Hydrochloric Acid → N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-3-carboxamide hydrochloride

HRID 1923797Notes

Reaction equation

HRID 1923797 reaction equation
[Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][O:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[ClH:33]>C(O)(C(F)(F)F)=O.CO.C(Cl)Cl.CCOCC>[ClH:33].[NH2:25][C@@H:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([CH:14]4[CH2:18][CH2:17][O:16][CH2:15]4)=[O:13])[C:4]=23)[CH2:20]1

Participants

6

Reactant 2

HCID 313Hydrochloric AcidHCID 60205428tert-butyl (3R)-1-(5-bromo-3-(tetrahydrofuran-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate

Product 1

HCID 60205429N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-3-carboxamide hydrochlorideYield 37%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 6422Trifluoroacetic acidSolventHCID 21226129Dichloromethane methanolSolvent

Procedure

A solution of tert-butyl (3R)-1-(5-bromo-3-(tetrahydrofuran-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (57 mg, 0.11 mmol) in neat TFA (5 mL) was stirred at room temperature for 30 minutes and concentrated in vacuo. The oily residue was dissolved in a few drops of CH2Cl2 and treated with 2M HCl in Et2O (3 mL). The solid formed was filtered, washed with additional Et2O and purified by C-18 reverse phase column chromatography (Biotage C-18, 12M+) on Biotage SP4 unit eluting with 5%-60% CH3CN/water gradient. The product isolated was dissolved in few drops of 10% MeOH/CH2Cl2 and treated with 2M HCl in Et2O (4 mL). The precipitate formed was filtered, washed with additional Et2O (2×2 mL) followed by CH3CN (1 mL) and dried to provide N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydro furan-3-carboxamide hydrochloride (20 mg, 37% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.84 (s, 1H), 9.49 (s, 1H), 8.24 (br s, 4H), 7.57 (s, 1H), 3.84-3.71 (m, 4H), 3.44-3.36 (m, 3H), 3.28-3.21 (m, 2H), 3.11-3.06 (m, 1H), 2.17-2.08 (m, 3H), 1.87-1.80 (m, 1H), 1.76-1.65 (m, 1H), 1.53-1.43 (m, 1H); LCMS (APCI+) m/z 408, 410 (M+H)+, Retention time=1.99 minutes (Method 2).

Workup

  1. concentrationconcentrated in vacuo
  2. dissolutionThe oily residue was dissolved in a few drops of CH2Cl2
  3. additiontreated with 2M HCl in Et2O (3 mL)
  4. customThe solid formed
  5. filtrationwas filtered
  6. washwashed with additional Et2O
  7. custompurified by C-18 reverse phase column chromatography (Biotage C-18, 12M+) on Biotage SP4 unit
  8. washeluting with 5%-60% CH3CN/water gradient
  9. customThe product isolated
  10. customThe precipitate formed
  11. filtrationwas filtered
  12. washwashed with additional Et2O (2×2 mL)
  13. customdried

Sources & evidence

ORD record
ord-e3c2080c00df4f31b98deedb1673245c
Source dataset
uspto-grants-2012_05
Patent number
US08178131B2

Reaction notes

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