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

Temperature

40 °C

(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% NR4OH/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).

1. customThe reaction was quenched with 3N HCl
2. stirringstirred for 30 minutes
3. additionThe reaction was neutralized to a pH of about 8 to about 8.5 with slow addition of saturated NaHCO3
4. additionThe reaction was diluted with methylene chloride
5. customseparated
6. washThe aqueous layer was washed with methylene chloride (2×)
7. dry with materialthe combined organics were dried over Na2SO4
8. concentrationconcentrated in vacuo
9. dissolutionThe recovered free base (51.2 mg) was dissolved in dioxane (1 mL)
10. additiontreated with 4N HCl in dioxane (1.5 mL)
11. stirringAfter stirring for 5 minutes
12. concentrationthe mixture was concentrated in vacuo
13. dissolutionThe mixture was re-dissolved
14. concentrationre-concentrated in vacuo three times from MeOH
15. dissolutionThe mixture was re-dissolved in MeOH (0.5 mL+0.25 mL wash)
16. additionadded dropwise
17. stirringto stirred Et2O (30 mL)
18. stirringThe resultant solid was stirred for 30 minutes
19. filtrationThe solid was then filtered
20. washwashed with Et2O
21. customdried under a blanket of nitrogen
22. custom(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%)

ORD record

ord-51eae096c8bc4aeeb9d9314fafabb5df

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08618097B2