合成路线1

Methoxycarbonylation of 5-bromo-2,2-difluoro-1,3-benzodioxole (I) under CO atmosphere in the presence of Pd(PPh3)4 and Et3N in MeOH/acetonitrile at 75 °C produces the benzodioxole carboxylate (II), which is reduced to primary alcohol (III) using LiAlH4 in THF . Similarly, alcohol (III) can be obtained by reduction of 2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (IV) with Red-Al in toluene . Chlorination of alcohol (III) with SOCl2, optionally in the presence of DMAP, in CH2Cl2 or MTBE affords 5-(chloromethyl)-2,2-difluoro-1,3-benzodioxole (V), which upon cyanation with NaCN in DMSO produces nitrile (VI) . In an alternative procedure, coupling of bromo benzodioxole (I) with ethyl cyanoacetate (VII) by means of Pd(dba)2, t-Bu3P and Na3PO4 in toluene/H2O at 70 °C yields the 2-cyanoacetate derivative (VIII), which undergoes decarboethoxylation to compound (VI) by means of HCl in DMSO/H2O at 75 °C . Dialkylation of nitrile (VI) with 1-bromo-2-chloroethane (IX) in the presence of either NaOH and BnNEt3Cl or KOH and Oct4NBr at 70 °C yields 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonitrile (X). After hydrolysis of nitrile (X) with NaOH in boiling H2O or EtOH, the resulting carboxylic acid (XI) is chlorinated with SOCl2 in the presence of DMF toluene at 60 °C to provide the acid chloride (XII) . Condensation of the cyclopropanecarbonyl chloride (XII) with 6-amino-2-chloro-3-methylpyridine (XIII) in pyridine at 110 °C affords the N-pyridyl amide (XIV), which finally undergoes Suzuki coupling with pinacol 3-carboxyphenylboronate (XV) by means of Pd(dppf)Cl2 and K2CO3 in hot DMF/H2O to furnish lumacaftor .
Alternatively, condensation of acid chloride (XII) with the biaryl amine (XVI) in the presence of Et3N and DMAP in toluene generates the tert-butyl ester (XVII), which is finally hydrolized by treatment with HCl in acetonitrile/water , followed by dissolving the obtained amino acid hydrochloride salt in aqueous NaOH or H2O, or by direct hydrolysis of ester (XVII) with HCOOH at 60-80 °C .