Practical synthesis of (R)-4-mercaptopyrrolidine-2-thione from L-aspartic acid. Preparation of a novel orally active 1-beta-methylcarbapenem, TA-949.
A facile and economical synthesis of a novel orally active 1-beta-methylcarbapenem, TA-949 (1), is described. The key process involves an efficient synthesis of the C-2 side chain (R)-4-mercaptopyrrolidine-2-thione 2 from L-aspartic acid and the construction of the 1-beta-methylcarbapenem skeleton. The mercapto group of 2 with an R-configuration was formed via deaminative bromination of the amino group of L-aspartic acid beta-methyl ester hydrochloride 12 followed by a complete S(N)2-type substitution with potassium benzenemethanethiolate. High-yield amination and cyclization of the chloride 15 to the pyrrolidin-2-one 16 was accomplished by a simple treatment with ammonia. Thiation of 16 and the Birch reduction of the resultant thiolactam 18 provided the C-2 side chain 2 in high yield with the asymmetric center retained as such. The side chain 2 was installed into the 1-beta-methylcarbapenem skeleton either by coupling with the vinyl phosphate 5 or by the use of the counterattack strategy involving the Dieckmann-type cyclization of the thioester 8. Removal of the protective groups of the coupling product 6 followed by esterification provided TA-949 (1) in high yield.
Seki
M
M
Product & Technology Development Laboratory and Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89 Kashima, Yodogawa-ku, Osaka 532-8505, Japan.
Yamanaka
T
T
Kondo
K
K
D000284:Administration, Oral; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry; D001224:Aspartic Acid / Q000737:chemistry*; D015780:Carbapenems / Q000138:chemical synthesis / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D013055:Spectrophotometry, Infrared; D013871:Thiones / Q000138:chemical synthesis* / Q000737:chemistry
C414088:4-mercaptopyrrolidine-2-thione; D000900:Anti-Bacterial Agents; D015780:Carbapenems; D011759:Pyrrolidines; C414087:TA 949; D013871:Thiones; D001224:Aspartic Acid