合成路线1

Daclatasvir can be prepared by two alternative methods:
Bromination of 4,4’-diacetylbiphenyl (I) with Br2 in CH2Cl2 generates 4,4’-bis(bromoacetyl)biphenyl (II), which is then condensed with NBoc-L-proline (III) in the presence of DIEA in acetonitrile to give the diester (IV). Subsequent cyclization of the keto ester (IV) with NH4OAc in toluene at 95-100 °C affords the bis(imidazole) precursor (V) . In an alternative method, coupling of N-Boc-L-proline (III) with 2-amino-4’-bromoacetophenone (VI) by means of HATU and DIEA in DMF provides the keto amide (VII), which undergoes cyclization to the imidazolyl-pyrrolidine (VIII) upon heating to 140 °C with NH4OAc in xylenes in a sealed tube. Treatment of the aryl bromide (VIII) with bis(pinacolato)diboron in the presence of Pd(PPh3)4 and KOAc in dioxane at 80 °C gives rise to the boronate ester (IX). Then, Suzuki coupling between bromide (VIII) and boronate (IX) using Pd(PPh3)4 and NaHCO3 in DME/H2O at 80 °C also affords the bis(imidazolyl)biphenyl precursor (V) . Deprotection of compound (V) with either TFA in CH2Cl2 or HCl in MeOH or i-PrOH/H2O at 50 °C provides the N-unsubstituted-bis(pyrrolidine) compound (X), which is then acylated with N-(methoxycarbonyl)-L-valine (XI) by means of EDC, HOBt·H2O and DIEA in acetonitrile, followed by treatment with HCl in EtOH .