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One-pot synthesis method of cefotaxime acid

A technology of cefotaxime acid and synthesis method, which is applied in the directions of organic chemistry, organic chemistry, etc., can solve problems such as potential safety hazards, difficulty in recovery, increase in production cost, etc., so as to ensure normal precipitation, reduce production cost and prolong service life. Effect

Inactive Publication Date: 2015-11-18
山东安弘制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The process is cumbersome to operate, the yield is low, and a large amount of waste residue containing phosphine is produced, which is easy to pollute the environment
[0007] (2) IN199059 and US6610845 disclose the triazone active ester method, the process yield is low and post-processing trouble
In addition, the method disclosed in IN199059 uses the highly toxic reagent phosphorus oxychloride in the synthesis process, which will violently decompose or even explode when exposed to water, posing potential safety hazards
The method disclosed in US6610845 uses strong acid sulfuric acid during crystallization, which is highly corrosive to equipment
[0008] (3) US6388070 discloses the oxadiazole active ester method, which has many unit operations, uses many types of solvents and is difficult to recycle
Post-processing is troublesome, the production cycle is long and the conditions are harsh, and the production cost is high
[0009] (4) The AE active ester method is the most common method for synthesizing cefotaxime acid at present, and there are many documents and patents of reports at home and abroad, such as patents CN101560217, US6384215, WO20044037866, which all disclose 7-ACA and AE active ester The synthetic method of synthetic cefotaxime acid, but this technique can produce by-product 2-mercaptobenzothiazole (2-MBT) in synthetic process, directly add acid crystallization during aftertreatment and can cause the product purity that obtains on the low side, thereby Seriously affect the quality and use value of drugs
Removal of 2-MBT by extraction during post-processing will cause difficulties in solvent recovery in the later stage, and the recovered 2-MBT is usually treated as waste residue, which not only pollutes the environment but also increases production costs

Method used

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  • One-pot synthesis method of cefotaxime acid
  • One-pot synthesis method of cefotaxime acid
  • One-pot synthesis method of cefotaxime acid

Examples

Experimental program
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Effect test

Embodiment 1

[0038] A kind of one-pot synthesis method of cefotaxime acid, the steps are as follows:

[0039] (1) Add 25.0 g of aminothiaxamic acid into 250 ml of dichloromethane, cool down to -12°C, and keep warm to dissolve 11 ml of oxalyl chloride in 10.5 ml of N,N-dimethylformamide, add and keep warm for 2 hours to obtain Organic solution of oximyl chloride;

[0040] (2) Add 33.0g of 7-ACA and 10ml of water to the organic solution containing aminothioxamyl chloride, add 37ml of triethylamine dropwise at -5°C under temperature control, keep the reaction for 1.5h after dropping, add 400ml of water, stir to take the water phase, and use Formic acid was used to adjust the pH of the water phase to 2.0, and a solid was precipitated. The crystal was grown for 1 hour, and the temperature was lowered to 0° C. to grow the crystal. After conventional filtration, washing, and drying, 52.32 g of cefotaxime acid was obtained.

Embodiment 2

[0042] A kind of one-pot synthesis method of cefotaxime acid, the steps are as follows:

[0043] (1) Add 25.0 g of aminothioxamic acid into 250 ml of dichloromethane, cool down to -8°C, and keep warm; Organic solution of aminothioxamyl chloride;

[0044] (2) Add 33.0g of 7-ACA and 10ml of water to the organic solution containing aminothioxamyl chloride, add 37.1ml of triethylamine dropwise at -3°C under temperature control, keep the reaction for 2.5 hours after dropping, add 400ml of water, stir to take the water phase, Use acetic acid to adjust the pH of the aqueous phase to 2.5, precipitate solids, grow crystals for 1 hour, cool down to 2°C to grow crystals, perform conventional filtration, wash, and dry to obtain 51.38 g of cefotaxime acid.

Embodiment 3

[0046] A kind of one-pot synthesis method of cefotaxime acid, the steps are as follows:

[0047] (1) Add 25.0 g of aminothioxamic acid into 200 ml of chloroform, lower the temperature to 1 °C, add 11 ml of oxalyl chloride dissolved in 10.5 ml of N,N-dimethylformamide under temperature control, and keep warm for 2 hours to obtain Organic solutions of acid chlorides;

[0048] (2) Add 33.0g of 7-ACA and 10ml of water to the organic solution containing aminothioxamyl chloride, add 27.5ml of diethylamine dropwise at -1°C at temperature control, keep the reaction for 2 hours after dropping, add 350ml of water, stir to take the water phase, and use Acetic acid was used to adjust the pH of the water phase to 2.7, and a solid was precipitated. The crystal was grown for 1 hour, and the temperature was lowered to 3°C to grow the crystal. After conventional filtration, washing, and drying, 51.95 g of cefotaxime acid was obtained.

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Abstract

The invention relates to a one-pot synthesis method of cefotaxime acid. The one-pot synthesis method mainly comprises the following steps: (1) adding 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetic acid and a chlorine acylating agent into an organic solvent, and reacting to obtain an organic solution containing ammonia cefotaxine acyl chloride; (2) adding 7-ACA and a small amount of water into the organic solution containing the ammonia cefotaxine acyl chloride, dropwise adding an organic base while controlling the temperature to be minus 5-5 DEG C, continuously performing heat preservation reaction, adding water after the end of the reaction, taking water phases by layers, enabling crystals to grow, filtering, washing, and drying, so as to obtain the cefotaxime acid. According to the invention, the one-pot method is adopted, the intermediate ammonia cefotaxine acyl chloride is not separated in a solid manner, and the enriched phase of the ammonia cefotaxine acyl chloride is directly adopted to carry out next step of the reaction for synthesis of the cefotaxime acid, so that the shortening of the production period is facilitated, the production operation is simplified, the energy consumption during the intermediate drying process can be reduced, and the effect of reducing the cost to a certain degree is achieved.

Description

technical field [0001] The invention relates to a one-pot synthesis method of cefotaxime acid, belonging to the technical field of pharmaceutical chemical synthesis. Background technique [0002] Cefotaxime sodium is a third-generation cephalosporin semi-synthetic broad-spectrum antibiotic with broad antibacterial spectrum, high efficiency, stability and safety. The drug was jointly developed by Hoechst of Germany and Roussel of France. listed. It is widely used clinically for sepsis, purulent meningitis, respiratory tract, urinary tract, biliary tract, bone and joints, skin and soft tissue, abdominal cavity, digestive tract, facial features, genitals and other infections caused by sensitive bacteria. It can also be used for immunocompromised patients Infectious diseases with low defense functions such as decreased antibody cells. Cefotaxime acid is the precursor for the production of cefotaxime sodium, the chemical name is (6R,7R)-3-[(acetoxy)methyl]-7-[(2-amino-4-thiazol...

Claims

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Application Information

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IPC IPC(8): C07D501/34C07D501/06
CPCC07D501/34C07B2200/13C07D501/06
Inventor 赵丹丹符淙淙冯宪东赵卫良
Owner 山东安弘制药有限公司
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