CN110878101A - Novel method for preparing cefixime mother nucleus 7-AMOCA - Google Patents
Novel method for preparing cefixime mother nucleus 7-AMOCA Download PDFInfo
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- CN110878101A CN110878101A CN201911269460.3A CN201911269460A CN110878101A CN 110878101 A CN110878101 A CN 110878101A CN 201911269460 A CN201911269460 A CN 201911269460A CN 110878101 A CN110878101 A CN 110878101A
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- mother nucleus
- amoca
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- cefixime
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/59—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3 with hetero atoms directly attached in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a novel method for preparing cefradine mother nucleus 7-AMOCA, which comprises the following steps: (1) preparation of methide: adding 3-hydroxy cephalosporin, N, N-dimethylformamide and potassium carbonate in the stirring process, heating, adding dimethyl carbonate, stirring until the reaction is finished, cooling to room temperature, adding water and dichloromethane, stirring uniformly, standing for layering, drying and concentrating to obtain a methylated substance; (2) and preparing a cefixadine mother nucleus: adding dichloromethane, dibromotriphenylphosphine and 2, 6-dimethylpyridine under the condition of introducing nitrogen, cooling, adding methylate and m-cresol, and stirring until the reaction is finished; and adding water, uniformly stirring, standing for layering, adjusting the pH of a water layer, crystallizing, and drying to obtain the white cefixime mother nucleus 7-AMOCA. The method has easily obtained raw materials, and reduces the three-step reaction into the two-step reaction; avoids the use of a highly toxic reagent dimethyl sulfate in the preparation of cefixime mother nucleus, has simple operation and improves the yield.
Description
Technical Field
The invention relates to the technical field of preparation of cephalosporin intermediates, in particular to a novel method for preparing cefixadine mother nucleus 7-AMOCA.
Background
Cefixime is taken as an oral cephalosporin, has broad-spectrum antibacterial activity, has bactericidal action on staphylococcus, escherichia coli, bacillus influenzae, klebsiella, and the like, is clinically used for infection of parts such as respiratory tracts, urinary tracts, skins, soft tissues, reproductive organs, and the like, and is also commonly used for otitis media. 7-AMOCA is a key mother nucleus for synthesizing cefixime, has a chemical name of (6R,7R) -7-amino-3-methoxy-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid, and has a molecular structural formula as follows:
the existing cefixime mother nucleus 7-AMOCA synthesis technical route mainly comprises 2, the route 1 is obtained by taking a 3-OH cephem compound as an initial reaction raw material and carrying out methylation and deprotection reactions, and the reaction route is as follows:
the route 2 is that 3-OH-3-cephem is used as an initial reaction raw material, reacts with diazomethane, and is subjected to deprotection to prepare a 3-methoxy-3-cephem compound; the reaction route is as follows:
route 1 dimethyl sulfate is used as a toxic raw material in the above synthesis method, and has strong irritation to eyes and upper respiratory tract and strong corrosion to skin. Inhalation can lead to necrosis of epithelial cells of the trachea and the bronchus, and puncture can lead to mediastinal diaphragm or subcutaneous emphysema; causing serious physical injury to workers operating in the workshop.
Route 2 the synthesis method uses diazomethane which belongs to explosive products, and the diazomethane is easy to explode when being heated, exposed to fire or vibrated and rubbed; the inhalation has strong stimulation effect on respiratory tract and inhibition effect on central nervous system, and can cause dyspnea and chest pain; therefore, it is not suitable for industrial production.
Disclosure of Invention
The invention provides a novel method for preparing cefradine mother nucleus 7-AMOCA, which solves the problems in the background art, avoids the use of a highly toxic reagent dimethyl sulfate in the preparation of cefradine, simplifies a process route, realizes the simultaneous performance of deamination protection and decarboxylation protection, changes a three-step method of the route 1 into a two-step method, shortens the operation time, simplifies the process route, reduces the cost and is convenient for industrial production.
The invention provides a novel method for preparing cefradine mother nucleus 7-AMOCA, which comprises the following steps:
(1) preparation of methide:
adding 3-hydroxy cephalosporin, N, N-dimethylformamide and potassium carbonate in the stirring process, heating, adding dimethyl carbonate, stirring until the reaction is finished, cooling to room temperature, adding water and dichloromethane, stirring uniformly, standing for layering, drying and concentrating to obtain a methylated substance;
(2) and preparing a cefixadine mother nucleus:
adding dichloromethane, dibromotriphenylphosphine and 2, 6-dimethylpyridine under the condition of introducing nitrogen, cooling, adding methylate and m-cresol, and stirring until the reaction is finished; adding water, stirring uniformly, standing for layering, adjusting pH of a water layer to crystallize, and drying to obtain white cefixime mother nucleus 7-AMOCA;
the chemical reaction formula of the synthetic route is as follows:
in the process of preparing 7-AMOCA from a methylated compound, dibromotriphenylphosphine is added to carry out deprotection to form immino-bromoimine, and the intermediate state is not separated; after the addition of m-cresol, deamination protection and carboxyl protection are carried out simultaneously, and the reaction mechanism is as follows:
preferably, in the step (1), the molar ratio of the dimethyl carbonate to the 3-OH cephalosporin is 6-10: 1.
Preferably, in step (1), the reaction temperature is 60 to 65 ℃.
Preferably, in the step (2), dichloromethane is used as a solvent, 2, 6-dimethylpyridine and dibromotriphenylphosphine are added, the reaction temperature is 5-10 ℃, the reaction time is 1h, and then methylate is added, and the reaction is carried out for 2h at-10 to-5 ℃.
Preferably, in the step (2), the mol ratio of the m-cresol to the methylated compound is 18-20: 1; the reaction temperature is 8-13 ℃; the reaction time is 4-5 h.
The novel method for preparing the cefradine mother nucleus 7-AMOCA has the beneficial effects that:
1. in the synthetic method, all reactants are domestic commercial products, the toxicity is low, the preparation of deamination protection intermediates is avoided, and the cost is reduced; meanwhile, the use of highly toxic dimethyl sulfate and the like is avoided.
2. The whole process has mild and controllable operation conditions, and m-cresol in deprotection can be recycled after recovery, so that the production safety is improved, and the method is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples.
Example 1
The invention provides a novel method for preparing cefradine mother nucleus 7-AMOCA, which comprises the following steps:
(1) preparation of methide:
taking a 1000ml dry three-mouth bottle, and adding 50g (0.099mol) of 3-hydroxy cephalosporin, 300ml of N, N-dimethylformamide and 22g (0.1584mol) of potassium carbonate under mechanical stirring; after being stirred uniformly, the temperature is raised to 60 to 65 ℃; then 53.99g (0.594mol) of dimethyl carbonate is dripped, and stirring reaction is carried out for 3 hours after the dripping is finished for 30 minutes; after the reaction is finished, cooling to 25 ℃; pouring the mixture into 500ml of water and 300ml of dichloromethane, stirring uniformly, and standing for layering; the aqueous phase was extracted with 130ml of dichloromethane, the dichloromethane layers were combined, dried over anhydrous magnesium sulfate for 2 hours, the drying agent was filtered off, and dichloromethane was recovered to the end to give 46.1g (0.090mol) of a white methylated solid with a yield of 89.7%.
(2) Preparation of cefixadine mother nucleus:
adding 300ml of dichloromethane under the condition of introducing nitrogen, cooling to 5-10 ℃, adding 66.44g (0.1574mol) of dibromotriphenylphosphine and 18.74g (0.1749mol) of 2, 6-dimethylpyridine, and stirring for 1 h; cooling to-10- -5 deg.C, adding 45g (0.087mol) of methylate in batches, and reacting for 2h after 30 min; then adding 170.2g (1.574mol) of m-cresol, heating to 8-13 ℃, stirring and reacting for 4 hours; after the reaction is finished, adding 200ml of cold water, stirring uniformly, standing for layering, washing an organic phase with 100ml of water, combining water phases, adding 2g of activated carbon, stirring for 30min, and filtering; controlling the temperature to be 8-13 ℃, dropwise adding ammonia water, adjusting the pH to 3.8-4.2, and stirring for 2 hours; filtering, and washing a filter cake twice by using 35ml of water; after being pumped to dryness, the filter cake is beaten in 100ml of acetone for 25 minutes; filtering and drying to obtain white cefradine mother nucleus 7-AMOCA ((6R,7R) -7-amino-3-methoxy-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid) solid 19.18g (0.083mol), with the yield of 95.3%.
Example 2
The invention provides a novel method for preparing cefradine mother nucleus 7-AMOCA, which comprises the following steps:
(1) preparation of a reduced product:
taking a 1000ml dry three-mouth bottle, and adding 62g (0.124mol) of 3-hydroxy cephalosporin, 350ml of N, N-dimethylformamide and 27.35g (0.198mol) of potassium carbonate under mechanical stirring; after being stirred uniformly, the temperature is raised to 60 to 65 ℃; then 111.58g (1.239mol) of dimethyl carbonate is added dropwise, and stirring reaction is carried out for 3 hours after the dropwise addition is finished for 30 minutes; after the reaction is finished, cooling to 25 ℃; pouring the mixture into 600ml of water and 320ml of dichloromethane, stirring uniformly, and standing for layering; the aqueous phase was extracted with further 150ml of dichloromethane, the dichloromethane layers were combined, dried over anhydrous magnesium sulfate for 2 hours, the drying agent was filtered off, and dichloromethane was recovered to the completion to obtain 60.1g (0.117mol) of a white methylated solid with a yield of 94.3%.
(2) Preparation of cefixadine mother nucleus:
adding 300ml of dichloromethane under the condition of introducing nitrogen, cooling to 5-10 ℃, adding 76.77g (0.182mol) of dibromotriphenylphosphine and 21.66g (0.202mol) of 2, 6-dimethylpyridine, and stirring for 1 h; then the temperature is reduced to-10 to-5 ℃, 52g (0.101mol) of methylate is added in batches, and the reaction lasts for 2 hours after the addition is finished for 30 minutes; adding 218.6g (2.021mol) of m-cresol, heating to 8-13 ℃, stirring and reacting for 5 h; after the reaction is finished, 210ml of cold water is added, the mixture is stirred evenly and then stands for layering, the organic phase is washed by 120ml of water again, the water phases are combined, 2.5g of active carbon is added into the mixture, and the mixture is filtered after being stirred for 30 min; controlling the temperature to be 8-13 ℃, dropwise adding ammonia water, adjusting the pH to 3.8-4.2, and stirring for 2 hours; filtering, and washing a filter cake twice by using 40ml of water; after pumping, the filter cake is pulped in 115ml of acetone for 25 minutes; filtering and drying to obtain white cefixime mother nucleus 7-AMOCA ((6R,7R) -7-amino-3-methoxy-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid) solid 22.36g (0.097mol), with the yield of 96.1%.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (5)
1. A novel method for preparing cefixime mother nucleus 7-AMOCA is characterized by comprising the following steps:
(1) preparation of methide:
adding 3-hydroxy cephalosporin, N, N-dimethylformamide and potassium carbonate in the stirring process, heating, adding dimethyl carbonate, stirring until the reaction is finished, cooling to room temperature, adding water and dichloromethane, stirring uniformly, standing for layering, drying and concentrating to obtain a methylated substance;
(2) and preparing a cefixadine mother nucleus:
adding dichloromethane, dibromotriphenylphosphine and 2, 6-dimethylpyridine under the condition of introducing nitrogen, cooling, adding methylate and m-cresol, and stirring until the reaction is finished; and adding water, uniformly stirring, standing for layering, adjusting the pH of a water layer, crystallizing, and drying to obtain the white cefixime mother nucleus 7-AMOCA.
2. The novel process for preparing cefixime mother nucleus 7-AMOCA according to claim 1, characterized in that: in the step (1), the molar ratio of the dimethyl carbonate to the 3-OH cephalosporin is 6-10: 1.
3. The novel process for preparing cefixime mother nucleus 7-AMOCA according to claim 1, characterized in that: in the step (1), the reaction temperature is 60-65 ℃.
4. The novel process for the preparation of cefixime mother nucleus 7-AMOCA according to claim 1, characterized in that: in the step (2), dichloromethane is used as a solvent, 2, 6-dimethylpyridine and dibromotriphenylphosphine are added, the reaction temperature is 5-10 ℃, the reaction time is 1h, and then a methylate is added to react for 2h at-10 to-5 ℃.
5. The novel process for the preparation of cefixime mother nucleus 7-AMOCA according to claim 1, characterized in that: in the step (2), the mol ratio of the m-cresol to the methylated compound is 18-20: 1; the reaction temperature is 8-13 ℃; the reaction time is 4-5 h.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112321611A (en) * | 2020-10-29 | 2021-02-05 | 湖北凌晟药业有限公司 | Preparation method of cefixadine mother nucleus |
| CN113563365A (en) * | 2021-08-17 | 2021-10-29 | 华中药业股份有限公司 | Preparation method of 7-amino-3-methoxy-4-cephalosporanic acid |
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| CN1338459A (en) * | 2000-08-10 | 2002-03-06 | 国家药品监督管理局天津药物研究院 | Process for preparing ancef |
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2019
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112321611A (en) * | 2020-10-29 | 2021-02-05 | 湖北凌晟药业有限公司 | Preparation method of cefixadine mother nucleus |
| CN113563365A (en) * | 2021-08-17 | 2021-10-29 | 华中药业股份有限公司 | Preparation method of 7-amino-3-methoxy-4-cephalosporanic acid |
| CN113563365B (en) * | 2021-08-17 | 2024-05-28 | 华中药业股份有限公司 | Preparation method of 7-amino-3-methoxy-4-cephalosporanic acid |
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