Trifluoroacetic acid → (R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl) picolinamide

HRID 408249Notes

Reaction equation

HRID 408249 reaction equation
[Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CN1CCCC1=O.C(Cl)Cl.C(OCC)(=O)C>[NH2:31][C@@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:23])[C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=4)[C:4]=23)[CH2:26]1

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 1514172(3R)-3-Aminopiperidine, 3-BOC protectedHCID 60205405N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)picolinamide

Product 1

HCID 67045085(R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl) picolinamideYield 10.3%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl) picolinamide (195 mg, 0.48 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (290 mg, 1.45 mmol) and DIEA (0.17 mL, 0.97 mmol) in N-methylpyrrolidone (“NMP”; 2 mL) were stirred at 148° C. (bath) for 18 hours and at 160° C. for 5 hours. Ethyl acetate (20 mL) was added, and the mixture was washed with water (10 mL), brine (10 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 45-85% CH3CN/water gradient; 30 CV) to give a solid. This solid was dissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected by filtration to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl) picolinamide (24 mg, 8% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.77 (s, 1H), 8.15 (s, 1H), 8.11 (d, 1H), 7.95 (d, 1H), 7.82 (s, 1H), 3.74 (m, 1H), 3.59 (m, 1H), 3.48 (m, 1H), 3.32 (m, 1H), 2.88 (m, 1H), 2.22 (m, 1H), 2.03 (m, 1H), 1.79 (m, 1H), 1.53 (m, 1H); LCMS (APCI+) m/z 483 (M+H)+.

Workup

  1. washthe mixture was washed with water (10 mL), brine (10 mL)
  2. dry with materialdried over sodium sulfate
  3. customAfter removal of the solvent
  4. customthe residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit
  5. custom30 CV) to give a solid
  6. customThe solvent was removed
  7. dissolutionThe residue was dissolved in DCM (1 mL)
  8. addition2N HCl in ether (3 mL) was added
  9. customThe solid formed
  10. filtrationwas collected by filtration

Sources & evidence

ORD record
ord-e763300987fc45618489e68373d05982
Source dataset
uspto-grants-2014_06
Patent number
US08758830B2

Reaction notes

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