Triethylamine → 6-((3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)ethynyl)nicotinonitrile

HRID 930338Notes

Reaction equation

HRID 930338 reaction equation
[C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:22])=[C:7]([C@:9]2([CH2:20][F:21])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH2:19])=[N:10]2)[CH:8]=1)#[CH:2].Br[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=1.C(N(CC)CC)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:19][C:11]1[O:12][C@H:13]([C:15]([F:16])([F:17])[F:18])[CH2:14][C@:9]([C:7]2[CH:8]=[C:3]([C:1]#[C:2][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=3)[CH:4]=[CH:5][C:6]=2[F:22])([CH2:20][F:21])[N:10]=1

Participants

7

Reactant 3

HCID 8471TriethylamineHCID 50057186-Bromopyridine-3-carbonitrileHCID 86732163(4S,6S)-4-(5-ethynyl-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine

Product 1

HCID 862791556-((3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)ethynyl)nicotinonitrileYield 53%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of (4S,6S)-4-(5-ethynyl-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (70 mg, 0.220 mmol), 6-bromonicotinonitrile (60.4 mg, 0.330 mmol), triethylamine (92 μl, 0.660 mmol), tetrakis (25.4 mg, 0.022 mmol), and copper(I) iodide (8.38 mg, 0.044 mmol) in 2 mL of THF in a microwave vial was heated at 80° C. for 20 min. The reaction mixture was filtered and purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 16 min. The desired fractions were combined, neutralized with 1N NaOH, extracted with 3×25 mL of DCM, dried over Na2SO4 and concentrated to afford the title compound as a white solid: 49 mg, 53% yield. MS m/z=421.0 [M+H]+. Calculated for C20H13F5N4O: 420.1.

Workup

  1. filtrationThe reaction mixture was filtered
  2. custompurified by reverse-phase preparative HPLC
  3. customover 16 min
  4. extractionextracted with 3×25 mL of DCM
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-cc73e03fb19c410197d42fcd9b5e27b6
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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