TAK-242 S enantiomer

S enantiomer of TAK-242. TAK-242 (Resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling. TAK-242 is in treatment of sepsis and septic shock.

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).[Pubmed:16394550]

Chem Pharm Bull (Tokyo). 2006 Jan;54(1):58-62.

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.