Process for preparing modulators of cystic fibrosis transmembrane conductance regulator

摘要

Disclosed herein is a process for producing the hydrochloride salt of Compound 1 having solid Form A-HCl comprising: (a) reacting Compound 2 with the hydrochloride salt of Formula 3 (3-HCl) in the presence of a coupling agent, a base, and a polar aprotic solvent; wherein the coupling agent is selected from the group consisting of 2-chloro-1,3-dimethyl-2-imidazolium tetrafluoroborate, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-chloro-4,6-dimethoxy-1,3,5-triazine, 1-H-benzotriazolium-1-[bis(dimethyl amino)methylene]-5-chlorohexafluorophosphate (HCTU), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (RA TU), 1-hydroxybenzotriazole (HOBT)/ 1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (EDCl), and propane phosphonic anhydride; wherein the base is selected from the group consisting of K2CO3, Et3N, N-methylmorpholine (NMM), pyridine, and diisopropylethyl amine (DIEA); and wherein the polar aprotic solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, tetrahydrofuran, methylethyl ketone, N-Methyl-2-pyrrolidone, acetonitrile, N,N-dimethyl formamide, and 2- methyltetrahydrofuran; and (b) treating a mixture comprising the product of step (a) with HCl; wherein step (a) is performed at a reaction temperature that is maintained between 15°C and 70°C.