Methylamine → HCID 178486478, compound

HRID 1014475Notes

Reaction equation

HRID 1014475 reaction equation
[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:27]=[C:26]4[C:22]([CH2:23][CH2:24][NH:25]4)=[CH:21][C:20]=3[O:28][CH3:29])[NH:15][C:14]3=[N:30][CH:31]=[CH:32][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5].C1N=[CH:36][N:35]([C:38](N2C=NC=C2)=[O:39])[CH:34]=1.CN>C1COCC1.CCOC(C)=O>[NH2:6][C:4]([C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=1[NH:11][C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:27]=[C:26]3[C:22]([CH2:23][CH2:24][N:25]3[C:38]([N:35]([CH3:36])[CH3:34])=[O:39])=[CH:21][C:20]=2[O:28][CH3:29])[NH:15][C:14]2=[N:30][CH:31]=[CH:32][C:13]=12)=[O:5]

Participants

6

Reactant 3

HCID 6329Methylamine2×HCID 682631,1'-CarbonyldiimidazoleHCID 178486468HCID 178486468, compound

Product 1

HCID 178486478HCID 178486478, compoundYield 56.8%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of of 2-fluoro-6-[(2-{[5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (67 mg, 0.15 mmol) and CDI (30 mg, 0.18 mmol) in THF (4 mL) was stirred for 15 min, then treated with a solution of methylamine (2M in THF, 4 mL, 8 mmol) and was heated for 2 days in a sealed vessel at 80° C. More methylamine (2M in THF, 5 mL) was added and the reaction mixture was heated for 22 h. The resulting mixture was allowed to cool to rt, diluted with EtOAc (50 mL), washed with a saturated Na2CO3 solution (50 mL), water (50 mL) and a saturated NaCl solution (50 mL). The aqueous layers were back extracted with EtOAc (50 mL). The organic layers were combined and concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 6-[(4-{[2-(aminocarbonyl)-3-fluorophenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-2-yl)amino]-N,N-dimethyl-5-(methyloxy)-2,3-dihydro-1H -indole-1-carboxamide as a yellow solid (43 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.83 (s, 6H), 2.94 (t, J=8.06 Hz, 2H), 3.73-3.86 (m, 5H), 6.18-6.28 (m, 1H), 6.84-6.95 (m, 2H), 6.97 (s, 1H), 7.31-7.42 (m, 1H), 7.47 (s, 1H), 7.82 (s, 1H), 8.01 (s, 1H), 8.07 (s, 1H), 8.41 (d, J=8.24 Hz, 1H), 10.47 (s, 1H), 11.21 (s, 1H); ESIMS (M+H)+=505.15.

Workup

  1. temperaturethe reaction mixture was heated for 22 h
  2. temperatureto cool to rt
  3. washwashed with a saturated Na2CO3 solution (50 mL), water (50 mL)
  4. extractionThe aqueous layers were back extracted with EtOAc (50 mL)
  5. concentrationconcentrated onto Celite
  6. custompurified by silica gel chromatography

Sources & evidence

ORD record
ord-cf652a48767a4a6c84c455b3756e82a1
Source dataset
uspto-grants-2011_07
Patent number
US07981903B2

Reaction notes

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