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A kind of preparation method of flucloxacillin sodium

A technology of flucloxacillin sodium and dichloromethane, which is applied in the field of antibiotic drug synthesis, can solve the problems of high product impurities, high product impurities, and low yield, and achieve the effects of good purity, simple operation, and mild reaction conditions

Active Publication Date: 2016-08-24
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above two documents all use acid chloride and 6-APA dissolved in water to carry out acylation reaction, and acid chloride is a compound that is easily decomposed when encountering water, so this method is easy to cause high product impurities and low yield
The above method also has the process of using a strong acid to adjust the pH. The lactam ring in the molecular structure of flucloxacillin is easy to open and degrade, resulting in increased product impurities and reduced yield.

Method used

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  • A kind of preparation method of flucloxacillin sodium
  • A kind of preparation method of flucloxacillin sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Add 100ml of dichloromethane and 12.0g (46.9mmol) of starting material 1 into a 250ml three-necked flask, stir, cool down to -5~0°C, add 5.2g (51.6mmol) of triethylamine dropwise, after the material liquid is clarified, drop Add 5.8g (48.3mmol) of pivaloyl chloride, control the temperature at -5-0°C, and react for 40 minutes after dropping to obtain mixed anhydride;

[0028] Add 100ml of dichloromethane, 10.0g (46.2mmol) of 6-APA, 9.3g (92.4mmol) of triethylamine into a 500ml three-neck flask, control the temperature at 30-35°C, and stir until the feed liquid is clear. Lower the temperature to -5°C, add the mixed anhydride prepared in the above steps dropwise, control the temperature at -5-0°C, react for 1 hour, and then distill off the dichloromethane under reduced pressure to obtain an oily substance. Add 30ml acetone in gained oil, stir 10 minutes, remove triethylamine hydrochloride by filtration, obtain flucloxacillin triethylamine salt acetone solution;

[0029] A...

Embodiment 2

[0031] Add 100ml of dichloromethane and 12.0g (46.9mmol) of starting material 1 into a 250ml three-necked flask, stir, cool down to -5~0°C, add 5.2g (51.6mmol) of triethylamine dropwise, after the material liquid is clarified, drop Add 5.8g (48.3mmol) of pivaloyl chloride, control the temperature at -5-0°C, and react for 50 minutes after the dropwise completion to obtain mixed anhydride;

[0032] Add 100ml of dichloromethane, 10.0g (46.2mmol) of 6-APA, 9.3g (92.4mmol) of triethylamine into a 500ml three-neck flask, control the temperature at 30-35°C, stir until the material liquid is clear, then cool down to -5°C, Add the mixed anhydride prepared in the above steps dropwise, control the temperature at 0-5°C, react for 1 h, then distill methylene chloride off under reduced pressure to obtain an oily substance, add 25ml of acetone to the obtained oily substance, stir for 10 minutes, filter to remove triethylamine Hydrochloride, get flucloxacillin triethylamine salt acetone solut...

Embodiment 3

[0035] Add 100ml of dichloromethane and 12.0g (46.9mmol) of starting material 1 into a 250ml three-necked flask, stir, cool down to -5~0°C, add 5.7g (56.3mmol) of triethylamine dropwise, and after the material liquid is clarified, drop Add 5.9g (49.2mmol) of pivaloyl chloride, control the temperature at -5-0°C, and react for 60 minutes after dropping to obtain mixed anhydride;

[0036] Add 100ml of dichloromethane, 10.0g (46.2mmol) of 6-APA, 9.3g (92.4mmol) of triethylamine into a 500ml three-neck flask, control the temperature at 30-35°C, stir until the material liquid is clear, then cool down to -5°C, Add the mixed anhydride prepared in the above steps dropwise, control the temperature at -5-0°C, react for 1 h, then distill off the dichloromethane under reduced pressure to obtain an oily substance, add 20ml of acetone to the obtained oily substance, stir for 10 minutes, filter to remove triethyl ether Amine hydrochloride, get flucloxacillin triethylamine salt acetone solutio...

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Abstract

The invention discloses a preparation method for flucloxacillin sodium. The method comprises: (1) adding an initial raw material 1 into dichloromethane, dropwise adding triethylamine, and then dropwise adding pivaloyl chloride for reaction, so as to obtain a mixed anhydride; (2) adding 6-APA into dichloromethane, then adding triethylamine, reacting until the material solution is clear, so as to obtain a 6-APA triethylamine salt solution; dropwise adding the mixed anhydride into the 6-APA triethylamine salt solution for reaction, then distilling at a reduced pressure to remove dichloromethane, so as to obtain an oily substance, then adding acetone into the oily substance, stirring, and filtering off triethylamine hydrochloride, so as to obtain an acetone solution of flucloxacillin triethylamine salt; and (4) adding water and an ethyl acetate solution of sodium 2-ethylhexanoate into the acetone solution of flucloxacillin triethylamine salt, controlling the temperature to be 0-40 DEG C after adding is finished, and crystallizing, so as to obtain flucloxacillin sodium monohydrate. The preparation method has the advantages of mild reaction conditions, high yield, good purity, simple operation, friendliness to environment, and the like.

Description

technical field [0001] The invention belongs to the field of antibiotic drug synthesis and relates to a preparation method of flucloxacillin sodium. Background technique [0002] Flucloxacillin sodium, chemical name: 6-[[[3-2-chloro-6-fluorophenyl]-5-methyl-4-isoxazole]carbonyl]amino]-3,3-dimethyl- Sodium 7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate. Flucloxacillin sodium usually exists in the form of monohydrate, molecular formula: C 19 h 16 Cl F N 3 NaO 5 S·H 2 O, molecular weight: 493.9. The chemical structure is: [0003] [0004] Flucloxacillin sodium is a semi-synthetic isoxazole penicillin, which is characterized by penicillinase resistance and has a bactericidal effect on penicillinase-producing drug-resistant Staphylococcus aureus. Its chemical structure is different from the other three currently used clinically. Isoxacillins (cloxacillin, dicloxacillin, oxacillin) are similar. It mainly inhibits the biosynthesis of bacterial cell walls and ac...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D499/76C07D499/16
CPCC07D499/16C07D499/76
Inventor 吴兆申李卓华于志海李文华李保勇吴柯张兆珍董廷华左景冉李法东周显峰
Owner 山东安信制药有限公司
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