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

HRID 2203748Notes

Reaction equation

HRID 2203748 reaction equation
[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]2[NH:12][CH:13]=[C:14]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=3)[C:3]=12.[NH:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]1.C(O)(C(F)(F)F)=O>CCCCO.C(Cl)Cl>[ClH:1].[NH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]3[NH:12][CH:13]=[C:14]([NH:15][C:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=4)[C:3]=23)[CH2:25]1

Participants

6

Reactant 3

HCID 6422Trifluoroacetic acidHCID 1514172(3R)-3-Aminopiperidine, 3-BOC protectedHCID 60205309HCID 60205309, compound

Product 1

HCID 67045359(R)-N-(4-(3-aminopiperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochlorideYield 53.3%

Reagents, catalysts & solvents 2

HCID 2631-ButanolSolventHCID 6344DichloromethaneSolvent

Procedure

N-(4-Chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (80 mg, 0.2 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.14 g, 0.70 mmol) in n-BuOH (3 mL) were stirred at 143° C. (bath) for 32 hours. The solvent was removed, and the residue was dissolved in ethyl acetate (20 mL), 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, 10-80% 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 30 minutes. The solvent was removed. The residue was dissolved in DCM (1 mL) and 2N HCl in ether (2 mL) was added. The solid formed was collected by filtration to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (0.047 g, 39% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.43 (d, 1H), 10.54 (s, 1H), 9.42 (d, 1H), 8.98 (dd, 1H), 8.88 (d, 1H), 8.53 (s, 1H), 8.25 (br s, 3H), 7.97 (dd, 1H), 7.74 (d, 1H), 3.36-3.29 (m, 1H), 3.12-3.05 (m, 2H), 3.04-2.95 (m, 2H), 1.94-1.84 (m, 1H), 1.67-1.57 (m, 1H), 1.54-1.42 (m, 1H), 1.33-1.19 (m, 1H); LCMS (APCI+) m/z 405.1 (M+H)+.

Workup

  1. customThe solvent was removed
  2. dissolutionthe residue was dissolved in ethyl acetate (20 mL)
  3. washwashed with water (10 mL), brine (10 mL)
  4. dry with materialdried over sodium sulfate
  5. customAfter removal of the solvent
  6. customthe residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit
  7. custom30 CV) to give a solid
  8. customThe solvent was removed
  9. dissolutionThe residue was dissolved in DCM (1 mL)
  10. addition2N HCl in ether (2 mL) was added
  11. customThe solid formed
  12. filtrationwas collected by filtration

Sources & evidence

ORD record
ord-f97a8de7a7cf4aeeae1bea2b222fc607
Source dataset
uspto-grants-2016_06
Patent number
US09365568B2

Reaction notes

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