Dichloromethane → 4-Methyl-7H-pyrrolo(2,3-d)pyrimidine

HRID 1396138Notes

Reaction equation

HRID 1396138 reaction equation
Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl[CH2:12]Cl.C[Mg]Br>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1

Participants

6

Reactant 3

HCID 6344DichloromethaneHCID 53566827H-Pyrrolo(2,3-d)pyrimidine, 4-chloro-HCID 178418573HCID 178418573, compound

Product 1

HCID 513419594-Methyl-7H-pyrrolo(2,3-d)pyrimidine

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Solvent

Conditions

Temperature
55 °C

Procedure

To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 5.03 g, 32.8 mmol) in 100 mL of toluene, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (0.627 g, 0.328 mmol) is added under an atmosphere of nitrogen. After stirring for 10 minutes, methylmagnesium bromide (62.9 mL, 3.00 M in ether, 189 mmol) is added slowly. The reaction is heated at 55° C. overnight, then cooled to −70 to −80° C. and quenched by adding ammonium chloride dropwise. Then 1N hydrochloric acid is added and the pH is adjusted to 7-8 with the addition of saturated sodium bicarbonate. This is extracted 3× with ethyl acetate. The combined organic layer is washed with saturated ammonium chloride and brine, then dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane, then methanol and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound as a tan solid (15). MS (ESI) [M+H+]+=134. This is reacted similarly to steps 2 and 3 of Scheme 4 to provide the desired compound 16.

Workup

  1. temperaturecooled to −70 to −80° C.
  2. customquenched
  3. additionby adding ammonium chloride dropwise
  4. additionThen 1N hydrochloric acid is added
  5. additionthe pH is adjusted to 7-8 with the addition of saturated sodium bicarbonate
  6. extractionThis is extracted 3× with ethyl acetate
  7. washThe combined organic layer is washed with saturated ammonium chloride and brine
  8. dry with materialdried with magnesium sulfate
  9. filtrationfiltered
  10. concentrationthe filtrate concentrated under vacuum
  11. customThe resulting material is purified by silica gel column chromatography
  12. washeluting with ethyl acetate and dichloromethane
  13. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-7f3a09ff430c428faf2e36cc40a7441d
Source dataset
uspto-grants-2014_12
Patent number
US08901118B2

Reaction notes

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