Flucloxacillin sodium

White Solid

Add 100 g of water to the reaction flask and add 20.0 g of 6-APA with stirring to cool to 0 to 5 ° C. Weigh 10.6 g of sodium carbonate dissolved in 100 mL of water, Dubbed 1 mol / L sodium carbonate solution; temperature control below 10 ° C, The sodium carbonate solution was added dropwise to the reaction flask, 6-APA sodium salt aqueous solution;A mixture of 28.0 g of 3- (2-chloro-6-fluorophenyl) -5-methylisoxazole-4-carboxylic acid chloride was added to the reaction flask, The feeding time is controlled to 1 hour.Insulation 20 ~ 25 ° C reaction 4 hours;1 mol / L dilute hydrochloric acid was added dropwise to the above reaction solution, Adjust the pH to 2.5; 400 g of ethyl acetate was added to the reaction flask, Stirring, dispensing, The ethyl acetate phase was separated.Ethyl acetate phase200 g of saturated brine, And then dried over 20 g of anhydrous sodium sulfate for 30 minutes;A solution of flucloxacin acid in ethyl acetate;Weigh 18.0 g of sodium isooctanoate was dissolved in 108 mL of ethyl acetate, Dubbed 1 mol / L sodium isooctanoate solution;Will be differentSodium octanoate solution was added dropwise to a solution of flushloxacin in ethyl acetate, Drop finished, precipitation of white solid; cooling to 5 ~ 10 ° C crystallization 3 hours, The filter cake was washed twice with ethyl acetate, 50 ° C vacuum drying, Fluorocillin sodium monohydrate 41.3 g, productPurity 99.8percent (HPLC), yield 90.6percent(1) In a clean enamel reactor, 9 L of dichloromethane, 3.0 kg of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid was added, and DM 4.0 kg was added.(2) Start stirring and temperature control materials to maintain the temperature of 5 ~ 15 C, (3) A mixture of 1.2 kg of triethylamine and triethyl phosphite 2.0 Kg was added dropwise, and the reaction was carried out for 3 to 5 hours.(4) Add 5 L of purified water at the end of the reaction, and add 2.8 kg of 6-APA.(5) Continue to add 0.3Kg of triethylamine to maintain the temperature of 8-15 C, pH 6.5 ~ 8.5. Sampling detection 6-APA is less than0.5%.(6) Dilute sulfuric acid was added dropwise, the pH was adjusted to 5.0 to 6.5, stirred for 5-10 minutes, and allowed to stand for stratification.(7) The aqueous phase was extracted with 4 L of dichloromethane, stirred for 5-10 minutes, and allowed to stand for stratification.(8) The aqueous phase was collected by adding 9 L of ethyl butyl acetate, and dilute sulfuric acid was continuously added dropwise to adjust the pH to 2.0-2.5. Stir for 10 minutesbell.(9) stratification, collecting the oil phase; the aqueous phase plus butyl acetate 5L was extracted once and layered.(10) Combine the oil phases, add 0.5 kg of activated carbon to the oil phase, and decolorize for 30 minutes.(11) Filtration, collection of the filtrate, and addition of 1.5 kg of anhydrous sodium acetate to the filtrate.(12) Stir the crystal for 30 minutes at a temperature of 20 to 35 C.(13) Add 50 L of n-butanol and raise the crystal for 20 minutes.(14) Filtration, and the product was washed with 25 L of butyl acetate.(15) drying under reduced pressure to obtain 5.6 kg of flucloxacillin sodium monohydrate, the total molar yield was 96.55%, HPLC pureThe degree is 99.82%.Add 100 g of water to the reaction flask and add 20.0 g of 6-APA with stirring to cool to 0 to 5 C. Weigh 10.6 g of sodium carbonate dissolved in 100 mL of water, Dubbed 1 mol / L sodium carbonate solution; temperature control below 10 C, The sodium carbonate solution was added dropwise to the reaction flask, 6-APA sodium salt aqueous solution;A mixture of 28.0 g of 3- (2-chloro-6-fluorophenyl) -5-methylisoxazole-4-carboxylic acid chloride was added to the reaction flask, The feeding time is controlled to 1 hour.Insulation 20 ~ 25 C reaction 4 hours;1 mol / L dilute hydrochloric acid was added dropwise to the above reaction solution, Adjust the pH to 2.5; 400 g of ethyl acetate was added to the reaction flask, Stirring, dispensing, The ethyl acetate phase was separated.Ethyl acetate phase200 g of saturated brine, And then dried over 20 g of anhydrous sodium sulfate for 30 minutes;A solution of flucloxacin acid in ethyl acetate;Weigh 18.0 g of sodium isooctanoate was dissolved in 108 mL of ethyl acetate, Dubbed 1 mol / L sodium isooctanoate solution;Will be differentSodium octanoate solution was added dropwise to a solution of flushloxacin in ethyl acetate, Drop finished, precipitation of white solid; cooling to 5 ~ 10 C crystallization 3 hours, The filter cake was washed twice with ethyl acetate, 50 C vacuum drying, Fluorocillin sodium monohydrate 41.3 g, productPurity 99.8% (HPLC), yield 90.6%Add the solution of flucloxacillin triethylamine in acetone500ml three-necked flask, Then, sodium isooctanoate ethyl acetate solution (8.0 g of sodium isooctanoate + 240 ml of ethyl acetate) and 1 ml of water were added, Temperature control 20 ~ 25 , stirring crystallization 3h, after filtration, Washed and dried to give 20.3 g of flucloxacillin sodium monohydrate, purity 99.2%, yield 87.6%.2-chloro-6-fluorobenzaldehyde (850g) is dissolved in methanol (2.5-2.6L) at room temperature. Hydroxylamine salt (475-500 g) was added and the reaction mixture was heated to 38-40aC for 1 hour followed by addition of sodium carbonate (460-500g). The pH is maintained at around 9.5 and the reaction mixture is cooled to room temperature. Triethylamine (4g) is added and chlorine gas (400-500g) is passed for about 24hrs by maintaining a temperature of 0-5aC. Nitrogen gas is purged for 4-5 hrs. After the completion of the chlorination reaction, methanol (approx 1000L) is added followed by addition of sodium carbonate (about 600g) to reach a pH of around 7-7.5. Methylacetoacetate (500-550g) and soda ash (25-50g) is added to the reaction mixture till an exothermic reaction is achieved. The solution thus obtained was saponified by the addition of caustic flakes (about 460g). Sulphuric acid was added and the pH was adjusted to around 8.6-8.8. Organic impurities are extracted in solvent , acid is isolated dried , added in Toluene(about 3.5) then Phosphorous pentachloride (about 540g) was added with constant stirring. After reaction is over , organic layer is washed with water , Toluene recovered under reduced pressure. To this resulting solution of 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazole-carbonyl chloride, ethyl acetate was added. 6-aminopenicillanic acid (300g) was dissolved in ammonium hydroxide (260- 270ml_) and pH was adjusted to 7.0-9.0. This solution was then added to the reaction solution containing 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazole-carbonyl chloride (399g) and the pH was maintained to be around 2.0-2.3. Common salt (1 OOg) was added with constant stirring and the layers were allowed to settle. Organic layers were separated and the combined extracts were then washed with brine followed by addition of sodium-2-ethyl hexanoate (590-630g) while maintaining the pH at 7.8-8.1 . The solution was then agitated and cooled to 0 to 5aC. The resulting precipitate was filtered under reduced pressure and nitrogen gas atmosphere. The wet precipitate was then subject to vacuum drying to yield sodium salt of 6-[[3-(2-chloro-6-fluorophenyl)-5-methyl-1 , 2-oxazole-4-carbonyl]amino]-3, 3- dimethyl-7-oxo-4-thia-1 -azabicyclo[3.2.0]heptane-2-carboxylic acid (flucloxacillin sodium).The following beta-lactam antibiotics were microencapsulated by a process analogous to that of Cloxacillin sodium

Flucloxacillin, a new semisynthetic penicillin