合成路线1

Mitsunobu reaction of 3-hydroxybenzaldehyde (XI) with cyclohexylmethanol (XII) using PPh3 and DEAD in THF or condensation of 3-hydroxybenzaldehyde (XI) with cyclohexylmethyl bromide (IX) using K2CO3 and NMP in DMF at 75 °C give ether (XIII), which by reaction with acetonitrile (II) by means of LDA in THF at –78 °C or t-BuOK in THF yields the b-hydroxynitrile (XIV). Reduction of nitrile (XIV) with LiAlH4 or BH3·Me2S in THF affords the primary amine (XV), which by N-protection with Fmoc-Cl and DIEA in CH2Cl2 provides carbamate (XVI). Oxidation of secondary alcohol (XVI) with MnO2 in CH2Cl2 leads to the ketone (XVII), which is finally submitted to enantioselective reduction using (–)-DIP-Cl (prepared in situ by treating (–)-a-pinene with chloroborane-methyl sulfide complex in hexane) and DIEA in THF, followed by deprotection of the obtained N-Fmoc protected compound with DBU in THF. Alternatively, resolution of racemic emixustat (XV) can be performed using D-mandelic acid .