Synthesis method of cefcapene acid

A technology of cefcapine acid and a synthesis method, which is applied in the field of synthesis of cefcapine acid, can solve the problems of little research on cefcapine acid, many impurities and low purity of cefcapine acid, and achieves a simple, efficient, and deoxidizing method. The effect of high removal efficiency and low environmental protection pressure

Pending Publication Date: 2022-02-08
湖北凌晟药业股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] There are not many studies on cefcapene acid reported at present. In the synthetic method of existing reports, the prepared cefcapene acid contains more impurities and has a lower purity.

Method used

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  • Synthesis method of cefcapene acid
  • Synthesis method of cefcapene acid
  • Synthesis method of cefcapene acid

Examples

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preparation example Construction

[0029] The invention provides a kind of synthetic method of cefcapene acid, comprises the following steps:

[0030] (1) BCN, organic solvent and inorganic acid are mixed to carry out acidification reaction, and gained acidification feed liquid is left standstill layered, obtains the organic phase that contains desalination BCN; Described BCN is the precursor acid of cefcapene pivoxil, and structural formula is as formula I Shown; The structural formula of described desalted BCN is shown in formula II:

[0031]

[0032] (2) The organic phase containing desalted BCN is mixed with an acid to perform a tert-butoxycarbonyl removal reaction, and the resulting product is subjected to solid-liquid separation to obtain a crude product of cefcapene acid;

[0033] (3) dispersing the crude product of cefcapene acid in water, adjusting the pH value of the obtained dispersion to 8.0-9.0 with alkali, and then performing solid-liquid separation to obtain a filtrate;

[0034] (4) adjusting...

Embodiment 1

[0047] At 25°C, add 10 g of crude BCN and 100 mL of dichloromethane to the flask. After stirring evenly, add dilute hydrochloric acid dropwise until the pH value is 1.5. Stir until the system dissolves. Add 20 mL of concentrated hydrochloric acid dropwise, crystals are obviously precipitated, and react for 60 minutes; filter and wash the filter cake with 20 mL of pure water; at 25°C, add the filter cake and 100 mL of pure water to the flask, stir well, then add 7% carbonic acid dropwise Sodium hydrogen solution, adjust the pH value to 8, stir for 30 minutes, filter, and collect the filtrate; add 3.6% hydrochloric acid dropwise to the filtrate, adjust the pH value to 2, precipitate crystals, cool down to 5°C, grow crystals for 60 minutes, filter, and drain , transferred to an oven at 30° C. and dried under reduced pressure for 3 hours; 6.7 g of dry product was obtained, and the product purity was 98.4%. The HPLC detection data of product are shown in Table 1, and the HPLC chrom...

Embodiment 2

[0051] At 25°C, add 10 g of crude BCN and 100 mL of ethyl acetate to the flask, stir evenly, then add dilute hydrochloric acid dropwise until the pH value is 2.0, stir until the system dissolves, let stand to separate layers, and then pour into the ethyl acetate layer Add 20 mL of concentrated hydrochloric acid dropwise, crystals are obviously precipitated, and react for 60 minutes; filter and wash the filter cake with 20 mL of pure water; at 25°C, add the filter cake and 100 mL of pure water to the flask, stir well, then add 7% carbonic acid dropwise Sodium hydrogen solution, adjust the pH to 9, stir for 30 minutes, filter, and collect the filtrate; add 3.6% hydrochloric acid dropwise to the filtrate, adjust the pH to 4, precipitate crystals, cool down to 5°C, grow crystals for 60 minutes, filter, and drain , transferred to an oven for drying under reduced pressure at 30° C. for 5 h; 5.5 g of dry product was obtained, and the product purity was 98.3%.

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Abstract

The invention relates to the technical field of synthesis of related impurities of medicines, and provides a synthesis method of cefcapene acid. The method comprises the following steps: taking BCN as a raw material, neutralizing diisopropylamine salt in BCN with acid to obtain desalted BCN, then removing a BOC protecting group to obtain a cefcapene acid crude product, then purifying with alkali to remove salt formed by cefcapene acid and inorganic acid and alkali-soluble impurities, and finally cooling and crystallizing under an acidic condition, so that the acid-soluble impurities are left in mother liquor, and the separated crystal is high-purity cefcapene acid. The synthesis method provided by the invention is high in production efficiency, the purity of the obtained product is more than 98%, the high-purity cefcapene acid can be used as a reference substance for analyzing the key impurity in the cefcapene pivoxil hydrochloride, and the method plays a positive role in quality control of the cefcapene pivoxil hydrochloride.

Description

technical field [0001] The invention relates to the technical field of synthesis of drug-related impurities, in particular to a synthesis method of cefcapene acid. Background technique [0002] Cefcapene Pivoxil Hydrochloride Hydrochloride (Cefcapene Pivoxil Hydrochloride Hydrate) is a third-generation oral cephalosporin antibiotic, which belongs to broad-spectrum antibiotics. It was developed by Shionogi Pharmaceutical Co., Ltd. in Japan. Antibacterial effect, highly stable to β-lactamases that can hydrolyze antibiotics. [0003] The chemical name of cefcapene pivoxil hydrochloride is: 7-[2-(2-amino-1,3-thiazol-4-yl)pent-3-enamido]-3-(carbamoyloxymethyl)- 8-Oxo-5-thio-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2,2-dimethylpropionyloxymethyl ester hydrochloride, its chemical structure is as follows: [0004] [0005] There are many methods for the synthesis of cefcapene pivoxil hydrochloride reported at present, but most of the techniques are similar to the method r...

Claims

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Application Information

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IPC IPC(8): C07D501/34C07D501/04
CPCC07D501/34C07D501/04Y02P20/55
Inventor 何健卢超王腾金联明门万辉黄金果
Owner 湖北凌晟药业股份有限公司
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