Hydrochloric Acid → 2-{4-[2-(2-Cyclopentyl-4-hydroxy-5-{[1-methyl-3-(6-methylpyridin-2-yl)-1H-1,2,4-triazol-5-yl]methyl}-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile

Participants

Reaction Conditions

Reaction Steps

A solution of 2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile (1.0 g, 2.70 mmol, from step 3 of example A(84) in hot (50° C.) isopropanol (7 mL) was treated with (CH3)2NHBH3 (175 mg, 2.97 mmol, 1.1 equiv), then with a solution of 1-methyl-3-(6-methylpyridin-2-yl)-1H-1,2,4-triazole-5-carbaldehyde hydrochloride hydrate (762 mg, 2.97 mmol, 1.1 equiv, from Step 4 below) in isopropanol (4 mL) containing triethylamine (301 mg, 2.97 mmol, 1.1 equiv). The reaction mixture was stirred heated at 47-50° C. for 18 h. The reaction mixture was treated with 1.1 equiv of 1 M aqueous HCl and concentrated in vacuo to afford an oily resin. This was diluted with water and extracted with dichloromethane containing 10% methanol (3×30 mL). The extract was dried over Na2SO4, filtered, and concentrated. The residue was triturated with hot ethyl acetate/methylene chloride, filtered, washed with cold ether, and dried, affording 584 mg (38%) of the title product. 1H NMR (400 MHz, DMSO-d6): δ 1.36-1.71 (m, 14 H), 2.05 (m, 2 H), 2.48 (m, 1 H), 2.46 (s, 3 H), 2.63 (m, 3 H), 2.78 (d, J=17.9 Hz, 1 H), 3.67 (d, J=15.7 Hz, 1 H), 3.74 (d, J=15.7 Hz, 1 H), 3.91 (s, 3 H), 6.99 (d, J=8.1 Hz, 1 H), 7.10-7.20 (m, 3 H), 7.57 (m, 2 H), 11.22 (s, 1 H). LC-MS (APCI) calcd for C32H36FN5O3: 557.28, found (M+H+): 558.40 m/z.

Provenance & Evidence