Dichloromethane → HCID 67045927, compound

HRID 408353Notes

Reaction equation

HRID 408353 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.[F:18][C@@H:19]1[CH2:24][CH2:23][NH:22][CH2:21][C@H:20]1[NH:25]C(=O)OC(C)(C)C.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:50]>CCCCO>[ClH:50].[NH2:25][C@H:20]1[C@H:19]([F:18])[CH2:24][CH2:23][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:16])[CH:13]([CH3:15])[CH3:14])[C:4]=23)[CH2:21]1

Participants

7

Reactant 5

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 58386785HCID 58386785, compoundHCID 60205321N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

Product 1

HCID 67045927HCID 67045927, compoundYield 11%

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 (0.10 g, 0.33 mmol; Example 15, Step A), tert-butyl trans-4-fluoropiperidin-3-ylcarbamate (0.22 g, 1.00 mmol, Example J) and DIEA (0.17 mL, 1.00 mmol) in n-BuOH (3 mL) was stirred at 146° C. (bath) for 40 hours. The solvent was removed, and 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+, 10-80% CH3CN/water, 20 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 MeOH (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected to give N-(4-(trans-3-amino-4-fluoropiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochloride (0.017 g, 11%) as a solid. 1H NMR (400 MHz, D2O) δ 8.24 (s, 1H), 7.27 (s, 1H), 3.83 (m 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.25 (m, 2H), 2.64 (m, 1H), 2.21 (m, 2H), 1.88 (m, 1H), 1.10 (m, 6H). LCMS (APCI+) m/z 398 (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 MeOH (1 mL)
  11. addition2N HCl in ether (3 mL) was added
  12. customThe solid formed
  13. customwas collected

Sources & evidence

ORD record
ord-2adb6f44eb4b4e1786e40fe050ddb385
Source dataset
uspto-grants-2014_06
Patent number
US08758830B2

Reaction notes

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