Methanesulfonic Acid → Saquinavir Mesylate

Participants

Reaction Steps

125.9 g (312 mmol) of 2-(3(S)-amino-2(R)-hydroxy-4-phenylbutyl)-N-t-butyl-decahydro-(4aS ,8aS)-isoquinoline-3(S)-carboxamide, 94.6 g (328 mmol) of N-(2-quinolylcarbonyl)-L-asparagine and 3.5 g (31 mmol) of 1-hydroxy-2(1H)-pyridone were treated with a mixture of 75 ml of tetrahydrofuran and 1925 ml of ethyl acetate. A solution of 70.9 g (344 mmol) of dicyclohexylcarbodiimide in 500 ml of ethyl acetate was subsequently added dropwise at 25° within 30 minutes while stirring. The reaction mixture was stirred for 10 hours. Then, 50 ml of water of low ion contents were added and the suspension was cooled to 2°-3° and stirred at this temperature for 1 hour. The dicyclohexylurea was then filtered off and washed on the filter with 2 500 ml portions of ethyl acetate. The filtrates were combined and treated slowly at 50° with a solution of 32.5 g (338 mmol) of methanesulphonic acid and 250 ml of ethyl acetate. The suspension was subsequently stirred at 20° for 14 hours. The crystals were then filtered off under suction, washed with a total of 600 ml of ethyl acetate and subsequently dried at 45°/2000 Pa for 24 hours. 229.5 g (95%) of N-t-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide methanesulphonate having a HPLC content of 97.1% were obtained.

Provenance & Evidence