Process of producing cycloalkylcarboxamido-indole compounds

A method for preparing a compound of formula IV:

• wherein, independently for each occurrence:
• ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
• R1 and R2 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;
• 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;
• m is an integer from 0 to 3 inclusive;
• n is an integer from 1 to 4 inclusive;
• and
• o is an integer from 1 to 3 inclusive;
• 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;
• o 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, —NRJSO2 RJ, —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, —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 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:
• 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;
• e reacting the compound of formula III in a fourth organic solvent with a compound of formula II:
• wherein, independently for each occurrence:
• ring A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;
• Hal is a halide;
• 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;
• and
• n is an integer from 1 to 4 inclusive;
• to form the compound of formula IV.