Hydrochloric Acid → (5R,7R)-7-fluoro-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride

Temperature

-20 °C

tert-Butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.843 g, 2.521 mmol) was dissolved in methylene chloride (40 mL) and cooled to −20° C. The solution was treated with DAST (0.9992 mL, 7.562 mmol) and stirred at −20° C. for 100 minutes. After 3 hours, the reaction was quenched with ice and then warmed to ambient temperature. The mixture was separated. The aqueous phase (pH of about 1) was extracted with methylene chloride (2×), and the combined organics were washed with 6% NaHCO3 (2×), dried over Na2SO4, and concentrated to a dark oil (0.91 g). This material was subjected to chromatography on SiO2 (Biotage 40S, load with eluant) and eluted with 2:1 Hexane/ethyl acetate (“EtOAc”). The desired tert-butyl 4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.6138 g, 72%) was recovered cleanly. tert-Butyl 4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.6138 g, 1.825 mmol) was dissolved in dioxane (5 mL) and cooled to 0° C. A solution of HCl in dioxane (11.40 mL, 45.61 mmol; 4M) was added dropwise, and then the reaction mixture was allowed to warm to ambient temperature while stirring for 60 hours. The reaction mixture was concentrated in vacuo, re-suspended in MeOH and re-concentrated (3×). The residue was dissolved in MeOH (3.7 mL) and added dropwise to a rapidly stirring flask containing ether (100 mL). The solid was filtered under a blanket of nitrogen gas, washed with ether and dried under nitrogen gas to give (5R,7R)-7-fluoro-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine di-hydrochloride as a solid (539 mg, 96%). LC/MS (APCI)+ m/z 237.2.

1. waitAfter 3 hours
2. customthe reaction was quenched with ice
3. temperaturewarmed to ambient temperature
4. customThe mixture was separated
5. extractionThe aqueous phase (pH of about 1) was extracted with methylene chloride (2×)
6. washthe combined organics were washed with 6% NaHCO3 (2×)
7. dry with materialdried over Na2SO4
8. concentrationconcentrated to a dark oil (0.91 g)
9. washeluted with 2:1 Hexane/ethyl acetate (“EtOAc”)
10. customThe desired tert-butyl 4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.6138 g, 72%) was recovered cleanly
11. temperaturecooled to 0° C
12. temperatureto warm to ambient temperature
13. stirringwhile stirring for 60 hours
14. concentrationThe reaction mixture was concentrated in vacuo
15. concentrationre-concentrated (3×)
16. dissolutionThe residue was dissolved in MeOH (3.7 mL)
17. additionadded dropwise to
18. stirringa rapidly stirring flask
19. additioncontaining ether (100 mL)
20. filtrationThe solid was filtered under a blanket of nitrogen gas
21. washwashed with ether
22. customdried under nitrogen gas

ORD record

ord-48a09038d8f54519a529aaf7e47cbda9

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09409886B2