6-(4-fluorophenoxy)nicotinic acid synthesis

Yield:-

Reaction Conditions:

Stage #1: 6-Chloronicotinic acid methyl ester;4-Fluorophenolwith caesium carbonate in dimethyl sulfoxide at 130 - 150;
Stage #2: with hydrogenchloride;water in diethyl ether; pH=7 - 8;Product distribution / selectivity;

Steps:

14.A

Description 14: Alternative Method (A); 6-[(4-Fluorophenyl)oxy]-3-pyridinecarboxylic acid (D14); A mixture of 4-fluorophenol (96.8g), methyl 6-chloropyridine-3-carboxylate (3Og) and cesium carbonate (285.3g) in DMSO (875mL) was stirred and heated to 130^cC over a period of 1.75h then cooled overnight. The reaction mixture was reheated to -15O⁰C over a period of 1.5h, kept at this temperature for ~1h, then cooled to ~40°C and poured into water (4L). The aqueous solution was extracted with ether (1.0L) then adjusted to pH7-8 by addition of 2M HCI. The solution was extracted with further ether (2x1.0L), then adjusted to pH 2 by addition of 2M HCI causing precipitation of a solid. The precipitate was collected by filtration, washed with water and dried overnight at 4O⁰C in vacuo to give the title compound as a beige/pink solid (36.7g).

References:

WO2008/729,2008,A1 Location in patent:Page/Page column 46-47