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

HRID 529062Notes

Reaction equation

HRID 529062 reaction equation
O=P(Cl)(Cl)[Cl:3].[CH3:6][C@H:7]1[C:15]2[C:14](O)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9][CH2:8]1.C([O-])(O)=O.[Na+]>ClCCCl>[Cl:3][C:14]1[C:15]2[C@H:7]([CH3:6])[CH2:8][CH2:9][C:10]=2[N:11]=[CH:12][N:13]=1

Participants

5

Reactant 3

HCID 24813Phosphorus oxychlorideHCID 516892Sodium BicarbonateHCID 178461168HCID 178461168, compound

Product 1

HCID 59670769(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidineYield 61.1%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

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 about room temperature, then heated to reflux and stirred for about 70 minutes. The reaction was complete as determined by HPLC. The reaction mixture was cooled to about room temperature, and the excess POCl3 was quenched in 4 portions as follows: Reaction mixture transferred to 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 completed, the quenched mixture was stirred about 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, silica settled under vacuum, topped with sand. The crude was loaded with a DCM/hexane mixture, and the compound was eluted using 1 L sidearm flasks under 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 an oil. NMR (CDCl3, 400 MHz) δ 8.81 (s, 1H), 3.47 (m, 1H), 3.20 (m, 1H), 3.05 (m, 1H), 2.41 (m, 1H), 1.86 (m, 3H), 1.47 (m, 3H).

Workup

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

Sources & evidence

ORD record
ord-440b976e2217428ca50f0f4e36a03ea6
Source dataset
uspto-grants-2016_05
Patent number
US09346805B2

Reaction notes

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