Trifluoroacetic anhydride → 5-(2-benzyl-2H-indazol-6-yl)-7-{1-[(dimethylamino)acetyl]-1,4,5,6-tetrahydropyridin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine

HRID 1972926Notes

Reaction equation

HRID 1972926 reaction equation
[NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:25]=[CH:26][C:27]4[C:31]([CH:32]=3)=[N:30][N:29]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:28]=4)[CH:9]=[C:10]([C:11]3(O)[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:22])[CH2:18][N:19]([CH3:21])[CH3:20])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl.CCO>[CH2:33]([N:29]1[CH:28]=[C:27]2[C:31]([CH:32]=[C:24]([C:8]3[CH:9]=[C:10]([C:11]4[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:22])[CH2:18][N:19]([CH3:20])[CH3:21])[CH:12]=4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:25]=[CH:26]2)=[N:30]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1

Participants

7

Reactant 4

HCID 9845Trifluoroacetic anhydrideHCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 585293593-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-1-(N,N-dimethylglycyl)piperidin-3-ol

Product 1

HCID 585295325-(2-benzyl-2H-indazol-6-yl)-7-{1-[(dimethylamino)acetyl]-1,4,5,6-tetrahydropyridin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amineYield 73.6%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6344DichloromethaneSolvent

Procedure

To a cooled (0° C.) mixture of 3-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-1-(N,N-dimethylglycyl)piperidin-3-ol (58 mg, 0.11 mmol) and N,N-diisopropylethylamine (58 μL, 0.33 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic anhydride (31 μL, 0.22 mmol), dropwise. The ice bath was removed and the mixture was stirred at rt for 2 h. The reaction was cooled (0° C.) and additional N,N-diisopropylethylamine (58 μL) and trifluoroacetic anhydride (31 μL) was added. The ice bath was removed and the reaction was stirred at rt for 5 h. Water (5 mL) was added and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×5 mL) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated. To a solution of the residue in EtOH (3 mL) was added NaOH (66 mg, 1.66 mmol). The mixture was stirred at rt for 17 h. The mixture was partitioned between EtOAc (10 mL) and H2O (10 mL). The layers were separated and the organic phase was washed with H2O (10 mL), brine, dried (Na2SO4) and concentrated. The material was crystallized from EtOAc/hexanes to afford 41 mg (73%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.66-8.70 (m, 1H,) 8.55 (s, 1 H), 7.94-7.98 (m, 1 H), 7.81 (d, 1 H), 7.61 (s, 1 H), 7.27-7.36 (m, 5 H), 7.15 (dd, 1 H), 6.76-6.80 (m, 1 H), 5.65 (s, 2 H), 3.56-3.79 (m, 2 H), 3.22-3.28 (m, 2 H), 2.48-2.59 (m, 2 H), 2.17-2.25 (m, 6 H), 1.85-1.94 (m, 2 H); ES-MS m/z 507.13 [M+H]+, HPLC RT (min) 2.31.

Workup

  1. temperatureTo a cooled
  2. customThe ice bath was removed
  3. temperatureThe reaction was cooled (0° C.) and additional N,N-diisopropylethylamine (58 μL) and trifluoroacetic anhydride (31 μL)
  4. additionwas added
  5. customThe ice bath was removed
  6. stirringthe reaction was stirred at rt for 5 h
  7. additionWater (5 mL) was added
  8. customthe layers were separated
  9. extractionThe aqueous phase was extracted with CH2Cl2 (2×5 mL)
  10. washthe combined organic layers were washed with brine
  11. dry with materialdried (Na2SO4)
  12. concentrationconcentrated
  13. stirringThe mixture was stirred at rt for 17 h
  14. customThe mixture was partitioned between EtOAc (10 mL) and H2O (10 mL)
  15. customThe layers were separated
  16. washthe organic phase was washed with H2O (10 mL), brine
  17. dry with materialdried (Na2SO4)
  18. concentrationconcentrated
  19. customThe material was crystallized from EtOAc/hexanes

Sources & evidence

ORD record
ord-e6f3fe5ae2c64bf0ae062af83b49618b
Source dataset
uspto-grants-2013_04
Patent number
US08431695B2

Reaction notes

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