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

HRID 492976Notes

Reaction equation

HRID 492976 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)=[C:4]([F:29])[CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])=[CH:33][CH:32]=1.C(=O)([O-])O.[Na+].C(OCC)C>O1CCCC1.C(OCC)(=O)C.CCCCCC>[F:29][C:4]1[CH:3]=[C:2]([NH:1][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)=[O:42])[CH:28]=[CH:27][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][N:19]([CH:22]3[CH2:23][N:24]([CH3:26])[CH2:25]3)[CH2:20][CH2:21]2)=[O:15])[CH:8]=1

Participants

8

Reactant 4

HCID 3283Diethyl EtherHCID 516892Sodium BicarbonateHCID 231530882-(4-Fluorophenyl)acetyl isocyanateHCID 576776664-(1-Methylazetidin-3-yl)piperazine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide

Product 1

HCID 576773614-(1-Methylazetidin-3-yl)piperazine-1-carboxylic acid [4-(2-fluoro-4-{3-[2-(4-fluorophenyl)acetyl]ureido}phenoxy)pyridin-2-yl]amideYield 31.9%

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolventHCID 8058HexaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 4-(1-methylazetidin-3-yl)piperazine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (40.0 mg) in tetrahydrofuran (15 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in ethyl acetate (0.25 M, 1.60 ml), followed by stirring at room temperature for 1 hr. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, followed by stirring at room temperature for 15 min. The organic layer was separated, 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, ethyl acetate:methanol=20:1, then 10:1). Fractions containing a target compound were concentrated to give a solid, to which diethyl ether (1 ml) and hexane (1 ml) were added to suspend. The solid was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (18.5 mg, 31.9%) as pale yellow powder.

Workup

  1. stirringby stirring at room temperature for 15 min
  2. customThe organic layer was separated
  3. dry with materialdried over anhydrous sodium sulfate
  4. concentrationThe organic layer was concentrated
  5. customto give a residue, which
  6. customwas then purified by silica gel column chromatography (FUJI Silysia NH, eluent
  7. additionFractions containing a target compound
  8. concentrationwere concentrated
  9. customto give a solid
  10. filtrationThe solid was filtered off
  11. washwashed with diethyl ether
  12. customdried under aeration

Sources & evidence

ORD record
ord-b7dad68d7ad244329a016afba8b7dab2
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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