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US 10,071,979 B2Granted
Process of producing cycloalkylcarboxamido-indole compounds
AssigneeVertex Pharmaceuticals Incorporated
InventorsGerald J. Tanoury, Cristian Harrison, Benjamin Joseph Littler, Peter Jamison Rose, Robert Michael Hughes, Young Chun Jung, David Andrew Siesel, Elaine Chungmin Lee, Daniel T. Belmont, William A. Nugent
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Abstract
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.
Claims28
A method of preparing a compound of formula III:
- wherein, independently for each occurrence:
- R2 is —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;
- R3 is C1-6 aliphatic optionally substituted with OH, OP, —O—C1-6 aliphatic, aryl, heteroaryl, —O-aryl, or —O-heteroaryl;
- P is a protecting group;
- and
- o is an integer from 0 to 3;
- comprising the steps of:
- a) reacting a compound of formula IIIA:
- wherein, independently for each occurrence:
- R2 is —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;
- and
- o is an integer from 0 to 3;
- with a halogenating reagent in a first organic solvent to form a compound of formula IIIB:
- wherein, independently for each occurrence:
- R2 is —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;
- is an integer from 0 to 3;
- and
- Hal is a halide;
- b) reacting the compound of formula IIIB in a second organic solvent with a compound of formula IIIC:
- wherein:
- P is a protecting group;
- followed by reduction and treatment with acid to form a compound of formula IIID:
- wherein:
- R2 is —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;
- o is an integer from 0 to 3;
- Hal is a halide;
- P is a protecting group;
- and
- A⊖ is an anion;
- c) neutralizing a compound of formula IIID in the presence of a base to form a compound of formula IIID-a:
- wherein:
- R2 is —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;
- o is an integer from 0 to 3;
- Hal is a halide;
- and
- P is a protecting group;
- d) reacting a compound of formula IIID-a in a third organic solvent with a compound of formula IIIE:
- wherein, independently for each occurrence:
- R3 is a C1-6 aliphatic optionally substituted with OH, OP, —O—C1-6 aliphatic, aryl, heteroaryl, —O-aryl, or —O-heteroaryl;
- in the presence of a catalyst to form a compound of formula III.
47 more elements
A compound of formula III:
- or a salt thereof,
- wherein, independently for each occurrence:
- R2 is —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, or —COCORJ;
- RJ is hydrogen or C1-6 aliphatic;
- R3 is C1-6 aliphatic optionally substituted with OH, OP, —O—C1-6 aliphatic, aryl, heteroaryl, —O-aryl, or —O-heteroaryl;
- P is a protecting group;
- and
- o is an integer from 0 to 3.
6 more elements
Dependencies are inferred from the claim text.