Tosylmethyl isocyanide → N-{4-[4-amino-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N'-[4-(trifluoromethyl)pyridin-yl]urea

HRID 73661Notes

Reaction equation

HRID 73661 reaction equation
C[O-].[Na+].CC1C=CC(S([CH2:14][N+:15]#[C-:16])(=O)=O)=CC=1.[NH2:17][C:18]1[C:23]2=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]4[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][N:40]=4)=[O:37])=[C:31]([F:49])[CH:30]=3)[C:25]([CH:27]=[O:28])=[CH:26][N:22]2[N:21]=[CH:20][N:19]=1>CCOC(C)=O.CO.C1COCC1>[NH2:17][C:18]1[C:23]2=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]4[CH:44]=[C:43]([C:45]([F:47])([F:46])[F:48])[CH:42]=[CH:41][N:40]=4)=[O:37])=[C:31]([F:49])[CH:30]=3)[C:25]([C:27]3[O:28][CH:16]=[N:15][CH:14]=3)=[CH:26][N:22]2[N:21]=[CH:20][N:19]=1

Participants

7

Reactant 3

HCID 161915Tosylmethyl isocyanideHCID 10942334Sodium MethoxideHCID 57758187HCID 57758187, compound

Product 1

HCID 57758190N-{4-[4-amino-6-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N'-[4-(trifluoromethyl)pyridin-yl]ureaYield 33%

Reagents, catalysts & solvents 3

HCID 887MethanolSolvent2×HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of THF (10 mL) and MeOH (10 mL) cooled in an ice/water bath was added 0.5 M sodium methoxide in MeOH (0.96 mL, 0.48 mmol) followed by TosMIC (93 mg, 0.48 mmol). The solution was allowed to stir for 5 min and then N-[4-(4-amino-6-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea (73 mg, 0.16 mmol) was added. The solution was heated to 60° C. for 17 h. The reaction mixture was allowed to cool and was transferred to a separatory funnel, diluted with EtOAc (20 mL), washed with aq saturated NaHCO3 (20 mL) and H2O (20 mL). The aqueous layer was back extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO4), filtered, evaporated in vacuo and purified by flash chromatography 5:4:1 v/v/v DCM/EtOAc/MeOH the resulting purified fractions were combined and evaporated providing 26 mg of the title compound as a white solid (0.052 mmol, yield 33%). 1H-NMR (DMSO-d6) δ 10.18 (s, 1H), 10.16 to 10.12 (br s, 1H), 8.55 to 8.54 (d, J=5.4 Hz, 1H), 8.35 to 8.31 (t, J=8.3 Hz, 1H), 8.30 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.39 to 7.36 (m, 2H), 7.23 to 7.21 (d, J=10.4 Hz, 1H), 6.63 (s, 1H); MS [M+H]+=499.0; LCMS RT=2.85 min.

Workup

  1. temperatureto cool
  2. customwas transferred to a separatory funnel
  3. washwashed with aq saturated NaHCO3 (20 mL) and H2O (20 mL)
  4. extractionThe aqueous layer was back extracted with EtOAc (2×20 mL)
  5. dry with materialThe combined organic layers were dried (MgSO4)
  6. filtrationfiltered
  7. customevaporated in vacuo
  8. custompurified by flash chromatography 5:4:1 v/v/v DCM/EtOAc/MeOH the resulting
  9. custompurified fractions
  10. customevaporated

Sources & evidence

ORD record
ord-af1266419c174e54b73a491fcf9458fb
Source dataset
uspto-grants-2014_09
Patent number
US08829185B2

Reaction notes

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