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Synthesis method of flomoxef sodium

A technology of sodium fluoxetine and a synthesis method, which is applied in the field of synthesis and preparation technology of high-purity sodium fluoxafen, can solve the problems of harsh conditions, high energy consumption, inability to be dried and removed, etc., and achieves easy industrialization and low energy consumption. Effect

Active Publication Date: 2016-07-27
LIVZON PHARM GRP INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in 1) the acid-forming reaction, nitrogen protection is required, and the temperature is lowered from -45°C to 10°C. The conditions are harsh, and water is introduced into the hydrochloric acid added at the same time. According to the long-term practice of researchers, the introduction of water has adverse effects on the reaction. ; 3) In the crystallization process, dichloromethane or ethyl acetate are used as solvents, however, dichloromethane and ethyl acetate can form crystalline compounds with fluoxetal sodium, which cannot be removed by drying
[0007] Because fluoxefor sodium is very easy to absorb moisture and is unstable to heat, it is easy to form solvent compounds with organic solvents such as methanol, dichloromethane, and n-hexane, and it is difficult to solve the problem of solvent removal. Dissolve cephalosporin in water, adjust the pH value with sodium carbonate or sodium hydroxide, and freeze-dry to produce fluoxetal sodium
The freeze-drying process produces raw materials, in addition to the production capacity being restricted by the freeze-drying equipment, the energy consumption per unit of output is high, and the degradation produced during the freeze-drying production process or the impurities inherent in the storage and transportation of fluoxetal acid will exist in the in the final product

Method used

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  • Synthesis method of flomoxef sodium
  • Synthesis method of flomoxef sodium
  • Synthesis method of flomoxef sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] 1) Synthesis of Fluoxetal

[0025] Put 50g FF-03 and 250ml m-cresol into the reaction bottle, and react at 65-70°C for 2-2.5h (pay attention to monitor the end point of the reaction). Fluoxetal solution system;

[0026] Cool to 0-5°C after the reaction, add 750ml ether and 200ml 20% NaCl aqueous solution, shake well, separate the aqueous layer W1, add 200ml 20% NaCl aqueous solution to the organic layer O1, separate the aqueous layer W2, combine W1 and the aqueous solution of W2; add 750ml of ethyl acetate to the aqueous solution, stir and lower the pH to 1-3, extract, and take the ethyl acetate layer. Add anhydrous MgSO 4 Appropriate amount, stir and dehydrate for 30-60 minutes, filter with suction, and transfer the filtrate into a reaction flask.

[0027] 2) Synthesis of Fluoxetin Triethylamine Salt

[0028] Drop the above reaction liquid to cool down to -15~-20°C, add triethylamine dropwise, precipitate solid, stir for 1-2h, filter, and dry under reduced pressure...

Embodiment 2

[0031] The influence that embodiment 2 step (1) temperature of reaction is selected on reaction carries out

[0032] 1. Put 50gFF-03 and 250ml m-cresol into the reaction bottle, and react at a certain reaction temperature (pay attention to monitoring the reaction end point). Fluoxetal solution system;

[0033] Cool to 0-5°C after the reaction, add 750ml ether and 200ml 20% NaCl aqueous solution, shake well, separate the aqueous layer W1, add 200ml 20% NaCl aqueous solution to the organic layer O1, separate the aqueous layer W2, combine W1 and the aqueous solution of W2; add 750ml of ethyl acetate to the aqueous solution, stir and lower the pH to 1-3, extract, and take the ethyl acetate layer. Add anhydrous MgSO 4 Appropriate amount, stirred and dehydrated for 30-60 minutes, filtered with suction, and transferred the filtrate into a reaction bottle. The results are shown in Table 1.

[0034] Table 1

[0035]

[0036] Conclusion: From the experimental results in the above...

Embodiment 3

[0037] In the embodiment 3 step (1), the sodium chloride concentration selection is carried out on the influence of reaction

[0038] [Reaction] Put 50g FF-03 and 150ml m-cresol into the reaction bottle, and react at 65-70°C for 2-2.5 hours (pay attention to monitoring the reaction end point). Defloxacin solution system

[0039][Post-processing] After the reaction, cool to 0-5°C, divide the obtained fluoxetal solution into 5 parts, add 750ml of diethyl ether and 200ml of NaCl aqueous solution with different concentrations, shake well, separate the water layer W1, and the organic layer Add 200ml of a certain concentration of NaCl aqueous solution to O1, separate the aqueous layer W2, combine the aqueous solutions of W1 and W2; add 750ml of ethyl acetate to the aqueous solution, stir and lower the pH to 1-3, extract, and take the ethyl acetate layer. Add anhydrous MgSO 4 Appropriate amount, stirred and dehydrated for 30-60 minutes, filtered, and the filtrate was transferred to...

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Abstract

The invention provides a synthesis method of flomoxef sodium. The synthesis method comprises steps as follows: a, (6R,7R)-3-chloro-7-(2-((difluoromethyl) sulfenyl) acetamido)-7-methoxy-8-oxo-5-oxa-1-azabicyalo[4.2.0] octan-2-ene-2-(benzhydryl) carboxylate ester and metacresol are added to a reaction bottle and subjected to a reaction at the temperature of 65-70 DEG C; after the reaction ends, the mixture is cooled, a solvent is added for follow-up treatment, and a flomoxef acid solution is obtained; b, triethylamine is added to the flomoxef acid solution, solids are separated out, filtration and drying are performed, and flomoxef triethylamine salt is obtained; c, the flomoxef triethylamine salt is added to the reaction bottle, an organic solvent is added for dissolution, the temperature is reduced to subzero 25 DEG C to subzero 20 DEG C, sodium salt and an organic solvent are continuously dropwise added, then, crystal growing, filtration, washing and drying are performed after adding, and flomoxef sodium is obtained.

Description

technical field [0001] The invention relates to a synthesis and preparation process of fluoxyceph sodium, in particular to a synthesis and preparation process of high-purity fluoxyceph sodium. Background technique [0002] Fluoxyceph sodium for injection was successfully developed by Shionogi Pharmaceutical Co., Ltd. in Japan, and was first listed in Japan under the trade name Flumarin in 1988. It is highly stable to β-lactamase, and its antibacterial spectrum is similar to other third-generation cephalosporins. It is characterized by strong activity against Staphylococcus aureus including methicillin-resistant Staphylococcus aureus (MRSA). Table Staphylococcus, Streptococcus pneumoniae, Peptostreptococcus, Moraxella catarrhalis, Salmonella, Klebsiella, Proteus, Escherichia coli, Haemophilus influenzae and Bacteroides all have good activity. [0003] At present, there are not many literature reports on the synthesis process of fluoxefom sodium. CN101440098 reports the use o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D505/20C07D505/08
CPCC07D505/08C07D505/20
Inventor 汪华菜景莉于娜娜黄滔陈斌王伟王涛徐朋陈亭亭
Owner LIVZON PHARM GRP INC
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