(3R)-3-Aminopiperidine, 3-BOC protected → HCID 67045439, compound

HRID 408274Notes

Reaction equation

HRID 408274 reaction equation
[Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][O:15][CH3:16])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1>CCCCO.CCOC(C)=O>[Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][O:15][CH3:16])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1

Participants

5

Reactant 2

HCID 1514172(3R)-3-Aminopiperidine, 3-BOC protectedHCID 60205435HCID 60205435, compound

Product 1

HCID 67045439HCID 67045439, compound

Reagents, catalysts & solvents 2

HCID 2631-ButanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
160 °C

Procedure

A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropanamide (110 mg, 0.348 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (279 mg, 1.39 mmol) in n-BuOH (5 mL) was stirred at 160° C. for 24 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (1×20 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by C-18 reverse phase chromatography (Biotage 25M+ column) on Biotage SP4 unit eluting with 10-85% CH3CN gradient (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(3-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate as a solid. This material was dissolved in TFA (3 mL) and stirred at room temperature for 20 minutes. TFA was then removed in vacuo, and the residue was dissolved in a few drops of methanol and purified by C-18 reverse phase chromatography (Biotage C-18, 12M+ column) on Biotage SP4 unit eluting with 1-50% CH3CN/water gradient (14 CV). The product isolated was dissolved in CH2Cl2 (1 mL), and 2M HCl in ether (2 mL) was added. The solid was dissolved in MeOH, evaporated from CH2Cl2 (3×2 mL) and dried under high vacuum to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropanamide hydrochloride (28 mg, 20% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.80 (s, 1H), 9.34 (s, 1H), 8.23 (br s, 4H), 7.57 (br s, 1H), 3.64 (t, 2H), 3.55-3.49 (m, 2H), 3.42-3.55 (m, 2H), 3.27 (s, 3H), 3.08-3.03 (m, 1H), 2.62 (t, 2H), 2.15-2.09 (m, 1H), 1.88-1.81 (m, 1H), 1.75-1.67 (m, 1H), 1.53-1.45 (m, 1H); LCMS (APCI+) m/z 396, 398 (M+H)+, Retention time=2.09 minutes (Method 2).

Workup

  1. washwashed with brine (1×20 mL)
  2. customThe organic layer was separated
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by C-18 reverse phase chromatography (Biotage 25M+ column) on Biotage SP4 unit
  7. washeluting with 10-85% CH3CN gradient (25 CV)

Sources & evidence

ORD record
ord-f66a6ebd2afd4fe58bc008bc7a411e94
Source dataset
uspto-grants-2014_06
Patent number
US08758830B2

Reaction notes

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