3-Chloro-5-methyl-thiophene-2-carboxylic acid methyl ester synthesis

Yield:229343-19-5 79%

Reaction Conditions:

Stage #1: methyl 3-amino-5-methylthiophene-2-carboxylatewith hydrogenchloride;sodium nitrite in water at 0; for 1 h;
Stage #2: with hydrogenchloride;copper(l) chloride in water at 0 - 65;

Steps:

Preparation of 3-Chloro-5-methyl-thiophene-2-carboxylic acid methyl ester A mixture of 3-Amino-5-methyl-thiophene-2-carboxylic acid methyl ester (5.0 g, 29.2 mmol) in 6N HCl (25 ml) was cooled to 0° C. (ice bath). A solution of sodium nitrite (2.01 g, 29.2 mmol) in water (5 ml) was added dropwise and the mixture was stirred at 0° C. for 60 min This mixture was then added to a solution of copper(I)chloride (2.89 g, 29.2 mmol) in conc. HCl (25 ml) at 0° C. The reaction mixture was stirred at room temperature then warmed to 65° C. until gas evolution had ceased. The reaction mixture was diluted with water and extracted with EtOAc (2*150 mL), washed with water, brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column (0-30% EtOAc in hexane) to give 4.4 g (79%) yellow oil product.

References:

US2012/238569,2012,A1 Location in patent:Page/Page column 41