2016
Grant date	—

Abstract

The present invention provides pyrroles having hypolipidemic hypocholesteremic activities. The invention provides saroglitazar and its pharmaceutically acceptable salts, hydrates, solvates, polymorphs or intermediates thereof. The invention also provides a process for the preparation of saroglitazar. The invention further provides intermediates as well process for preparation thereof.

First claim

We claim:

1 . A substantially amorphous form of saroglitazar magnesium of Formula (I).

2 . A substantially amorphous form of saroglitazar magnesium having a purity of at least about 98% by area percentage of HPLC and less than about 0.5% residual solvent.

3 . The substantially amorphous form of saroglitazar magnesium according to claim 1 having less than about 25% of crystalline saroglitazar magnesium.

4 . The substantially amorphous form of saroglitazar magnesium according to claim 1 having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1 or by X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 4.5°, 7.9° and 9.0°±0.2° 2θ.

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

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

(b) hydrolyzing the alkoxy ester compound of Formula (II) with a base to obtain saroglitazar; and
(c) reacting the saroglitazar with a magnesium source to obtain saroglitazar magnesium of Formula (I).

6 . The process according to claim 5 , 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 mixtures thereof.

7 . The process according to claim 5 , 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 hydride, potassium hydride, potassium tert-butoxide, and sodium pentoxide.

8 . The process according to claim 5 , wherein the phase transfer catalyst comprises one or more of tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium iodide (TBAI), benzyl triethyl ammonium chloride (TEBAC), polyethylene Glycol (PEG-200, 400, 600, 800, 1000), crown ethers selected from 12-crown-4, 15-crown-5, 18-crown-6, dibenzo-18-crown-6, and diaza-18-crown-6.

9 . A process for the preparation of saroglitazar of Formula (IA) or its pharmaceutically acceptable salt,

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

wherein, R is mesylate, tosylate, or triflate;
(b) hydrolyzing the alkoxy ester compound of Formula (II) with a base to obtain saroglitazar; and
(c) optionally, converting the saroglitazar to its pharmaceutically acceptable salt.

10 . A process for the preparation of hydroxy compound of Formula (A),

the process comprising:
(a) reacting L-tyrosine (E) with cupric sulphate pentahydrate in the presence of a base to obtain copper complex of L-tyrosine;

(b) reacting the copper complex of L-tyrosine with benzyl halide in the presence of a base, followed by hydrolysis to obtain compound (D);

(c) diazotization of the compound (D) in the presence of sodium nitrite and an acid followed by hydrolysis with water to obtain compound (C);

(d) reacting the compound (C) with diethyl sulfate in one or more organic solvents in the presence of a base and a phase transfer catalyst to obtain compound (B); and

(e) deprotecting the compound (B) to obtain the hydroxy compound (A).

11 . The process according to claim 10 , 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, and potassium hydride.

12 . The process according to claim 10 , wherein the organic solvent comprises one or more of esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; hydrocarbons selected from toluene, xylene, ethyl benzene, heptane, hexane, and cyclohexane; and chlorinated solvents selected from methylene dichloride, ethylene dichloride, chlorobenzene, chloroform, and carbontetrachloride.

13 . A crystalline hydroxy compound of Formula (A).

14 . A crystalline hydroxy compound of Formula (A),

having an X-ray powder diffraction having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at about 7.0, 13.4, 13.9, 14.6, 15.3, 16.6, 19.0, 21.7, 22.1, 23.5, 24.4, 26.1, 26.8 and 29.5±0.2° 2θ.

15 . A process for the preparation of mesylate compound of Formula (A1),

the process comprising:
(a) reacting 2-bromo-1-(4-(methylthio)phenyl)ethanone (E1) with methyl acetoacetate in one or more organic solvents in the presence of a base to obtain compound (D1);

(b) hydrolyzing the compound (D1) with a base followed by decarboxylation to obtain compound (C1);

(c) reacting the compound (C1) with ethanolamine under Paal-Knorr conditions in the presence of an acid to obtain compound (B1); and

(d) reacting the compound (B1) with methane sulphonyl chloride in the presence of a base in one or more organic solvents to obtain the mesylate compound (A1).

16 . The process according to claim 15 , wherein the organic solvent comprises one or more of esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; hydrocarbons selected from toluene, xylene, eth

Assignees

• Cadila Healthcare Ltd

Inventors

• Dwivedi Shriprakash Dhar
• Singh Ramesh Chandra
• Chavda Rajendra Gokalbhai
• Patel Jagdish Maganlal
• Pal Daya Ram
• Raval Jigar Mukundhai
• Sharma Mukul Hariprasad
• Gangwar Pranav Jitendra
• Patil Sachin Ashokrao
• Patel Vikas
• Tripathi Vishwadeepak Rama Patil

Classifications

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07D207/32 Primary

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

• C07D207/325

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

• C07D207/333 Primary

  Radicals substituted by oxygen or sulfur atoms · CPC title

• A61K31/402

  1-aryl substituted, e.g. piretanide · CPC title