1-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester trihydrochloride → 1-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid trihydrochloride

HRID 388505Notes

Reaction equation

HRID 388505 reaction equation
[ClH:1].Cl.Cl.C([O:11][C:12]([C:14]1([C:17](=[O:49])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]([N:35]4[CH2:40][CH2:39][CH:38]([N:41]5[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]5)[CH2:37][CH2:36]4)=[O:34])[CH:27]=3)=[CH:21][C:20]=2[F:48])[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1>O.C(O)C.[Pd]>[ClH:1].[ClH:1].[ClH:1].[F:48][C:20]1[CH:21]=[C:22]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]([N:35]3[CH2:40][CH2:39][CH:38]([N:41]4[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]4)[CH2:37][CH2:36]3)=[O:34])[CH:27]=2)[CH:23]=[CH:24][C:19]=1[NH:18][C:17]([C:14]1([C:12]([OH:13])=[O:11])[CH2:16][CH2:15]1)=[O:49]

Participants

5

Reactant 1

HCID 247886931-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester trihydrochloride

Product 1

HCID 247886291-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid trihydrochlorideYield 291%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 702EthanolSolventHCID 962WaterSolvent

Procedure

1-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester trihydrochloride (5 g) was dissolved in a mixed solvent of water (10 ml) and ethanol (20 ml), and palladium on carbon (250 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (0.2 MPa) for 7 hours and 50 minutes. The reaction mixture was filtered, and the residue was washed with a mixed solvent of water (6 ml) and ethanol (10 ml). Ethanol (50 ml) was added to the filtrate, which was azeotropically distilled off and concentrated, and water (0.6 g) and ethanol (8.3 ml) were added. 2-Propanol (10 ml) was added to the solution, followed by stirring at room temperature for 5 minutes. 1-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid trihydrochloride (150 mg) was added, followed by stirring for 13 hours and 45 minutes. 2-Propanol (50 ml) was further added, and the mixture was stirred at room temperature for 24 hours and 35 minutes. The crystals were filtered and dried to give the title compound (4.26 g) as a white solid.

Workup

  1. additionwas added
  2. custom50 minutes
  3. filtrationThe reaction mixture was filtered
  4. washthe residue was washed with a mixed solvent of water (6 ml) and ethanol (10 ml)
  5. additionEthanol (50 ml) was added to the filtrate, which
  6. distillationwas azeotropically distilled off
  7. concentrationconcentrated
  8. additionwater (0.6 g) and ethanol (8.3 ml) were added
  9. addition2-Propanol (10 ml) was added to the solution
  10. stirringby stirring at room temperature for 5 minutes
  11. addition1-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid trihydrochloride (150 mg) was added
  12. stirringby stirring for 13 hours and 45 minutes
  13. addition2-Propanol (50 ml) was further added
  14. stirringthe mixture was stirred at room temperature for 24 hours and 35 minutes
  15. filtrationThe crystals were filtered
  16. customdried

Sources & evidence

ORD record
ord-a6bb9e3c06974f78b142ee4f4eee8077
Source dataset
uspto-grants-2013_02
Patent number
US08377938B2

Reaction notes

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