Potassium methyl malonate → HCID 15232215, compound

HRID 1769269Notes

Reaction equation

HRID 1769269 reaction equation
[C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([O-])=[O:4].[K+].C[Mg]Cl.[Cl:13][C:14]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:15]=1C(Cl)=O>O1CCCC1>[CH3:8][O:7][C:1](=[O:6])[CH2:2][C:3]([C:15]1[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:14]=1[Cl:13])=[O:4]

Participants

5

Reactant 3

HCID 2724687Potassium methyl malonateHCID 101982172-Chloro-4,5-difluorobenzoyl chlorideHCID 178418332HCID 178418332, compound

Product 1

HCID 15232215HCID 15232215, compoundYield 91.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
32 °C

Procedure

A 400 liter glass-lined reactor was charged with 257 liters of tetrahydrofuran and 32.05 kg (205.2 moles, 2.1 eq) of potassium methyl malonate. While the reaction mixture was cooled to maintain the temperature below 40° C., 82.5 liters of 2.4M (198 moles, 2.02 eq) methyl magnesium chloride were added over about 1.5 hours. The addition resulted in a thick slurry of the malonate magnesium complex. The slurry was stirred for 0.5 hours at about 32° C. Then 2-chloro-4,5-difluorobenzoyl chloride (20.7 kg, 98.1 moles) was added with cooling, maintaining the temperature between 32° and 23° C. After the addition was complete, the turbid solution was stirred for 0.5 hours and was quenched into 154 1 of 2N HCl. The product was extracted with 114 1 of toluene. The organic layer was washed with 91 1 of saturated sodium bicarbonate/sodium chloride solution. The product/organic layer held 2.5% water (by Karl Fischer titration) which was higher than usual (i.e. 0.5 to 1.5%), so it was washed with 76 1 of saturated sodium chloride solution. The organic layer was concentrated by vacuum distillation to about 26 1 and 28 1 of isopropyl alcohol were then added. The product was crystallized by cooling to -10° to -12° C. The product was collected by filtration and then vacuum dried to give 22.3 kg (89.7 moles, 91.4 % yield) of the title compound. The high field NMR of the product was typical of that for a mixture of the keto (60%) and enol (40%) forms of the title compound. 300 MHz 1H NMR (CDCl3): 12.4 (s, 0.4H) , 7.5 (m, 1H), 7.3 (m, 1H), 5.6 (s, 0.4H), 4.0 (s, 1.2H), and the methyl esters 3.7 (s, 1.3H), 3.6 (s, 1.7H).

Workup

  1. temperatureWhile the reaction mixture was cooled
  2. additionwere added over about 1.5 hours
  3. additionThe addition
  4. customresulted in a thick slurry of the malonate magnesium complex
  5. temperaturewith cooling
  6. temperaturemaintaining the temperature between 32° and 23° C
  7. additionAfter the addition
  8. stirringthe turbid solution was stirred for 0.5 hours
  9. customwas quenched into 154 1 of 2N HCl
  10. extractionThe product was extracted with 114 1 of toluene
  11. washThe organic layer was washed with 91 1 of saturated sodium bicarbonate/sodium chloride solution
  12. washwas washed with 76 1 of saturated sodium chloride solution
  13. concentrationThe organic layer was concentrated by vacuum distillation to about 26 1 and 28 1 of isopropyl alcohol
  14. additionwere then added
  15. customThe product was crystallized
  16. temperatureby cooling to -10° to -12° C
  17. filtrationThe product was collected by filtration
  18. customvacuum dried

Sources & evidence

ORD record
ord-3d85c0b096994cceaae4f6744ddd1264
Source dataset
uspto-grants-1995_01
Patent number
US05380860

Reaction notes

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