Potassium Carbonate → N-(5-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-6-fluoropyridin-3-yl)-5-chloropicolinamide

HRID 930302Notes

Reaction equation

HRID 930302 reaction equation
Br[C:2]1[CH:3]=[C:4]([C@:9]2([CH3:20])[CH2:14][C@@H:13]([C:15]([F:18])([F:17])[F:16])[O:12][C:11]([NH2:19])=[N:10]2)[C:5]([F:8])=[N:6][CH:7]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([NH2:30])=[O:29])=[N:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[NH2:19][C:11]1[O:12][C@H:13]([C:15]([F:18])([F:17])[F:16])[CH2:14][C@:9]([C:4]2[CH:3]=[C:2]([NH:30][C:28](=[O:29])[C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][N:26]=3)[CH:7]=[N:6][C:5]=2[F:8])([CH3:20])[N:10]=1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 218831585-Chloropyridine-2-carboxamide2×HCID 86732132(4S,6S)-4-(5-bromo-2-fluoropyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine

Product 1

HCID 78321763N-(5-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-6-fluoropyridin-3-yl)-5-chloropicolinamideYield 53.3%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
125 °C

Procedure

A sealable vial was charged with (4S,6S)-4-(5-bromo-2-fluoropyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (5l, 0.093 g, 0.261 mmol), 5-chloropicolinamide (intermediate 18, 0.082 g, 0.522 mmol), copper(I) iodide (10 mg, 0.052 mmol) and potassium carbonate (0.108 mg, 0.783 mmol). The vial was purged with Nitrogen, followed by the addition of 1,4-dioxane (2.0 mL) and (1R,2R)-N,N′-dimethyl-cyclohexane-1,2-diamine (0.033 mL, 0.209 mmol). The vial was sealed and heated to 125° C. for 17 h. The reaction mixture was allowed to cool to room temperature and partitioned between EtOAc and water. The aqueous layer was backextracted with EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. The filtrate was concentrated and the residue was purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 80% over 20 min. The product containing fractions were combined and neutralized with aqueous saturated sodium bicarbonate solution. The free-based product was extracted with DCM. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford the title compound (0.060 g, 0.139 mmol, 53.2% yield) as white solid (free base). MS m/z=432.0 [M+H]+. Calculated for C17H14ClF4N5O2: 431.8

Workup

  1. customThe vial was purged with Nitrogen
  2. customThe vial was sealed
  3. temperatureto cool to room temperature
  4. custompartitioned between EtOAc and water
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried over sodium sulfate
  7. concentrationThe filtrate was concentrated
  8. customthe residue was purified by reversed-phase preparative HPLC
  9. customover 20 min
  10. additionThe product containing fractions
  11. extractionThe free-based product was extracted with DCM
  12. dry with materialThe organic phase was dried over MgSO4
  13. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-ac6830ae054b4e059fefe664e68bc0bb
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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