合成路线1

The precursor (1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexylamine (V) can be prepared as follows. Ring opening of cyclohexene oxide (XXXI) with benzylamine affords racemic trans-2-benzylaminocyclohexanol (XXXII) which, after resolution with L-(–)-di-p-toluoyltartaric acid, is treated with benzyl chloroformate to produce the chiral carbamate (XXXIII). Subsequent condensation of the cyclohexanol derivative (XXXIII) with imidate (X) yields the dimethoxyphenethyl ether (XXXIV), from which the N-benzyl and carbobenzoxy protecting groups are removed by hydrogenolysis over Pd/C to furnish the target intermediate (V). Similarly, ring opening of epoxide (XXXI) with trimethylsilyl azide utilizing either Jacobsen’s (salen)Cr(III) catalyst or Nugent’s Zr C3-symmetrical complex, followed by acidic desilylation, furnishes (R,R)-2-azidocyclohexanol (XXXV). After coupling of (XXXV) with imidate (X), catalytic hydrogenation of the resulting azido ether (XXXVI) provides amine (V). In an alternative method, aminolysis of cyclohexene oxide (XXXI) produces racemic trans-2-aminocyclohexanol (XXXVII), which, after resolution with L-tartaric acid, is reacted with benzyl chloroformate to give (R,R)-2-(benzyloxycarbonylamino)cyclohexanol (XXXVIII). Optionally, the chiral carbamate (XXXVIII) can be obtained by reaction of racemic aminocyclohexanol (XXXVII) with benzyl chloroformate, followed by enantioselective acetylation of the obtained compound (XXXIX) with vinyl acetate in the presence of lipase, to furnish the (R,R)-acetate (XL), which is then hydrolyzed to (XXXVIII) under alkaline conditions. Coupling of (R,R)-2-(benzyloxycarbonylamino)cyclohexanol (XXXVIII) with imidate (X) produces the carbobenzoxy-protected amino ether (XLI), which is then hydrolyzed to (V) in refluxing 6N HCl. A different route to the intermediate amine (V) consists of displacement of tosylate (I) with NaN3, followed by catalytic hydrogenation of the resulting alkyl azide (2). Scheme 3.