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7-phenylacetamide-3-deacetoxycephalosporanate and preparation method and application thereof

A technology of acetoxycephalosporanic acid salt and acetoxycephalosporanic acid, which is applied in the field of drug synthesis, can solve the problems of raw material drug quality impact, poor quality of 7-ADCA, etc., and achieve the effect of quality improvement and good yield

Active Publication Date: 2019-08-16
方长明
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] At present, the quality of 7-ADCA synthesized by existing methods is poor, and its content is about 98wt%.
In addition, impurities such as isomers are generated during the preparation of 7-ADCA, especially the residual amount of the impurity Δ2-7-ADCA shown in the following structural formula (VIII) is very high, reaching 0.5 to 1.0%. The quality of the raw drug also has a big impact

Method used

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  • 7-phenylacetamide-3-deacetoxycephalosporanate and preparation method and application thereof
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  • 7-phenylacetamide-3-deacetoxycephalosporanate and preparation method and application thereof

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preparation example Construction

[0066] The preferred synthetic route for preparing high-content 7-ADCA of the present invention is as follows:

[0067]

[0068] In order to obtain the 7-ADCA of high content, the present invention takes preferred technical scheme and comprises the steps:

[0069] (1) Preparation of high-content 7-phenylacetamido-3-desacetoxycephalosporanic acid and salts thereof.

[0070] The crude product of 7-phenylacetamido-3-desacetoxycephalosporanic acid is salt-formed and crystallized to obtain high-purity 7-phenylacetamido-3-desacetoxycephalosporanic acid salt; Add 7-phenylacetamido-3-desacetoxycephalosporanic acid salt into water, adjust the pH to 1-3 with acid, crystallize, and obtain high content of 7-phenylacetamido-3-desacetoxycephalosporanic acid .

[0071] (2) Preparation of high content 7-ADCA

[0072] The high-purity 7-phenylacetamido-3-desacetoxycephalosporanic acid or its salt obtained in the above step (1) is catalyzed by penicillin acylase to obtain 7-ADCA lysate, an...

Embodiment 1

[0111] Add 20g of crude product of cyclohexanoic acid (content 95.3wt%) into a 500ml reaction bottle, add 40ml of deionized water, add 50ml of acetone (for dispersion, can reduce the amount of water), stir, and dropwise add about 4.2ml of 24wt% ammonia water , adjust the pH to 6.5-7.0, stir for 30 min, add dropwise 400 ml of acetone, cool down to 0-5°C, and stir for 30 min. Filter, wash with 50 ml of acetone, filter dry, and dry under reduced pressure to obtain 19.53 g of cycloexpanded acid ammonium salt (HPLC purity 99.8%), yield 97.5% (mol / mol).

[0112] Add 10 g of the prepared ammonium cyclocyclate salt to 100 ml of water, adjust the pH to 6-8 to dissolve, add 5 g of immobilized penicillin acylase (immobilized enzyme), keep warm at 28-32°C, and maintain pH 7.5-8.5 with ammonia water , until the cleavage reaction is complete, the immobilized enzyme is filtered off to obtain the enzymatic hydrolysis solution. The temperature of the enzymolysis solution was raised to 30-35° ...

Embodiment 2

[0114] Add 20g of the crude product of cyclohexanoic acid (content 95.3wt%) into a 500ml reaction bottle, add 100ml of absolute ethanol, stir to dissolve, add about 4.2ml of 24wt% ammonia water dropwise, adjust the pH to 6.5-7.0, stir for 30min, and then add dropwise Add 200ml of ethanol, cool down to 0-5°C, and stir for 30min. Filter, wash with 50 ml of absolute ethanol, filter dry, and dry under reduced pressure to obtain 19.45 g of cycloexpanded ammonium salt (HPLC purity 99.8%). Yield 97.1% (mol / mol).

[0115] Add 10 g of the prepared cycloexpandant ammonium salt into 100 ml of water, adjust the pH to 6 to 8 to dissolve, add 5 g of immobilized penicillin acylase (immobilized enzyme), keep warm at 28 to 32 ° C, and maintain it with 4 wt % sodium hydroxide aqueous solution. pH 7.5-8.5, until the cleavage reaction is complete, filter out the immobilized enzyme, and obtain the enzymatic hydrolysis solution. The temperature of the enzymolysis solution was raised to 30-35° C.,...

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Abstract

This invention relates to 7-phenylacetamide-3-deacetoxycephalosporanate, and a preparation method and an application thereof. The 7-phenylacetamido-3-deacetoxycephalosporanate has the structural formula shown as the specification; M+ is selected from a metal ion or an ammonium ion. The preparation method comprises the steps of: perfomring a reaction on 7-phenylacetamido-3-desacetoxycephalosporanicacid with an alkaline salt forming agent; or performing a reaction on 7-phenylacetamido-3-desacetoxycephalosporin trimethylsilicon ester with an alkaline salt forming agent. 7-ADCA can be prepared from the 7-phenylacetamido-3-desacetoxycephalosporanate. The content of the 7-ADCA product produced is very high, especially the content of the isomer [delta] 2-7-ADCA is less than 0.5%. The product ismore suitable for the synthesis of high quality cephalexin, cefradine, cefadroxil and ceftazidime and other cephalosporin bulk drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, in particular to cephalosporin intermediate 7-phenylacetamido-3-desacetoxycephalosporanic acid salt, and 7-amino-3-desacetoxycephalosporanic acid (7- ADCA) preparation method. Background technique [0002] 7-amino-3-desacetoxy cephalosporanic acid (7-ADCA for short), its chemical structural formula is shown in following formula (I): [0003] [0004] 7-ADCA is an important mother nucleus for the synthesis of cephalosporin antibiotic raw materials, and a key intermediate for the synthesis of cephalexin, cephradine, cefadroxil and ceftazidime pivoxil. [0005] Regarding the synthetic method of 7-ADCA, the semi-synthetic chemical method is commonly used at present, that is, the cheap penicillin G potassium industrial salt with sufficient market supply is used as a raw material, and it is prepared through oxidation, ring expansion rearrangement, enzymatic cleavage, crystallization and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/22C07D501/04C07D501/12C12P17/18
CPCC07D501/22C07D501/04C07D501/12C12P17/18
Inventor 方长明
Owner 方长明
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