Sodium hydride → 4-Chloro-7-[(phenylmethoxy)methyl]-7H-pyrrolo[2,3-d]pyrimidine

HRID 880557Notes

Reaction equation

HRID 880557 reaction equation
[H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.Cl[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:16]([O:15][CH2:14][N:10]1[C:6]2[N:7]=[CH:8][N:9]=[C:4]([Cl:3])[C:5]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1

Participants

5

Reactant 3

HCID 24758Sodium hydride2×HCID 137983Benzyl chloromethyl etherHCID 53566827H-Pyrrolo(2,3-d)pyrimidine, 4-chloro-

Product 1

HCID 594201884-Chloro-7-[(phenylmethoxy)methyl]-7H-pyrrolo[2,3-d]pyrimidineYield 70.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
2.5 °C

Procedure

To a oven dried 250 mL three-neck round bottom flask equipped with a stir bar, thermocouple, septa and nitrogen inlet was charged sodium hydride (NaH, 60 wt %, 1.56 g, 0.0391 mol, 1.2 equiv) and anhydrous tetrahydrofuran (THF, 25.0 mL, 0.308 mol) and the resulting mixture was chilled to 0-5° C. To a 100 ml oven dried round bottom flask was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 5.00 g, 0.0326 mol) and anhydrous tetrahydrofuran (50 mL, 0.616 mol), and the resulting slurry was added portion wise via large bore canula over 20 minutes to the sodium hydride (NaH) suspension in THF. The cooling bath was removed after the addition is complete and the reaction mixture was stirred at room temperature for 1 hour. The slurry becomes green in color after it is warmed to 16.5° C. The mixture was cooled to 0-5° C. before neat benzyl chloromethyl ether (5.28 mL, 0.0342 mol, 1.05 equiv) was charged over 13 minutes via syringe. The cold bath was removed and the reaction mixture was warmed to room temperature gradually and stirred at room temperature for 20 h. The reaction mixture was quenched with 20% aqueous brine (50 mL) and diluted with ethyl acetate (100 mL) when the reaction was deemed complete. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrate under reduced pressure. The residue was then purified by flash chromatography (SiO2, 10% to 15% ethyl acetate/hexane gradient elution) to afford 7-[(benzyloxy)methyl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3e, 6.31 g, 8.92 g theoretical, 70.7%) as a green oil. For 3e: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.69 (s, 1H), 7.90 (d, 1H, J=3.7 Hz), 7.26 (m 5H), 6.71 (d, 1H, J=3.7 Hz), 5.75 (s 2H), 4.51 (s, 2H); C14H12ClN3O (MW, 273.72), LCMS (EI) m/e 274/276 (M++H).

Workup

  1. customTo a oven dried 250 mL three-neck round bottom flask
  2. customequipped with a stir bar
  3. customTo a 100 ml oven dried round bottom flask
  4. additionthe resulting slurry was added portion wise
  5. customover 20 minutes
  6. customThe cooling bath was removed
  7. additionafter the addition
  8. temperatureis warmed to 16.5° C
  9. additionwas charged over 13 minutes via syringe
  10. customThe cold bath was removed
  11. temperaturethe reaction mixture was warmed to room temperature gradually
  12. stirringstirred at room temperature for 20 h
  13. customThe reaction mixture was quenched with 20% aqueous brine (50 mL)
  14. additiondiluted with ethyl acetate (100 mL) when the reaction
  15. customThe two layers were separated
  16. extractionthe aqueous layer was extracted with ethyl acetate (50 mL)
  17. dry with materialThe combined organic fractions were dried over magnesium sulfate
  18. filtrationfiltered
  19. concentrationconcentrate under reduced pressure
  20. customThe residue was then purified by flash chromatography (SiO2, 10% to 15% ethyl acetate/hexane gradient elution)

Sources & evidence

ORD record
ord-f92c3e94c94347edb90f297e38710f4e
Source dataset
uspto-grants-2015_03
Patent number
US08993582B2

Reaction notes

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