Ammonium Chloride → (R)-N-(4-(3-aminopiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride

HRID 408341

Reaction equation

HRID 408341 reaction equation
Br[C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26]C(=O)OC(C)(C)C)[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Li]C.C([Li])CCC.[Cl-:41].[NH4+]>O1CCOCC1>[ClH:41].[NH2:26][C@@H:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:3]2[CH:2]=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[C:4]=23)[CH2:21]1

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 67045441(R)-tert-butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamateHCID 178418339ButyllithiumHCID 178418348HCID 178418348, compound

Product 1

HCID 67045963(R)-N-(4-(3-aminopiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochlorideYield 17%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
-78 °C

Procedure

(R)-tert-Butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (125 mg, 0.243 mmol; Example 1A, Step A) was dissolved in dioxane (20 mL) and cooled to −78° C. MeLi (455 μL, 0.728 mmol) was slowly added, and the reaction was stirred for 10 minutes. n-Butyl lithium (146 μL, 0.364 mmol) was slowly added, and the reaction was stirred for 10 minutes at −78° C. Saturated ammonium chloride was then added, and the mixture was extracted several times with DCM. The layers were separated, dried, filtered, and concentrated. The residue was purified by reverse phase chromatography (Biotage Horizon, C-18 25M+, 0-80% CH3CN/water+10 mM ammonium acetate and 1% IPA). The product was dissolved in TFA (2 mL), stirred for 30 minutes, concentrated and purified by reverse phase chromatography (Biotage Horizon, C-18 12M+, 0-30% CH3CN/water+0.1% TFA). The product was redissolved in 10% MeOH in DCM (2 mL) and added dropwise to a stirred solution of 2M HCl in ether. The reaction was concentrated to give (R)—N-(4-(3-aminopiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (18.5 mg, 17% yield). 1H NMR (400 MHz, D2O) δ 9.10 (s, 1H), 8.78 (d, 1H), 8.62 (dt, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.39 (s, 1H), 6.78 (d, 1H), 3.89 (d, 1H), 3.72 (d, 1H), 3.33 (m, 1H), 3.21-3.09 (m, 2H), 1.93 (m, 1H), 1.58 (m, 1H), 1.47 (m, 1H), 1.36 (m, 1H). LCMS (APCI+) m/z 337.1 (M+H)+, Retention time=0.43 minutes (Method 3).

Workup

  1. stirringthe reaction was stirred for 10 minutes at −78° C
  2. extractionthe mixture was extracted several times with DCM
  3. customThe layers were separated
  4. customdried
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by reverse phase chromatography (Biotage Horizon
  8. dissolutionThe product was dissolved in TFA (2 mL)
  9. stirringstirred for 30 minutes
  10. concentrationconcentrated
  11. custompurified by reverse phase chromatography (Biotage Horizon
  12. dissolutionThe product was redissolved in 10% MeOH in DCM (2 mL)
  13. additionadded dropwise to a stirred solution of 2M HCl in ether
  14. concentrationThe reaction was concentrated

Sources & evidence

ORD record
ord-347b324e95374df68ab9f77cc5a8ae0e
Source dataset
uspto-grants-2014_06
Patent number
US08758830B2

Linked notes

Loading…