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A kind of synthetic method of sulbactamic acid

A technology of sulbactamic acid and its synthetic method, which is applied in the field of sulbactamic acid synthesis, can solve the problems of cumbersome feeding operations, serious dust pollution, dark color, etc., and achieve the goals of improving reaction quality, avoiding dust pollution, and improving working environment Effect

Active Publication Date: 2017-02-15
JIANGXI FUSHINE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 mode; Side reaction, when feeding, it is necessary to add 6-aminopenicillanic acid in batches for many times, the feeding operation is cumbersome, and the dust pollution is serious, and the operating environment of the workers is bad; at the same time, due to the artificial solid addition, the product quality is difficult to be guaranteed; and , even if it is added in batches, it is impossible to completely avoid the occurrence of self-decomposition side reactions (2) in the oxidation process, when excessive potassium permanganate is quenched, the color of the product obtained is darker, and the final product is difficult to meet the quality requirements; Requires multiple decolorization treatments, etc.

Method used

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  • A kind of synthetic method of sulbactamic acid
  • A kind of synthetic method of sulbactamic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Add 200 mL of ethyl acetate into a four-necked flask, cool down to 0°C, add bromine (40.0 g, 0.235 mol), stir, and simultaneously add a saturated aqueous solution of sodium nitrite (12.5 g, 0.14 mol) and 6-aminopenicillium The acid solution of alkanoic acid (dissolve 20.0g of 6-aminopenicillanic acid in 20mL of 5% sulfuric acid solution) was added dropwise to the reaction solution at 0-5°C, and the drop was completed in about 1.0-1.5 hours. No trace was detected during the reaction. 6-aminopenicillanic acid breakdown products. After reacting at 10-15°C for 30 minutes, 1 mol / L sodium bisulfite solution was added dropwise until the reaction solution turned yellow, and the layers were separated after standing. The aqueous layer was extracted once with ethyl acetate (30 mL), and the organic phases were combined. The organic phase was extracted twice with 10% NaOH, and the organic phase was applied mechanically. After the combined aqueous phase HPLC detected that the compoun...

Embodiment 2

[0044] Add 220 mL of tetrahydrofuran into a four-necked flask, cool down to 0°C, add bromine (37.0 g, 0.231 mol), stir, and simultaneously add a saturated solution of sodium nitrite (12.5 g, 0.14 mol) and 6-aminopenicillanic acid Acid solution (20.0g of 6-aminopenicillanic acid dissolved in 15mL of 8% sulfuric acid solution), was added dropwise into the reaction solution at 0-5°C, and the drop was completed in about 1.0-1.5h. After reacting at 10-15°C for 30 minutes, 1 mol / L sodium bisulfite solution was added dropwise until the reaction solution turned yellow, and the layers were separated after standing. The aqueous layer was extracted once with tetrahydrofuran (30 mL), and the organic phases were combined. The organic phase was extracted twice with 10% NaOH, and the organic phase was used mechanically. After the combined aqueous phase HPLC detected that the compound I content was more than 99.0%, it was directly put into the next step reaction.

[0045] Add the aqueous solu...

Embodiment 3

[0048] Add 200 mL of ethyl acetate into a four-neck flask, cool down to 0°C, add bromine (48.0 g, 0.282 mol), stir, and simultaneously add a saturated aqueous solution of sodium nitrite (9.0 g, 0.101 mol) and 6-aminopenicillium The acid solution of alkanoic acid (dissolve 20.0g of 6-aminopenicillanic acid in 20mL of 15% hydrobromic acid aqueous solution) was added dropwise to the reaction solution at 0-5°C, and the drop was completed in about 1.0-1.5h. After reacting at 10-15°C for 30 minutes, 1 mol / L sodium bisulfite solution was added dropwise until the reaction solution turned yellow, and the layers were separated after standing. The aqueous layer was extracted once with ethyl acetate (30 mL), and the organic phases were combined. The organic phase was extracted twice with 10% NaOH, and the organic phase was used mechanically. After the combined aqueous phase HPLC detected that the compound I content was more than 99.0%, it was directly put into the next step reaction.

[0...

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Abstract

The invention discloses a synthetic method of salbactam acid. The synthetic method comprises the following steps: carrying out diazotized bromination reaction on 6-aminopenicillanic acid to form bromopenicillanic acid; and then, carrying out oxidation reaction and reduction reaction to obtain salbactam acid, wherein in the diazotized bromination reaction, 6-aminopenicillanic acid is continuously added in form of an acidic solution, the acidic solution of 6-aminopenicillanic acid is 5-8% sulfuric acid aqueous solution, 13-15% hydrobromic acid aqueous solution or 5-8% hydrochloric acid aqueous solution. 6-aminopenicillanic acid is dropwise added in form of the acidic solution, so that dust pollution is avoided and the work environment of field personnel is improved. Meanwhile, 6-aminopenicillanic acid exists in form of stable salt, decomposition reaction is avoided, and the reaction quality is improved. The three-step yield of the method is over 70%, the HPCL purity is over 99.7%, the individual impurity content is less than 0.1% and the total impurity content is less than 0.5%.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and in particular relates to a synthesis method of sulbactam acid. Background technique [0002] Sulbactam (sulbactam acid) is a semi-synthetic broad-spectrum β-lactamase inhibitor, it is a competitive irreversible β-lactamase inhibitor, combined with β-lactam antibiotics, It has a good synergistic effect and has been widely used in medicine in recent years. The structure of sulbactam is as follows: [0003] [0004] The traditional synthesis process of sulbactam is to use 6-aminopenicillanic acid as the starting material, carry out diazotization reaction with sodium nitrite under acidic conditions, then carry out double bromination reaction with bromine, and then undergo high manganese Potassium acid oxidation, and finally use metal powder zinc powder, magnesium powder or catalytic hydrogenation reduction to obtain the desired compound sulbactam acid. [0005] For example, the patent docu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D499/86C07D499/04
CPCC07D499/04C07D499/86
Inventor 郑裕义郭靖宁张祥明程荣武余远福
Owner JIANGXI FUSHINE PHARMA CO LTD
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