Potassium methyl malonate → HCID 15232215, compound

Participants

Reaction Conditions

Reaction Steps

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).

Provenance & Evidence