4-Fluoroaniline → Golvatinib

HRID 1712674Notes

Reaction equation

HRID 1712674 reaction equation
O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[F:20][C:21]1[CH:26]=[C:25]([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[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]4)[CH2:39][CH2:38]3)=[O:36])[CH:29]=2)[CH:24]=[CH:23][C:22]=1[NH:50][C:51]([C:53]1([C:56](O)=[O:57])[CH2:55][CH2:54]1)=[O:52].[F:59][C:60]1[CH:66]=[CH:65][C:63]([NH2:64])=[CH:62][CH:61]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1>[F:20][C:21]1[CH:26]=[C:25]([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:24]=[CH:23][C:22]=1[NH:50][C:51]([C:53]1([C:56]([NH:64][C:63]2[CH:65]=[CH:66][C:60]([F:59])=[CH:61][CH:62]=2)=[O:57])[CH2:54][CH2:55]1)=[O:52]

Participants

7

Reactant 4

HCID 97314-FluoroanilineHCID 516892Sodium BicarbonateHCID 231494114-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrateHCID 247886301-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid

Product 1

HCID 16118392Golvatinib

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

4-(4,6-Dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (164 mg) was added to a suspension of 1-[2-fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid (100 mg) in mixture of tetrahydrofuran (1 ml), N,N-dimethylformamide (0.2 ml) and 4-fluoroaniline (0.0526 ml), followed by stirring at room temperature for 2.5 hours. A 5% aqueous solution of sodium hydrogencarbonate was added to the reaction mixture to quench the reaction, and ethyl acetate was added and the layers were separated. The organic layer was washed with water and concentrated. The residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, ethyl acetate:methanol=95:5). The eluate was concentrated. Ethyl acetate (2 ml) was added to the resultant residue, followed by stirring at room temperature for 30 minutes. Heptane (2 ml) was added, and the mixture was stirred for 30 minutes. The crystals were collected by filtration and dried to give the title compound (74 mg) as white crystals.

Workup

  1. customto quench
  2. customthe reaction, and ethyl acetate
  3. additionwas added
  4. customthe layers were separated
  5. washThe organic layer was washed with water
  6. concentrationconcentrated
  7. customThe residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, ethyl acetate:methanol=95:5)
  8. concentrationThe eluate was concentrated
  9. additionEthyl acetate (2 ml) was added to the resultant residue
  10. stirringby stirring at room temperature for 30 minutes
  11. additionHeptane (2 ml) was added
  12. stirringthe mixture was stirred for 30 minutes
  13. filtrationThe crystals were collected by filtration
  14. customdried

Sources & evidence

ORD record
ord-2e83e027ca22421f8b30de5fcc78768d
Source dataset
uspto-grants-2010_09
Patent number
US07790885B2

Reaction notes

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