1-Butanol → tert-butyl (3R)-1-(5-bromo-3-(2,2-difluorocyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate

HRID 1034826Notes

Reaction equation

HRID 1034826 reaction equation
[Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][C:15]3([F:18])[F:17])=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(N(C(C)C)C(C)C)C.CCCCO>CC#N.O>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][C:15]3([F:18])[F:17])=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1

Participants

6

Reactant 4

HCID 2631-ButanolHCID 81531DiisopropylethylamineHCID 1514172(3R)-3-Aminopiperidine, 3-BOC protectedHCID 60205543N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-difluorocyclopropanecarboxamide

Product 1

HCID 60205544tert-butyl (3R)-1-(5-bromo-3-(2,2-difluorocyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamateYield 35.1%

Reagents, catalysts & solvents 1

HCID 18373917Acetonitrile--water (1/1)Solvent

Conditions

Temperature
120 °C

Procedure

A sealed tube was charged with N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-difluorocyclopropanecarboxamide (150 mg, 0.449 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (270 mg, 1.35 mmol), N-ethyl-N-isopropylpropan-2-amine (235 μL, 1.35 mmol) and n-BuOH (3 mL). Then N2 was bubbled through the mixture for 5 minutes. The tube was sealed under N2 and stirred at 120° C. for 5 hours and then at 130° C. for 48 hours. The mixture was concentrated in vacuo, and the residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-85% CH3CN/water, 23 CV) to yield tert-butyl (3R)-1-(5-bromo-3-(2,2-difluorocyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (81 mg, 35% yield) as a solid. LCMS (APCI+) m/z 514.1, 516.1 (M+H)+.

Workup

  1. customThen N2 was bubbled through the mixture for 5 minutes
  2. customThe tube was sealed under N2
  3. waitat 130° C. for 48 hours
  4. concentrationThe mixture was concentrated in vacuo
  5. customthe residue was purified by reverse phase chromatography (Biotage SP4

Sources & evidence

ORD record
ord-a68feae255184500935a0768947b4a37
Source dataset
uspto-grants-2013_10
Patent number
US08545897B2

Reaction notes

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