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Synthesis method of flucloxacillin sodium

A technology of flucloxacillin sodium and a synthesis method, applied in the field of antibiotic drug synthesis, can solve the problems of complicated operation process, poor product crystal shape, complicated operation and the like, and achieve the effects of simple operation steps, moderate reaction conditions and obvious technological advantages.

Active Publication Date: 2015-06-17
HEZE RUIZHI TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The yield of this method is not high, and cationic resin is used, which is easy to introduce impurities, and the operation is complicated, which is not conducive to industrial production; patent document CN102351882A discloses another preparation method of flucloxacillin sodium, which first dissolves flucloxacillin sodium in Water, after adding solvent for extraction, the water phase is treated with alkaline earth metal oxide or alkali metal, and then purified by neutral alumina column, and the eluent is concentrated and crystallized under reduced pressure to obtain flucloxacillin sodium. The operation process of this method is complicated, and the crystal form of the product is Poor, poor stability; the synthetic method of the disclosed flucloxacillin sodium of patent literature CN102702227A, first side chain acyl chloride and 6-APA are acylated in acetone solution, then the reaction product is extracted after acidification, flucloxacillin acid Salt with sodium isooctanoate in the extract
The method adopts a one-pot cooking process, which simplifies the operation process, but has the disadvantages of no crystallization and purification of flucloxacillin acid, resulting in the disadvantages of high impurities in the salt-forming step, difficult crystallization, and low quality of flucloxacillin sodium

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add 110ml of dichloromethane, add 20.7ml of phosphorus oxychloride, add 16.3ml of N,N-dimethylformamide dropwise at 20~25℃, after the addition is complete, keep it warm for 1 hour, and add in batches 3 -(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid 28.4g, keep warm for 2 hours, lower to 5°C for later use.

[0031] Sodium bicarbonate 15.17g, water 200ml, stir to dissolve, 6-APA 20g, after dissolution, cool down to 15-20°C, add step acid chloride solution dropwise, drop in 30 minutes, control temperature for 30-60 minutes, the reaction is complete , acidified with 2N hydrochloric acid, acidified to PH=2.0, static layered, the aqueous phase was extracted with 80ml of dichloromethane, and the organic phases were combined.

[0032] Concentrate under reduced pressure to a viscous oil, add 100ml of methanol, cool down to 0-5°C, slowly add 100ml of water dropwise, after crystallization, keep stirring for 20 minutes, continue to add 100ml of water dropwise, then ...

Embodiment 2

[0035] Add 150ml of isopropyl ether, add 11ml of phosphorus oxychloride, add 9ml of N,N-dimethylacetamide dropwise at 20~25℃, after the dropwise addition is completed, keep it warm for 1 hour, and add in batches 3 -(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid 14.2g, heat-retained for 2 hours, lowered to 5°C for later use.

[0036] Sodium bicarbonate 7.6g, water 100ml, stir to dissolve, 6-APA 10g, after dissolution, cool down to 15-20°C, add step acid chloride solution dropwise, drop over 30 minutes, control temperature for 30-60 minutes, the reaction is complete , acidified with 2N hydrochloric acid, acidified to PH = 2.0, static layered, the aqueous phase was extracted with 50ml isopropyl ether, and the organic phases were combined.

[0037] Concentrate under reduced pressure to viscous oil, add 60ml of ethanol, cool down to 0-5°C, slowly add 60ml of water dropwise, after crystallization, keep stirring for 20 minutes, continue to add 60ml of water dropwise, t...

Embodiment 3

[0040] Add 12ml of phosphorus oxychloride to 130ml of methyl tert-butyl ether, add 9ml of N,N-dimethylformamide dropwise at 20~25°C, after the addition is complete, keep it warm for 1 hour, and add in batches 3 -(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid 15g, keep warm for 2 hours, lower to 5°C for later use.

[0041]Sodium bicarbonate 8g, water 100ml, stir to dissolve, 6-APA 10g, after dissolution, cool down to 15-20°C, add step acid chloride solution dropwise, drop over 30 minutes, control temperature for 30-60 minutes, the reaction is complete, Acidify with 2N hydrochloric acid, acidify to PH=2.0, let the layers rest, extract the aqueous phase with 50ml of methyl tert-butyl ether, and combine the organic phases.

[0042] Concentrate under reduced pressure to viscous oil, add 30ml of isopropanol and 30ml of methanol mixture, cool down to 0-5°C, slowly add 60ml of water dropwise, after crystallization, keep stirring for 20 minutes, continue to add 60ml of w...

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Abstract

The invention particularly discloses a synthesis method of flucloxacillin sodium and belongs to the field of synthesis of antibiotic medicines. The synthesis method comprises the following steps: reacting 3-(2-chloro-6-fluorobenzene)-5-methyl isoxazole-4-formic acid as a raw material with phosphorus oxychloride under the catalysis of organic amine to generate acyl chloride; dissolving 6-APA (6-aminopenicillanic acid) and inorganic alkaline in water, dripping an acyl chloride solution obtained in the previous step, acidizing by using hydrochloric acid after the reaction is completed, and then layering; concentrating under a reduced pressure, adding residues into an alcohols solvent for dissolution, dripping water to separate out flucloxacillin crystals; and dissolving flucloxacillin acid in an organic solvent, dripping a sodium iso-octoate solution for reaction to produce a product, namely flucloxacillin sodium monohydrate. The synthesis method disclosed by the invention has the advantages that the process advantages are obvious, the product quality is promoted, the yield is improved, and the operation steps are simplified so as to achieve greater production benefits and social benefits.

Description

(1) Technical field [0001] The invention belongs to the field of synthesis of antibiotic drugs, in particular to a synthesis method of flucloxacillin sodium. (2) Background technology [0002] Flucloxacillin sodium, also known as fluclopine, has a chemical name of 5-methyl-3-(2-chloro-6-fluorophenyl)-4-isoxazole penicillin sodium, and its molecular formula 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 other three currently used clinically. Oxacillins (cloxacillin, dicloxacillin, oxacillin) are similar. Mainly by inhibiting the biosynthesis of bacterial cell walls and accelerating the decomposition of bacterial cell walls, thus playing an antibacterial role. It has good antibacterial effect on Streptococcus such as Hemolytic Streptococcus, Strep...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D499/76C07D499/16
Inventor 韩振玉孟宪丽高博齐步祥张翠华商勇超
Owner HEZE RUIZHI TECH DEV
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