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

Readily synthesized monosubstituted aliphatic acyclic carboxamides have a physiological cooling effect similar to that obtained with menthol. Among the monosubstituted aliphatic acyclic carboxamides, WS-231 (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 2,2diisopropylpropionitrile (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.