Optically active cyclohexene derivative as a new antisepsis agent: an efficient synthesis of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242).
Two new synthetic methods were established for the efficient synthesis of optically active cyclohexene antisepsis agent, ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate [(R)-1: TAK-242)]. The first method involved recrystallization from methanol of the diastereomeric mixture (6RS,1'R)-7, obtained by esterification of carboxylic acid 3 with (S)-1-(4-nitrophenyl)ethanol [(S)-5)] to give the desired isomer (6R,1'R)-7 with 99% de in 32% yield. Subsequent catalytic hydrogenolysis and esterification gave (R)-1 with >99% ee. The second method employed enantioselective hydrolysis of acetoxymethyl ester 9a (prepared by alkylation of 3 with bromomethyl acetate) with Lipase PS-D to give the eutomeric enantiomer (R)-9a with excellent enantioselectivity (>99% ee) and high yield (48%). The desired (R)-1 was then obtained by transesterification with ethanol in the presence of concentrated sulfuric acid without loss of ee. Of these, the procedure employing enzymatic kinetic resolution using Lipase PS-D is the more efficient and practical preparation of (R)-1.
Yamada
Masami
M
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Jusohonmachi, Osaka, Japan. Yamada_Masami1@takeda.co.jp
Ichikawa
Takashi
T
Yamano
Toru
T
Kikumoto
Fumio
F
Nishikimi
Yuji
Y
Tamura
Norikazu
N
Kitazaki
Tomoyuki
T
D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D007202:Indicators and Reagents; D008049:Lipase / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D018805:Sepsis / Q000188:drug therapy*; D013055:Spectrophotometry, Infrared; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*
D007202:Indicators and Reagents; D013449:Sulfonamides; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; D008049:Lipase