Dichloromethane → (R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-fluorobenzamide hydrochloride

HRID 1923735

Reaction equation

HRID 1923735 reaction equation
[Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28]C(=O)OC(C)(C)C)[CH2:23]1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:44]>CCCCO>[ClH:44].[NH2:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([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:20])[C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:4]=23)[CH2:23]1

Participants

6

Reactant 4

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 1514172(3R)-3-Aminopiperidine, 3-BOC protectedHCID 60205349N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-fluorobenzamide

Product 1

HCID 67045238(R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-fluorobenzamide hydrochlorideYield 41%

Reagents, catalysts & solvents 1

HCID 2631-ButanolSolvent

Procedure

N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-fluorobenzamide (0.24 g, 0.67 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.40 g, 2.01 mmol) in n-BuOH (2 mL) were stirred at 143° C. (bath) for 24 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, 20-80% CH3CN/water gradient; 30 CV) to give a solid. The 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)-4-fluorobenzamide hydrochloride (0.14 g, 41% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.94 (s, 1H), 9.95 (s, 1H), 8.26 (s, 1H), 8.17-8.-9 (m, 6H), 7.65 (br s, 1H), 7.42 (t, 2H), 3.43-3.35 (m, 2H), 3.25-3.15 (m, 2H), 3.10-3.04 (m, 1H), 1.92-1.85 (m, 1H), 1.66-1.59 (m, 1H), 1.46-1.28 (m, 2H); LCMS (APCI+) m/z 432 (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 (3 mL) was added
  11. customThe solid formed
  12. filtrationwas collected by filtration

Sources & evidence

ORD record
ord-e96e55553895420fb4e05eaffa12f393
Source dataset
uspto-grants-2012_05
Patent number
US08178131B2

Linked notes

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