ジルチアゼム鍵合成中間体の実用的不斉合成法の開発

抄録

A practical synthesis of methyl (2R, 3S) -3- (4-methoxyphenyl) glycidate (-)-2, a key intermediate for diltiazem (1), was accomplished through chiral dioxirane-mediated asymmetric epoxidation of methyl (E) -4-methoxycinnamate 3 with C₂-symmetric binaphthyl ketone 4 (Yang catalyst) used as chiral catalyst. An efficient synthesis of 4 was developed, which involves novel optical resolution combined with efficient racemization of unwanted enantiomer and subsequent non-high diluted macrolactonization. The use of inexpensive sodium metal and a catalytic amount of methanol in the Claisen-Schmidt condensation of p-anisaldehyde with methyl acetate allowed an economical access to 3. Treatment of 3 with chiral dioxirane, generated in situ from chiral ketone 4, provided (-) -2 in 78% ee and 87% yield. The crude mixture of (-) -2 and 4 was efficiently separated by the use of a novel and simple equipment performing lipase-catalyzed transesterification and continuous dissolution and crystallization to furnish desired optically pure (-) -2 and recovery of 4 both in excellent yield [74% (based on 3) and 91%, respectively].