Process for making HCV protease inhibitors

1. A process, comprising:

reacting

with

to form

wherein:

Z is O, S, SO, SO 2 , N(R N ), OC(O), C(O)O, N(R N )C(O), or C(O)N(R N ), wherein R N is H or optionally substituted C 1 -C 6 alkyl;

R 1 is optionally substituted C 3 -C 10 carbocycle or optionally substituted 5- to 10-membered heterocycle having at least one ring atom selected from nitrogen, oxygen, and sulfur;

R 2 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;

R 4 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;

X is H or halogen; and

each optionally substituted C 1 -C 6 alkyl; C 3 -C 10 carbocycle, 5- to 10-membered heterocycle having at least one ring atom selected from nitrogen, oxygen, and sulfur, C 2 -C 6 alkenyl; or C 2 -C 6 alkynyl is optionally substituted with one or more substituents, each independently selected from the group consisting of —F, —Cl, —Br, —I, hydroxy, protected hydroxy, —NO 2 , —N 3 , —CN, —NH 2 , protected amino, oxo, thioxo, —NH—C 1 -C 12 -alkyl, —NH—C 2 -C 8 -alkenyl, —NH—C 2 -C 8 -alkenyl, NH—C 3 -C 12 -cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, —O—C 1 -C 12 -alkyl, —O—C 2 -C 8 -alkenyl, —O—C 2 -C 8 -alkenyl, —O—C 3 -C 12 -cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —C(O)—C 1 -C 12 -alkyl, —C(O)—C 2 -C 8 -alkenyl, —C(O)—C 2 -C 8 -alkynyl, —C(O)—C 3 -C 12 -cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl, C(O)-heterocycloalkyl, —CONH 2 , —CONH—C 1 -C 12 -alkyl, —CONH—C 2 -C 8 -alkenyl, —CONH—C 2 -C 8 -alkenyl, —CONH—C 3 -C 12 -cycloalkyl, —CONH-aryl, CONH-heteroaryl, —CONH-heterocycloalkyl, —OCO 2 —C 1 -C 12 -alkyl, —OCO 2 —C 2 -C 8 -alkenyl, —OCO 2 —C 2 -C 8 -alkenyl, —OCO 2 —C 3 -C 12 -cycloalkyl, —OCO 2 -aryl, —OCO 2 -heteroaryl, —OCO 2 -heterocycloalkyl, —OCONH 2 , —OCONH—C 1 -C 12 -alkyl, —OCONH—C 2 -C 8 -alkenyl, —OCONH—C 2 -C 8 -alkynyl, —OCONH—C 3 -C 12 -cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl, —NHC(O)—C 1 -C 12 -alkyl, —NHC(O)—C 2 -C 8 -alkenyl, NHC(O)—C 2 -C 8 -alkenyl, —NHC(O)—C 3 -C 12 -cycloalkyl, —NHC(O)-aryl, NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHCO 2 —C 1 -C 12 -alkyl, NHCO 2 —C 2 -C 8 -alkenyl, —NHCO 2 —C 2 -C 8 -alkynynl, —NHCO 2 —C 3 -C 12 -cycloalkyl, —NHCO 2 -aryl, —NHCO 2 -heteroaryl, —NHCO 2 -heterocycloalkyl, NHC(O)NH 2 , —NHC(O)NH—C 1 -C 12 -alkyl, —NHC(O)NH—C 2 -C 8 -alkenyl, NHC(O)NH—C 2 -C 8 -alkenyl, —NHC(O)NH—C 3 -C 12 -cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH 2 , —NHC(S)NH—C 1 -C 12 -alkyl, —NHC(S)NH—C 2 -C 8 -alkenyl, —NHC(S)NH—C 2 -C 8 -alkynyl, —NHC(S)NH—C 3 -C 12 -cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH 2 , —NHC(NH)NH—C 1 -C 12 -alkyl, —NHC(NH)NH—C 2 -C 8 -alkenyl, —NHC(NH)NH—C 2 -C 8 -alkynyl, NHC(NH)NH—C 3 -C 12 -cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH— heteroaryl, —NHC(NH)NH-heterocycloalkyl, —NHC(NH)—C 1 -C 12 -alkyl, —NHC(NH)—C 2 -C 8 -alkenyl, —NHC(NH)—C 2 -C 8 -alkynyl, —NHC(NH)—C 3 -C 12 -cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl, —NHC(NH)— heterocycloalkyl, —C(NH)NH—C 1 -C 12 -alkyl, —C(NH)NH—C 2 -C 8 -alkenyl, C(NH)NH—C 2 -C 8 -alkynyl, —C(NH)NH—C 3 -C 12 -cycloalkyl, —C(NH)NH-aryl, C(NH)NH-heteroaryl, —C(NH)NH-heterocycloalkyl, —S(O)—C 1 -C 12 -alkyl, —S(O)—C 2 -C 8 -alkenyl, —S(O)—C 2 -C 8 -alkynyl, —S(O)—C 3 -C 12 -cycloalkyl, —S(O)-aryl, —S(O)-heteroaryl, —S(O)-heterocycloalkyl, —SO 2 NH 2 , —SO 2 NH—C 1 -C 12 -alkyl, —SO 2 NH—C 2 -C 8 -alkenyl, —SO 2 NH—C 2 -C 8 -alkynyl, —SO 2 NH—C 3 -C 12 -cycloalkyl, —SO 2 NH-aryl, —SO 2 NH-heteroaryl, —SO 2 NH-heterocycloalkyl, NHSO 2 —C 1 -C 12 -alkyl, —NHSO 2 —C 2 -C 8 -alkenyl, —NHSO 2 —C 2 -C 8 -alkynyl, —NHSO 2 —C 3 -C 12 -cycloalkyl, —NHSO 2 -aryl, —NHSO 2 -heteroaryl, —NHSO 2 -heterocycloalkyl, —CH 2 NH 2 , —CH 2 SO 2 CH 3 , -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C 3 -C 12 -cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH, —S—C 1 -C 12 -alkyl, —S—C 2 -C 8 -alkenyl, —S—C 2 -C 8 -alkynyl, —S—C 3 -C 12 -cycloalkyl, —S-aryl, -heteroaryl, —S-heterocycloalkyl, and methylthiomethyl.

2. A process comprising:

reacting

with

to form

wherein:

Z is O, S, SO, SO 2 , N(R N ), OC(O), C(O)O, N(R N )C(O), or C(O)N(R N ), wherein R N is H or optionally substituted C 1 -C 6 alkyl;

R 1 is optionally substituted C 3 -C 10 carbocycle or optionally substituted 5- to 10-membered heterocycle having at least one ring atom selected from nitrogen, oxygen, and sulfur;

R 2 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;

R 4 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;

X is H or halogen; and

each optionally substituted C 1 -C 6 alkyl; C 3 -C 10 carbocycle, 5- to 10-membered heterocycle having at least one ring atom selected from nitrogen, oxygen, and sulfur, C 2 -C 6 alkenyl; or C 2 -C 6 alkynyl is optionally substituted with one or more substituents, each independently selected from the group consisting of —F, —Cl, —Br, —I, hydroxy, protected hydroxy, —NO 2 , —N 3 , —CN, —NH 2 , protected amino, oxo, thioxo, —NH—C 1 -C 12 -alkyl, —NH—C 2 -C 8 -alkenyl, —NH—C 2 -C 8 -alkenyl, NH—C 3 -C 12 -cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, —O—C 1 -C 12 -alkyl, —O—C 2 -C 8 -alkenyl, —O—C 2 -C 8 -alkenyl, —O—C 3 -C 12 -cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —C(O)—C 1 -C 12 -alkyl, —C(O)—C 2 -C 8 -alkenyl, —C(O)—C 2 -C 8 -alkynyl, —C(O)—C 3 -C 12 -cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl, C(O)-heterocycloalkyl, —CONH 2 , —CONH—C 1 -C 12 -alkyl, —CONH—C 2 -C 8 -alkenyl, —CONH—C 2 -C 8 -alkenyl, —CONH—C 3 -C 12 -cycloalkyl, —CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl, —OCO 2 —C 1 -C 12 -alkyl, —OCO 2 —C 2 -C 8 -alkenyl, —OCO 2 —C 2 -C 8 -alkenyl, —OCO 2 —C 3 -C 12 -cycloalkyl, —OCO 2 -aryl, —OCO 2 -heteroaryl, —OCO 2 -heterocycloalkyl, —OCONH 2 , —OCONH—C 1 -C 12 -alkyl, —OCONH—C 2 -C 8 -alkenyl, —OCONH—C 2 -C 8 -alkynyl, —OCONH—C 3 -C 12 -cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl, —NHC(O)—C 1 -C 12 -alkyl, —NHC(O)—C 2 -C 8 -alkenyl, NHC(O)—C 2 -C 8 -alkenyl, —NHC(O)—C 3 -C 12 -cycloalkyl, —NHC(O)-aryl, NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHCO 2 —C 1 -C 12 -alkyl, NHCO 2 —C 2 -C 8 -alkenyl, —NHCO 2 —C 2 -C 8 -alkynynl, —NHCO 2 —C 3 -C 12 -cycloalkyl, —NHCO 2 -aryl, —NHCO 2 -heteroaryl, —NHCO 2 -heterocycloalkyl, NHC(O)NH 2 , —NHC(O)NH—C 1 -C 12 -alkyl, —NHC(O)NH—C 2 -C 8 -alkenyl, NHC(O)NH—C 2 -C 8 -alkenyl, —NHC(O)NH—C 3 -C 12 -cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH 2 , —NHC(S)NH—C 1 -C 12 -alkyl, —NHC(S)NH—C 2 -C 8 -alkenyl, —NHC(S)NH—C 2 -C 8 -alkynyl, —NHC(S)NH—C 3 -C 12 -cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH 2 , —NHC(NH)NH—C 1 -C 12 -alkyl, —NHC(NH)NH—C 2 -C 8 -alkenyl, —NHC(NH)NH—C 2 -C 8 -alkynyl, —NHC(NH)NH—C 3 -C 12 -cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl, —NHC(NH)—C 1 -C 12 -alkyl, —NHC(NH)—C 2 -C 8 -alkenyl, —NHC(NH)—C 2 -C 8 -alkynyl, —NHC(NH)—C 3 -C 12 -cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl, —NHC(NH)— heterocycloalkyl, —C(NH)NH—C 1 -C 12 -alkyl, —C(NH)NH—C 2 -C 8 -alkenyl, C(NH)NH—C 2 -C 8 -alkynyl, —C(NH)NH—C 3 -C 12 -cycloalkyl, —C(NH)NH-aryl, C(NH)NH-heteroaryl, —C(NH)NH-heterocycloalkyl, —S(O)—C 1 -C 12 -alkyl, —S(O)—C 2 -C 8 -alkenyl, —S(O)—C 2 -C 8 -alkynyl, —S(O)—C 3 -C 12 -cycloalkyl, —S(O)-aryl, —S(O)-heteroaryl, —S(O)-heterocycloalkyl, —SO 2 NH 2 , —SO 2 NH—C 1 -C 12 -alkyl, —SO 2 NH—C 2 -C 8 -alkenyl, —SO 2 NH—C 2 -C 8 -alkynyl, —SO 2 NH—C 3 -C 12 -cycloalkyl, —SO 2 NH-aryl, —SO 2 NH-heteroaryl, —SO 2 NH-heterocycloalkyl, NHSO 2 —C 1 -C 12 -alkyl, —NHSO 2 —C 2 -C 8 -alkenyl, —NHSO 2 —C 2 -C 8 -alkynyl, NHSO 2 —C 3 -C 12 -cycloalkyl, —NHSO 2 -aryl, —NHSO 2 -heteroaryl, —NHSO 2 -heterocycloalkyl, —CH 2 NH 2 , —CH 2 SO 2 CH 3 , -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C 3 -C 12 -cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH, —S—C 1 -C 12 -alkyl, —S—C 2 -C 8 -alkenyl, —S—C 2 -C 8 -alkynyl, —S—C 3 -C 12 -cycloalkyl, —S-aryl, -heteroaryl, —S-heterocycloalkyl, and methylthiomethyl.

3. The process of claim 2 , further comprising reacting

with R 3 —OH to form

wherein R 3 is optionally substituted C 1 -C 6 alkyl.

4. The process according to claim 3 , wherein:

Z is O;

R 1 is phenanthridine;

R 2 is tert-butyloxycarbonyl;

R 4 is vinyl;

X is H or Cl; and

R 3 is —CH 2 CH 3 .

5. A process comprising:

coupling

with

to form

wherein:

R 4 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, or optionally substituted C 2 -C 6 alkynyl;

X is H or halogen;

R 5 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; and

each optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl is optionally substituted with one or more substituents, each independently selected from the group consisting of —F, —Cl, —Br, —I, hydroxy, protected hydroxy, —NO 2 , —N 3 , —CN, —NH 2 , protected amino, oxo, thioxo, —NH—C 1 -C 12 -alkyl, —NH—C 2 -C 8 -alkenyl, —NH—C 2 -C 8 -alkynyl, —NH—C 3 -C 12 -cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, —O—C 1 -C 12 -alkyl, —O—C 2 -C 8 -alkenyl, —O—C 2 -C 8 -alkenyl, —O—C 3 -C 12 -cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —C(O)—C 1 -C 12 -alkyl, —C(O)—C 2 -C 8 -alkenyl, —C(O)—C 2 -C 8 -alkenyl, —C(O)—C 3 -C 12 -cycloalkyl, C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH 2 , —CONH—C 1 -C 12 -alkyl, —CONH—C 2 -C 8 -alkenyl, —CONH—C 2 -C 8 -alkenyl, —CONH—C 3 -C 12 -cycloalkyl, —CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl, —OCO 2 —C 1 -C 12 -alkyl, —OCO 2 —C 2 -C 8 -alkenyl, —OCO 2 —C 2 -C 8 -alkynyl, —OCO 2 —C 3 -C 12 -cycloalkyl, —OCO 2 -aryl, —OCO 2 -heteroaryl, —OCO 2 -heterocycloalkyl, —OCONH 2 , —OCONH—C 1 -C 12 -alkyl, —OCONH—C 2 -C 8 -alkenyl, —OCONH—C 2 -C 8 -alkenyl, —OCONH—C 3 -C 12 -cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl, —NHC(O)—C 1 -C 12 -alkyl, —NHC(O)—C 2 -C 8 -alkenyl, —NHC(O)—C 2 -C 8 -alkynyl, —NHC(O)—C 3 -C 12 -cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHCO 2 —C 1 -C 12 -alkyl, —NHCO 2 —C 2 -C 8 -alkenyl, —NHCO 2 —C 2 -C 8 -alkynynl, —NHCO 2 —C 3 -C 12 -cycloalkyl, —NHCO 2 -aryl, —NHCO 2 -heteroaryl, —NHCO 2 -heterocycloalkyl, —NHC(O)NH 2 , —NHC(O)NH—C 1 -C 12 -alkyl, —NHC(O)NH—C 2 -C 8 -alkenyl, —NHC(O)NH—C 2 -C 8 -alkynyl, —NHC(O)NH—C 3 -C 12 -cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH 2 , —NHC(S)NH—C 1 -C 12 -alkyl, —NHC(S)NH—C 2 -C 8 -alkenyl, —NHC(S)NH—C 2 -C 8 -alkynyl, —NHC(S)NH—C 3 -C 12 -cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH 2 , —NHC(NH)NH—C 1 -C 12 -alkyl, —NHC(NH)NH—C 2 -C 8 -alkenyl, —NHC(NH)NH—C 2 -C 8 -alkynyl, —NHC(NH)NH—C 3 -C 12 -cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl, —NHC(NH)—C 1 -C 12 -alkyl, —NHC(NH)—C 2 -C 8 -alkenyl, —NHC(NH)—C 2 -C 8 -alkynyl, —NHC(NH)—C 3 -C 12 -cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl, —NHC(NH)-heterocycloalkyl, —C(NH)NH—C 1 -C 12 -alkyl, —(NH)NH—C 2 -C 8 -alkenyl, —C(NH)NH—C 2 -C 8 -alkynyl, —C(NH)NH—C 3 -C 12 -cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl, —C(NH)NH-heterocycloalkyl, —S(O)—C 1 -C 12 -alkyl, —S(O)—C 2 -C 8 -alkenyl, —S(O)—C 2 -C 8 -alkynyl, —S(O)—C 3 -C 12 -cycloalkyl, —S(O)-aryl, —S(O)-heteroaryl, —S(O)-heterocycloalkyl, —SO 2 NH 2 , —SO 2 NH—C 1 -C 12 -alkyl, —SO 2 NH—C 2 -C 8 -alkenyl, —SO 2 NH—C 2 -C 8 -alkynyl, —SO 2 NH—C 3 -C 12 -cycloalkyl, —SO 2 NH-aryl, —SO 2 NH-heteroaryl, —SO 2 NH-heterocycloalkyl, —NHSO 2 —C 1 -C 12 -alkyl, —NHSO 2 —C 2 -C 8 -alkenyl, —NHSO 2 —C 2 -C 8 -alkynyl, —NHSO 2 —C 3 -C 12 -cycloalkyl, —NHSO 2 -aryl, —NHSO 2 -heteroaryl, —NHSO 2 -heterocycloalkyl, —CH 2 NH 2 , —CH 2 SO 2 CH 3 , -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C 3 -C 12 -cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH, —S—C 1 -C 12 -alkyl, —S—C 2 -C 8 -alkenyl, —S—C 2 -C 8 -alkynyl, —S—C 3 -C 12 -cycloalkyl, —S-aryl, -heteroaryl, —S-heterocycloalkyl, and methylthiomethyl.

6. The process according to claim 2 , wherein:

Z is O;

R 1 is phenanthridine;

R 2 is tert-butyloxycarbonyl;

R 4 is vinyl; and

X is H or Cl.