Process for preparing an intermediate of the macrocyclic protease inhibitor TMC 435

摘要

The present invention relates to an improved process for preparing (2R,3aR,10Z,11aS,2aR,14aR)-cyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxylic acid, 2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4-10(1-methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5-methyl-4,14-dioxo-, ethyl ester. This compound is an intermediate in the overall synthesis route of the macrocyclic compound TMC 435. TMC 435 is an inhibitor of NS3/4A protease which plays an important role in the replication of the hepatitis C virus.

主权项

1. A process for preparing a compound comprising,wherein:
n is 0-8; Rx represents hydrogen; G represents —ORx1 or —N(H)SO2Rx2; Rx1 represents hydrogen or C1-6 alkyl; Rx2 represents C1-6 alkyl or C3-6 cycloalkyl; X represents N or CH; Y represents N or CH; when Y represents N, then Y1 represents hydrogen or C1-6 alkyl; when Y represents CH, then Y represents —C(O)—Rx3, —S(O)1-2—Rx3, —C(S)Rx3, —N(Rx3)—Rx4, —N(H)—C(O)—O—Rx3 or —N(H)—C(O)—Rx4; Rx3 and Rx4 independently represent C1-6 alkyl, C3-6 cycloalkyl, aryl or heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from halo and C1-6 alkyl); L represents —O— or —O—C(O)—; and Ry represents aryl, heteroaryl or cyclic non-aromatic group, all of which are optionally substituted by one or more substituents, wherein
a) the first compound is acylated (at Rx), with a halogenated acyl compound (R2—CO)2O or R2—COCl, wherein R2 is polyhaloC1-4alkyl, followed by a ring-closing metathesis reaction of the acylated reaction product with a suitable catalyst in a reaction-inert solvent to yield a compound; andb) the halogenated acyl group is removed from the compound obtained at (a).