Hydrazine hydrate (1:1) → 1-(1-(Cyano(4-(trifluoromethoxy)phenyl)methyl)piperidin-4-yloxy)-3-(4-fluorophenyl)urea

HRID 1895944Notes

Reaction equation

HRID 1895944 reaction equation
O.NN.O=C1C2C(=CC=CC=2)[C:7](=[O:14])[N:6]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:23]#[N:24])[CH2:18][CH2:17]1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]=C=O)=[CH:39][CH:38]=1>C(Cl)Cl>[C:23]([CH:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:29][CH:30]=1)[N:19]1[CH2:20][CH2:21][CH:16]([O:15][NH:6][C:7]([NH:43][C:40]2[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=2)=[O:14])[CH2:17][CH2:18]1)#[N:24]

Participants

5

Reactant 3

HCID 24654Hydrazine hydrate (1:1)HCID 709554-Fluorophenyl isocyanateHCID 671184582-(4-(1,3-Dioxoisoindolin-2-yloxy)piperidin-1-yl)-2-(4-(trifluoromethoxy)phenyl)acetonitrile

Product 1

HCID 866527401-(1-(Cyano(4-(trifluoromethoxy)phenyl)methyl)piperidin-4-yloxy)-3-(4-fluorophenyl)ureaYield 121.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Hydrazine monohydrate (0.063 ml, 1.303 mmol) was added to a solution of 2-(4-(1,3-dioxoisoindolin-2-yloxy)piperidin-1-yl)-2-(4-(trifluoromethoxy)phenyl)acetonitrile (258 mg, 0.434 mmol) in CH2Cl2 (5 ml) and the whole was stirred at room temperature for 16 hours. The resulting solid was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 ml), treated with 4-fluorophenyl isocyanate (0.023 ml, 0.200 mmol) and stirred at room temperature for 14 hours. The reaction mixture was concentrated in vauo and the residue was purified by column chromatography (ethyl acetate/hexane: 50/50 to 0/100) and the resulting solid was triturated with ethyl acetate/hexane to give 1-(1-(cyano(4-(trifluoromethoxy)phenyl)methyl)piperidin-4-yloxy)-3-(4-fluorophenyl)urea (110 mg, 56%) as a white solid: LCMS: 442 [M+1]+. 1H NMR (DMSO-d6) δ: 1.67 (m, 1H), 1.81 (m, 1H), 1.94 (m, 2H), 2.33 (m, 2H), 2.58 (m, 1H), 2.88 (m, 1H), 3.76 (m, 1H), 5.47 (s, 1H), 7.10 (m, 2H), 7.46-7.60 (m, 6H), 8.62 (s, 1H), 9.43 (s, 1H).

Workup

  1. filtrationThe resulting solid was filtered off
  2. concentrationthe filtrate was concentrated in vacuo
  3. dissolutionThe residue was dissolved in tetrahydrofuran (5 ml)
  4. stirringstirred at room temperature for 14 hours
  5. concentrationThe reaction mixture was concentrated in vauo
  6. customthe residue was purified by column chromatography (ethyl acetate/hexane: 50/50 to 0/100)
  7. customthe resulting solid was triturated with ethyl acetate/hexane

Sources & evidence

ORD record
ord-428d2c8307964228889cd7075521af19
Source dataset
uspto-grants-2013_08
Patent number
US08518934B2

Reaction notes

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