Sodium hydride → 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-8-methyl-8-azabicyclo[3.2.1]octane

HRID 51510Notes

Reaction equation

HRID 51510 reaction equation
[H-].[Na+].[O:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:24]3[C:23]([NH2:25])=[N:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(O[CH:31]1[CH2:37][CH:36]2[N:38]([CH3:39])[CH:33]([CH2:34][CH2:35]2)[CH2:32]1)(C)(=O)=O>CN(C)C=O>[NH2:25][C:23]1[C:24]2[C:16]([C:13]3[CH:12]=[CH:11][C:10]([O:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:15][CH:14]=3)=[CH:17][N:18]([CH:31]3[CH2:32][CH:33]4[N:38]([CH3:39])[CH:36]([CH2:35][CH2:34]4)[CH2:37]3)[C:19]=2[N:20]=[CH:21][N:22]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 1419518-Azabicyclo(3.2.1)octan-3-ol, 8-methyl-, 3-methanesulfonateHCID 120422345-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

Product 1

HCID 227362203-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-8-methyl-8-azabicyclo[3.2.1]octane

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
75 °C

Procedure

Sodium hydride (168 mg, of a 60% dispersion in mineral oil) was added to a mixture of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (770 mg, in dimethylformamide (30 ml). 3-Mesyloxy-8-methyl-8-azabicyclo[3.2.1 ]octane (900 mg, prepared as described in J.A.C.S. 1958, 80, 4679) in dimethylformamide (10 ml) was added under nitrogen with stirring. The mixture was warmed at 75° C. for 5 hours (and left standing at ambient temperature for 7 days). The solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate to give a residue which was purified by flash column chromatography on silica using ethyl acetate/methanol (50:50) as the mobile phase to remove starting material and then a mixture of ethyl acetate/methanol/triethylamine (5:5:1) as the mobile phase to elute the product. Appropriate fractions were combined and evaporated to give a solid which was triturated with ether and filtered to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-8-methyl-8-azabicyclo[3.2.1]octane, m.p. 238-250° C.

Workup

  1. customThe solvent was removed under reduced pressure
  2. additionWater was added to the residue
  3. extractionthe mixture was extracted with ethyl acetate
  4. customto give a residue which
  5. customwas purified by flash column chromatography on silica
  6. customto remove
  7. additiona mixture of ethyl acetate/methanol/triethylamine (5:5:1) as the mobile phase
  8. washto elute the product
  9. customevaporated
  10. customto give a solid which
  11. customwas triturated with ether
  12. filtrationfiltered

Sources & evidence

ORD record
ord-7d7fdc2bfa5b49b29fe5091915eea031
Source dataset
uspto-grants-2004_03
Patent number
US06713474B2

Reaction notes

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