Phosphorus oxychloride → (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

Neat POCl3 (463.9 mL, 5067 mmol) was added slowly by addition funnel to a 0° C. solution of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (152.2 g, 1013 mmol) in DCE (1.2 L). After the addition was complete, the reaction mixture was warmed to room temperature. The reaction mixture was then heated to reflux and stirred for 70 minutes. The reaction was complete as determined by HPLC. The reaction mixture was cooled to room temperature, and the excess POCl3 was quenched in 4 portions as follows: The reaction mixture was transferred to a separatory funnel and dripped into a beaker containing ice and a saturated NaHCO3 solution cooled in an ice bath. Once the addition of each portion of the reaction mixture was completed, the quenched mixture was stirred 30 minutes to ensure complete destruction of POCl3 prior to transfer to separatory funnel. The mixture was transferred to the separatory funnel and extracted twice with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel as follows: silica gel (1 kg) was slurried in 9:1 hexane:ethyl acetate onto a 3 L fritted funnel, the silica settled under vacuum and topped with sand. The crude was loaded with a DCM/hexane mixture, and the compound was eluted using 1 L sidearm flasks under vacuum to give (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (104.4 g, 61.09% yield) as an oil.

1. additionAfter the addition
2. temperatureThe reaction mixture was then heated
3. temperatureto reflux
4. temperatureThe reaction mixture was cooled to room temperature
5. customthe excess POCl3 was quenched in 4 portions
6. customThe reaction mixture was transferred to a separatory funnel
7. additioncontaining ice
8. temperaturea saturated NaHCO3 solution cooled in an ice bath
9. additionOnce the addition of each portion of the reaction mixture
10. stirringthe quenched mixture was stirred 30 minutes
11. customdestruction of POCl3
12. customto transfer to separatory funnel
13. extractionextracted twice with DCM
14. dry with materialThe combined extracts were dried (Na2SO4)
15. filtrationfiltered
16. concentrationconcentrated
17. customThe crude was purified on silica gel
18. customethyl acetate onto a 3 L fritted funnel, the silica settled under vacuum
19. washthe compound was eluted

ORD record

ord-989044136505462b880594ceacb874cb

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09328091B2