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Diethyl Ether → 4-(1-Methylazetidin-3-yl)piperazine-1-carboxylic acid [4-(4-{3-[2-(4-fluorophenyl)acetyl]ureido}phenoxy)pyridin-2-yl]amide

HRID 492969
Notes
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Reaction equation

HRID 492969 reaction equation
[NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][N:24]([CH3:26])[CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([N:39]=[C:40]=[O:41])=[O:38])=[CH:32][CH:31]=1.C(OCC)C>O1CCCC1.C(OCC)(=O)C>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([NH:39][C:40](=[O:41])[NH:1][C:2]2[CH:28]=[CH:27][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:21][CH2:20][N:19]([CH:22]5[CH2:23][N:24]([CH3:26])[CH2:25]5)[CH2:18][CH2:17]4)=[O:15])[CH:8]=3)=[CH:4][CH:3]=2)=[O:38])=[CH:34][CH:35]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 3283Diethyl EtherHCID 231530882-(4-Fluorophenyl)acetyl isocyanateHCID 576774204-(1-Methylazetidin-3-yl)piperazine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide

Product 1

HCID 576774014-(1-Methylazetidin-3-yl)piperazine-1-carboxylic acid [4-(4-{3-[2-(4-fluorophenyl)acetyl]ureido}phenoxy)pyridin-2-yl]amideYield 48%

Reagents, catalysts & solvents 2

HCID 8028
Tetrahydrofuran
Solvent
HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 4-(1-methylazetidin-3-yl)piperazine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (100 mg) in tetrahydrofuran (5.0 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in ethyl acetate (0.25 M, 2.61 ml) at room temperature, followed by stirring at room temperature for 4.5 hrs. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=100:7). Fractions containing a target compound were concentrated to give a residue, to which diethyl ether was added to give a precipitate. The precipitate was suspended in the solvent. Then the precipitate was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (70.4 mg, 48.0%) as pale yellow powder.

Workup

  1. customThe reaction mixture was partitioned between ethyl acetate
  2. extractionThe aqueous layer was extracted with ethyl acetate
  3. washThe combined organic layer was washed with brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. concentrationThe organic layer was concentrated
  6. customto give a residue, which
  7. customwas then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=100:7)
  8. additionFractions containing a target compound
  9. concentrationwere concentrated
  10. customto give a residue
  11. customto give a precipitate
  12. filtrationThen the precipitate was filtered off
  13. washwashed with diethyl ether
  14. customdried under aeration

Sources & evidence

ORD record
ord-2c45b97616764515b0cf06ef52c94f9b
Source dataset
uspto-grants-2009_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07531532B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes