Formic Acid → (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-1-methylpyrrolidin-2-yl)ethanone

Participants

Reaction Steps

(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone di-hydrochloride (0.213 g, 0.4027 mmol) was treated with 37% aqueous formaldehyde (0.1109 mL, 4.027 mmol), formic acid (0.1519 mL, 4.027 mmol) and water (400 uL). The mixture was heated to reflux for 6 hours. After cooling, the reaction was neutralized with saturated NaHCO3 and then extracted with methylene chloride. The aqueous was extracted with methylene chloride (2×). The combined organic portions were dried over Na2SO4 and concentrated in vacuo. The residue was subjected to chromatography on SiO2 and eluted with a stepped gradient from 2% MeOH/1% NH4OH/dichloromethane to 5% MeOH/1% NH4OH/dichloromethane. The free base was collected and concentrated in vacuo. The residue was concentrated from MeOH and then re-dissolved in MeOH. The solution was treated with HCl in dioxane (4M, 1 mL, 4 mmol). The solution was concentrated in vacuo, re-suspended in MeOH and re-concentrated three times. The solution was re-dissolved in MeOH (0.25 mL+0.125 mL wash) and added dropwise to a stirred flask containing Et2O (15 mL). The suspension was stirred for 30 minutes. The suspension was then filtered, washed with Et2O and dried under a blanket of nitrogen. (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-1-methylpyrrolidin-2-yl)ethanone dihydrochloride was recovered as a solid (0.117 g, 62%). MS (ESI+) [M+H] 470.1/472.1. 1H NMR (CD3OD, 400 MHz) δ 8.57 (s, 1H), 7.47-7.41 (dd, 4H), 5.31 (t, J=8.0 Hz, 1H), 4.54 (d, J=9.1 Hz, 1H), 4.25-4.16 (m, 2H), 4.11-4.05 (m, 1H), 3.93-3.62 (m, 6H), 3.51-3.42 (m, 1H), 3.26-3.17 (m, 1H), 2.95 (s, 3H), 2.34-2.26 (m, 1H), 2.23-2.06 (m, 3H), 2.05-1.92 (m, 1H), 1.85-1.73 (m, 1H), 1.21-1.16 (d, 3H).

Provenance & Evidence