Acetone → (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-isopropylpyrrolidin-2-yl)ethanone

Participants

Reaction Conditions

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 (0.074 g, 0.1399 mmol) was dissolved in 1,2-dichloroethane (0.50 mL) and treated with diisopropylethylamine (0.04874 mL, 0.2798 mmol), propan-2-one (0.03082 mL, 0.4197 mmol) and sodium triacetoxyborohydride (0.1483 g, 0.6996 mmol). The mixture was stirred at 40° C. for 18 hours. The reaction was quenched with 3N HCl and stirred for 30 minutes. The reaction was neutralized to a pH of about 8 to about 8.5 with slow addition of saturated NaHCO3. The reaction was diluted with methylene chloride and separated. The aqueous layer was washed with methylene chloride (2×), and the combined organics were dried over Na2SO4 and concentrated in vacuo. The material was subjected to chromatography on SiO2 eluting with 5% MeOH/1% NH4OH/methylene chloride. The recovered free base (51.2 mg) was dissolved in dioxane (1 mL) and treated with 4N HCl in dioxane (1.5 mL). After stirring for 5 minutes, the mixture was concentrated in vacuo. The mixture was re-dissolved and re-concentrated in vacuo three times from MeOH. The mixture was re-dissolved in MeOH (0.5 mL+0.25 mL wash) and added dropwise to stirred Et2O (30 mL). The resultant solid was stirred for 30 minutes. The solid 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-isopropylpyrrolidin-2-yl)ethanone dihydrochloride was recovered as a solid (0.026 g, 59%). MS (ESI+) [M+H] 498.2/500.1. 1H NMR (CD3OD, 400 MHz) δ 8.56 (s, 1H), 7.44 (dd, 4H), 5.29 (t, J=8.1 Hz, 1H), 4.56 (d, J=10.3, 1H), 4.44-4.35 (m, 1H), 4.29-4.06 (m, 3H), 3.87-3.75 (m, 3H), 3.72-3.62 (m, 1H), 3.60-3.35 (m, 5H), 2.31-2.25 (m, 1H), 2.23-2.08 (m, 2H), 2.07-1.95 (m, 1H), 1.90-1.78 (m, 1H), 1.78-1.68 (m, 1H), 1.39 (d, 3H), 1.32 (d, 3H), 1.18 (d, 3H).

Provenance & Evidence