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Synthesis method of sulbactam

A technology of sulbactam acid and a synthesis method, applied in the field of sulbactam acid synthesis, can solve the problems of increasing three waste discharges, dust pollution, complicated steps, etc., and achieves reduction of the occurrence of side reactions, high product quality and yield, Avoid the effects of the oxidation process

Pending Publication Date: 2020-10-23
QINGDAO UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In the process of industrialized production, the methods provided by the above-mentioned documents all have the following problems: (1) 6-aminopenicillanic acid is added in a solid manner, and this step is prone to side reactions, cumbersome feeding operations, and serious dust pollution. And there is certain danger; (2) oxidation process needs to use excessive potassium permanganate, and the product color obtained during quenching is darker, needs decolouring repeatedly, and step is loaded down with trivial details; And the by-product manganese dioxide of potassium permanganate is carried out Acidic reduction to manganese sulfate produces a large amount of waste salt and waste water, which increases the discharge of three wastes and does not meet the requirements of green production

Method used

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  • Synthesis method of sulbactam
  • Synthesis method of sulbactam

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Experimental program
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Effect test

Embodiment 1

[0028] (1) Add 21.6g of pure water, 18.0g of 98% concentrated sulfuric acid, and bromine (40.3g, 0.25mol) into a 500mL four-necked bottle, stir at -5°C, and mix sodium nitrite (13.8g, 0.2mol) of saturated solution and 6-APA and water slurry (21.6g, 0.1mol of 6-APA and 64.8g of pure water) were added to the substrate composed of strong acid and bromine, and dripped for 1.0h Afterwards, react at 0°C for 30min, then add dropwise 1mol / L sodium bisulfite solution until the reaction solution turns yellow, react at -5°C for 3h, let stand to separate layers, extract the aqueous layer with ethyl acetate (33mL) 3 times, combine The organic phase was washed with saturated sodium chloride solution, dehydrated with anhydrous magnesium sulfate, and filtered to remove magnesium sulfate to obtain 6,6-dibromopenicillanic acid ethyl acetate solution.

[0029] (2) Cool the 6,6-dibromopenicillanic acid ethyl acetate solution obtained in (1) to 0°C, add tantalum chloride 0.72g, and slowly add 30% ...

Embodiment 2

[0032] (1) Add 25.9g of pure water, 23.5g of 31% concentrated hydrochloric acid, 51.1g of bromine into a 500mL four-necked bottle, stir at -5°C, and mix 13.8g of saturated sodium nitrite and 6-APA with the Add 21.6g of the slurry formed by water beating (0.1mol of 6-APA and 64.8g of pure water) into the substrate composed of strong acid and bromine. After 1.0h of dripping, react at 5°C for 30min, and then drop 1mol / L sodium bisulfite solution until the reaction solution was yellow, reacted at 5°C for 4h, allowed to stand and separate layers, and the aqueous layer was extracted 3 times with dichloromethane (33mL), and the combined organic phase was washed with saturated sodium chloride solution, and then Dehydrate with anhydrous magnesium sulfate, filter the magnesium sulfate to obtain 6,6-dibromopenicillanic acid dichloromethane solution.

[0033] (2) Cool the 6,6-dibromopenicillanic acid ethyl acetate solution obtained in (1) to 15°C, add 0.58g of zirconium tetrachloride, an...

Embodiment 3

[0036](1) Add 23.8g of pure water, 19g of 98% concentrated sulfuric acid, and 45.5g of bromine into a 500mL four-necked bottle, stir at -5°C, and mix 13.8g of saturated sodium nitrite and 6-APA with water The slurry formed by beating (21.6g, 0.1mol of 6-APA and 64.8g of pure water) was added to the substrate composed of strong acid and bromine. After 1.0h of dripping, reacted at 3°C ​​for 35min, and then added dropwise 1mol / L sodium bisulfite solution until the reaction solution is yellow, react at 0°C for 5h, let stand to separate layers, extract the aqueous layer with chloroform (33mL) for 3 times, wash the combined organic phase with saturated sodium chloride solution, and then wash with Dehydrate with magnesium sulfate in water, and filter to remove magnesium sulfate to obtain chloroform solution of 6,6-dibromopenicillanic acid.

[0037] (2) Cool the 6,6-dibromopenicillanic acid ethyl acetate solution obtained in (1) to 30°C, add 0.19g of boric acid, and slowly add 55g of...

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Abstract

The invention relates to a synthesis method of sulbactam, and belongs to the field of beta-lactamase inhibitor synthesis. In the method, 6-aminopenicillanic acid (6-APA) as a raw material is dissolvedin an organic solvent, and is adopted together with bromine as substrates under a strong acid condition, 6,6-dibromo penicillanic acid is formed through diazotization bromination in a manner of dropwise adding a sodium nitrite solution, and then one-step oxidation and reduction are performed to obtain sulbactam. According to the method, a hydrogen peroxide one-step oxidation mode is adopted, andthe use of potassium permanganate is avoided from the source, so that the generation of waste salt is reduced, and meanwhile, the use of a large amount of ethyl acetate is avoided. The method not onlyreduces the emission of three wastes from the source and greatly reduces the emission of organic matters and waste salt in the original process, but also greatly reduces the side reaction and the rawmaterial cost.

Description

Technical field: [0001] The invention relates to the field of synthesis of β-lactamase inhibitors, in particular to a synthesis method of sulbactam acid. Background technique: [0002] Sulbactam Acid (Sulbactam), the chemical name is (2S-5R)-3,3-Dimethyl-7-oxo-4-thio-1-azabicyclo[3,2,0]heptane Alkane-2-carboxylic acid-4,4-dioxide is a semi-synthetic broad-spectrum β-lactamase inhibitor, which is a synthetic irreversible competitive β-lactamase inhibitor It is usually used in combination with penicillins and cephalosporins to prevent it from being destroyed by β-lactamase and strengthen its antibacterial activity. It is suitable for respiratory system, urinary system, skin and soft tissue infections, and has been used in medicine in recent years. Wide range of applications. The structure of sulbactam is as follows: [0003] [0004] The traditional synthesis process of sulbactamic acid is to use 6-aminopenicillanic acid as the starting material, carry out diazotization ...

Claims

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Application Information

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IPC IPC(8): C07D499/86C07D499/04
CPCC07D499/86C07D499/04
Inventor 陈贵军王瑞菲程远志杨旭张晨赵相柱
Owner QINGDAO UNIV OF SCI & TECH