A practical and facile synthesis of azetidine derivatives for oral carbapenem, L-084.
An orally active carbapenem L-084, which exhibits high bioavailability in humans, has a 1-(1,3-thiazolin-2-yl)azetidin-3-ylthio moiety at the C-2 position of the 1beta-methylcarbapenem skeleton. We established a practical and cost-effective synthesis of 3-mercapto-1-(1,3-thiazolin-2-yl)azetidine (1) for further scale-up production of L-084. This synthesis method entails an industry-oriented reaction of azetidine ring-closure to yield N-benzyl-3-hydroxyazetidine (16), which is eventually converted to 1 via key intermediates, Bunte salts 19 and 20.
Isoda
Takeshi
T
Medical Research Laboratories, Wyeth K.K., Shiki, Saitama, Japan. isoda@konicaminolta.jp
Yamamura
Itsuki
I
Tamai
Satoshi
S
Kumagai
Toshio
T
Nagao
Yoshimitsu
Y
D000284:Administration, Oral; D001384:Azetidines / Q000138:chemical synthesis* / Q000737:chemistry; D015780:Carbapenems / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry; D004345:Drug Industry; D006801:Humans; D015394:Molecular Structure; D013237:Stereoisomerism; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry
C516193:3-mercapto-1-(1,3-thiazolin-2-yl)azetidine; D001384:Azetidines; D015780:Carbapenems; D013844:Thiazoles; C082735:azetidine; C120999:L 084