Tetrahydrofuran → 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)-4,5-dihydro-1,3-oxazole-4-carboxylate

HRID 2198082Notes

Reaction equation

HRID 2198082 reaction equation
C1COCC1.[NH2:6][C:7]1[C:12]2=[C:13]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]4[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][N:38]=4)=[O:35])=[CH:29][CH:28]=3)[C:14]([C:16]([NH:18][C@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20]O)=[O:17])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1.CCN(S(F)(F)F)CC.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C(Cl)Cl.CCOC(C)=O.CO>[NH2:6][C:7]1[C:12]2=[C:13]([C:27]3[CH:28]=[CH:29][C:30]([NH:33][C:34]([NH:36][C:37]4[CH:42]=[C:41]([C:43]([F:45])([F:46])[F:44])[CH:40]=[CH:39][N:38]=4)=[O:35])=[CH:31][CH:32]=3)[C:14]([C:16]3[O:17][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:18]=3)=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 11430Potassium CarbonateHCID 123472(Diethylamino)sulfur trifluorideHCID 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 57758298Ethyl 2-(4-amino-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-6-yl)-4,5-dihydro-1,3-oxazole-4-carboxylateYield 18%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 21901258Dichloromethane ethyl acetate methanolSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of THF (2 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) (50 mg, 0.09 mmol) which was cooled to −78° C. DAST (13 μL, 0.10 mmol) was added and the reaction proceeded for 1 h while stirring under N2. Anhydrous K2CO3 was then added and the solution was allowed to warm to rt over the following 30 min. The reaction mixture was transferred to a separatory funnel, diluted with EtOAc (20 mL), washed with aq saturated NaHCO3 (20 mL) and H2O (20 mL). The organic was collected, dried (MgSO4), and evaporated in vacuo. The crude material was purified by preparative HPLC (10-90% ACN/H2O with 0.1% TFA). The fractions were left overnight resulting in the partial formation of a new product. The two products were separated by column chromatography 5:4:1 v/v/v DCM/EtOAc/MeOH resulting in the isolation of 9 mg of the title compound (0.016 mmol, 18%). 1H-NMR (DMSO-d6) δ 9.91 (s, 1H), 9.78 (s, 1H), 8.54 to 8.53 (d, J=5.0 Hz, 1H), 8.08 (s, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 7.58 to 7.56 (d, J=8.6 Hz, 2H), 7.37 to 7.36 (d, J=5.1 Hz, 1H), 7.34 to 7.32 (d, J=8.6 Hz, 2H), 4.75 to 4.71 (m, 1H), 4.38 to 4.29 (m, 2H), 4.13 to 4.08 (q, J=7.1 Hz, 2H), 1.21 to 1.18 (t, J=7.0 Hz, 3H); MS [M+H]+=555.1; LCMS RT=2.84 min.

Workup

  1. temperatureto warm to rt over the following 30 min
  2. customThe reaction mixture was transferred to a separatory funnel
  3. washwashed with aq saturated NaHCO3 (20 mL) and H2O (20 mL)
  4. customThe organic was collected
  5. dry with materialdried (MgSO4)
  6. customevaporated in vacuo
  7. customThe crude material was purified by preparative HPLC (10-90% ACN/H2O with 0.1% TFA)
  8. waitThe fractions were left overnight
  9. customresulting in the partial formation of a new product

Sources & evidence

ORD record
ord-5aa50a1c0ab545349d5ff3569d6fbb03
Source dataset
uspto-grants-2012_12
Patent number
US08338595B2

Reaction notes

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