G. Dozeman, P. J. Fiore, A. Puls
Mar 14, 1997
Citations
0
Influential Citations
22
Citations
Journal
Organic Process Research & Development
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 ...