Chemical Development of a Pilot Scale Process for the ACAT Inhibitor 2,6-Diisopropylphenyl [(2,4,6-Triisopropylphenyl)acetyl]sulfamate

Abstract

A manufacturing process to prepare the ACAT inhibitor 2,6-diisopropylphenyl [(2,4,6-triisopropylphenyl)acetyl]sulfamate ( 1; CI-1011) has been developed and successfully demonstrated on a pilot scale. Commercially available 1,3,5-triisopropylbenzene ( 9 ) was chloromethylated to give 2,4,6-triisopropylbenzyl chloride ( 8 ). Cyanation of 8 under phase-transfer-catalyzed conditions followed by basic hydrolysis of the intermediate and nonisolated 2,4,6-triisopropylbenzyl cyanide ( 7 ) gave 2,4,6-triisopropylphenylacetic acid ( 2 ), a key intermediate in the convergent synthesis of 1 . Commercially available 2,6-diisopropylphenol ( 12 ) was converted to [(2,6-diisopropylphenyl)oxy]sulfonyl isocyanate ( 13 ) when reacted with chlorosulfonyl isocyanate under thermodynamically controlled conditions. Hydrolysis and decarboxylation of 13 in situ gave 2,6-diisopropylphenyl sulfamate ( 3 ), the other key intermediate. A robust process to couple 2 and 3 was developed via the intermediacy of (2,4,6-triisopropylphenyl)acetyl chloride ( 15 ) to give the final pharmaceutical product that met specifications for clinical and toxicological use. Cost, operational, safety, environmental, and equipment considerations were taken into account during the course of development.