CN109503629B

CN109503629B - Synthesis method of ceftizoxime acid

Info

Publication number: CN109503629B
Application number: CN201811641348.3A
Authority: CN
Inventors: 高红军; 徐之存; 张会
Original assignee: Shandong Luoxin Pharmaceutical Group Hengxin Pharmaceutical Co ltd; Shandong Yuxin Pharmaceutical Co ltd; Shandong Luoxin Pharmaceutical Group Co Ltd
Current assignee: Shandong Luoxin Pharmaceutical Group Hengxin Pharmaceutical Co ltd; Shandong Yuxin Pharmaceutical Co ltd; Shandong Luoxin Pharmaceutical Group Co Ltd
Priority date: 2018-12-29
Filing date: 2018-12-29
Publication date: 2021-02-26
Anticipated expiration: 2038-12-29
Also published as: CN109503629A

Abstract

The invention discloses a method for synthesizing ceftizoxime acid, and belongs to the technical field of medicine synthesis. The invention adopts 7-ANCA and AE active ester to react to prepare ceftizoxime acid. The synthesis method has the advantages of simplicity, easy operation of reaction, higher yield and purity and less by-products of products, and is suitable for industrial production.

Description

Synthesis method of ceftizoxime acid

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing ceftizoxime acid.

Background

Ceftizoxime acid, chemical name: (6R, 7R) -7- [ (Z) -2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido ] -8-oxo-5-thia-1-aminoheterobicyclo [4.2.0] oct-2-ene-2-carboxylic acid having the formula:

。

ceftizoxime was first marketed in japan in 1982 under the trade name Ceftizox, a third generation cephalosporin antibiotic developed by japan tenuzolk chemical industries co. The product is used as third generation cephalosporin antibiotic, has the action mechanism of inhibiting biosynthesis of bacterial cell wall mucopeptide to achieve bactericidal effect, and has the characteristics of broad spectrum, high efficiency, enzyme resistance, low toxicity and capability of passing through blood brain barrier. Are stable against a broad spectrum of beta-lactamases (including penicillinase and cephalosporinase) produced by a wide variety of gram-positive and gram-negative bacteria. Has strong antibacterial effect on Enterobacteriaceae bacteria such as Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis, and Pseudomonas aeruginosa and Acinetobacter have poor sensitivity to the product. Ceftizoxime has good antibacterial effect on haemophilus influenzae and neisseria gonorrhoeae. The effect on staphylococcus aureus and staphylococcus epidermidis is inferior to that of the first and second generation cephalosporins, methicillin-resistant staphylococcus aureus and enterococcus are resistant to the product, and various streptococci are highly sensitive to the product. The anaerobic bacteria such as the digestive coccus, the digestive streptococcus, part of bacteroides and the like are sensitive to the product, and the clostridium difficile is resistant to the product. The traditional Chinese medicine composition is clinically used for treating lower respiratory tract infection, urinary tract infection, abdominal cavity infection, pelvic cavity infection, septicemia, skin soft tissue infection, bone and joint infection, meningitis caused by streptococcus pneumoniae or haemophilus influenzae and simple gonorrhea caused by sensitive bacteria.

The following cases are reported about the synthesis process of ceftizoxime at present:

1. U.S. Pat. No. 4,4427674 discloses two routes, one of which is to prepare ceftizoxime sodium from 7-phenylacetamido-3-cephalosporin-4 carboxylic p-methoxybenzyl ester through removing protective groups for many times and then reacting with a salt forming agent. The protecting group is removed by the route for many times, so that the reaction step is long, and the operation procedure and the production cost are increased. The other method is that 7-amino-nor-3-cephem-4-formic acid is directly condensed with aminothiazoly loximate, and then salified, and the product of the method needs to be purified by column chromatography, and the operation is complicated.

2. Chinese patent CN102603771A reports that 7-ANCN and AE active ester are taken as raw materials to react at 20-40 ℃ to prepare ceftizoxime acid, but the product yield and purity are still not high, and the problems of impurities such as byproducts generated by carbonyl and amido bond and the like exist.

Disclosure of Invention

The invention aims to provide a novel synthesis method of ceftizoxime acid aiming at the defects of the prior art, and the synthesis method is simple in reaction operation, high in yield and purity, less in by-product and suitable for industrial production.

A synthetic method of ceftizoxime acid comprises the following steps:

adding 7-ANCA, dichloromethane and an acid-binding agent into a reactor in sequence, stirring and dissolving, dropwise adding AE active ester under the condition of low temperature, adding the AE active ester for 15 minutes, adding 4-dimethylaminopyridine, keeping the condition of low temperature unchanged, stirring and reacting for a certain time, adding water at room temperature for layering after the reaction is finished, separating an organic phase, retaining a water phase, adding dichloromethane for washing, adding activated carbon for decoloring, adding hydrochloric acid for crystallizing, centrifuging and drying to obtain ceftizoxime acid;

the synthetic route is as follows:

。

preferably, the ratio of 7-ANCA to AE active ester is 1: 1.1; the acylation reaction temperature is-5 ℃ to 10 ℃, and further preferably-5 ℃ to 0 ℃.

Preferably, the acid-binding agent is triethylamine, N-diisopropylethylamine or 4-dimethylaminopyridine; the molar dosage of the acid-binding agent is 2 times of that of 7-ANCA.

Preferably, the molar amount of 4-dimethylaminopyridine is 0.5 times that of 7-ANCA.

Preferably, the acylation reaction time is 3-4 h.

Further preferably, the specific reaction steps are: adding 7-ANCA, dichloromethane and 4-dimethylaminopyridine into a reactor in sequence, stirring and dissolving, controlling the temperature to be-5-0 ℃ for reaction, dropwise adding AE active ester, adding 4-dimethylaminopyridine after 15 minutes, stirring and reacting for 3-4 hours, adding water at room temperature for layering after the reaction is finished, separating an organic phase, retaining a water phase, adding dichloromethane for washing, adding activated carbon for decoloring, adding hydrochloric acid for crystallization, centrifuging and drying to obtain ceftizoxime acid.

Compared with the prior art, the invention has the beneficial effects that:

(1) the acylation reaction is controlled to react at low temperature, so that the side reaction of carbonyl and amido bond is reduced, and the total yield and purity of the product are improved.

(2) The reaction parameter conditions are controlled in a proper proportion, the product yield and the purity are ensured to be high, the production cost is reduced to the minimum, and the method is suitable for industrial production.

Detailed Description

The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.

Example 1

Preparation of ceftizoxime acid

Adding 20.01g (0.1mol) of 7-ANCA, 150ml of dichloromethane and 0.2mol of triethylamine into a reactor in sequence, stirring and dissolving, dropwise adding 35.02g (0.1mol) of AE active ester under the condition of 5-10 ℃, adding 0.05mol of 4-dimethylaminopyridine after 15 minutes, keeping the temperature condition unchanged, stirring and reacting for 3-4 hours, adding water at room temperature after the reaction is finished, layering, separating an organic phase, keeping a water phase, adding dichloromethane, washing, adding activated carbon for decolorization, adding hydrochloric acid for crystallization, centrifuging and drying to obtain 32.64g of ceftizoxime acid, wherein the product yield is 85%, the purity is 99.5%, the maximum single impurity content is 0.06% and the total impurity content is 0.36%.

Example 2

Preparation of ceftizoxime acid

Adding 20.02g (0.1mol) of 7-ANCA, 150ml of dichloromethane and 0.2mol of 4-dimethylaminopyridine into a reactor in sequence for stirring and dissolving, dropwise adding 38.52g (0.11mol) of AE active ester under the condition of-5-0 ℃, adding 0.05mol of 4-dimethylaminopyridine after 15 minutes, keeping the temperature condition unchanged, stirring and reacting for 3-4 hours, adding water at room temperature for layering after the reaction is finished, separating an organic phase, reserving a water phase, adding dichloromethane for washing, adding activated carbon for decoloring, adding hydrochloric acid for crystallizing, centrifuging and drying to obtain 37.13g of ceftizoxime acid, wherein the yield is 97%, the purity is 99.8%, the maximum single impurity content is 0.05% and the total impurity content is 0.18%.

Example 3

Preparation of ceftizoxime acid

Adding 20.02g (0.1mol) of 7-ANCA, 150ml of dichloromethane and 0.2mol of N, N-diisopropylethylamine into a reactor in sequence, stirring and dissolving, controlling the temperature to be 0-5 ℃, dropwise adding 42.01g (0.12mol) of AE active ester, finishing adding after 15 minutes, keeping the temperature condition unchanged, stirring and reacting for 3-4 hours, adding water at room temperature after the reaction is finished, layering, separating an organic phase, keeping a water phase, adding dichloromethane for washing, adding activated carbon for decoloring, adding hydrochloric acid for crystallizing, centrifuging and drying to obtain 30.65g of ceftizoxime acid, wherein the yield is 80%, the purity is 99.7%, the maximum single impurity content is 0.07%, and the total impurity content is 0.25%.

Example 4

Preparation of ceftizoxime acid

Adding 20.02g (0.1mol) of 7-ANCA, 150ml of dichloromethane and 0.2mol of triethylamine into a reactor in sequence, stirring and dissolving, dropwise adding 38.52g (0.11mol) of AE active ester at 5-10 ℃, adding 0.05mol of 4-dimethylaminopyridine after 15 minutes, keeping the temperature condition unchanged, stirring and reacting for 3-4 hours, adding water at room temperature after the reaction is finished, layering, separating an organic phase, reserving a water phase, adding dichloromethane, washing, adding activated carbon, adding hydrochloric acid, crystallizing, centrifuging and drying to obtain 36.48g of ceftizoxime acid, wherein the yield is 95%, the purity is 99.5%, the maximum single impurity content is 0.21% and the total impurity content is 0.39%.

Claims

1. The synthesis method of ceftizoxime acid is characterized by comprising the following steps:

adding 7-ANCA, dichloromethane and an acid-binding agent into a reactor in sequence, stirring and dissolving, dropwise adding AE active ester under a low-temperature condition, adding the AE active ester for 15 minutes, adding 4-dimethylaminopyridine, keeping the low-temperature condition unchanged, stirring and reacting for a certain time, adding water at room temperature for layering after the reaction is finished, separating an organic phase, retaining a water phase, adding dichloromethane for washing, adding activated carbon for decoloring, adding hydrochloric acid for crystallization, centrifuging and drying to obtain ceftizoxime acid, wherein the maximum single impurity content is 0.05%, and the total impurity content is 0.18%; the 7-ANCA and AE active ester is 1: 1.1; the low temperature is-5 ℃ to 0 ℃; the molar dosage of the 4-dimethylaminopyridine is 0.5 time of that of 7-ANCA; the reaction time is 3-4 h; the acid-binding agent is 4-dimethylaminopyridine, and the molar dosage of the acid-binding agent is 2 times of that of 7-ANCA;

the synthetic route is as follows:

。