Tetrahydrofuran → 2-Amino-3-ethoxy-3-oxopropyl 4-amino-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate

HRID 229631

Reaction equation

HRID 229631 reaction equation
C1[CH2:5][O:4]CC1.[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](N[C@H](C(OCC)=O)CO)=[O:17])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1.CC[N:49](S(F)(F)F)CC.C([O-])([O-])=O.[K+].[K+].[CH3:62][CH2:63][O:64][C:65]([CH3:67])=[O:66]>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:44])([F:46])[F:45])[CH:40]=[CH:39][N:38]=4)=[O:35])=[CH:31][CH:32]=3)[C:14]([C:16]([O:4][CH2:5][CH:67]([NH2:49])[C:65]([O:64][CH2:63][CH3:62])=[O:66])=[O:17])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1

Participants

7

Reactant 5

HCID 8028TetrahydrofuranHCID 8857Ethyl AcetateHCID 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 687146762-Amino-3-ethoxy-3-oxopropyl 4-amino-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylateYield 9%

Reagents, catalysts & solvents 1

HCID 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 4 mg of the title compound (0.0075 mmol, 9%). 1H-NMR (DMSO-d6) δ 9.92 (s, 1H), 9.78 (s, 1H), 8.54 to 8.53 (d, J=5.4 Hz, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.93 (s, 1H), 7.60 to 7.58 (d, J=8.8 Hz, 2H), 7.37 to 7.35 (d, J=6.4 Hz, 1H), 7.33 to 7.31 (d, J=8.6 Hz, 2H), 4.25 to 4.21(m, 1H), 4.12 to 4.08 (m, 1H), 4.07 to 4.02 (q, J=7.0 Hz, 2H), 3.55 to 3.52 (t, J=4.9 Hz, 1H), 1.15 to 1.11 (t, J=7.2 Hz, 3H); MS [M+H]+=573.1; LCMS RT=2.38 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-5fc0958a5802496baa3727e1a3002733
Source dataset
uspto-grants-2009_07
Patent number
US07563791B2

Linked notes

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