反应详情

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 addition was complete, the reaction mixture was warmed to room temperature and then heated to reflux while being stirred at reflux for 70 minutes, after which the reaction was complete by HPLC. The reaction mixture was cooled to room temperature, and the excess POCl3 was quenched in 4 portions. The reaction mixture was transferred to a separatory funnel and dripped into a beaker containing ice and saturated NaHCO3 solution cooled in an ice bath. Once the addition of each portion of the reaction mixture was complete, the quenched mixture is stirred for 30 minutes to ensure complete destruction of POCl3 prior to transferring it to a separatory funnel. The mixture was transferred to a separatory funnel and extracted with DCM (2 X). The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (1 kg silica gel slurried in 9:1 hex:ethyl acetate onto a 3 L fitted funnel, silica settled under vacuum, topped with sand). The crude was loaded with a DCM/hexane mixture, and compound was eluted using 1 L sidearm flasks with vacuum. High Rf byproducts eluted first, then (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (104.4 g, 61.09% yield) as a brown oil. Triethylamine (93.0 mL, 534 mmol) and tert-butyl piperazine-1-carboxylate (34.8 g, 187 mmol) were added to a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (30.0 g, 178 mmol) in n-BuOH (250 mL). The reaction mixture was heated to reflux under nitrogen and stirred overnight (17 hours). The reaction mixture was concentrated on a rotavap. The resulting oil was dissolved in DCM, washed with H2O, dried (Na2SO4), filtered, and concentrated. The resulting brown oil was purified on silica gel eluting first with 2:1 hexanes:ethyl acetate until product eluting cleanly, then gradient 1:1 to 1:5 DCM:ethyl acetate to give (R)-tertbutyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (42.0 g, 74.1% yield) as a beige powder. LC/MS (APCI+) m/z 319.1 [M+H]+.

1. additionAfter addition
2. temperatureheated
3. temperatureto reflux
4. temperatureat reflux for 70 minutes
5. temperatureThe reaction mixture was cooled to room temperature
6. customthe excess POCl3 was quenched in 4 portions
7. customThe reaction mixture was transferred to a separatory funnel
8. additioncontaining ice and saturated NaHCO3 solution
9. temperaturecooled in an ice bath
10. additionOnce the addition of each portion of the reaction mixture
11. stirringthe quenched mixture is stirred for 30 minutes
12. customdestruction of POCl3
13. customThe mixture was transferred to a separatory funnel
14. extractionextracted with DCM (2 X)
15. dry with materialThe combined extracts were dried (Na2SO4)
16. filtrationfiltered
17. concentrationconcentrated
18. customThe crude was purified on silica gel (1 kg silica gel
19. customethyl acetate onto a 3 L fitted funnel
20. washwas eluted
21. washHigh Rf byproducts eluted first