Method for preparing ceftizoxime alapivoxil hydrochloride

A technology of ceftizoxime propivoxil and hydrochloride, applied in the field of drug synthesis, can solve the problems of low product yield, unfavorable industrial production, and no literature reports yet

Active Publication Date: 2013-04-24
江苏慈星药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has many by-products, requires column chromatography to carry out product purification, difficult post-treatment, and the yield of the product is relatively low (total yield 33.6%, based on ceftizoxime acid), which is not conducive to industrial production
Chinese patent (CN100366625C) uses Fmoc-L-Ala as raw material to replace Boc-L-Ala and ceftizoxime ester reaction, although it overcomes the trifluoroacetic acid used when removing the Boc protecting group, it is significant for the improvement of the total yield of the product It is not large, and the price of Fmoc protecting group is also relatively expensive. At the same time, the purification of intermediates requires column chromatography, and the total yield is 31.9% (based on ceftizoxime acid)
[0016] According to the analysis and evaluation of the above five synthetic processes, it is not difficult to find that one of the reasons for the low yield is the use of a "linear" synthetic route
For this reason, we have designed a more reasonable "convergent" synthetic new route, which has not been reported in the literature so far.

Method used

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  • Method for preparing ceftizoxime alapivoxil hydrochloride
  • Method for preparing ceftizoxime alapivoxil hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0071] (1) Preparation of formula III compound 7-N-tert-butoxycarbonyl-amino-3-cephem-4-carboxylic acid (7-Boc-ANCA)

[0072] 7-ANCA (4 g, 20 mmol) was dissolved in 50 ml of dioxane and water (1:1) mixed solvent, NaOH (1.2 g, 30 mmol) was added at 10 °C, and stirring was continued for 10 min. Join (Boc) 2 O (6.1 g, 28 mmol), reacted at 10 °C. TLC detection, after the reaction, add 50 ml of cold water to dilute, and use 4 mol L -1 After HCl was adjusted to pH = 2~3, it was extracted with cold ethyl acetate, then washed with 5% citric acid aqueous solution and saturated NaCl aqueous solution, and finally anhydrous NaCl was added. 2 SO 4 Let dry overnight. Concentrate under reduced pressure and recrystallize from dichloromethane and petroleum ether. 5.5 g of white crystals were obtained with a yield of 91.6%. Melting point 107~108℃; IR(KBr)ν(cm -1 ): 3315.97, 2979.81, 1790.33, 1750.12, 1638.93.

[0073] (2) Preparation of formula IV compound 7-N-tert-butoxycarbonylamin...

Embodiment 2

[0085] (1) Preparation of formula III compound 7-N-tert-butoxycarbonyl-amino-3-cephem-4-carboxylic acid (7-Boc-ANCA)

[0086] Dissolve 7-ANCA (4 g, 20 mmol) in 50 ml ethanol at about 0°C with stirring, add Na 2 CO 3 (2.6 g, 24 mmol), continue stirring for 10 min. Then join (Boc) 2 O (5.7 g, 26 mmol), reacted in an ice-water bath, and detected by TLC. After the reaction, concentrate under reduced pressure to recover the solvent, add 50 ml of cold water to dilute, and extract twice with cold dichloromethane; then adjust the pH of the aqueous phase to 2~3 in an ice-water bath, and then extract three times with cold dichloromethane; Combine the organic phases, wash with 5% citric acid aqueous solution, distilled water or saturated NaCl aqueous solution three times successively, add anhydrous NaCl 2 SO 4 Let dry overnight. Concentrate the solvent to crystallize, and then recrystallize with dichloromethane and petroleum ether. 5.73 g of white crystals were obtained with a y...

Embodiment 3

[0099] (1) Preparation of formula III compound 7-N-tert-butoxycarbonyl-amino-3-cephem-4-carboxylic acid (7-Boc-ANCA)

[0100] Add 7-ANCA (4 g, 20 mmol) into 50 ml of methanol, stir at about 5°C for 10 min, then drop triethylamine (4.2 ml, 30 mmol) and continue stirring for 10 min, add (Boc) 2 O (5.2 g, 24 mmol), the system was naturally warmed to room temperature and stirred for 12 h. The reaction solution was concentrated under reduced pressure to recover the solvent, diluted with 50 ml of cold distilled water, extracted twice with cold ethyl acetate, and then the water phase was adjusted to pH=2-3 in an ice bath, extracted three times with cold ethyl acetate, Combine the organic phases, wash with 5% citric acid aqueous solution, distilled water or saturated NaCl aqueous solution three times successively, add anhydrous NaCl 2 SO 4 Let dry overnight. The desiccant was filtered off, the solvent was evaporated under reduced pressure, and recrystallized directly with dichlor...

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Abstract

The invention discloses a new method for preparing ceftizoxime alapivoxil hydrochloride and belongs to the technical field of medicine synthesis. The method comprises the following steps: step (1), performing Boc protection on 7-amino of raw material 7-amino-3-cephem-4-carboxylic acid (7-ANCA) and then making the raw material have reaction with iodomethyl pivalate, then removing Boc protection group to obtain a midbody 7-amino-3-cephem-4-carboxylic pivaloyl oxymethyl ester (7-ANCA-POM); step (2), making N-t-butyloxycarboryl-L-alanine (Boc-L-Ala) and methoxyiminoacetic acid (ATMA) have condensation reaction to obtain a midbody 2-(2-N-t-butyloxycarboryl-amino-(S)-triacylamino-thiazole-4-yl)-2-(Z)-methoxyimino-acetic acid (Boc-L-Ala-ATMA); step (3), activating the midbody Boc-L-Ala-ATMA and making the midbody Boc-L-Ala-ATMA have condensation reaction with the midbody 7-ANCA-POM, and then removing the Boc protection group to prepare a target compound ceftizoxime alapivoxil hydrochloride (CZX-AP-HC1,I). The method adopts a collection type synthesis route, is simple and convenient to operate and mild in technical conditions, has high product quality and low cost, and avoids the problem about benzothiazole residue caused by the use of AE active ester in the present technique, so the collection type synthesis route is a good synthesis route suitable for industrial production.

Description

technical field [0001] The invention relates to a new method for preparing oral cephalosporin ceftizoxime propivoxil hydrochloride (Ceftizoxime Alapivoxil Hydrochloride), which belongs to the technical field of drug synthesis. Background technique [0002] Ceftizoxime propivoxil is a bifunctional prodrug of the third-generation cephalosporin ceftizoxime for injection. It has a broad and strong antibacterial spectrum, is stable against β-lactamase produced by various bacteria, and has basically no nephrotoxicity. Literature (Chem.Pharm.Bull. 1999, 47(8): 1081-1088) studies have shown that ceftizoxime propivoxil not only has balanced water solubility and fat solubility (lipid-water partition coefficient is 1.15), it is beneficial to intestinal absorption, The blood concentration is greatly improved, the dosage is reduced, and it can be taken orally. Its sweetness is 300 times that of sucrose, and it has no peculiar smell of other cephalosporins. It is especially suitable for ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/20C07D501/04C07D501/06
CPCY02P20/55
Inventor 施秀芳李硕旭周建华邱启平
Owner 江苏慈星药业有限公司
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