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.