Bromotrichloromethane → Ethyl 2-(4-amino-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-6-yl)-1,3-oxazole-4-carboxylate

HRID 2198084Notes

Reaction equation

HRID 2198084 reaction equation
[NH2:1][C:2]1[C:7]2=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][N:33]=4)=[O:30])=[CH:24][CH:23]=3)[C:9]([C:11]([NH:13][C@H:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15]O)=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.CCN(S(F)(F)F)CC.CC(C)=O.C(=O)=O.C1CCN2C(=NCCC2)CC1.BrC(Cl)(Cl)Cl>CCOC(C)=O.C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][N:33]=4)=[O:30])=[CH:26][CH:27]=3)[C:9]([C:11]3[O:12][CH:15]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:13]=3)=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1

Participants

8

Reactant 5

HCID 6383Bromotrichloromethane2×HCID 811841,8-Diazabicyclo(5.4.0)undec-7-ene2×HCID 123472(Diethylamino)sulfur trifluoride2×HCID 18522661Acetone cardiceHCID 68711530ethyl N-[(4-amino-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-6-yl)carbonyl]serinate

Product 1

HCID 57758202Ethyl 2-(4-amino-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-6-yl)-1,3-oxazole-4-carboxylateYield 8%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of THF (16 mL) was added ethyl N-[(4-amino-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-6-yl)carbonyl]serinate (Example 221) (437 mg, 0.76 mmol) which was cooled to −78° C. DAST (0.14 mL, 1.07 mmol) was added and the reaction proceeded for 1 h while stirring under N2. Additional DAST (0.14 mL, 1.07 mmol) was added and the solution was stirred for 30 min. The acetone/dry ice cooling bath was replaced with an ice/water bath and DBU (0.41 mL, 2.75 mmol) and BrCCl3 (0.27 mL, 2.75 mmol) were added and the solution was allowed to warm to rt over 17 h. Additional DBU (0.41 mL, 2.75 mmol) and BrCCl3 (0.27 mL, 2.75 mmol) were added and the solution was allowed to stir for 6 h. The reaction mixture was transferred to a separatory funnel, diluted with EtOAc (50 mL), washed with aq saturated NaHCO3 (50 mL) and H2O (50 mL). The aqueous fraction was back extracted with DCM (3×30 mL). The combined organic layers were dried (MgSO4), evaporated in vacuo and flashed 5:4:1 v/v/v DCM/EtOAc/MeOH resulting in the isolation of 33 mg of the title compound (0.060 mmol, yield 8%). 1H-NMR (DMSO-d6) δ 9.93 (s, 1H), 9.77 (s, 1H), 8.70 (s, 1H), 8.55 to 8.54 (d, J=5.0 Hz, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.64 to 7.61 (d, J=8.8 Hz, 2H), 7.42 to 7.40 (d, J=8.8 Hz, 2H), 7.38 to 7.36 (d, J=6.2 Hz, 1H), 4.28 to 4.23 (q, J=7.6 Hz, 2H), 1.28 to 1.25 (t, J=7.1 Hz, 3H); MS [M+H]+=553.1; LCMS RT=3.04 min.

Workup

  1. stirringthe solution was stirred for 30 min
  2. temperatureto warm to rt over 17 h
  3. stirringto stir for 6 h
  4. customThe reaction mixture was transferred to a separatory funnel
  5. washwashed with aq saturated NaHCO3 (50 mL) and H2O (50 mL)
  6. extractionThe aqueous fraction was back extracted with DCM (3×30 mL)
  7. dry with materialThe combined organic layers were dried (MgSO4)
  8. customevaporated in vacuo

Sources & evidence

ORD record
ord-2160589b49e7470e89eeb27f2657e71d
Source dataset
uspto-grants-2012_12
Patent number
US08338595B2

Reaction notes

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