Cisapride monohydrate

Cisapride monohydrate Propulsid Janssen Pharmaceuticals Heartburn 7/29/1993 7/14/2000 7 years Heart rhythm abnormalities US 2.5 billion... 

To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (20.2 g) in methyl isobutylketone (250 ml) and triethyl amine (15.3 ml) was slowly dropped ethyl chloroformate (9.6 ml). The reaction mixture was stirred for 30 min at room temperature. To the formed mixed anhydride was then added l-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine (28.2 g) and the reaction mixture was stirred for 2 hours at room temperature. Subsequently, the reaction mixture was washed with water (80 ml) and a NaOH solution (6.5% w/v, 50 ml). The organic layer was warmed to 65°C and methanol (50 ml) and water (8.5 ml) were added. The solution was cooled slowly and stirred for 2 days during which crystallisation occurred, yielding benzamide, 4-amino-5-chloro-N-(l-(3-(4-fluorophenoxy)propyl)-3-methoxy-4-piperidinyl)-2-methoxy-, monohydrate, cis- (Cisapride) having a cis/trans ratio higher than 99/1. 

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