Propylphosphonic anhydride → N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluoro-5-methylphenyl)-5-(difluoromethyl)-3-methylpicolinamide

HRID 930424Notes

Reaction equation

HRID 930424 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([CH3:22])[C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:23][CH:24]([F:35])[C:25]1[CH:26]=[C:27]([CH3:34])[C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31](=[O:32])[C:28]3[C:27]([CH3:34])=[CH:26][C:25]([CH:24]([F:23])[F:35])=[CH:30][N:29]=3)[CH:3]=[C:4]([CH3:22])[C:5]=2[F:21])([CH2:19][F:20])[N:9]=1

Participants

5

Reactant 3

HCID 111923Propylphosphonic anhydrideHCID 681103795-(Difluoromethyl)-3-methylpicolinic acidHCID 86732263HCID 86732263, compound

Product 1

HCID 86732264N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluoro-5-methylphenyl)-5-(difluoromethyl)-3-methylpicolinamideYield 12.69%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of (4S,6S)-4-(5-amino-2-fluoro-3-methylphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.075 g, 0.232 mmol) and 5-(difluoromethyl)-3-methylpicolinic acid (0.048 g, 0.255 mmol) in DMF (2 mL) at 0° C. was added 1-propanephosphonic acid cyclic anhydride (0.177 ml, 0.278 mmol) and the resulting mixture was stirred at 0° C. for 2 h, the ice bath was removed and stirred at rt for 1 h. The reaction was diluted with EtOAc, washed with water, sat. NaHCO3, and chromatographed on silica gel using 0-4% MeOH/DCM to afford a white solid as N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluoro-5-methylphenyl)-5-(difluoromethyl)-3-methylpicolinamide (0.0145 g, 0.029 mmol, 12.69% yield). MS m/z=492.9 [M+H]+. Calculated for C21H19F7N4O2: 492.14.

Workup

  1. customthe ice bath was removed
  2. stirringstirred at rt for 1 h
  3. additionThe reaction was diluted with EtOAc
  4. washwashed with water, sat. NaHCO3
  5. customchromatographed on silica gel using 0-4% MeOH/DCM

Sources & evidence

ORD record
ord-38a1c55a8f0a4fe1b866a279d08b71d0
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

Loading…