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Method for compounding flucloxacillin sodium-hydrate

A technology of flucloxacillin sodium and monohydrate, applied in the field of pharmaceutical synthesis, can solve the problems of large amount of organic solvent, low yield and high cost, and achieve the effects of improving yield, reducing pollution and low cost

Active Publication Date: 2015-09-16
CHENGDU LIKAI CHIRAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The object of the present invention is to, in view of the problems referred to above, provide a kind of synthetic method of flucloxacillin sodium monohydrate, solve the deficiency that the organic solvent consumption that existing method exists is large, cost is high, pollution is high, yield is low

Method used

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  • Method for compounding flucloxacillin sodium-hydrate
  • Method for compounding flucloxacillin sodium-hydrate

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Example 1 Preparation of flucloxacillin sodium monohydrate

[0033] Add 100 g of water into the reaction flask, add 20.0 g of 6-APA under stirring, and cool down to 0-5 °C. Weigh 10.6 g of sodium carbonate and dissolve it in 100 mL of water to make a 1 mol / L sodium carbonate solution; control the temperature below 10°C, and add the sodium carbonate solution dropwise into the reaction bottle to obtain a 6-APA sodium salt solution;

[0034] 28.0 g of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonyl chloride was added into the reaction flask in 4 batches, and the addition time was controlled to be 1 hour. Keep warm at 20-25 ℃ for 4 hours; add 1 mol / L dilute hydrochloric acid dropwise to the above reaction solution, and adjust the pH to 2.5;

[0035] 400 g of ethyl acetate was added to the reaction flask, stirred, separated, and the ethyl acetate phase was separated. The ethyl acetate phase was washed with 200 g of saturated brine, separated, and then dried with 2...

Embodiment 2

[0038] Example 2 Preparation of flucloxacillin sodium monohydrate

[0039] Add 100 g of water into the reaction flask, add 20.0 g of 6-APA while stirring, and cool down to 0-5°C. Weigh 12.8 g of sodium carbonate and dissolve it in 80 mL of water to make a 1.5 mol / L sodium carbonate solution; control the temperature below 10°C, add the sodium carbonate solution dropwise into the reaction flask to obtain a 6-APA sodium salt solution;

[0040]Add 30.0 g of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-formyl chloride into the reaction flask in 4 batches, and the feeding time is controlled at 1.5 hours; keep warm at 20-25 °C React for 3 hours; add 1 mol / L dilute hydrochloric acid dropwise to the above reaction solution, and adjust the pH to 3.0;

[0041] Add 300 g of methyl tert-butyl ether into the reaction flask, stir, separate liquids, and separate the organic phase. The organic phase was washed with 200 g of saturated brine, separated, and then dried with 20 g of anhydrous...

Embodiment 3

[0043] Example 3 Preparation of flucloxacillin sodium monohydrate

[0044] Add 100 g of water to the reaction flask, add 20.0 g of 6-APA while stirring, and cool down to 15-20 °C; weigh 13.8 g of potassium bicarbonate and dissolve it in 150 mL of water to prepare a 0.93 mol / L potassium bicarbonate solution. Control the temperature below 10°C, add potassium bicarbonate solution dropwise into the reaction flask to obtain 6-APA sodium salt solution;

[0045] Add 27.0 g of 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-formyl chloride into the reaction flask in 4 batches, and the feeding time is controlled at 1 hour; keep warm at 15-20°C React for 4 hours; add 2 mol / L dilute sulfuric acid dropwise to the above reaction solution, and adjust the pH to 3.0;

[0046] 200 g of dichloromethane was added to the reaction flask, stirred, separated, and the ethyl acetate phase was separated. The dichloromethane phase was washed with 200 g of saturated brine, separated, and then dried wit...

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Abstract

The invention discloses a method for compounding flucloxacillin sodium-hydrate, which belongs to the technical field of drug synthesis, and comprises the steps: 6-aminopenicillanic acid (6-APA) is salified, then 3-(2-chloro-6-fluorophenyl)-5- methyl isoxazole-4-formyl chloride or equivalents thereof are added to do an acylation reaction, and then acids are added drop by drop to adjust a potential of hydrogen (pH) value to obtain flucloxacillin acid aqueous solutions. Organic solution is used to extract, and organic phases are washed, dried and filtered to obtain flucloxacillin acid solutions through saturated salt water, then white solids are dissolved out in the flucloxacillin acid solutions which are added with sodium iso-octoate solutions, and products are obtained by controlling temperature and crystallizing. The method for compounding the flucloxacillin sodium-hydrate does not separate intermediate flucloxacillin acids, obtained flucloxacillin acids are directly salified with sodium iso-octoate after being extracted trough the organic solution, reduces separation steps and operation process, also reduces usage amount and times of organic solution simultaneously, greatly reduces discharge amount of organic solution relative to patent documentation CN 102964356A, reduces production cost above 20%, and obviously improves economic and environmental values.

Description

technical field [0001] The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of flucloxacillin sodium monohydrate. Background technique [0002] Flucloxacillin, Sodium, chemical name (2S,5R,6R)-6-[[3-(2-chloro-6-fluorophenyl)-5-methyl-1,2-oxazole Sodium-4-formyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate monohydrate, molecular formula C 19 h 16 ClFN 3 NaO 5 S·H 2 O, molecular weight 493.9, structural formula: [0003] [0004] Flucloxacillin sodium is a semi-synthetic penicillinase-resistant isoxazole penicillin, which achieves antibacterial effect by interfering with the biosynthesis of bacterial cell wall mucopeptides, and can effectively fight against penicillin-resistant Staphylococcus aureus infection and penicillin-sensitive gold Infections caused by Staphylococcus aureus, hemolytic streptococcus (Streptococcus pyogenes), and Diplococcus pneumoniae. The preparation method current...

Claims

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Application Information

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IPC IPC(8): C07D499/76C07D499/12
CPCC07D499/12C07D499/76
Inventor 袁伟成左健周鸣强徐小英张晓梅
Owner CHENGDU LIKAI CHIRAL TECH
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