Development of a Scalable Process for CI-1020, A Novel Endothelin Antagonist¹

Abstract

The process development of a route for preparing CI-1020 on pilot-plant scale is described in 55% overall yield. Hydrocyanation conditions are described which use acetone cyanohydrin catalyzed by tetramethylammonium hydroxide and which provide the desired ketonitrile intermediate (4) in 85% yield with excellent quality. The penultimate intermediate (7), a hydroxybutenolide, is prepared in a two-step process using an aldol condensation followed by acid-catalyzed ring closure to give product in 86.8% yield. The active pharmaceutical ingredient (API) (8) is prepared by ring-opening of the hydroxybutenolide with sodium carbonate to provide the sodium salt. The use of ReactIR to monitor the API reaction is described. ReactIR was required to determine an endpoint for the reaction. The use of chromatographic analysis to determine the endpoint was not possible. The API and the penultimate hydroxybutenolide are not separable by chromatographic methods.