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A kind of synthetic method of flucloxacillin sodium

A technology of flucloxacillin sodium and its synthetic method, which is applied in the field of antibiotic synthesis, can solve the problems of equipment corrosion, seriousness, difficulty in storage, etc., and achieve the effect of high purity

Active Publication Date: 2021-07-02
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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  • A kind of synthetic method of flucloxacillin sodium
  • A kind of 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, comprising the following steps: (1) under the action of triethylamine and triethyl phosphite, 3-(2-chloro-6-fluorophenyl)-5 -Methylisoxazole-4-formic acid and dibenzothiazole disulfide are condensed in dichloromethane to obtain active ester reaction liquid; (II) add water and 6-aminopenicillanic acid, and then triethylamine is added dropwise to carry out amidation reaction, and after the reaction finishes, obtain described flucloxacillin sodium through aftertreatment. The synthesis method avoids the use of the acid chloride intermediate, and at the same time the intermediate does not need to be purified, and the subsequent steps are directly carried out through a one-pot method, the operation is simple, and the yield and purity of the product are high, which is convenient for industrialization.

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 Patents(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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