Synthesis Of Ivacaftor For Treatment Of Cystic Fibrosis

Ivacaftor (VX-770, KALYDECOTM, N-(5-hydroxy-2,4-Di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide) was developed by Vertex Pharmaceuticals andCFFT (Cystic Fibrosis Foundation Therapeutics, Inc.) which is affiliated with TheCystic Fibrosis Foundation. On January31,2012, Ivacaftor was approved by FDA forthe treatment of cystic fibrosis caused by G551D mutation.The purpose of our research was to find a good synthetic method with low cost,simple operation, high yield and suitable for industrialized production of Ivacaftor. Inour research, we studied and determined the more suitable conditions of each reactionin detail, finally confirmed a more suitable synthetic method. The confirmed syntheticroutine was: Ivacaftor was synthesized from5-amino-2,4-di-tert-butylphenol byreaction with4-oxo-1,4-dihydroquinoline-3-carboxylic acid with an overall yield ofabout13%based on aniline. The former was obtained from2,4-di-tert-butylphenol byesterification, nitration, hydrolysis and reduction. The latter was afforded from anlineby reaction with diethyl-2-(ethoxymethylene)malonate, which is a Gould-JacobsReaction.Meanwhile, we got N-(2-hydroxy-3,5-Di-tert-butyl-phenyl)-4-oxo-1H-quin-oline-3-carboxamide which is an important impurity in Ivacaftor industrializedproduction. We used2,4-di-tert-butyl-6-nitrophenol as a starting material.2,4-di-tert-butyl-6-nitrophenol went through reduction and amidation to obtainN-(2-hydroxy-3,5-Di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide. At prese-nt there is no detail synthetic method of the impurity.In our research, the structure of Ivacaftor was determined by1H-NMR and13C-NMR.