HCID 68312397, compound → HCID 68312912, compound

HRID 1472891Notes

Reaction equation

HRID 1472891 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)=[N:6][C:7]=1[CH:8]=[N:9][C@H:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([OH:13])[CH3:12].[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=2)=[N:6][C:7]=1[CH2:8][NH:9][C@H:10]([CH:14]([CH3:15])[CH3:16])[CH:11]([OH:13])[CH3:12]

Participants

5

Reactant 2

HCID 68312397HCID 68312397, compoundHCID 178418361HCID 178418361, compound

Product 1

HCID 68312912HCID 68312912, compoundYield 49.7%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Procedure

Example 28A (399 mg, 1.477 mmol) and Example 107B (238 mg, 1.551 mmol) were dissolved in methanol (20 mL) and triethylamine (0.225 mL, 1.624 mmol). The orange solution was stirred at ambient temperature for 1 hour and 55 minutes, followed by the addition of sodium borohydride (123 mg, 3.25 mmol). After 4 hours, additional sodium borohydride (123 mg, 3.25 mmol) was added, and 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-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methylene}amino)-4-methylpentan-2-ol (500 mg, 1.354 mmol) as an orange oil. The imine (500 mg, 1.354 mmol) in methanol (20 mL) was added to 5% palladium on carbon (100 mg) in a 250 mL stainless steel pressure bottle. The mixture was pressurized with hydrogen (30 psi), and stirred for 18 hours at ambient temperature. The mixture was filtered through a nylon membrane, concentrated to a yellow oil, and chromatographed on a Grace Reveleris 40 g column, eluted with 0-50% EtOAc in dichloromethane (30 mL/min) to provide the title compound (250 mg, 0.673 mmol, 49.7% yield) as a yellow oil, a 3:1 mix of diastereomers by proton NMR. MS (ESI+) m/z 372.0 (M+H); 1H NMR (300 MHz, MeOH-D4) δ 9.39 (d, J=1.8, 1H), 8.71-8.64 (m, 1H), 8.02 (dd, J=8.6, 3.6, 1H), 7.92 (d, J=8.3, 1H), 7.76-7.66 (m, 1H), 4.27-4.04 (m, 2H), 3.95-3.86 (m, 0.25H), 3.83-3.73 (m, 0.75H), 2.37 (t, J=5.6, 0.25H), 2.27 (dd, J=6.1, 4.6, 0.75H), 2.00-1.88 (m, 1H), 1.25-1.18 (m, 3H), 1.08-1.01 (m, 3H), 1.00-0.93 (m, 3H).

Workup

  1. filtrationThe mixture was filtered through a nylon membrane
  2. concentrationconcentrated to a yellow oil
  3. customchromatographed on a Grace Reveleris 40 g column
  4. washeluted with 0-50% EtOAc in dichloromethane (30 mL/min)

Sources & evidence

ORD record
ord-e1f811c268c945f4bd37f8fe83b6bda9
Source dataset
uspto-grants-2015_04
Patent number
US09012651B2

Reaction notes

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