Processes and intermediates for preparing a macrocyclic protease inhibitor of HCV

1. A process for preparing the lactone VII comprising

(a) reacting 4-oxo-1,2-cyclopentanedicarboxylic acid (V) with brucine or (1R,2S)-(−)-ephedrine, thus preparing the bis-brucine or bis-(1R,2S)-(−)-ephedrine salt of (V), and

(b) precipitating selectively the bis-brucine or bis-(1R,2S)-(−)-ephedrine salt of (1R,2R)-4-oxo-1,2-cyclopentanedicarboxylic acid II, while the bis-brucine or bis-(1R,2S)-(−)-ephedrine salt of [(1S,2S)-4-oxo-1,2-cyclopentanedicarboxylic acid stays in solution;

(c) liberating the acid II by removal of brucine or (1R,2S)-(−)-ephedrine from the precipitated salt obtained in step (b);

as outlined in the following reaction scheme:

(d) reducing 4-ketocyclopentanedicarboxylic acid II, or a salt thereof, to 4-hydroxy-1,2-cyclopentanedicarboxylic acid (VI), which is cyclized to the lactone (VII), in water, and conducting the cyclization of the intermediate VI to VII without isolation of VI or removing water, with or without adding an organic solvent, using a triazine derivative, as outlined in the following reaction scheme:

2. The process of claim 1 wherein an organic solvent is used in step (d) and the organic solvent is selected from the group consisting of acetone, methylethylketone (MEK), tetrahydrofuran (THF), MeTHF, CPME (cyclopentyl methyl ether), C 1-4 alkyl acetate, C 1-4 alkyl propionate, C 1-4 alkyl butyrate or toluene, and the triazine is 2,4,6-trichloro-1,3,5-triazine (TCT), chloro-dimethoxytriazine (CDMT), dichloromethoxytriazine (DCMT), and N-(3,5-dimethoxytriazinyl)-N-methylmorpholinium chloride (DMTMM).