Ethyl Acetate → N-Desmethyl sorafenib

HRID 655815Notes

Reaction equation

HRID 655815 reaction equation
[Cl:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14].[NH2:25][C:26]1[CH:41]=[CH:40][C:29]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]([NH2:39])=[O:38])[CH:32]=2)=[CH:28][CH:27]=1.CCOC(C)=O>ClC(Cl)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:13]([NH:25][C:26]2[CH:41]=[CH:40][C:29]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([C:37](=[O:38])[NH2:39])[CH:32]=3)=[CH:28][CH:27]=2)=[O:14])=[CH:7][C:8]=1[C:9]([F:10])([F:11])[F:12]

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 675744-Chloro-3-(trifluoromethyl)anilineHCID 682631,1'-CarbonyldiimidazoleHCID 230883384-(4-Aminophenoxy)pyridine-2-carboxamide

Product 1

HCID 10151557N-Desmethyl sorafenibYield 82%

Reagents, catalysts & solvents 2

HCID 63651,1-DichloroethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
65 °C

Procedure

A mixture of 4-chloro-5-trifluoromethylaniline (451 mg, 2.31 mmol, 1.1 equiv.) and 1,1′-carbonyl diimidazole (419 mg, 2.54 mmol, 1.2 equiv.) in anh dichloroethane (5.5 mL) was stirred under argon at 65° C. for 16 h. Once cooled to room temperature, a solution of 4-(4-aminophenoxy)-2-pyridinecarboxamide (480 mg, 2.09 mmol) in anh THF (4.0 mL) was added, and the reaction mixture was stirred at 60° C. for 4 h. The reaction mixture was poured into EtOAc, and the organic layer was washed with water (2×) and a saturated NaCl solution (1×), dried (MgSO4), filtered, and evaporated in vacuo. Purification using MPLC chromatography (Biotage®; gradient from 100% EtOAc to 2% MeOH/EtOAc) gave N-[4-chloro-3-(trifluoromethyl)phenyl]N′-{4-[2-carbamoyl-(4-pyridyloxy)]phenyl}urea as a white solid (770 mg, 82%): TLC (EtOAc) Rf 0.11, 100% ethyl acetate 1H-NMR (DMSO-d6) δ 9.21 (s, 1H), 8.99 (s, 1H), 8.50 (d, J=5.6 Hz, 1H), 8.11 (s, 1H), 8.10 (s, 1H), 7.69 (broad s, 1H), 7.64 (dd, J=8.2 Hz, 2.1 Hz, 1H), 7.61 (s, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.39 (d, J=2.5 Hz, 1H), 7.15 (d, J=8.9 Hz, 2H), 7.14 (m, 1H); MS LC-MS (MH+=451). Anal. calcd for C20H14ClF3N4O3: C 53.29% H 3.13% N 12.43%. Found: C 53.33% H 3.21% N 12.60%;.

Workup

  1. temperatureOnce cooled to room temperature
  2. stirringthe reaction mixture was stirred at 60° C. for 4 h
  3. washthe organic layer was washed with water (2×)
  4. dry with materiala saturated NaCl solution (1×), dried (MgSO4)
  5. filtrationfiltered
  6. customevaporated in vacuo
  7. customPurification

Sources & evidence

ORD record
ord-118930553caf46c1a7d03afe514e74df
Source dataset
uspto-grants-2011_12
Patent number
US08071616B2

Reaction notes

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