Synthetic method of flucloxacillin sodium

A technology of flucloxacillin sodium and a synthesis method, which is applied in the field of antibiotic synthesis, can solve problems such as seriousness, equipment corrosion, and storage difficulties, and achieves the effects of reducing production costs, facilitating production operations, and having high purity

Active Publication Date: 2019-03-01
ZHEJIANG APELOA TOSPO PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] For the above literature reports, we found that the synthesis of flucloxacillin sodium generally requires the use of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-formyl chloride (compound 3) intermediate, compound 3 As acyl chloride, the equipment is seriously corroded in the production process, and it is difficult to store

Method used

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  • Synthetic method of flucloxacillin sodium
  • Synthetic method of flucloxacillin sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] (1) Add 9L of dichloromethane, 3.0kg of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid, and 4.3kg of DM into a clean enamel reaction kettle.

[0054] (2) Start stirring and temperature control, and maintain the temperature of the material at 5-15°C.

[0055] (3) Add 1.3kg of triethylamine and 2.3Kg of triethyl phosphite mixture dropwise, and react for 3 hours.

[0056] (4) After the reaction, add 4L of purified water and 2.5kg of 6-APA,

[0057] (5) Continue to add 0.5Kg of triethylamine dropwise, maintain the temperature at 8-15°C, and keep the pH value at 6.5-8.5. Sampling and detection of 6-APA was less than 0.5%.

[0058] (6) Add dilute sulfuric acid dropwise, adjust the pH value to 5.0-6.5, stir for 5-10 minutes, and let stand to separate layers.

[0059] (7) Add 4 L of dichloromethane to the aqueous phase for extraction, stir for 5-10 minutes, and let stand to separate layers.

[0060] (8) Water phase collection Add 9 L of methyl acetate, cont...

Embodiment 2

[0069] (1) Add 10L of dichloromethane, 3.0kg of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid, and 5.0kg of DM into a clean enamel reaction kettle.

[0070] (2) Start stirring and temperature control materials to maintain a temperature of 5 ~ 15 ℃,

[0071] (3) Add 1.5 kg of triethylamine and 2.5 kg of triethyl phosphite mixture dropwise, and react for 3 to 5 hours.

[0072] (4) After the reaction, add 5L of purified water and 2.8kg of 6-APA,

[0073] (5) Continue to drop 0.8Kg of triethylamine to maintain the temperature at 8-15°C and the pH at 6.5-8.5. Sampling and detection of 6-APA was less than 0.5%.

[0074] (6) Add dilute sulfuric acid dropwise, adjust the pH to 5.0-6.5, stir for 5-10 minutes, and let stand to separate layers.

[0075] (7) Add 5 L of dichloromethane to the aqueous phase for extraction, stir for 5-10 minutes, and let stand to separate layers.

[0076] (8) Add 10 L of ethyl acetate for water phase collection, continue to add dilute s...

Embodiment 3

[0085] (1) Add 9L of dichloromethane, 3.0kg of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid, and 4.0kg of DM into a clean enamel reaction kettle.

[0086] (2) Start stirring and temperature control materials to maintain a temperature of 5 ~ 15 ℃,

[0087] (3) Add 1.2kg of triethylamine and 2.0Kg of triethyl phosphite mixture dropwise, and react for 3 to 5 hours.

[0088] (4) After the reaction, add 5L of purified water and 2.8kg of 6-APA,

[0089] (5) Continue to drop 0.5Kg of triethylamine to maintain the temperature at 8-15°C and the pH at 6.5-8.5. Sampling and detection of 6-APA was less than 0.5%.

[0090] (6) Add dilute sulfuric acid dropwise, adjust the pH to 5.0-6.5, stir for 5-10 minutes, and let stand to separate layers.

[0091] (7) Add 4 L of dichloromethane to the aqueous phase for extraction, stir for 5-10 minutes, and let stand to separate layers.

[0092] (8) Collect the aqueous phase and add 9 L of ethyl butyl acetate, continue to drop di...

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Abstract

The invention discloses a synthetic method of flucloxacillin sodium. The synthetic method of the flucloxacillin sodium comprises the following steps: (I) under the actions of triethylamine and triethyl phosphite, carrying out condensation reaction on 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-methanoic acid and dibenzothiazyl disulfide in dichloromethane to obtain an active ester reaction solution; and (II) adding water and 6-aminopenicillanic acid in the active ester reaction solution obtained in step (I), then dropwise adding triethylamine for amidation, and after reaction is finished,carrying out aftertreatment to obtain the flucloxacillin sodium. By the synthetic method, an acyl chloride intermediate is avoided, meanwhile, the intermediate does not need to be purified, followed-up steps are carried out directly through a one-pot method, the synthetic method is simple and convenient to operate, the yield and purity of the product are high, and industrialization is facilitated.

Description

technical field [0001] The invention belongs to the technical field of antibiotic synthesis, and in particular relates to a method for synthesizing improved flucloxacillin sodium. Background technique [0002] Flucloxacillin sodium, the chemical name is (2S,5R,6R)-6-[[[3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl]carbonyl]amino Sodium ]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate monohydrate, a semisynthetic penicillin-resistant enzyme Penicillin, which is an isoxazole derivative of penicillin, is similar in chemical structure to the other three isoxazole penicillins (cloxacillin, dicloxacillin, and oxacillin) currently in clinical use. It is mainly used to treat severe infections of penicillin-resistant Staphylococcus aureus, respiratory tract infections (such as acute pharyngitis, suppurative tonsillitis), treatment of secondary bacterial infections of colds, acute and chronic tracheitis, bronchitis, pneumonia, lung abscess, empyema , osteomye...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D499/76C07D499/06C07D499/18
CPCC07D499/06C07D499/18C07D499/76
Inventor 陈亮厉昆赵胜贤祝占根李如宏厉梦琳杨彩霞
Owner ZHEJIANG APELOA TOSPO PHARMA
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