A practical synthetic method for the synthesis of the chiral benzhydrol 8, which is the key intermediate of the squalene synthase inhibitor TAK-475 (1), has been developed. The method, via asymmetric hydrogenation of the benzophenone 7, employed Noyori's ruthenium precatalyst of the type [RuCl 2 (diphosphine)(diamine)]. We focused on tuning of the chiral diphosphine, and have discovered a novel ligand, DADMP-BINAP (18c), for the catalyst that has allowed reduction of the operating pressure in the asymmetric hydrogenation. The precatalyst containing 18c performed effectively at low hydrogen pressure (<1 MPa) with sufficient enantioselectivity, and the result enabled us to successfully obtain enantiomerically pure 8 on a multikilogram scale.

A manufacturing process suitable for large-scale production of the peptide-like amorphous compound N-((2R)-1-{(3R)-6-chloro- 3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2H)-yl}-3-(1Hindol-3-yl)-1-oxopropan-2-yl)-1-[(1-methyl-1H-indol-2-yl)carbonyl]piperidine-4-carboxamide (1) as a drug for treating diabetes has been developed. The first kilogram quantities of 1 were prepared Wia a single-chromatography process that employed recyclable cation-exchange resin chromatography for an amorphous intermediate (2R)-2-amino-1-[(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2H)-yl]-3-(1H-indol-3-yl)-propan-1-one (syn-3a). We have also developed a chromatography-free process that involves a combination purification of extraction of syn-3a with crystallization of syn-3a • 0.25H 3 PO 4 • 0.5H 2 O. The latter process afforded amorphous compound 1 with >98% purity by HPLC area analysis, the same quality as that provided by the former process.