4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride → N-(5-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-6-fluoropyridin-3-yl)-3-chloro-5-cyanopicolinamide

HRID 930303Notes

Reaction equation

HRID 930303 reaction equation
[NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:29])([F:28])[F:27])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16]C(=O)C3C=CC(Cl)=CN=3)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1.[Cl:30][C:31]1[C:32]([C:39]([OH:41])=O)=[N:33][CH:34]=[C:35]([C:37]#[N:38])[CH:36]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CO>[NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:27])([F:29])[F:28])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16][C:39](=[O:41])[C:32]3[C:31]([Cl:30])=[CH:36][C:35]([C:37]#[N:38])=[CH:34][N:33]=3)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1

Participants

6

Reactant 3

HCID 27340594-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride2×HCID 508531763-Chloro-5-cyanopyridine-2-carboxylic acid2×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-chloropicolinamide

Product 1

HCID 86732133N-(5-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-6-fluoropyridin-3-yl)-3-chloro-5-cyanopicolinamideYield 22.2%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

A flask was charged with (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (6a, 0.075 g, 0.257 mmol) and 3-chloro-5-cyanopicolinic acid (Bionet Research, 0.047 g, 0.257 mmol). The solids were dissolved in a mixture of THF (2 mL)/MeOH (1 mL) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (Aldrich, 0.129 g, 0.436 mmol) was added. The reaction was stirred at RT for 25 min. Additional 0.5 equiv. chloro-5-cyanopicolinic acid and 1 equiv. 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride were added. After 1 hour, the reaction was quenched with aqueous saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine and dried over sodium sulfate. The filtrate was concentrated and 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 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 (0.026 g, 0.057 mmol, 22.18% yield) as white solid. MS m/z=457 [M+H]+. Calculated for C18H13ClF4N6O2: 456.8

Workup

  1. additionwas added
  2. waitAfter 1 hour
  3. customthe reaction was quenched with aqueous saturated sodium bicarbonate solution
  4. extractionextracted with EtOAc
  5. washThe organic layer was washed with brine
  6. dry with materialdried over sodium sulfate
  7. concentrationThe filtrate was concentrated
  8. custompurified 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-fefad994b38c490497019103e2f5fdff
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

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