Stereoselective Bulk Synthesis of CCR2 Antagonist BMS-741672: Assembly of an All-cis (S,R,R)-1,2,4-Triaminocyclohexane (TACH) Core via Sequential Heterogeneous Asymmetric Hydrogenations

A concise bulk synthesis of stereochemically complex CCR2 antagonist BMS-741672 is reported. A distinct structural feature is the chiral all-cis 1,2,4-triaminocyclohexane (TACH) core, which was assembled through consecutive stereocontrolled heterogeneous hydrogenations: efficient Pt-catalyzed reduction of a beta-enaminoester, directed by (S)-alpha-methylbenzylamine as a low-cost chiral template, and reductive amination of a 3,4-cis-disubstituted cyclohexanone over sulfided Pt/C introduced a tent-amine, setting the third stereocenter in the all-cis cyclohexane core. The heterogeneous catalysts were recycled. Ester hydrolysis produced a gamma-amino acid, isolated as its Na salt. A challenging Curtius reaction to introduce the remaining C-N bond at C-2 was strongly influenced by the presence of the basic tert-amine, providing a stereoelectronically highly activated isocyanate. Detailed mechanistic and process knowledge was required to enable clean trapping with an alcohol (t-BuOH) while avoiding formation of side products, particularly an unusual carbamoyl phosphate. Deprotection, N-acetylation, and uncatalyzed SNAr coupling with known 4-chloroquinazoline provided the fmal product. The resulting 12-step synthesis was used to prepare 50 kg of the target compound in an average yield of 82% per step.