Phosphorus oxychloride → 2-Butyl-4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine

HRID 1487248Notes

Reaction equation

HRID 1487248 reaction equation
P(Cl)(Cl)([Cl:3])=O.[CH2:6]([C:10]1[NH:11][C:12](=O)[C:13]2[NH:18][C:17]([CH3:19])=[CH:16][C:14]=2[N:15]=1)[CH2:7][CH2:8][CH3:9]>C(#N)C>[CH2:6]([C:10]1[N:11]=[C:12]([Cl:3])[C:13]2[NH:18][C:17]([CH3:19])=[CH:16][C:14]=2[N:15]=1)[CH2:7][CH2:8][CH3:9]

Participants

4

Reactant 2

HCID 24813Phosphorus oxychloride3×HCID 1369342832-Butyl-6-methyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one

Product 1

HCID 1184166922-Butyl-4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidineYield 37.9%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

Phosphorus oxychloride (42.8 mL, 70.4 g, 0.459 mol) was added dropwise to a solution of 2-butyl-6-methyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (37.5 g, 0.183 mol) in acetonitrile (750 mL) under an atmosphere of nitrogen. The reaction mixture was heated at reflux overnight. After cooling to room temperature an additional portion of phosphorus oxychloride (42.8 mL, 70.4 g, 0.459 mol) was added dropwise and heating continued for a further 3.5 hours. The reaction was cooled to room temperature again and a further portion of phosphorus oxychloride (42.8 mL, 70.4 g, 0.459 mol) was added dropwise and heating continued for 3 hours. The reaction mixture was allowed to stand at room temperature overnight then heated at reflux for 3.5 hours. The reaction mixture was cooled then concentrated. The residue was cooled in an ice-bath and ice-cold water (650 mL) was added carefully. The pH was adjusted to 8 using aqueous potassium hydroxide solution and then mixture stirred for 45 minutes. The mixture was partitioned between dichloromethane (1000 mL) and water (1000 mL). The aqueous layer and solid material was re-extracted with dichloromethane (2×500 mL). The combined organic layers were dried (Na2SO4) and filtered through a plug of neutral alumina. The filtrate was concentrated to a yellow oil, a seed crystal and hexane were added. The solid material was filtered, washed with hexane and dried to give the title compound as an off-white solid (15.5 g).

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureat reflux overnight
  3. additionwas added dropwise
  4. temperatureheating
  5. temperatureheating
  6. waitcontinued for 3 hours
  7. waitto stand at room temperature overnight
  8. temperaturethen heated
  9. temperatureat reflux for 3.5 hours
  10. temperatureThe reaction mixture was cooled
  11. concentrationthen concentrated
  12. temperatureThe residue was cooled in an ice-bath
  13. additionice-cold water (650 mL) was added carefully
  14. customThe mixture was partitioned between dichloromethane (1000 mL) and water (1000 mL)
  15. extractionThe aqueous layer and solid material was re-extracted with dichloromethane (2×500 mL)
  16. dry with materialThe combined organic layers were dried (Na2SO4)
  17. filtrationfiltered through a plug of neutral alumina
  18. concentrationThe filtrate was concentrated to a yellow oil
  19. additiona seed crystal and hexane were added
  20. filtrationThe solid material was filtered
  21. washwashed with hexane
  22. customdried

Sources & evidence

ORD record
ord-67a134b3c09d4e089aa1aec7f43428a9
Source dataset
uspto-grants-2016_08
Patent number
US09428512B2

Reaction notes

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