Process Development of the PDE4 Inhibitor K-34

Abstract

A short and practical synthesis of the PDE4 inhibitor K-34 ( 1 ) was developed. This synthesis was achieved in four steps and with a 58% overall yield. The unique spiro acetal was created with exceptionally high yield by utilizing the neighbor carboxylic acid assistance. This synthesis also features efficient ketone construction with 4-pyridinylmethyl anion 9 and ester 18, in which overreaction should be prohibited by quick in situ enolate formation. The overall synthesis was carried out under mild conditions and used a simple procedure suitable for large-scale production.