Water → N-{4-[(6-{[(4-Azetidin-1-ylpiperidin-1-yl)carbonyl]amino}pyrimidin-4-yl)oxy]-3-fluorophenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 2265657Notes

Reaction equation

HRID 2265657 reaction equation
C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4([C:29](=[O:38])[NH:30][C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:28][CH2:27]4)=[O:25])=[CH:19][C:18]=3[F:39])[N:13]=[CH:12][N:11]=2)C=CC=CC=1.Cl.Cl.[N:43]1([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:46][CH2:45][CH2:44]1.C(N(CC)CC)C.O>CN(C)C=O>[N:43]1([CH:47]2[CH2:52][CH2:51][N:50]([C:8]([NH:9][C:10]3[N:11]=[CH:12][N:13]=[C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]5([C:29]([NH:30][C:31]6[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=6)=[O:38])[CH2:27][CH2:28]5)=[O:25])=[CH:19][C:18]=4[F:39])[CH:15]=3)=[O:7])[CH2:49][CH2:48]2)[CH2:46][CH2:45][CH2:44]1

Participants

6

Reactant 4

HCID 962WaterHCID 8471TriethylamineHCID 231531084-(Azetidin-1-yl)piperidine dihydrochlorideHCID 59596966HCID 59596966, compound

Product 1

HCID 59596994N-{4-[(6-{[(4-Azetidin-1-ylpiperidin-1-yl)carbonyl]amino}pyrimidin-4-yl)oxy]-3-fluorophenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 68.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

[6-(2-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyrimidin-4-yl]carbamic acid phenyl ester (35.5 mg) was dissolved in N,N-dimethylformamide (1.0 ml), and 4-(azetidin-1-yl)piperidine dihydrochloride (21 mg), triethylamine (0.0198 ml) and water (0.10 ml) were added thereto in this order, followed by stirring for 21 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of ammonium chloride (20 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (2 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (26.5 mg, 68.8%).

Workup

  1. customThe reaction mixture was partitioned between ethyl acetate (50 ml)
  2. washThe organic layer was washed with a saturated aqueous solution of ammonium chloride (20 ml), water (20 ml) and brine (20 ml) in this order
  3. dry with materialdried over anhydrous sodium sulfate
  4. customThe solvent was removed under reduced pressure
  5. customthe resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent
  6. additionFractions containing the target compound
  7. concentrationwere concentrated under reduced pressure
  8. filtrationThe solid was collected by filtration
  9. customdried under aeration

Sources & evidence

ORD record
ord-9bda60e3141341b4a1cdcfc2143f628b
Source dataset
uspto-grants-2010_12
Patent number
US07855290B2

Reaction notes

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