Process for making HCV protease inhibitors

摘要

Efficient processes for making HCV protease inhibitors are described. In one embodiment, the process uses novel idazolide derivatives of vinyl-ACCA. In another embodiment, the process comprises reacting;
with
;
to form
;
In still another embodiment, the process comprises coupling
;
with
;
to form
;

主权项

1. A process, comprising:
reactingwithto form wherein: Z is O, S, SO, SO2, N(RN), OC(O), C(O)O, N(RN)C(O), or C(O)N(RN), wherein RN is H or optionally substituted C1-C6alkyl; R1 is optionally substituted C3-C10carbocycle or optionally substituted 5- to 10-membered heterocycle having at least one ring atom selected from nitrogen, oxygen, and sulfur; R2 is H or an amino protecting group selected from the group consisting of carboxybenzyl group, p-methoxybenzyl carbonyl group, tert-butyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, acetyl group, benzoyl group, benzyl group, carbamate group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, p-methoxyphenyl group, tosyl group, and sulfonamide group; R4 is optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, or optionally substituted C2-C6alkynyl; X is H or halogen; and each optionally substituted C1-C6alkyl; C3-C10carbocycle, 5- to 10-membered heterocycle having at least one ring atom selected from nitrogen, oxygen, and sulfur, C2-C6alkenyl; or C2-C6alkynyl is optionally substituted with one or more substituents, each independently selected from the group consisting of —F, —Cl, —Br, —I, hydroxy, protected hydroxy, —NO2, —N3, —CN, —NH2, protected amino, oxo, thioxo, —NH—C1-C12-alkyl, —NH—C2-C8-alkenyl, —NH—C2-C8-alkenyl, NH—C3-C12-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, —O—C1-C12-alkyl, —O—C2-C8-alkenyl, —O—C2-C8-alkenyl, —O—C3-C12-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —C(O)—C1-C12-alkyl, —C(O)—C2-C8-alkenyl, —C(O)—C2-C8-alkynyl, —C(O)—C3-C12-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl, C(O)-heterocycloalkyl, —CONH2, —CONH—C1-C12-alkyl, —CONH—C2-C8-alkenyl, —CONH—C2-C8-alkenyl, —CONH—C3-C12-cycloalkyl, —CONH-aryl, CONH-heteroaryl, —CONH-heterocycloalkyl, —OCO2—C1-C12-alkyl, —OCO2—C2-C8-alkenyl, —OCO2—C2-C8-alkenyl, —OCO2—C3-C12-cycloalkyl, —OCO2-aryl, —OCO2-heteroaryl, —OCO2-heterocycloalkyl, —OCONH2, —OCONH—C1-C12-alkyl, —OCONH—C2-C8-alkenyl, —OCONH—C2-C8-alkynyl, —OCONH—C3-C12-cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl, —NHC(O)—C1-C12-alkyl, —NHC(O)—C2-C8-alkenyl, NHC(O)—C2-C8-alkenyl, —NHC(O)—C3-C12-cycloalkyl, —NHC(O)-aryl, NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHCO2—C1-C12-alkyl, NHCO2—C2-C8-alkenyl, —NHCO2—C2-C8-alkynynl, —NHCO2—C3-C12-cycloalkyl, —NHCO2-aryl, —NHCO2-heteroaryl, —NHCO2-heterocycloalkyl, NHC(O)NH2, —NHC(O)NH—C1-C12-alkyl, —NHC(O)NH—C2-C8-alkenyl, NHC(O)NH—C2-C8-alkenyl, —NHC(O)NH—C3-C12-cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH2, —NHC(S)NH—C1-C12-alkyl, —NHC(S)NH—C2-C8-alkenyl, —NHC(S)NH—C2-C8-alkynyl, —NHC(S)NH—C3-C12-cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH2, —NHC(NH)NH—C1-C12-alkyl, —NHC(NH)NH—C2-C8-alkenyl, —NHC(NH)NH—C2-C8-alkynyl, NHC(NH)NH—C3-C12-cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH— heteroaryl, —NHC(NH)NH-heterocycloalkyl, —NHC(NH)—C1-C12-alkyl, —NHC(NH)—C2-C8-alkenyl, —NHC(NH)—C2-C8-alkynyl, —NHC(NH)—C3-C12-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl, —NHC(NH)— heterocycloalkyl, —C(NH)NH—C1-C12-alkyl, —C(NH)NH—C2-C8-alkenyl, C(NH)NH—C2-C8-alkynyl, —C(NH)NH—C3-C12-cycloalkyl, —C(NH)NH-aryl, C(NH)NH-heteroaryl, —C(NH)NH-heterocycloalkyl, —S(O)—C1-C12-alkyl, —S(O)—C2-C8-alkenyl, —S(O)—C2-C8-alkynyl, —S(O)—C3-C12-cycloalkyl, —S(O)-aryl, —S(O)-heteroaryl, —S(O)-heterocycloalkyl, —SO2NH2, —SO2NH—C1-C12-alkyl, —SO2NH—C2-C8-alkenyl, —SO2NH—C2-C8-alkynyl, —SO2NH—C3-C12-cycloalkyl, —SO2NH-aryl, —SO2NH-heteroaryl, —SO2NH-heterocycloalkyl, NHSO2—C1-C12-alkyl, —NHSO2—C2-C8-alkenyl, —NHSO2—C2-C8-alkynyl, —NHSO2—C3-C12-cycloalkyl, —NHSO2-aryl, —NHSO2-heteroaryl, —NHSO2-heterocycloalkyl, —CH2NH2, —CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C3-C12-cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH, —S—C1-C12-alkyl, —S—C2-C8-alkenyl, —S—C2-C8-alkynyl, —S—C3-C12-cycloalkyl, —S-aryl, -heteroaryl, —S-heterocycloalkyl, and methylthiomethyl.