Ethanol → Alvimopan dihydrate

Participants

Reaction Steps

A solution of a compound of Example 1 (12.5 g, 0.026 mol, 1.0 equiv) in 315 mL of 3A ethanol was charged to round bottom flask. Water (74.0 mL) was added to the mixture. Aqueous solution of sodium hydroxide ((1.0 M) 0.077 mol, 3.0 equiv) was added dropwise over 10-15 minutes at 25°-30° C. The solution was stirred and then filtered. The pH of the solution was adjusted from 12.50 to 6.00 by addition of concentrated hydrochloric acid. The solution was seeded and (2S,3R,4R)[[2-[[4-(3-hydroxyphenyl)-3,4-dimethYl-1-piperidinyl]methyl]-1-oxo -3-phenylpropyl]amino]acetic acid began to precipitate within 10-15 minutes. The crystallization was stirred at 25° C. for two hours and then (2S,3R,4R)[[2-[[4-(3-hydroxyphenyl)-3,4-dimethYl-1-piperidinyl]methyl]-1-oxo -3-phenylpropyl] amino]acetic acid was filtered under slight suction to a wet cake. The crystals were slurried with 60 mL of water and filtered to a hard cake under suction. The crystals were dried to the dihydrate overnight (16 hours) under open air at 33% relative humidity at 25° C. by pulling air over the product in the filter funnel under slight suction. The title compound was isolated in 85% yield (10.2 g), from (αS,3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl -α-(phenylmethyl)-1-piperidine propanoic acid monohydrate, as white crystals with a sharp melting point of 208° C. The sample was analyzed using x-ray powder diffraction.

Provenance & Evidence