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 388504Notes

Reaction equation

HRID 388504 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 266.4%

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 (2 g) was dissolved in a mixed solvent of water (4 ml) and ethanol (8 ml), palladium on carbon (100 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (ca. 1 atmospheric pressure) for 5 hours and 10 minutes. The reaction mixture was filtered, and the residue was washed with a mixed solvent of water (1 ml) and ethanol (2 ml). Ethanol (20 ml) was added to the filtrate, which was concentrated. Addition of ethanol (10 ml) to the residue and subsequent concentrate were repeated four times. The mixture was filtered with heating and ethyl acetate (40 ml) was added dropwise with stirring at the same time. After stirring at room temperature for 25 hours and 30 minutes, the crystals were filtered with washing with a mixed solvent of ethanol (2 ml) and ethyl acetate (2 ml) and dried to give the title compound (1.56 g) as a white solid.

Workup

  1. additionwas added
  2. custom10 minutes
  3. filtrationThe reaction mixture was filtered
  4. washthe residue was washed with a mixed solvent of water (1 ml) and ethanol (2 ml)
  5. additionEthanol (20 ml) was added to the filtrate, which
  6. concentrationwas concentrated
  7. additionAddition of ethanol (10 ml) to the residue
  8. concentrationsubsequent concentrate
  9. filtrationThe mixture was filtered
  10. temperaturewith heating
  11. additionethyl acetate (40 ml) was added dropwise
  12. stirringwith stirring at the same time
  13. stirringAfter stirring at room temperature for 25 hours and 30 minutes
  14. filtrationthe crystals were filtered
  15. washwith washing with a mixed solvent of ethanol (2 ml) and ethyl acetate (2 ml)
  16. customdried

Sources & evidence

ORD record
ord-f7a8a68ceb55485eb080b7c0619194e8
Source dataset
uspto-grants-2013_02
Patent number
US08377938B2

Reaction notes

Loading…