A practical procedure for the large-scale preparation of methyl (2R,3S)-3-(4-methoxyphenyl)glycidate, a key intermediate for diltiazem.
A practical synthesis of methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (-)-2, a key intermediate for diltiazem (1), was developed. Treatment of methyl (E)-4-methoxycinnamate 3 with chiral dioxirane, generated from chiral ketone 4, provided (-)-2 in 77% ee and 89% yield. The crude mixture of (-)-2 and 4 was efficiently separated by the use of novel and simple equipment performing a lipase-catalyzed transesterification and a continuous dissolution and crystallization to furnish the optically pure (-)-2 and recovery of 4 in 74% and 91% yield, respectively.
Furutani
Toshiyuki
T
Product & Technology Development Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima, Yodogawa-ku, Osaka 532-8505, Japan.
Imashiro
Ritsuo
R
Hatsuda
Masanori
M
Seki
Masahiko
M
D002384:Catalysis; D002625:Chemistry, Organic / Q000295:instrumentation / Q000379:methods; D002851:Chromatography, High Pressure Liquid; D002934:Cinnamates / Q000737:chemistry; D004110:Diltiazem / Q000737:chemistry*; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D004951:Esterification; D008049:Lipase / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011422:Propionates / Q000138:chemical synthesis*; D013237:Stereoisomerism
D002934:Cinnamates; D004852:Epoxy Compounds; D011422:Propionates; C061799:dioxirane; C055263:3-(-methoxyphenyl)glycidic acid methylester; C063318:4-methoxycinnamic acid; D008049:Lipase; D004110:Diltiazem