Dismiss
The Prior Art Database and Publishing service will be updated on Sunday, February 25th, from 1-3pm ET. You may experience brief service interruptions during that time.
Browse Prior Art Database

Crystalline Form of Elafibranor

IP.com Disclosure Number: IPCOM000252802D
Publication Date: 2018-Feb-13

Publishing Venue

The IP.com Prior Art Database

Related People

Zsuzsanna Szokol: AUTHOR

This text was extracted from a Microsoft Word document.
At least one non-text object (such as an image or picture) has been suppressed.
This is the abbreviated version, containing approximately 22% of the total text.

Crystalline Form of Elafibranor

Zsuzsanna Szokol, Daniel Ulej

Egis Pharmacetuticals Plc., Directorate of Drug Substance Development and Directorate of Finished Product Development, P.O. Box 100, H-1475 Budapest, Hungary

Abstract

A crystalline form of Elafibranor was produced, and is described herein below. Elafibranor is a drug used as a treatment for non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH). The crystalline Elafibranor, presented in this article, was produced according to the general synthesis method of the originator, described in WO2004005233A1[1], and WO2005005369[2], and it is designated as crystalline Elafibranor from now on. Nevertheless a chemically purified crystalline Elafibranor was produced, which has the same crystal structure as the crystalline Elafibranor, despite it has higher purity according to HPLC measurements. It is designated as chemically purified crystalline Elafibranor hereinafter.

Preparation of crystalline Elafibranor

·         Synthesis of 1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-hydroxyphenyl]prop-2-en-1-one (Compound 1)

30 g (0.175 mol) 4-methylthioacetophenone and 26.83 g (0.175 mol) 3,5-dimethyl-4-hydroxybenzaldehyde are dissolved in 200 ml ice-cooled methanol solution saturated with gaseous hydrochloric acid. The mixture is stirred at room temperature for 2 hours, and the solvent is eliminated by vacuum evaporation. The residue is stirred with 200 ml isopropylalcohol for 2 hours. The orange crystals are eliminated by filtration.

Yield: 49.37 g (94.5 %). Melting point: 147.7-151.4 °C. HPLC purity: 99.8 %.

·         Synthesis of 1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-tert-butyloxycarbonyl-dimethylmethyloxyphenyl]prop-2-en-1-one (Compound 2)

10 g (33.512 mmol) Compound 1 is dissolved in 100 ml acetonitrile and 13.9 g
(100.536 mmol, 3 molar-equivalents) potassium carbonate and 19.137 ml (22.888 g, 100.536 mmol, 3 molar-equivalents) tert-butyl bromoisobutyrate are then added. The mixture is stirred at 80 °C for 16 hours, then brought to room temperature. The salts are eliminated by filtration. 13.9 g (100.536 mmol, 3 molar-equivalents) potassium carbonate and 19.137 ml (22.888 g, 100.536 mmol, 3 molar-equivalents) tert-butyl bromoisobutyrate are then added. The mixture is stirred at 80 °C for 16 hours again, then brought to room temperature. The salts are eliminated by filtration. 13.9 g (100.536 mmol, 3 molar-equivalents) potassium carbonate and 19.137 ml (22.888 g, 100.536 mmol, 3 molar-equivalents) tert-butyl bromoisobutyrate are then added. The mixture is stirred at 80 °C for further 16 hours, then brought to room temperature. The salts are eliminated by filtration. The solvents and the excess of the reagent are eliminated by vacuum evaporation. HPLC purity: 58.6 %.

Purification by flash chromatography (cyclohexane/ethyl acetate), yield: 11.38 g (77 %). Colorless oil. HPLC purity: 95.4 %

·         Synthesis of 1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-carboxydimethylmethoxy-phen...