Borane;tetrahydrofuran → HCID 68973173, compound

HRID 1782565Notes

Reaction equation

HRID 1782565 reaction equation
[C:1]([CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13](=[O:21])[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[N:16][CH:15]=2)[CH2:8][CH2:7]1)[CH3:5])#[N:2].B.C1C[O:32]CC1>C1COCC1>[CH3:13][OH:21].[NH4+:2].[OH-:32].[NH2:2][CH2:1][CH2:3][C@H:4]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:11]1)[CH3:5]

Participants

5

Reactant 2

HCID 2723981Borane;tetrahydrofuranHCID 68973493(R)-N-[1-(2-cyano-1-methyl-ethyl)-piperidin-4-yl]-4-methyl-N-phenyl-nicotinamide

Product 2

HCID 21894508Ammonium hydroxide methanolHCID 68973173HCID 68973173, compoundYield 79%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
65 °C

Procedure

To a solution of (R)-N-[1-(2-cyano-1-methyl-ethyl)-piperidin-4-yl]-4-methyl-N-phenyl-nicotinamide (3.85 g, 10.62 mmol) in THF (150 mL) was added a solution of borane-THF in THF (1.0 M, 63.72 mL, 63.7 mmol) and the reaction was refluxed for 16 h. The reaction was cooled and carefully quenched with 6N HCl (150 mL) and heated to 65° C. for 2 h. The mixture was cooled and concentrated to remove the THF. The remaining aqueous solution was neutralized to pH>12 with 10N NaOH and diluted with CH2Cl2 (100 mL). The two phases were separated and the aqueous layer was extracted with CH2Cl2 (4×100 mL). The combined organic extracts were dried (Na2SO4) and purified by column chromatography on silica gel (83:15:2, CH2C2/MeOH/NH4OH) to give [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methyl-pyridin-3-ylmethyl)-phenyl-amine as a yellow oil (2.97 g, 79%). 1H-NMR (CDCl3) δ 0.97 (d, 3H, J=6 Hz), 1.43 (m, 4H), 1.64 (m, 4H), 1.90 (m, 2H), 2.26 (dt, 1H, J=2 Hz, 11 Hz), 2.34 (s, 3H), 2.45 (dt, 1H, J=2 Hz, 11 Hz), 2.77 (m, 5H), 3.76 (m, 1H), 4.39 (s, 2H), 6.65 (m, 2H), 6.71 (m, 1H), 7.07 (d, 1H, J=5 Hz), 7.17 (m, 2H), 8.36 (d, 1H, J=5 Hz), 8.38 (s, 1H).

Workup

  1. temperaturethe reaction was refluxed for 16 h
  2. temperatureThe reaction was cooled
  3. customcarefully quenched with 6N HCl (150 mL)
  4. temperatureThe mixture was cooled
  5. concentrationconcentrated
  6. customto remove the THF
  7. additiondiluted with CH2Cl2 (100 mL)
  8. customThe two phases were separated
  9. extractionthe aqueous layer was extracted with CH2Cl2 (4×100 mL)
  10. dry with materialThe combined organic extracts were dried (Na2SO4)
  11. custompurified by column chromatography on silica gel (83:15:2

Sources & evidence

ORD record
ord-eafe50b759a641cfb474d19673f6e6eb
Source dataset
uspto-grants-2009_03
Patent number
US07498346B2

Reaction notes

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