Diisopropylethylamine → N-(3-((4S,6S)-2-benzamido-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide

HRID 930280Notes

Reaction equation

HRID 930280 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9]2)[CH:7]=1.[CH3:30][O:31][C:32]1[N:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>CN(C=O)C.O.CCOC(C)=O>[C:19]([NH:18][C:10]1[O:11][C@H:12]([C:14]([F:15])([F:16])[F:17])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:38]([C:35]3[CH:34]=[N:33][C:32]([O:31][CH3:30])=[CH:37][N:36]=3)=[O:39])[CH:3]=[CH:4][C:5]=2[F:29])([CH2:27][F:28])[N:9]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 457898115-Methoxy-2-pyrazinecarboxylic acidHCID 86732108N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamideHCID 178484293HCID 178484293, compound

Product 1

HCID 86732110N-(3-((4S,6S)-2-benzamido-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of crude N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1k, 0.25 g, 0.605 mmol, step 9) in DMF (3 ml) was added 5-methoxypyrazine-2-carboxylic acid (0.117 g, 0.756 mmol, Ark Pharm), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.345 g, 0.907 mmol, Oakwood Products) and di-isopropylethylamine (0.156 g, 1.210 mmol, Aldrich). The reaction was stirred at ambient temperature for 10 minutes. The reaction was diluted with water and EtOAc. The organic layer was separated and washed sequentially with aqueous saturated sodium bicarbonate solution, 1 M aqueous LiCl solution, and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude material was purified via silica gel flash chromatography using a gradient of 0-45% EtOAc in hexanes to afford the title compound as a white solid (0.110 g, 0.2 mmol, 33% overall yield for this step and steps 9 in Example 1). MS m/z=550.0 [M+H]+. Calculated for C25H20F5N5O4: 549.449

Workup

  1. customThe organic layer was separated
  2. washwashed sequentially with aqueous saturated sodium bicarbonate solution, 1 M aqueous LiCl solution, and brine
  3. dry with materialThe organic layer was dried over magnesium sulfate
  4. concentrationconcentrated under reduced pressure
  5. customThe crude material was purified via silica gel flash chromatography

Sources & evidence

ORD record
ord-6777f98723194166bfdea2bbab74638d
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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