合成路线1

Several alternative routes to the intermediate amine (V) are shown in Scheme 4. The asymmetric reduction of ethyl 2-oxocyclohexanecarboxylate (XLII) gives the (1R,2S)-hydroxy ester (XLIII), which is converted to amide (XLIV) by treatment with aqueous ammonia and ammonium chloride. After activation of the hydroxyl group of (XLIV) as the corresponding mesylate (XLV), displacement with the potassium alkoxide of 3,4-dimethoxyphenethyl alcohol (XI) affords the trans-amide ether (XLVI). The target amine (V) is then obtained by Hofmann rearrangement of carboxamide (XLVI) employing NaOCl and NaOH. A different resolution method involves transesterification of ethyl 2-oxocyclohexanecarboxylate (XLII) with benzyl alcohol, followed by enzymatic reduction of the resulting benzyl keto ester (XLVII) with carbonyl reductase to provide the (1R,2R)-hydroxy ester (XLVIII). Coupling of (XLVIII) with imidate (X) furnishes the benzyl phenethoxycyclohexanecarboxylate (XLIX), which is subjected to benzyl group hydrogenolysis to provide acid (L). This compound can also be obtained by condensation of ethyl 2(R)-hydroxy-1(R)-cyclohexanecarboxylate (LI) with 3,4-dimethoxyphenethyl trichloroacetimidate (X), followed by alkaline hydrolysis of the obtained ethyl 2-phenethoxycyclohexanecarboxylate (LII). Optionally, the ethyl ester (LII) can be converted to amide (XLVI) by reaction with methanolic ammonia, or to hydrazide (LIII) by treatment with hydrazine hydrate in EtOH. Conversion of acid (L) to the target amine (V) can then be accomplished by Curtius rearrangement employing diphenylphosphoryl azide. Analogously, diazotization of hydrazide (LIII), followed by Curtius rearrangement of the intermediate acyl azide and alkaline hydrolysis results in the target amine (V) (2). Scheme 4.