Hydrochloric Acid → HCID 86695098, compound

Participants

Reaction Steps

HCl (gas) was introduced into DCM (50 mL) at 0° C. for 30 min with stirring. Then a solution of tert-butyl N-(4-[[(3R)-3-[[(carbamoylmethyl)carbamoyl]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (140 mg, 0.27 mmol, 1.00 equiv) in 5 mL of DCM was added and the resulting solution was stirred overnight at room temperature. The solvent was removed under vacuum to provide 120 mg of N-(carbamoylmethyl)-2-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide hydrochloride as a yellow solid. The solid was dissolved in methanol (10 mL) and HCHO (37%, 0.5 mL) and acetic acid (0.5 mL) were added at room temperature. After stirring for 20 min at room temperature, NaBH3CN (100 mg) was added and the resulting mixture was stirred for 1 h at ambient temperature. After concentration in vacuo, the residue was purified by preparative HPLC under the following conditions (Waters): column: X-briage C18, 19*150 mm 5 um; mobile phase: CH3CN and water with 20 mM NH4HCO3 (10.0% CH3CN up to 50.0% in 10 min, up to 95% in 2 min, down to 10.0% in 2 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired N-(2-amino-2-oxoethyl)-2-((R)-4-(((1r,4R)-4-(dimethylamino)cyclohexyl)oxy)-6,7-dihydro-SH-cyclopenta[4,5]thieno[2,3-d]pyrimidin-5-yl)acetamide (154.3 mg, 71%) as a white solid. MS: m/z 432 [M+H]+, 454 [M+Na]+; 1H NMR (400 MHz, CD3OD): δ 8.47 (1H, s), 5.28-5.23 (1H, m), 3.89 (2H, s), 3.86-3.77 (1H, m), 3.15-2.99 (3H, m), 2.74-2.68 (1H, m), 2.44-2.34 (11H, m), 2.06-2.04 (2H, m), 1.73-1.58 (2H, m), 1.57-1.43 (2H, m).

Provenance & Evidence