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Process for the Preparation of Lumacaftor

IP.com Disclosure Number: IPCOM000249793D
Publication Date: 2017-Apr-05
Document File: 2 page(s) / 81K

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Process for the Preparation of Lumacaftor

Lumacaftor, 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid  having the following structure (Formula I), is useful for treating or lessening the severity of a variety of cystic fibrosis transmembrane conductance regulator (CFTR) mediated diseases.

The present disclosure relates to the process for the preparation of 3-(6-( 1 -(2,2-difluorobenzo[d] [ 1 ,3]dioxol-5-yl)cyclopropanecarboxamido)-3- methylpyridin-2-yl)benzoic acid as shown below.

Preparation of Lumacaftor

a) Preparation of    3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropane carboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate

A mixture of 100 g 1-(2-2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid amide, 2.78 g palladium acetate, 14.38 g Xantphos, and 68.75 g Potassium carbonate in 500 ml of toluene were stirred.  To the reaction mixture, tert-butyl 3-(6-chloro-3-methylpyridin-2-yl)benzoate solution in toluene (180 g) was added at room temperature.  The reaction mixture was heated to reflux for 60-75 min.  After completion of the reaction, the reaction mass was cooled to room temperature.  Reaction mixture was filtered. Filtrate was washed with water and concentrated under vacuum. Acetonitrile was added and heated to reflux. Cooled the reaction mass to room temperature and filter the product to get 3-(6-(1-(2,2-      difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane carboxamido) -3-methy...