Industrially Viable Preparation of 2,2-Diisopropylpropionitrile, a Key Intermediate of Physiological Coolant WS-23 (2-Isopropyl-N,2,3-trimethylbutyramide)

摘要

Readily synthesized monosubstituted aliphatic acyclic carboxamides have a physiological cooling effect similar to that obtained with menthol. Among the monosubstituted aliphatic acyclic carboxamides, WS-23 (2-isopropyl-N,2,3-trimethylbutyramide, (2) is a nearly odorless white powder, characterized by a high cooling capacity with no side effects such as burning, stinging, or tingling sensations. It has been used as a coolant in medicinal preparations, oral care products, foodstuffs, drinks, tobacco products, cosmetics, toiletries, and confectionery products. It has been synthesized2 by the Ritter reaction of 2,2-diisopropylpropionitrile (1) with methanol in the presence of acid (Scheme 1). Although 2,2-diisopropylpropionitrile (1) is commercially available, it is very expensive, hence, it was our endeavor to develop an eco-friendly methodology for its preparation in good yields.