Pivaloyl chloride → 4-Hydroxy-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl 2,2-dimethylpropanoate

HRID 347450Notes

Reaction equation

HRID 347450 reaction equation
[OH:1][C:2]1[C:3]([CH3:12])=[C:4]2[N:9]([CH:10]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:11].C(N(C(C)C)CC)(C)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].P([O-])(O)(O)=O.[K+]>C1(C)C=CC=CC=1.C1COCC1>[CH3:12][C:3]1[C:2]([O:1][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:10][N:9]2[C:4]=1[C:5](=[O:11])[NH:6][CH:7]=[N:8]2

Participants

7

Reactant 4

HCID 62493Pivaloyl chlorideHCID 81531DiisopropylethylamineHCID 516951Monobasic potassium phosphateHCID 1355031166-Hydroxy-5-methylpyrrolo[2,1-F][1,2,4]triazin-4(3H)-one

Product 1

HCID 1356205694-Hydroxy-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl 2,2-dimethylpropanoateYield 91.4%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
20 °C

Procedure

A mixture of 2.9 kg 6-hydroxy-5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one, 4.6 kg of diisopropylethylamine and 17.0 kg of THF was cooled to 0–10° C., then treated with 2.6 kg pivaloyl chloride at a rate to maintain the temperature<20° C. The mixture was stirred until the reaction was complete by HPLC, then 17.8 kg of toluene was added, followed by 20.6 kg of 15% aqueous potassium dihydrogen phosphate solution. The phases were separated and the organic was washed with 10.2 kg water. The organic phase was filtered, then distilled under vacuum with a maximum temperature of 65° C. Additional toluene can be added and distillation continued until the concentration of THF was <8%, and the total reactor volume was reduced to 31 L. The resulting slurry was cooled to 20–25° C. and treated with 20.3 kg heptane over 1.5 h. The slurry was cooled to 0–5° C. and held for 1 h, then the solid was collected by filtration and dried to yield 4.0 kg of 2,2-dimethyl-propionic acid 5-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-6-yl ester with a purity of 95-99%.

Workup

  1. temperaturewas cooled to 0–10° C.
  2. customThe phases were separated
  3. washthe organic was washed with 10.2 kg water
  4. filtrationThe organic phase was filtered
  5. distillationdistilled under vacuum with a maximum temperature of 65° C
  6. additionAdditional toluene can be added
  7. distillationdistillation
  8. temperatureThe resulting slurry was cooled to 20–25° C.
  9. additiontreated with 20.3 kg heptane over 1.5 h
  10. temperatureThe slurry was cooled to 0–5° C.
  11. filtrationthe solid was collected by filtration
  12. customdried

Sources & evidence

ORD record
ord-a57e18e15d474dfc86cb17e896da7361
Source dataset
uspto-grants-2007_02
Patent number
US07173031B2

Reaction notes

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