合成路线1

Resolution of racemic 3-cyclohexene-1-carboxylic acid (VIII) with (R)-α-methylbenzylamine results in the target (S)-enantiomer, which undergoes intramolecular iodolactonization to compound (IX) by means of I2, KI and NaHCO3 in H2O/CH2Cl2. The bicyclic iodolactone (IX) then rearranges to epoxy ester (X) by treatment with NaOH in EtOH/H2O. Ring opening of epoxide (X) with NaN3 in the presence of NH4Cl in DMF at 76 °C affords the trans-azido alcohol (XI), which is converted to the tert-butyl carbamate (XII) by catalytic hydrogenation in the presence of Pd/C and Boc2O in EtOAc . Carbamate (XII) can also be obtained by reaction of epoxide (X) with ethanolic ammonia at 50 °C, followed by protection of the resultant amino alcohol with Boc2O in EtOH . After conversion of alcohol (XII) to the corresponding mesylate (XIII) by means of methanesulfonyl chloride and Et3N in CH2Cl2 or EtOAc , substitution of the mesylate group with NaN3 in the presence or the absence of phase transfer catalysts, including Aliquat 336, Hex4NCl, PhCH2NEt3Cl, Me4NCl , or Bu4NCl or Et4NCl , in NMP at 60 °C affords the cis-azido-carbamate (XIV) . Reduction of azide (XIV) by either hydrogenation with H2 and Pd/C in EtOH/EtOAc or transfer hydrogenation with ammonium formate and Pd/C in EtOH/H2O gives amine (XV), which is optionally converted to the corresponding oxalate salt . Subsequent protection of the free amine group in compound (XV) or its oxalate with benzyl chloroformate in the presence of NaHCO3 in THF/H2O or EtOAc/H2O yields the fully protected diamine (XVI), which undergoes ester hydrolysis by means of LiOH in H2O/THF or H2O/EtOH to furnish the carboxylic acid (XVII). After condensation of carboxylic acid (XVII) with dimethylamine hydrochloride by means of EDC and HOBt in CH2Cl2 or DMF , the resulting N,N-dimethylcarboxamide (XVIII) is selectively deprotected by catalytic hydrogenolysis over Pd/C in MeOH or EtOH yielding amine (XIX), which is optionally isolated as the oxalate salt by precipitation with oxalic acid in EtOAc . Coupling of the cyclohexylamine (XIX) with N-(5-chloro-2-pyridyl)oxamic acid lithium salt (VI) by means of EDC and HOBt in CH2Cl2 then leads to amide (XX) , which can be alternatively obtained by condensation of the corresponding oxalate salt of (XIX) with ethyl N-(5-chloro-2-pyridyl)oxamate (XXI) in the presence of Et3N in acetonitrile . Finally, subsequent deprotection of amide (XX) by means of HCl in ethanol or MsOH in acetonitrile provides the target cyclohexanediamine (I).