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Preparation method of E-type cefditoren sodium

The technology of cefditoren sodium and sodium isooctanoate is applied in the field of preparation of E-type cefditoren sodium, which can solve the problem of poor activity of E-type 7-ATCA, low purity and yield of E-type cefditoren sodium, and inability to control impurities. product use, etc.

Pending Publication Date: 2021-12-14
湖北凌晟药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the preparation method of E-type 7-ATCA is disclosed in the prior art, the activity of E-type 7-ATCA is extremely poor. If the method for preparing cefditoren pivoxil is directly applied by 7-ATCA, the E-type 7-ATCA is used to prepare E type cefditoren sodium, then the purity and yield of the E type cefditoren sodium that obtains are extremely low, can't be used as the impurity reference substance in the drug quality monitoring

Method used

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  • Preparation method of E-type cefditoren sodium
  • Preparation method of E-type cefditoren sodium

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Experimental program
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Effect test

Embodiment 1

[0025] Add 6.6mL of water and 30mL of acetone into the reaction vessel, cool down to 0°C, add 3g (9.28mmol) of E-type 7-ATCA and 3.25g (9.28mmol) of AE active ester (MAEM), and dropwise add triethylamine to make the reaction liquid The pH value of the solution reached 8.0, and then the temperature was raised to 15°C for reaction. During the reaction, the pH of the reaction solution was maintained at 8.0-8.5 by adding triethylamine. After the reaction was complete (3h), 1.54g of sodium octanoate (9.28mmol) was added. 45mL of acetone solution, the crystal was grown for 1 hour, and a light yellow solid was obtained by suction filtration. The light yellow solid that obtains is transferred to 25 ℃ of vacuum dryings in oven for 5 hours, obtains 2.78g dry product, detects through HPLC, and the purity of E type cefditoren sodium in the dry product is 98.6%, and detection result is as follows: figure 1 Shown, the mass yield of the calculated E-type cefditoren sodium is 91.4%.

[0026]...

Embodiment 2

[0031] Add 4.5mL of water and 15mL of acetone to the reaction vessel, cool down to 5°C, add 3g (9.28mmol) of E-type 7-ATCA and 4.87g (13.92mmol) of AE active ester (MAEM), and dropwise add diethylamine to make the reaction liquid The pH value of the solution reaches 8.5, and then the temperature is raised to 20°C for reaction. During the reaction, the pH of the reaction solution is maintained at 8.0-8.5 by adding diethylamine. After the reaction is complete (2.5h), add 2.31g of sodium isooctanoate (13.92mmol ) of 45 mL of acetone solution, crystal growth for 1.5 hours, and suction filtration to obtain a pale yellow solid. The light yellow solid that obtains is transferred to 35 ℃ of vacuum dryings in the oven for 3 hours, obtains 2.75g dry product, detects by HPLC, the purity of E-type cefditoren sodium in the dry product is 98.3%, the calculated E-type cefditoren The mass yield of len sodium is 90.1%.

Embodiment 3

[0033] Add 6mL of water and 20mL of acetone into the reaction vessel, cool down to 2°C, add 3g (9.28mmol) of E-type 7-ATCA (9.28mmol) and 3.90g (11.14mmol) of AE active ester (MAEM), and drop diisopropylethylamine to make the reaction The pH value of the solution reaches 8.2, and then the temperature is raised to 20°C for reaction. During the reaction, the pH of the reaction solution is maintained at 8.0-8.5 by adding diisopropylethylamine. After the reaction is complete (3.5hh), 1.85g of isooctanoic acid Sodium (11.14 mmol) in 45 mL of acetone solution was grown for 1.2 hours, and a light yellow solid was obtained by suction filtration. The light yellow solid that obtains is transferred to 30 ℃ of vacuum dryings in the oven for 4 hours, obtains 2.88g dry product, detects by HPLC, the purity of E-type cefditoren sodium in the dry product is 98.1%, the calculated E-type cefditoren The mass yield of len sodium is 94.2%.

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Abstract

The invention relates to the technical field of synthesis of drug related substances, and particularly discloses a preparation method of E-type cefditoren sodium. The preparation method of the E-type cefditoren sodium comprises the following steps: cooling a mixed solution composed of water and acetone to 0-5 DEG C, adding E-type 7-ATCA and AE active ester, adjusting the pH value to 8-8.5 by using organic alkali, heating to 15-25 DEG C, reacting, and maintaining the pH value of the reaction solution at 8-8.5 in the reaction process; and after the reaction is finished, adding an acetone solution of sodium isooctoate, growing crystals, carrying out suction filtration, and drying to obtain the E-type cefditoren sodium. According to the preparation method of the E-type cefditoren sodium provided by the invention, the E-type cefditoren sodium with high purity and high yield can be obtained, the whole preparation method is simple to operate, the reaction condition is mild, and the finally obtained E-type cefditoren sodium completely meets the requirement of serving as a cefditoren pivoxil reference substance and has good application prospects. Important data support is provided for ensuring the quality detection of the cefditoren pivoxil.

Description

technical field [0001] The invention relates to the technical field of synthesis of drug-related substances, in particular to a preparation method of E-type cefditoren sodium. Background technique [0002] Cefditoren pivoxil is a third-generation cephem antibiotic with a wide range of antibacterial effects, especially against Gram-positive bacteria such as Staphylococcus, Streptococcus (including Streptococcus pneumoniae), Escherichia coli, Haemococcus catarrhalis, Gram-negative bacteria such as Klebsiella, Proteus and Haemophilus influenzae, and anaerobic bacteria such as Peptostreptococcus and Bacteroides have superior antibacterial ability. Cefditoren pivoxil is mainly used clinically to treat skin infection, mastitis, perianal abscess, genitourinary system infection, cholecystitis, cholangitis, otitis media, sinusitis, periodontitis, hordeolum, dacryocystitis, Pharyngitis, tonsillitis and acute and chronic bronchitis. [0003] In the process of research and development...

Claims

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Application Information

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IPC IPC(8): C07D501/24C07D501/12C07D501/06
CPCC07D501/24C07D501/12C07D501/06
Inventor 何健黄金果金联明门万辉王腾
Owner 湖北凌晟药业股份有限公司
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