Sodium hydride → HCID 77231601, compound

HRID 1467462Notes

Reaction equation

HRID 1467462 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.[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>O1CCCC1>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=[CH:8][N:9]=1

Participants

5

Reactant 3

HCID 24758Sodium hydride2×HCID 139400Triisopropylsilyl chlorideHCID 53566827H-Pyrrolo(2,3-d)pyrimidine, 4-chloro-

Product 1

HCID 77231601HCID 77231601, compoundYield 99%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
2.5 °C

Procedure

To a 250 mL oven dried three-neck round bottom flask equipped with a stir bar, condenser, septa, nitrogen inlet and thermocouple was charged sodium hydride (NaH, 60 wt %, 1.56 g, 0.0391 mol, 1.2 equiv) and anhydrous tetrahydrofuran (THF, 26 mL, 0.320 mol). The mixture was chilled to 0-5° C. To a oven dried 100 mL round bottom flask was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 5.00 g, 0.0326 mol) and anhydrous tetrahydrofuran (42 mL, 0.520 mol), and the resulting slurry was then added portion wise via large bore canula over 15 minutes to the sodium hydride (NaH) suspension in THF. The reaction temperature rose to 6.8° C. after the addition of the substrate. The reaction mixture was stirred at 0-5° C. for 40 minutes before being charged neat triisopropylsilyl chloride (6.6 g, 7.24 mL, 0.0342 mol, 1.05 equiv) via syringe over 5 minutes. The cooling bath was removed and the reaction mixture was warmed to reflux for 4 hours. The reaction was monitored by TLC (80% hexane/ethyl acetate). When the reaction was deemed complete, the reaction mixture was cooled to room temperature and dilute with ethyl acetate (100 mL) and 20% aqueous brine (50 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic fractions were washed with 1M sodium bicarbonate (NaHCO3) aqueous solution (100 mL) and 20% aqueous brine (100 mL), dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 10% ethyl acetate/hexane gradient elution) to afford 4-chloro-7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidine (3d, 10.0 g, 10.10 g theoretical, 99%) as an amber oil. For 3d: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.61 (s, 1H), 7.67 (d, 1H, J=3.7 Hz), 6.76 (d, 1H, J=3.5 Hz), 1.86 (m, 3H), 1.02 (d, 18H, J=7.5 Hz); C15H24ClN3Si (MW, 309.91), LCMS (EI) m/e 310/312 (M++H).

Workup

  1. customTo a 250 mL oven dried three-neck round bottom flask
  2. customequipped with a stir bar, condenser
  3. customTo a oven dried 100 mL round bottom flask
  4. additionthe resulting slurry was then added portion wise
  5. customover 15 minutes
  6. customrose to 6.8° C.
  7. additionafter the addition of the substrate
  8. customThe cooling bath was removed
  9. temperaturethe reaction mixture was warmed
  10. temperatureto reflux for 4 hours
  11. temperaturethe reaction mixture was cooled to room temperature
  12. additiondilute with ethyl acetate (100 mL) and 20% aqueous brine (50 mL)
  13. customThe two layers were separated
  14. extractionthe aqueous layer was extracted with ethyl acetate (100 mL)
  15. washThe combined organic fractions were washed with 1M sodium bicarbonate (NaHCO3) aqueous solution (100 mL) and 20% aqueous brine (100 mL)
  16. dry with materialdried over magnesium sulfate (MgSO4)
  17. filtrationfiltered
  18. concentrationconcentrated under reduced pressure
  19. customThe residue was purified by flash chromatography (SiO2, 10% ethyl acetate/hexane gradient elution)

Sources & evidence

ORD record
ord-b869711fd2c148f39e118aa2919b3116
Source dataset
uspto-grants-2015_04
Patent number
US09000161B2

Reaction notes

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