合成路线1

The synthesis of suvorexant by the medicinal route starts with conjugate addition of monoprotected diamine (I) to methyl vinyl ketone (II) in Et2O, followed by in situ trapping with benzyl chloroformate in the presence of Et3N to yield the fully protected diaminoketone (III), from which the Boc-protecting group is cleaved by means of HCl in EtOAc to provide primary amine (IV). Intramolecular reductive cyclization of amino ketone (IV) in the presence of NaBH(OAc)3 and AcOH in CH2Cl2 affords benzyl 5-methyl-1,4-diazepane-1-carboxylate (V), which is then N-protected with di-tert-butyl dicarbonate in the presence of Et3N in CH2Cl2 to give the diprotected diazepine derivative (VI). Resolution of racemic diazepine (VI) by means of chiral HPLC provides the desired (R)-enantiomer (VII), which is then N-deprotected with HCl in EtOAc to afford benzyl 5(R)-methyl-1,4-diazepane-1-carboxylate (VIII). Coupling of cyclic amine (VIII) or its hydrochloride with 5-methyl-2-(1,2,3-triazol-2-yl)benzoic acid (IX) [prepared by condensation of 2-iodo-5-methylbenzoic acid (X) with 1,2,3-triazole (XI) in the presence of Cs2CO3, CuI and t-DAMCH in DMF at 120 °C] using EDC, HOAt and NMM in DMF produces the corresponding amide (XII). N-Deprotection of N-Cbz-amine (XII) by means of H2 over Pd(OH)2/C in EtOAc/MeOH or EtOAc generates the 7(R)-methyldiazepane derivative (XIII), which is finally condensed with 2,5-dichloro-1,3-benzoxazole (XIV) [prepared by the chlorination of 5-chloro-2-mercaptobenzoxazole (XV) with POCl3 and PCl5 in CH2Cl2] in the presence of Et3N in DMF at 75 °C .