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EXAMPLE 3 A mixture of 606 kg of diethyl ethoxymethylenemalonate and 400 kg of 6-fluorotetrahydroquinaldine was stirred and heated at about 125 C. for 5 hours. The mixture was cooled to about 95 C. and evaporated. To the stirred reaction mixture was added 450 liters of toluene, then 908 kg of polyphosphoric acid at a rate to maintain a reaction temperature of 90 to 100 C. The mixture was then heated at reflux for fourteen hours. To this mixture was added 950 liters of water over five hours. The ester was saponified by heating for 13 hours at 110 to 115 C. while removing the toluene via the toluene-water azeotrope. The solid product flumequine was separated by filtration, washed thrice with hot water, then with N,N-dimethylformamide. Recrystallization form N,N-dimethylformamide gave white solid flumequine.
In sodium hydroxide; toluene;
EXAMPLE 2 6-Fluorotetrahydroquinaldine (12.05 kg containing 10% of toluene) and diethyl ethoxymethylene malonate (16.2 kg) were charged to a 225 liter Pfaudler reactor and heated at 125 C. under vacuum for 4 hours. Ethanol (3.1 kg) was recovered. The product was cooled, diluted with toluene (35 liters) and tetraphosphoric acid (35 kg), reheated to reflux for 2 hours, cooled to 80 C., diluted with water (128 liters) and refluxed for 6 hours to complete the hydrolysis. The crude flumequine was collected, washed acid free with water and rinsed with methanol. The damp cake was dissolved in sodium hydroxide solution (2.94 kg/59 liters) filtered hot through a cartridge filter heated to 90 C. and acidified with hydrochloric acid (6.64 liters). The product was collected, washed acid free, rinsed with methanol and dried in a vacuum oven. The yield of flumequine was 15.4 kg (90.8%). The dry solid was dissolved in N,N-dimethylformamide (70 liters) at 125 C., allowed to cool with stirring to 100 C. then cooled to 7 C. with cold water. The product was collected, washed with methanol and dried as before. The yield of recrystallized flumequine was 14.4 kg (82.3%) overall.
With PPA; In water; toluene;
EXAMPLE 4 A mixture of 606 kg of diethyl ethoxymethylenemalonate and 400 kg of 6-fluorotetrahydroquinaldine was stirred and heated at about 125 C. for 5 hours. The mixture was cooled to about 95 C. and evaporated. To the stirred reaction mixture was added 450 liters of toluene, then 908 kg of polyphosphoric acid at a rate to maintain a reaction temperature of 90 to 100 C. The mixture was then heated at reflux for fourteen hours. To this mixture was added 950 liters of water over five hours. The ester was saponified by heating for 13 hours at 110 to 115 C. while removing the toluene via the toluene-water ezeotrope. The solid product flumequine was separated by filtration, washed thrice with hot water, then with N,N-dimethylformamide. Recrystallization form N,N-dimethylformamide gave white solid flumequine.
In sodium hydroxide; toluene;
EXAMPLE 3 6-Fluorotetrahydroquinaldine (12.05 kg containing 10% of toluene) and diethyl ethoxymethylene malonate (16.2 kg) were charged to a 225 liter Pfaudler reactor and heated at 125 C. under vacuum for 4 hours. Ethanol (3.1 kg) was recovered. The product was cooled, diluted with toluene (35 liters) and tetraphosphoric acid (35 kg), reheated to reflux for 2 hours, cooled to 80 C., diluted with water (128 liters) and refluxed for 6 hours to complete the hydrolysis. The crude flumequine was collected, washed acid free with water and rinsed with methanol. The damp cake was dissolved in sodium hydroxide solution (2.94 kg/59 liters) filtered hot through a cartridge filter heated to 90 C. and acidified with hydrochloric acid (6.64 liters). The product was collected, washed acid free, rinsed with methanol and dried in a vacuum oven. The yield of flumequine was 15.4 kg (90.8%). The dry solid was dissolved in N,N-dimethylformamide (70 liters) at 125 C., allowed to cool with stirring to 100 C. then cooled to 7 C. with cold water. The product was collected, washed with methanol and dried as before. The yield of recrystallized flumequine was 14.4 kg (82.3%) overall.
Example N. 6 Preparation of 5- [1-(6-fluoro-2-methyl-1,2,3,4-tetrahydroquinolyl) ] -methylene-2,2-dimethyl 1,3-dioxan-4,6-dione 1.65 g (10 mmole) of 6-fluoro-2-methyl-1,2-3,4-tetrahydroquinoline and 2,05 g (11 mmole) of 2,2-dimethyl-5-methoxymethylene-1,3-dioxan-4,6-dione [prepared according to Monatshafte fuer Chemie, 98 , 565 (1967)] are reached under stirring and heating at 100-110C for 1 hour. The cooled reaction mass is taken up in tetrahydrofurane and the solids are filtered and dried. Yield: 2.5 g m.p.: 163-5C Flumequine is prepared from the resulting product according to the procedure of Example 1b.
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