Borane;tetrahydrofuran → HCID 68971363, compound

HRID 1782574Notes

Reaction equation

HRID 1782574 reaction equation
[C:1]([CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[C:13](=O)[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.C1COCC1>C1COCC1>[NH2:2][CH2:1][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][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:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[CH2:8][CH2:7]1)[CH3:5]

Participants

4

Reactant 2

HCID 2723981Borane;tetrahydrofuranHCID 68971677HCID 68971677, compound

Product 1

HCID 68971363HCID 68971363, compoundYield 58.5%

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-(6-trifluoromethyl-pyridin-3-yl)-nicotinamide (0.62 g, 1.44 mmol) in THF (25 mL) was added a solution of borane-THF in THF (1.0 M, 8.62 mL, 8.62 mmol) and the reaction was refluxed for 16 h. The reaction was cooled and carefully quenched with 9N HCl (14 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>13 with 10N NaOH and diluted with CH2Cl2 (50 mL). The two phases were separated and the aqueous layer was extracted with CH2Cl2 (4×50 mL). The combined organic extracts were dried (Na2SO4) and purified by column chromatography on silica gel (92:7:1, CH2Cl2/MeOH/NH4OH) to afford [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methyl-pyridin-3-ylmethyl)-(6-trifluoromethyl-pyridin-3-yl)-amine as a pale yellow oil (0.355 g, 58%). 1H-NMR (CDCl3) δ 0.98 (d, 3H, J=7 Hz), 1.41 (m, 2H), 1.51 (m, 2H), 1.68 (m, 4H), 1.91 (m, 2H), 2.72 (dt, 1H, J=2 Hz, 12 Hz), 2.35 (s, 3H), 2.51 (dt, 1H, J=2 Hz, 11 Hz), 2.72 (m, 3H), 2.86 (m, 2H), 3.84 (m, 1H), 4.46 (s, 2H), 6.90 (dd, 1H, J=3 Hz, 9 Hz), 7.11 (d, 1H, J=5 Hz), 7.42 (d, 1H, J=9 Hz), 8.08 (d, 1H, J=3 Hz), 8.24 (s, 1H), 8.39 (d, 1H, J=5 Hz).

Workup

  1. temperaturethe reaction was refluxed for 16 h
  2. temperatureThe reaction was cooled
  3. customcarefully quenched with 9N HCl (14 mL)
  4. temperatureThe mixture was cooled
  5. concentrationconcentrated
  6. customto remove the THF
  7. additiondiluted with CH2Cl2 (50 mL)
  8. customThe two phases were separated
  9. extractionthe aqueous layer was extracted with CH2Cl2 (4×50 mL)
  10. dry with materialThe combined organic extracts were dried (Na2SO4)
  11. custompurified by column chromatography on silica gel (92:7:1, CH2Cl2/MeOH/NH4OH)

Sources & evidence

ORD record
ord-4d29fa598da24304a5781972f6286d78
Source dataset
uspto-grants-2009_03
Patent number
US07498346B2

Reaction notes

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