HCID 68312715, compound → HCID 68312623, compound

HRID 1472890Notes

Reaction equation

HRID 1472890 reaction equation
[F:1][C:2]1[C:3]([CH:18]=[N:19][C@H:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([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]>C1COCC1.[Ni]>[F:1][C:2]1[C:3]([CH2:18][NH:19][C@H:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([OH:23])[CH3:22])=[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 68312715HCID 68312715, compoundHCID 178418361HCID 178418361, compound

Product 1

HCID 68312623HCID 68312623, compoundYield 52.5%

Reagents, catalysts & solvents 2

HCID 935NickelCatalystHCID 8028TetrahydrofuranSolvent

Procedure

Example 17A (767 mg, 2.85 mmol) and Example 107B (460 mg, 2.99 mmol) were dissolve in methanol (20 mL) and triethylamine (0.434 mL, 3.13 mmol). The orange solution was stirred at ambient temperature for 2 hours and 20 minutes, followed by the addition of sodium borohydride (237 mg, 6.27 mmol). After 4 hours, additional sodium borohydride (237 mg, 6.27 mmol) was added. The reaction was stirred overnight at ambient temperature, quenched with 100 mL 1.0 N NaOH, and extracted twice with 100 mL dichloromethane. The combined organic phase was dried over Na2SO4, filtered, and concentrated to provide (3R)-3-[({3-fluoro-6-[4-(trifluoromethyl)phenyl]pyridin-2-yl}methylene)amino]-4-methylpentan-2-ol (1.009 g, 2.74 mmol) as an orange oil. The imine (1.009 g, 2.74 mmol) in THF (40 mL) was added to Raney Nickel (1.009 g) in a 250 mL stainless steel pressure bottle. The mixture was pressurized with hydrogen (30 psi), and stirred for 20 hours at ambient temperature. The mixture was filtered through a nylon membrane, concentrated, and chromatographed on a Grace Reveleris 40 g column, eluted with 0-30% EtOAc in dichloromethane (30 mL/min) to provide the title compound (0.533 g, 1.439 mmol, 52.5% yield) as a yellow oil, a 3:1 mix of diastereomers by proton NMR. MS (ESI+) m/z 371.1 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.29 (d, J=8.3, 2H), 8.05 (dd, J=8.6, 3.7, 1H), 7.89-7.77 (m, 3H), 4.43 (d, J=4.8, 0.75H), 4.38 (d, J=5.2, 0.25H), 4.14-3.95 (m, 2H), 3.71-3.58 (m, 1H), 2.40-2.29 (m, 0.75H), 2.25-2.17 (m, 0.25H), 2.15-2.06 (m, 1H), 1.93-1.73 (m, 1H), 1.11-1.04 (m, 3H), 0.96-0.79 (m, 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 0-30% EtOAc in dichloromethane (30 mL/min)

Sources & evidence

ORD record
ord-cc898c8fcd5c487bbc76953d7c50b45c
Source dataset
uspto-grants-2015_04
Patent number
US09012651B2

Reaction notes

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