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

HRID 409933Notes

Reaction equation

HRID 409933 reaction equation
[OH-:1].[Na+].[ClH:3].Cl.Cl.C([O:13][C:14]([C:16]1([C:19](=[O:51])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]([N:37]4[CH2:42][CH2:41][CH:40]([N:43]5[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]5)[CH2:39][CH2:38]4)=[O:36])[CH:29]=3)=[CH:23][C:22]=2[F:50])[CH2:18][CH2:17]1)=[O:15])C1C=CC=CC=1>O1CCCC1>[OH2:13].[OH2:1].[ClH:3].[ClH:3].[ClH:3].[F:50][C:22]1[CH:23]=[C:24]([O:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]([N:37]3[CH2:42][CH2:41][CH:40]([N:43]4[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]4)[CH2:39][CH2:38]3)=[O:36])[CH:29]=2)[CH:25]=[CH:26][C:21]=1[NH:20][C:19]([C:16]1([C:14]([OH:15])=[O:13])[CH2:18][CH2:17]1)=[O:51]

Participants

4

Reactant 2

HCID 14798Sodium HydroxideHCID 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 867078741-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid trihydrochloride dihydrate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A 5N sodium hydroxide aqueous solution (40 ml) was added at room temperature to a solution of 1-[2-fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester trihydrochloride (20 g) in tetrahydrofuran (200 ml) and stirred for 2 hours and 42 minutes. After completion of the reaction, the reaction mixture was allowed to stand and the layers were separated. The obtained organic layer was added dropwise over a period of 1 hour and 5 minutes at room temperature to a suspension solution of acetone (200 ml), water (20 ml), 35% hydrochloric acid (16 ml) and seed crystals (0.2 g) of 1-[2-fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid trihydrochloride dihydrate obtained by the method described in Example 8-2 in WO 2008/026577. The mixture was stirred for 2 hours and 28 minutes at room temperature, and after confirming the crystal precipitation, acetone (100 ml) was added and the mixture was further stirred for 1 hour and 25 minutes. The obtained solid was collected by filtration and dried to give 19.2 g of the title compound.

Workup

  1. customAfter completion of the reaction
  2. customthe layers were separated
  3. additionThe obtained organic layer was added dropwise over a period of 1 hour and 5 minutes at room temperature to a suspension solution of acetone (200 ml), water (20 ml), 35% hydrochloric acid (16 ml) and seed crystals (0.2 g) of 1-[2-fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid trihydrochloride dihydrate
  4. customobtained by the method
  5. stirringThe mixture was stirred for 2 hours and 28 minutes at room temperature
  6. customthe crystal precipitation, acetone (100 ml)
  7. additionwas added
  8. stirringthe mixture was further stirred for 1 hour and 25 minutes
  9. filtrationThe obtained solid was collected by filtration
  10. customdried

Sources & evidence

ORD record
ord-91f1b153079e48e294d7ec1b21b8343d
Source dataset
uspto-grants-2014_06
Patent number
US08759530B2

Reaction notes

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