Preparation method of cefditoren pivoxil

A technology of cefditoren pivoxil and cefditoren sodium, which is applied in the field of preparation of cefditoren pivoxil, can solve the problems of high reaction temperature, large amount of iodomethyl pivalate, poor purity stability, etc., and achieve process operation Simple, cheap and easy to obtain, high yield effect

Active Publication Date: 2015-04-15
LUNAN BETTER PHARMA
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Problems solved by technology

In this technical scheme, in order to make cefditoren sodium react completely, selected-20 ℃ was selected as reaction temperature and increased the consumption of iodomethyl pivalate (ceftitoren sodium: iodomethyl pivalate=1:2.1, mol ratio), under this condition, the cefditoren sodium participating in the reaction is basically not left, and the purity of the obtained cefditoren pivoxil can also reach 97%-99%, but the stability of the purity is poor, basically all at 97%-98%, Seldom exceeding more than 98.5%, it is not suitable for suitability for suitability for industrialized production, in addition because the used reaction temperature is too high, the consumption of iodomethyl pivalate is too large, causes the impurity that produces as hydroxymethyl cefditoren pivoxil, Λ3 isomer, The E isomer and α-pivaloyl cefditoren pivoxil are too large, which directly reduces the drug efficacy and quality of the product, and the obtained cefditoren pivoxil product is difficult to meet the requirements of the Pharmacopoeia, which is absolutely unacceptable for pharmaceutical companies. Allowed

Method used

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  • Preparation method of cefditoren pivoxil

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Experimental program
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Effect test

Embodiment 1

[0035] The preparation method of embodiment 1 cefditoren pivoxil (small test process)

[0036] Step 1, cefditoren sodium reaction

[0037] At room temperature and protected from light, add 200g of 7ATCA and 260g of AE-active ester into 2000ml of dichloromethane, add 110ml of methanol and 12.6ml of sulfurous acid, stir and cool down to 0°C to 5°C, slowly add 126ml of triethylamine dropwise, and finish adding Afterwards, heat-preserve at 0°C to 5°C for 4 hours, and sample HPLC at 3 hours (the remaining 7ATCA<0.5% means the reaction is complete), the result shows that the reaction is complete, add 400ml of pure water to the reaction solution, stir for 15min, separate the liquid, collect the water phase, and Heat the water phase to 20°C-25°C, add sodium isooctanoate / acetone solution prepared by 200g sodium isooctanoate and 2300ml acetone dropwise into the water phase, keep stirring at 20°C-25°C for 2 hours, filter, the filter cake is below 40°C After drying under reduced pressure...

Embodiment 2

[0042] The preparation method of embodiment 2 cefditoren pivoxil (industrialization process)

[0043] Step 1, cefditoren sodium reaction

[0044] Under the condition of avoiding light at room temperature, add 240L dichloromethane into the 500L glass-lined reaction kettle, start stirring, then add 24.0kg7ATCA, 31.2kg AE-active ester, 13.2L methanol, 1512ml sulfurous acid into the kettle, and cool it with -15℃ Cool the brine to 0°C-5°C, add 15.1L triethylamine to the kettle, control the temperature not to exceed 5°C during the period, keep stirring at 0°C-5°C for 4 hours after the addition is complete. After 4 hours, add 96L of pure water into the kettle, stir for 20 minutes, then let it stand for 20 minutes, separate the liquid, collect the water phase, add the water phase to the glass-lined reaction kettle, stir, and heat up to 20°C to 25°C with process hot water. Add sodium isooctanoate / acetone solution prepared by 24.0kg sodium isooctanoate and 100L acetone from the high-le...

Embodiment 3

[0049] Embodiment 3 step one, cefditoren sodium reaction, reaction temperature is-5 ℃~0 ℃

[0050] Under the condition of avoiding light at room temperature, add 100g of 7ATCA and 130g of AE-active ester into 1000ml of dichloromethane, add 55ml of methanol and 6.3ml of sulfurous acid, stir and cool down to -5℃~0℃, slowly add 63ml of triethylamine dropwise, add After completion, the reaction was incubated at -5°C to 0°C for 4 hours. At 3 hours, HPLC was sampled (remaining 7ATCA<0.5% was the reaction was complete), and the result showed that the reaction was not complete. At 4 hours, the reaction was sampled by HPLC, and the result showed that the reaction was complete. Add 400ml pure water, stirred for 15 minutes, separated, collected the water phase, raised the temperature of the water phase to 20°C to 25°C, and added dropwise the sodium isooctanoate / acetone solution prepared by 100g sodium isooctanoate and 1150ml acetone to the water phase 25 Stir at ℃~30℃ for 2 hours, filter...

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Abstract

The invention belongs to the technical field of medicines and particularly relates to a preparation method of cefditoren pivoxil. The preparation method particularly includes following steps: (1) carrying out a reaction between cefditoren mother nucleus 7ATCA and AE-activated ester with dichloromethane as a solvent under an alkaline condition at 0-5 DEG C; (2) performing extraction with pure water and adding a sodium iso-octoate/acetone solution to obtain cefditoren sodium; (3) carrying out a reaction between the cefditoren sodium and iodomethyl pivalate under the alkaline condition at -40 DEG C to obtain a cefditoren pivoxil solution; (4) adding pure water to separate out a crystal to obtain a crude product of the cefditoren pivoxil. The technical scheme also comprises steps of dissolving the crude product of the cefditoren pivoxil in a mixed solution including dichloromethane and anhydrous ethanol, washing the material solution with a 1% sodium bicarbonate solution and pure water, collecting an organic phase, and performing a pressure-reducing evaporate-drying process to obtain the cefditoren pivoxil being higher than 99% in purity and less in impurities. The preparation method is simple in operation, is easy to control, is high in yield, allows the raw material to be obtained easily and is suitable for industrialized large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicines, and relates to a preparation method of cefditoren pivoxil. Background technique [0002] Cefditoren Pivoxil (Cefditoren Pivoxil) belongs to the third-generation oral cephalosporin antibiotics. It is a new type of cephalosporin antibiotics listed in Japan in 1994 by Meiji Seika Company under the trade name of Meiact. , belonging to cefditoren's pivaloyloxymethyl ester, was launched in China in 2000 as a tablet, and its mechanism of action is that after oral absorption, it is hydrolyzed into the active body cefditoren to exert an antibacterial effect. Studies have shown that cefditoren pivoxil has excellent therapeutic effects on experimental infections caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, Proteus, etc. The therapeutic effect of the enzyme-producing strain infection is equal to or superior to that of similar drugs. The specific mole...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/24C07D501/04
CPCC07D501/04C07D501/24
Inventor 赵志全张乃华冯晓亮崔世密
Owner LUNAN BETTER PHARMA
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