Sodium Methoxide → 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide

HRID 1014433Notes

Reaction equation

HRID 1014433 reaction equation
[CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:37]=4[C:38]([NH2:40])=[O:39])[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].C[O-].[Na+]>C1COCC1>[CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:37]=4[C:38]([NH2:40])=[O:39])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]

Participants

4

Reactant 2

HCID 10942334Sodium MethoxideHCID 594417202-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide

Product 1

HCID 1784864742-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamideYield 42%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (6.7 g, 10 mmol), a solution of NaOMe (0.5M in MeOH, 200 mL, 100 mmol) and THF (400 mL) was stirred at rt overnight. The resulting mixture was filtered through a pad of silica gel, which was rinsed with a solution of NH3 (2N in MeOH). The filtrate was concentrated. The residue was dissolved in THF and purified by silica gel chromatography using 0-10% MeOH (containing 0.2% NH3)/THF. The crude product was dissolved in a mixture of THF and MeOH (200 mL) and washed with a 2N NaOH solution (200 mL) and a saturated NaCl solution (100 mL). The organic layer was dried (Na2SO4), concentrated and triturated using Et2O to obtain 2.18 g of 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide as a beige solid. The impure fractions from the column were combined and concentrated. The residue was dissolved in THF. MeOH (100 mL) was added, followed by NaOMe (2.6 g). After 2 h the resulting mixture was diluted with EtOAc (100 mL) and a 2N NaOH solution (200 mL). The organic layer was washed with a saturated NaCl solution (200 mL), dried (Na2SO4) and concentrated down to about 20 mL volume. The resulting slurry was filtered and the solids were washed with Et2O to obtain 0.95 g of 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide as a light brown solid (combined yield 3.13 g, 61%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.24 (s, 6 H), 3.11 (t, J=8.25 Hz, 2 H), 3.31 (s, 3 H), 3.76 (s, 2 H), 4.17 (t, J=8.25 Hz, 2 H), 6.21 (dd, J=3.48, 1.65 Hz, 1 H), 6.80-6.90 (m, 1 H), 6.90-7.01 (m, 2 H), 7.25-7.37 (m, 1 H), 7.59 (s, 1 H), 8.01 (s, 1 H), 8.09 (s, 1 H), 8.50 (d, J=8.43 Hz, 1 H), 8.60 (s, 1 H), 10.53 (s, 1 H), 11.28 (s, 1 H). ESIMS (M+H)=519.

Workup

  1. filtrationThe resulting mixture was filtered through a pad of silica gel, which
  2. washwas rinsed with a solution of NH3 (2N in MeOH)
  3. concentrationThe filtrate was concentrated
  4. dissolutionThe residue was dissolved in THF
  5. custompurified by silica gel chromatography
  6. dissolutionThe crude product was dissolved in a mixture of THF and MeOH (200 mL)
  7. washwashed with a 2N NaOH solution (200 mL)
  8. dry with materialThe organic layer was dried (Na2SO4)
  9. concentrationconcentrated
  10. customtriturated

Sources & evidence

ORD record
ord-b181202dc0724a668d0c3c0c10e768d8
Source dataset
uspto-grants-2011_07
Patent number
US07981903B2

Reaction notes

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