Pyridine → Carbonic acid 2-(3-{1-(4-cyanophenylamino)-2-[ethoxycarbonylimino]-2-methylsulfanylethyl]-2-fluoro-5-methoxyphenoxy)ethyl ester ethyl ester

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Reaction Steps

After the atmosphere in the reaction vessel had been replaced with nitrogen, toluene (1126 mL) and acetonitrile (1126 mL) were added. While stirring the resulting mixture at room temperature, 2-(4-cyanophenylamino)-2-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxypheny l]thioacetamide (837.5 g, net weight 750.4 g, 1.999 mol) was added portionwise. After rinsing in with a mixed solvent of toluene:acetonitrile=1:1 (750 mL), the bath temperature was set at 18° C. To this mixture, trimethyloxonium tetrafluoroborate (311 g, 1.999 mol) was added portionwise over a period of about 2 hours, rinsing in with acetonitrile (750 mL), and the mixture was stirred 3 hours at a bath temperature of 22° C. Trimethyloxonium tetrafluoroborate (15.6 g, 0.100 mol) was additionally added, the mixture was further stirred for about 2 hours, and then the bath temperature was set at 0° C. and the mixture was stirred for 12 hours. At the bath temperature of 0° C., ethyl chloroformate (911 g, 8.395 mol) was added dropwise to the reaction solution obtained, followed by dropwise addition of pyridine (889 g, 11.233 mol) at an internal temperature of 16° C. or less. Thereafter, the resulting mixture was stirred at a bath temperature of 22° C. for 2 hours, ethyl acetate (7504 mL) and water (7504 mL) were added to the mixture, and the organic layer was collected. The organic layer was sequentially washed with water (7504 mL) and 5% sodium bicarbonate water, then with 10% aqueous sodium chloride solution (7504 g) twice, and concentrated under reduced pressure to about 2300 mL. To the residue obtained, tetrahydrofuran was added and the mixture was further subjected to azeotropic distillation three times (2500 mL, 2500 mL, then 2250 mL of tetrahydrofuran was used) to obtain a tetrahydrofuran solution of the captioned compound.

Provenance & Evidence