Process of Producing Cycloalkylcarboxamido-indole Compounds

摘要

The present invention features processes for preparing compounds, such as (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound 1), useful for treating CFTR mediated diseases such as cystic fibrosis.

主权项

1. A method for preparing a compound of formula I: wherein, independently for each occurrence: ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; R1 is independently selected from —RJ, —ORJ, —N(RJ)2, —NO2, halogen, —CN, —C1-4haloalkyl, —C1-4haloalkoxy, —C(O)N(RJ)2, —NRJC(O)RJ, —SORJ, —SO2RJ, —SO2N(RJ)2, —NRJSO2RJ, —CORJ, —CO2RJ, —NRJSO2N(RJ)2, —COCORJ; RJ is hydrogen or C1-6 aliphatic; X is CN or CO2R; R is C1-6 aliphatic or aryl; and m is an integer from 0 to 3 inclusive; comprising the steps of
b) reacting a compound of formula IA in a first organic solvent wherein, independently for each occurrence:ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;R1 is independently selected from —RJ, —ORJ, —N(RJ)2, —NO2, halogen, —CN, —C1-4haloalkyl, —C1-4haloalkoxy, —C(O)N(RJ)2, —NRJC(O)RJ, —SORJ, —SO2RJ, —SO2N(RJ)2, —NRJSO2RJ, —CORJ, —CO2RJ, —NRJSO2N(RJ)2, —COCORJ;RJ is hydrogen or C1-6 aliphatic;m is an integer from 0 to 3 inclusive; andHal is a halide;with a compound of formula IB: wherein RJ is hydrogen or C1-6 aliphatic, to form a compound of formula IC: wherein, independently for each occurrence:ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;R1 is independently selected from —RJ, —ORJ, —N(RJ)2, —NO2, halogen, —CN, —C1-4haloalkyl, —C1-4haloalkoxy, —C(O)N(RJ)2, —NRJC(O)RJ, —SORJ, —SO2RJ, —SO2N(RJ)2, —NRJSO2RJ, —CORJ, —CO2RJ, —NRJSO2N(RJ)2, —COCORJ;RJ is hydrogen or C1-6 aliphatic;X is CN or CO2R;R is R is C1-6 aliphatic or aryl; andm is an integer from 0 to 3 inclusive; andb) removing the —CO2RJ group from compound IC in a second organic solvent to form a compound of formula I.