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 chromatographed on SiO2 (Biotage 40S, load with eluant) and eluted with 2:1 hexane/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 white 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 dihydrochloride as a white 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. customThis material was chromatographed on SiO2 (Biotage 40S, load with eluant)
10. washeluted with 2:1 hexane/EtOAc
11. 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
12. temperaturecooled to 0° C
13. temperatureto warm to ambient temperature
14. stirringwhile stirring for 60 hours
15. concentrationThe reaction mixture was concentrated in vacuo
16. concentrationre-concentrated (3×)
17. dissolutionThe residue was dissolved in MeOH (3.7 mL)
18. additionadded dropwise to
19. stirringa rapidly stirring flask
20. additioncontaining ether (100 mL)
21. filtrationThe white solid was filtered under a blanket of nitrogen gas
22. washwashed with ether
23. customdried under nitrogen gas

ORD record

ord-ecb87f7354e64a1d8331b3562e7f5da6

Source dataset

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08003651B2