Stereoselective Bulk Synthesis of CCR2 Antagonist BMS-741672: Assembly of an All-<i>cis</i> (<i>S,R,R</i>)‑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-<i>cis</i> 1,2,4-triamino­cyclohexane (TACH) core, which was assembled through consecutive stereocontrolled heterogeneous hydrogenations: efficient Pt-catalyzed reduction of a β-enaminoester, directed by (<i>S</i>)-α-methyl­benzyl­amine as a low-cost chiral template, and reductive amination of a 3,4-<i>cis</i>-disubstituted cyclohexanone over sulfided Pt/C introduced a <i>tert-</i>amine, setting the third stereocenter in the all-<i>cis</i> cyclohexane core. The heterogeneous catalysts were recycled. Ester hydrolysis produced a γ-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 <i>tert-</i>amine, providing a stereoelectronically highly activated isocyanate. Detailed mechanistic and process knowledge was required to enable clean trapping with an alcohol (<i>t</i>-BuOH) while avoiding formation of side products, particularly an unusual carbamoyl phosphate. Deprotection, <i>N</i>-acetylation, and uncatalyzed S_NAr coupling with known 4-chloroquinazoline provided the final product. The resulting 12-step synthesis was used to prepare 50 kg of the target compound in an average yield of 82% per step