合成路线1

Esterification of 3,4-dichlorophenylacetic acid (I) with HCl/EtOH at reflux followed by radical bromination of the resulting ethyl ester (II) with NBS in the presence of HBr or (PhCOO)2 in refluxing CCl4 provides ethyl α-bromo-(3,4-dichlorophenyl)acetate (III). Tandem Michael addition and cyclization of ethyl bromoacetate (III) with ethyl acrylate (IV) by means of NaH and a catalytic amount of EtOH in ethyl ether gives diethyl cis-1-(3,4-dichlorophenyl)-1,2-cyclopropanedicarboxylate (V). After saponification with KOH in EtOH/H2O, the resulting diacid (VI) is cyclized with urea in refluxing xylene to yield the bicyclic imide (VII). Subsequent reduction of imide (VII) with BH3/THF or sodium bis(2-methoxyethoxy)aluminum hydride (Vitride, Red-Al) affords racemic 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (VIII) , which is finally treated with HCl in Et2O and submitted to enantiomeric separation by chiral chromatography .
Cyclocondensation of (3,4-dichlorophenyl)acetonitrile (X) with racemic epichlorohydrin (XIa) in the presence of NaNH2 in THF gives 1-(3,4-dichlorophenyl)-2-(hydroxymethyl)cyclopropanecarbonitrile as a diastereomeric mixture enriched in the cis-isomers (XIIa). Oxidation of alcohol (XIIa) with H5IO6 and CrO3 gives the carboxylic acid (XIII), which by esterification with MeOH in the presence of SOCl2 affords the methyl ester (XIV). Finally, reductive cyclization of the cyano ester (XIV) using BH3·Me2S in refluxing THF affords 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (VIII) .
In a stereospecific route, cyclization of nitrile (X) with (S)-epichlorohydrin (XIb) by means of NaHMDS in THF provides the cis-cyclopropanecarbonitrile (XIIb) as the major diastereoisomer, which is then reduced to aminoalcohol (XV) by means of BH3·Me2S. Chlorination of alcohol (XV) with SOCl2 in isopropyl acetate leads to the chlorinated amine (XVI), which is finally cyclized in the presence of NaOH, and then crystallized with HCl .