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Preparation method of 3-hydroxy-cepham compound

A compound, cephalosporin technology, applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of pollution, high cost, low yield, etc., and achieve the effects of safe operation, low cost, and low toxicity of raw materials

Active Publication Date: 2012-07-04
浙江东邦药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Using 7-aminocephalosporanic acid (7-ACA) as the starting material cost is higher, the yield is low, and the phenomenon of serious pollution

Method used

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  • Preparation method of 3-hydroxy-cepham compound
  • Preparation method of 3-hydroxy-cepham compound
  • Preparation method of 3-hydroxy-cepham compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Add 2000ml dichloromethane and 300g structural formula in reaction bottle and be the compound thiazoline enol ester derivative of formula II (wherein R 1 for PhCH 2 Base; R 2(p-nitrobenzyl) and p-toluenesulfonyl chloride 138.7g, stirred and dissolved, cooled to 0-5°C in ice water. Dilute ammonia water was slowly added dropwise to carry out sulfonylation reaction to obtain p-toluenesulfonate, a compound of formula III. After the reaction, a sample was taken to detect that the content of the compound of formula II in the reaction solution was less than 0.1%. The aqueous layer was removed, and dried by adding anhydrous magnesium sulfate. The temperature was lowered to 0° C. to -10° C., 57.6 g of morpholine was added, and then triethylamine was added dropwise to carry out enamination reaction to obtain a compound of formula IV. After the enamination reaction, the residual p-toluenesulfonate of the compound of formula III was monitored by HPLC to be less than 0.1%. Conti...

Embodiment 2

[0036] Add 2000ml tetrahydrofuran and 300g structural formula in reaction bottle and be the thiazoline enol ester derivative of formula II (wherein R 1 for PhCH 2 Base; R 2 (p-nitrobenzyl) and p-toluenesulfonyl chloride 138.7g, stirred and dissolved, cooled to 5-10°C in ice water. Ammonia gas is slowly introduced to carry out sulfonylation reaction to obtain p-toluenesulfonate, a compound of formula III, and after the reaction, a sample is taken to detect that the content of the compound of formula II is less than 0.1%. The solvent tetrahydrofuran was removed under reduced pressure, and 1500 ml of dichloromethane and anhydrous magnesium sulfate were added to dry it. The temperature was lowered to -10°C to -20°C, 57.6g of morpholine was added, and then triethylamine was added dropwise to carry out enamination reaction to obtain the compound of formula IV. After the enamination reaction, the residual tosylate of the compound of formula III was monitored by HPLC to be less tha...

Embodiment 3

[0038] Add 2000ml dichloromethane and 300g structural formula in reaction bottle and be the thiazoline enol ester derivative of formula II (wherein R 1 for PhCH 2 Base; R 2 (p-nitrobenzyl) and p-toluenesulfonyl chloride 138.7g, stirred and dissolved, cooled to 5-10°C in ice water. Dilute ammonia water was slowly added dropwise to carry out sulfonylation reaction to obtain the compound p-toluenesulfonate with the structural formula III. After the reaction, a sample was taken to detect that the content of the compound of the formula II was less than 0.1%. The aqueous layer was removed, and dried by adding anhydrous magnesium sulfate. Cool down to -20°C to -35°C, add 57.6g of morpholine, and then pass through ammonia gas to carry out enamination reaction to obtain the compound of formula IV. After the reaction was completed, the remaining p-toluenesulfonate of the compound of formula III was monitored by HPLC to be less than 0.1%. Continue to lower the temperature to -45°C to...

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Abstract

The invention provides a preparation method of a 3-hydroxy-cepham compound, belonging to the technical field of medicine intermediate synthesis. The method comprises the following steps: A. sulfonylation reaction, B. enamine reaction, C. bromination reaction and D. cyclization reaction, thus obtaining the target product through extraction, concentration, crystallization, filtration and drying. The preparation method of the invention has the advantages of enjoying safe and simple operation, reasonable technique and design, low cost, environmental protection, high efficiency and no side reaction effects, effectively utilizing the reactivity of raw materials, improving the yield and purity of the product and being suitable for large-scale industrial production, etc.

Description

technical field [0001] The invention relates to a preparation method of a cephalosporin antibiotic intermediate, in particular to a preparation method of a 3-hydroxycephalosporin compound; it belongs to the technical field of synthesis of pharmaceutical intermediates. Background technique [0002] Since the discovery of penicillin by the British doctor Fleming in 1929, human research on antibiotics has made great progress, but due to the narrow antibacterial spectrum of penicillin, it is easy to cause anaphylactic shock and instability, and its application is limited. The chemical structure of penicillin has been modified a lot to find antibiotics with high efficiency, broad spectrum, low toxicity, enzyme resistance and stability. Among them, cephalosporin antibiotics such as cefaclor, ceftibuten, and ceftizoxime are highly effective antibiotics commonly used in clinical practice. 1 / 4, especially the cases of anaphylactic shock are less than penicillins, and it is safer to ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/59C07D501/08
Inventor 池正明南宫润叶张云华
Owner 浙江东邦药业有限公司
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