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Method for preparing ceftibuten mother nucleus 7-ANCE

A technology of 7-ANCE and ceftibuten core, which is applied in organic chemistry and other fields, can solve the problems of physical injury of workshop workers, long steps, and increased cost of 7-ANCE raw materials, etc.

Active Publication Date: 2021-05-07
湖北凌晟药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Route 1 has complicated process, long steps and low yield in the above synthesis method. In the route, methanesulfonyl chloride needs to be used for hydroxyl protection, which is extremely harmful to the operator and is not conducive to industrial production.
[0007] Route 2 is obtained by taking hydrazine hydrate as the starting reaction raw material through diphenyldiazomethane, and then condensing with 7-ANCA (7-amino-3 hydrogen cephalosporanic acid). In the above-mentioned synthetic method, hydrazine hydrate, Diethyl ether, yellow mercuric oxide and other raw materials, of which hydrazine hydrate and diethyl ether are flammable and explosive products are prone to explosion or fire during workshop operation; yellow mercuric oxide is a heavy metal poisonous substance, and it is cumulative poisoning, which cannot be decomposed in the human body , causing serious bodily injury to workshop operators
At the same time, another main raw material is 7-ANCA as the mother nucleus of ceftizoxime, which is expensive and increases the cost of raw materials for preparing 7-ANCE

Method used

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  • Method for preparing ceftibuten mother nucleus 7-ANCE
  • Method for preparing ceftibuten mother nucleus 7-ANCE
  • Method for preparing ceftibuten mother nucleus 7-ANCE

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Compound A was prepared as follows:

[0038] Add 50.02g (0.1mol) of 3-hydroxycephalosporin and 600mL of dichloromethane into a 1000mL reaction flask, stir for 20min, and cool down to -60~-50°C; add 11.4g (0.22mol) of potassium borohydride, and control the temperature at -60°C 200ml of methanol was added dropwise at ~-50°C, and the reaction was stirred for 2 hours. After the reaction is completed and the temperature rises to room temperature, wash with 200ml of 5% sodium chloride solution and 200ml of water successively, separate layers, concentrate and dry the organic layer under reduced pressure, and then add dichloromethane to the system: cyclohexane volume ratio = 2 : 200ml of mixed solvent crystallization of 1, filter after the temperature drops to -10~0°C, and dry under reduced pressure at 50°C to obtain compound A shown in formula 1, 45.3g of white solid, yield 90.6%, purity 98.5%, reaction The formula is as follows:

[0039]

[0040] Compound A prepared by t...

Embodiment 2

[0044] Step S1: Add 50.2g (0.1mol) of compound A and 500mL of dichloromethane into a 1000mL reaction flask, stir for 20min, and cool down to -20°C; add 58.3g (0.28mol) of phosphorus pentachloride, stir for 10 minutes and drop Add 22.1 g (0.28 mol) of pyridine, and control the temperature at -20°C to keep stirring and react for 3 hours.

[0045] Step S2: After the reaction, control the temperature below 0°C and add HCl isobutanol solution (300ml, acid mass concentration 15%) dropwise, control the temperature -5°C, keep stirring for 4 hours, filter after the stirring, and filter out the ammonium salt.

[0046] Step S3: Put the ammonium salt into 150ml of water, use 10% sodium bicarbonate solution to adjust the pH value to 7.6, control the temperature at 25°C and keep stirring for 2 hours, filter, and dry under reduced pressure at 50°C to obtain 7-ANCE, a white solid of 36.1 g.

Embodiment 3

[0048] Step S1: Add 50.2g (0.1mol) of compound A and 400mL of dichloromethane into a 1000mL reaction flask, stir for 20min, and cool down to -20°C; add 62.5g (0.30mol) of phosphorus pentachloride, stir for 10 minutes and drop 27.9 g (0.30 mol) of 2-methylpyridine was added, and the temperature was controlled at -15°C to keep stirring and react for 2 hours.

[0049] Step S2: After the reaction, control the temperature below -10°C and add HBr isopropanol solution (300ml, acid mass concentration 13%) dropwise, control the temperature at 0°C, keep stirring for 3 hours, filter after the stirring, and filter out the ammonium salt.

[0050] Step S3: Put the ammonium salt into 200ml of water, adjust the pH value to 8.3 with 10% ammonia solution, control the temperature at 25°C and keep stirring for 2 hours, filter, and dry under reduced pressure at 50°C to obtain 7-ANCE, 36.0g of white solid.

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Abstract

The invention belongs to a method for preparing a ceftibuten mother nucleus 7-ANCE. The method for preparing the ceftibuten mother nucleus 7-ANCE comprises the following steps: S1, reacting a compound A as shown in a formula I with halogenated phosphorus and an acid-binding agent; S2, adding an acid solution to react to generate ammonium salt; and S3, adjusting the pH value of the ammonium salt generated in the step S2 to be neutral or alkaline to obtain a crude product, and purifying to obtain the ceftibuten mother nucleus 7-ANCE, wherein the molar ratio of the compound A to the halogenated phosphorus is 1: (2.5-3.5). Compared with the prior art, the method has the beneficial effects that the reaction is carried out in the rearrangement direction by controlling the molar ratio of the compound A to the phosphorus halide, so that the hydroxyl protection step in the prior art can be omitted, the use of a methylsulfonyl chloride irritant raw material is avoided, and a product with higher purity and yield is obtained.

Description

technical field [0001] The invention belongs to the field of compound synthesis, in particular to a method for preparing ceftibuten core 7-ANCE. Background technique [0002] Ceftibuten is a third-generation oral cephalosporin with broad-spectrum antibacterial activity and strong antibacterial effect on most Gram-negative bacilli and some positive cocci. 7-ANCE is the key mother nucleus for the synthesis of ceftibuten. The chemical name is 7-amino-8-oxo-5-thio-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester, and its molecular structure is: [0003] [0004] There are mainly 2 synthesis and technical routes of the existing ceftibuten core 7-ANCE, and the reaction routes are as follows: [0005] [0006] Route 1 has complicated process, long steps and low yield in the above synthesis method. In the route, methanesulfonyl chloride needs to be used for hydroxyl protection, which is extremely harmful to the operators and is not conducive to industrial p...

Claims

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Application Information

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IPC IPC(8): C07D501/18C07D501/04
CPCC07D501/18C07D501/04
Inventor 何健李鹏程龙金联明金大俊门万辉邹菁
Owner 湖北凌晟药业股份有限公司
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