Dichloromethane → N-(4-(trans-3-amino-4-cyclopropylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochloride

HRID 408371Notes

Reaction equation

HRID 408371 reaction equation
[Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(OC(=O)[NH:24][C@H:25]1[C@H:30]([CH:31]2[CH2:33][CH2:32]2)[CH2:29][CH2:28][NH:27][CH2:26]1)(C)(C)C.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:52]>CCCCO>[ClH:52].[NH2:24][C@H:25]1[C@H:30]([CH:31]2[CH2:33][CH2:32]2)[CH2:29][CH2:28][N:27]([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:16])[CH:13]([CH3:15])[CH3:14])[C:4]=23)[CH2:26]1

Participants

7

Reactant 5

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 60205321N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramideHCID 86652140Tert-butyl-trans-4-cyclopropylpiperidin-3-ylcarbamate

Product 1

HCID 67045541N-(4-(trans-3-amino-4-cyclopropylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochlorideYield 52%

Reagents, catalysts & solvents 1

HCID 2631-ButanolSolvent

Conditions

Temperature
146 °C

Procedure

A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (0.20 g, 0.67 mmol; Example 15, Step A), tert-butyl-trans-4-cyclopropylpiperidin-3-ylcarbamate (0.48 g, 2.00 mmol; Example K) and DIEA (0.35 mL, 2.00 mmol) in n-BuOH (2 mL) was stirred at 146° C. (bath) for 20 hours. The solvent was removed. The residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20-80% CH3CN/water, 25 CV). The product isolated was dissolved in DCM (2 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 to give N-(4-(trans-3-amino-4-cyclopropylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochloride (0.17 g, 52%) as a solid. 1H NMR (400 MHz, D2O) δ 8.21 (s, 1H), 7.26 (s, 1H), 3.81 (m, 1H), 3.48 (m, 1H), 3.38 (m, 1H), 3.11 (m, 2H), 2.60 (m, 1H), 1.88 (m, 1H), 1.82 (m, 1H), 1.52 (m, 1H), 1.16 (m, 1H), 1.07 (t, 6H), 0.77 (m, 1H), 0.39 (m, 1H), 0.14 (m, 1H), 0.11 (m, 1H). LCMS (APCI+) m/z 420 (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 (sodium sulfate)
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by reverse phase chromatography (Biotage SP4
  7. customThe product isolated
  8. stirringThe mixture was stirred at room temperature for 1 hour
  9. customThe solvent was removed
  10. dissolutionThe residue was dissolved in DCM (1 mL)
  11. addition2N HCl in ether (3 mL) was added
  12. customThe solid formed
  13. customwas collected

Sources & evidence

ORD record
ord-c4f286aee5484894a2dc92882203fa7e
Source dataset
uspto-grants-2014_06
Patent number
US08758830B2

Reaction notes

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