合成路线1

Condensation of ethyl glycinate hydrochloride (I) with benzaldehyde in the presence of Na2SO4 and Et3N in tert-butyl methyl ether gives ethyl N-benzylideneglycinate (II), which is then cyclocondensed with trans-1,4-dibromo-2-butene (III) by means of t-BuOLi in toluene to yield ethyl 1-amino-2-vinylcyclopropanecarboxylate (IV). Alternatively, condensation of ethyl N-(diphenylmethylene)glycinate (V) also with trans-1,4-dibromo-2-butene (III) by means of t-BuOK in THF affords cyclopropanecarboxylate (IV), which is then N-protected with Boc2O at reflux to generate N-Boc derivative (VI). Enzymatic resolution of the racemate (VI) by means of acalase or savinase (proteases from Bacillus clausii) or esperase (protease from Bacillus halodurans) in DMSO at 40 °C leads to the desired ethyl (1R,2S)-N-Boc-cyclopropanecarboxylate diastereomer (VII). Hydrolysis of ethyl ester (VII) with LiOH in THF/MeOH leads to the carboxylic acid (VIII), which is then coupled with cyclopropanesulfonamide (IX) using CDI and DBU in THF to provide the sulfonamide (X). N-Deprotection of this compound by means of TFA in CH2Cl2 followed by treatment with HCl in Et2O gives amine hydrochloride (XI) .
Cyclopropanesulfonamide (IX) is prepared by amination of 3-chloropropane-1-sulfonyl chloride (XII) with t-BuNH2 in THF to provide N-tert-butyl-3-chloropropane-1-sulfonamide (XIII), which is then cyclocondensed in the presence of BuLi in THF to yield N-tert-butylcyclopropanesulfonamide (XIV). Finally, the tert-butyl group of intermediate (XIV) is removed with TFA, affording cyclopropanesulfonamide (IX), which can also be prepared by direct amination of cyclopropanesulfonyl chloride (XV) with NH3 in THF .