Methanol → Clopidogrel

Participants

Reaction Conditions

Reaction Steps

Concentrated sulfuric acid (˜98%; 496 ml; 9.30 mol) was charged into methanol (1.75 l) with sting between 25-38° C. followed by dimethyl sulfate (250 ml; 2.636 mol). The contents were heated to reflux for 3 hours, after which the reaction mixture was cooled to 40-50° C. and (+)-(S)-2-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5yl)acetamide (500 g; 1.55 mol) was charged. The reaction mixture was heated to 65° C. and maintained between 65-66° C. for a period of 60 hours. The reaction mixture was cooled to 25-30° C. and poured into water (10.0 l) with stirring. Dichloromethane (5.0 l) was added, stirred for 1 hour, after which the organic layer was separated. To the aqueous layer dichloromethane (2.5 l) was added and stirred for 1 hour and the separated organic layer was combined with the earlier separated layer and washed with water (2.5 l). 5% (w/v) aqueous sodium bicarbonate solution (2.5 l) was added to this organic layer and stirred for a period of an hour and the separated organic layer was washed with 0.25% sulfuric acid (2.5 l) followed by water (2.5 l) and treated with activated carbon (40.0 g) for a period of 3 hours with stirring. The activated carbon was removed by filtration through a celite bed and the celite bed was washed with dichloromethane (1.0 l). This washing was coupled with the filtrate and the solvent removed under vacuum to yield (+)-(S)-2-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetic acid methyl ester as a pale yellow oil. Yield: 380 g (73.0% by theory). The product was identified by IR spectrum, 1H and 13C NMR investigation.

Provenance & Evidence