1,4-Dioxane → HCID 49848229, compound

HRID 538654Notes

Reaction equation

HRID 538654 reaction equation
[Na].[CH2:2]([O:4][C:5](=[O:25])[CH2:6][NH:7][C:8]([C:10]1[C:15]([OH:16])=[CH:14][C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][N:11]=1)=[O:9])[CH3:3].O1CCOCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>O>[CH2:2]([O:4][C:5](=[O:25])[CH2:6][NH:7][C:8]([C:10]1[C:15]([OH:16])=[CH:14][C:13]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([F:40])[CH:46]=2)=[CH:12][N:11]=1)=[O:9])[CH3:3]

Participants

6

Reactant 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 27339863-Fluorophenylboronic acidHCID 86674850HCID 86674850, compound

Product 1

HCID 49848229HCID 49848229, compoundYield 90%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

To a 5 L round-bottomed flask was charged [(3-hydroxy-5-trifluoromethanesulfonyloxypyridine-2-carbonyl)-amino]-acetic acid ethyl ester sodium salt, 4, (310 g, 0.78 mol), 1,4-dioxane (3 L) and water (150 mL). The solution was subjected to a vacuum-nitrogen purge cycle, followed by the addition of potassium phosphate (50 g, 0.234 mol) and 3-fluorophenylboronic acid (163 g, 1.17 mol). After addition, the vacuum-nitrogen purge cycle was repeated once. 1,1-Bis(diphenyl-phosphino)ferrocenepalladium (II) chloride CH2Cl2 complex (72 g, 0.088 mol, 0.11 eq.) was then added. After another vacuum-nitrogen purge cycle, the reaction mixture was then heated to 75 to 85° C. The progress of the reaction was monitored by TLC. The reaction was complete after 14-16 hours. The reaction was cooled to 15 to 25° C. and concentrated by rotary evaporation at up to 45° C. bath temperature until solvent collection had ceased. The residue was treated with an aqueous solution of HCl (1M, 1.5 L) and ethyl acetate (1.5 L) and stirred for 30 minutes at room temperature. The layers were then separated. The organic layer was washed with water (1.5 L), brine (1.5 L), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethylacetate/acetic acid: 3:1:0.01 by vol/vol) to afford 226 g (90% yield) of the desired product. MS (ESI+): m/z 319 (M+1); 1H NMR (300 MHz, CDCl3) δ 11.88 (s, 1H), 8.44 (s, 1H), 8.32-0.31 (d, J=1.5 Hz, 1H), 7.51-7.44 (m, 2H), 7.40-7.37 (m, 1H), 7.32-7.27 (m, 1H), 7.17-7.13 (t, J=6.6 Hz, 1H), 4.33-4.25 (m, 4H), 1.36-1.31 (t, J=7.2 Hz, 3H).

Workup

  1. custompurge cycle
  2. additionAfter addition
  3. customthe vacuum-nitrogen purge cycle
  4. customAfter another vacuum-nitrogen purge cycle
  5. temperatureThe reaction was cooled to 15 to 25° C.
  6. concentrationconcentrated by rotary evaporation at up to 45° C. bath temperature
  7. customuntil solvent collection
  8. additionThe residue was treated with an aqueous solution of HCl (1M, 1.5 L) and ethyl acetate (1.5 L)
  9. customThe layers were then separated
  10. washThe organic layer was washed with water (1.5 L), brine (1.5 L)
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe crude product was purified by silica gel column chromatography (hexane/ethylacetate/acetic acid: 3:1:0.01 by vol/vol)

Sources & evidence

ORD record
ord-6e38335d3ba84282aaeefe6f3df15f47
Source dataset
uspto-grants-2014_10
Patent number
US08865748B2

Reaction notes

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