Hydrochloric Acid → 2,6-Difluoro-N-{3-[3-(2-{[4-(4-morpholinyl)phenyl]amino}-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}benzamide

HRID 1159888Notes

Reaction equation

HRID 1159888 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[N:34]1([C:40]2[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.Cl>CCO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:43]4[CH:42]=[CH:41][C:40]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:46][CH:45]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:33]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 75655Benzenamine, 4-(4-morpholinyl)-HCID 59513803N-{3-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide

Product 1

HCID 595137082,6-Difluoro-N-{3-[3-(2-{[4-(4-morpholinyl)phenyl]amino}-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}benzamideYield 43%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
80 °C

Procedure

To a slurry of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (100 mg, 0.216 mmol.) in 1 mL of EtOH, added 4-(4-morpholinyl)aniline (38 mg, 0.216 mmol.) and 5 μL of conc. HCl. The reaction contents were heated to 80° C. After heating for 18 h, the reaction was cooled to rt and partitioned between EtOAc and sat. aq. NaHCO3. The layers were separated, extracted the aqueous layer with EtOAc (2×10 mL), the organic layers were pooled, dried over MgSO4, filtered, reduced in vacuo onto silica. Purified via ISCO chromatography (hexanes:EtOAc) to afford the desired compound as a yellow solid, 56 mg, 43% yield. 1H NMR (400 MHz, CD3OD): δ 8.61 (d, J=7 Hz, 1H); 8.40 (d, J=9 Hz, 1H); 8.14 (d, J=5 Hz, 1H); 7.98 (bs, 1H); 7.86 (d, J=7H, 1H); 7.56-7.48 (m, 3H); 7.48-7.37 (m, 3H); 7.12-7.05 (m, 3H); 6.92 (d, J=9 Hz, 2H) 6.58 (d, J=5 Hz, 1H); 3.85-3.83 (m, 4H); 3.11-3.09 (m 4H). HRMS calculated C34H28F2N7O2 [M+H]+ 604.2273, found 604.2271.

Workup

  1. customThe reaction contents
  2. temperatureAfter heating for 18 h
  3. temperaturethe reaction was cooled to rt
  4. custompartitioned between EtOAc and sat. aq. NaHCO3
  5. customThe layers were separated
  6. extractionextracted the aqueous layer with EtOAc (2×10 mL)
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. customPurified via ISCO chromatography (hexanes:EtOAc)

Sources & evidence

ORD record
ord-eeeeff0750104a90a51f457efa23792d
Source dataset
uspto-grants-2010_10
Patent number
US07812022B2

Reaction notes

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