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

HRID 875839Notes

Reaction equation

HRID 875839 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.[CH3:18][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.[ClH:49]>CCCCO.C(Cl)Cl.CO.CCOCC>[ClH:49].[NH2:25][C@H:20]1[C@H:19]([CH3:18])[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

10

Reactant 5

HCID 313Hydrochloric AcidHCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 57931128trans-tert-Butyl (4-methylpiperidin-3-yl)carbamateHCID 60205321N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

Product 1

HCID 67045573N-(4-(trans-3-amino-4-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochlorideYield 4%

Reagents, catalysts & solvents 4

HCID 2631-ButanolSolventHCID 887MethanolSolventHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolvent

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-methylpiperidin-3-ylcarbamate (0.43 g, 2.00 mmol; Example I) and DIEA (0.35 mL, 2.00 mmol) in n-BuOH (3 mL) was stirred at 146° 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), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 10-80% CH3CN/water, 30 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 in vacuo. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 12M+, 0-80% CH3CN/water gradient, 20 CV). The product isolated 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-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide hydrochloride (0.011 g, 4%) as a solid. 1H NMR (400 MHz, D2O) δ 8.20 (s, 1H), 7.27 (s, 1H), 3.72 (m, 1H), 3.26 (m, 1H), 3.19 (m, 3H), 2.63 (m, 1H), 1.76 (m, 1H), 1.68 (m, 1H), 1.41 (m, 1H), 1.10 (t, 6H), 1.00 (d, 3H). LCMS (APCI+) m/z 394 (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 in vacuo
  10. customThe residue was purified by reverse phase chromatography (Biotage SP4
  11. customThe product isolated
  12. customThe solid formed
  13. customwas collected

Sources & evidence

ORD record
ord-f23af794b1cc485faac9d1291a36e39c
Source dataset
uspto-grants-2015_03
Patent number
US08981085B2

Reaction notes

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