HCID 68312472, compound → HCID 68312643, compound

HRID 1472888Notes

Reaction equation

HRID 1472888 reaction equation
[F:1][C:2]1[C:3]([CH:18]=[N:19][C@H:20]([CH:25]([CH3:27])[CH3:26])[C:21]([CH3:24])([OH:23])[CH3:22])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[H][H]>CO.[Ni]>[F:1][C:2]1[C:3]([CH2:18][NH:19][C@H:20]([CH:25]([CH3:27])[CH3:26])[C:21]([CH3:22])([OH:23])[CH3:24])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1

Participants

5

Reactant 2

HCID 68312472HCID 68312472, compoundHCID 178418361HCID 178418361, compound

Product 1

HCID 68312643HCID 68312643, compoundYield 54.6%

Reagents, catalysts & solvents 2

HCID 935NickelCatalystHCID 887MethanolSolvent

Procedure

Example 17A (800 mg, 2.97 mmol) and Example 105C (498 mg, 2.97 mmol) were dissolved in methanol (20 mL) and triethylamine (0.453 mL, 3.27 mmol). The yellow solution was stirred at ambient temperature for 90 minutes, followed by the addition of sodium borohydride (247 mg, 6.54 mmol). The reaction mixture was stirred over the weekend at ambient temperature, quenched with 100 mL 1.0 N NaOH, and extracted twice with 100 mL dichloromethane, dried over Na2SO4, filtered, and concentrated to obtain (R)-3-[({3-fluoro-6-[4-(trifluoromethyl)phenyl]pyridin-2-yl}methylene)amino]-2,4-dimethylpentan-2-ol (1.147 g, 3.00 mmol) as an orange oil. The imine (1.147 g, 3.00 mmol) in methanol (20 mL) was added to Raney Nickel (1.147 g) in a 50 mL pressure bottle. The mixture was pressurized with hydrogen (30 psi), and stirred for 48 hours at ambient temperature. The mixture was filtered through a nylon membrane, concentrated, and chromatographed on a Grace Reveleris 40 g column, eluted with 0-20% EtOAc in dichloromethane (30 mL/min) to provide the title compound (0.629 g, 1.636 mmol, 54.6% yield) as a colorless oil. MS (ESI+) m/z 385.0 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.29 (d, J=8.2, 2H), 8.06 (dd, J=8.7, 3.7, 1H), 7.92-7.78 (m, 3H), 4.25 (s, 1H), 4.16-3.99 (m, 2H), 2.36 (q, J=6.2, 1H), 2.26 (dd, J=5.9, 2.4, 1H), 2.03-1.89 (m, 1H), 1.11 (d, J=9.2, 6H), 0.93 (dd, J=6.8, 5.8, 6H).

Workup

  1. filtrationThe mixture was filtered through a nylon membrane
  2. concentrationconcentrated
  3. customchromatographed on a Grace Reveleris 40 g column
  4. washeluted with 0-20% EtOAc in dichloromethane (30 mL/min)

Sources & evidence

ORD record
ord-12336bf5a048494495e0fc6c1126180d
Source dataset
uspto-grants-2015_04
Patent number
US09012651B2

Reaction notes

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