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Intermediate isomer for preparing cefovecin by taking penicillin potassium salt as raw material and preparation method of intermediate isomer

A technology of penicillin potassium salt and cefvecin, applied in organic chemistry and other directions, can solve the problems of harsh reaction conditions, high environmental protection requirements, and difficult operation, and achieve the effects of good product quality, improved quality, and good reaction selectivity.

Inactive Publication Date: 2020-11-06
CHONGQING MEDICAL & PHARMA COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has the problems of long route, low yield, harsh reaction conditions, high requirements for environmental protection and difficult operation

Method used

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  • Intermediate isomer for preparing cefovecin by taking penicillin potassium salt as raw material and preparation method of intermediate isomer
  • Intermediate isomer for preparing cefovecin by taking penicillin potassium salt as raw material and preparation method of intermediate isomer
  • Intermediate isomer for preparing cefovecin by taking penicillin potassium salt as raw material and preparation method of intermediate isomer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Esterification, Oxidation

[0046]

[0047] Add 200kg DMF and 69.6kg p-nitrobenzyl bromide into a 300L glass-lined reactor, stir at room temperature to dissolve and clarify the feed solution. Add 100kg (0.2685mol) penicillin potassium salt; raise the temperature to 42-45°C; stir and react at 42-45°C for 2h until the reaction is complete.

[0048] Add the reaction solution to 400kg of dichloromethane and 350kg of deionized water cooled to -5-0°C, stir, then add sulfuric acid solution to adjust the pH to less than 5, stir, separate the organic layer, and discard the water layer.

[0049] Cool the organic layer to about 0-5°C, add about 102kg of 32% peroxyacetic acid (freshly prepared) dropwise, and stir for about 2 hours until the reaction is complete. The layer was discarded, and the organic layer was added with about 28kg10% sodium sulfite aqueous solution until there was no oxidation (starch potassium iodide test paper does not change color) in the material, stirri...

Embodiment 2

[0051] Esterification, Oxidation

[0052]Add 200kg DMF and 62kg p-nitrobenzyl bromide into a 300L glass-lined reactor, stir at room temperature to dissolve and clarify the feed solution. Add 100kg (0.2685mol) penicillin potassium salt; raise the temperature to 42-45°C; stir the reaction at 42-45°C until the reaction is complete.

[0053] Add the reaction solution to 400kg of dichloromethane and 350kg of deionized water cooled to -5-0°C, stir, then add sulfuric acid solution to adjust the pH to less than 5, stir, separate the organic layer, and discard the water layer.

[0054] Cool the organic layer to about 0-5°C, add about 130kg of 32% peroxyacetic acid (freshly prepared) dropwise, stir the reaction until the reaction is complete after the dropwise addition, add 380kg of deionized water, stir, then let the layers stand, discard the water layer Go, organic layer is in adding about 30kg10% sodium sulfite aqueous solution, until there is no oxidation in the material (starch po...

Embodiment 3

[0056] Ring-opening rearrangements and isomerizations

[0057]

[0058] Add 460kg of dehydrated toluene to the reaction kettle, add 100kg of intermediate oxides, wash the feeding port with 20kg of toluene, adjust the internal temperature to 90-100°C, stir until dissolved and clear, add 51.1kg of TMP, adjust the vacuum to control the internal temperature at 90°C -100°C, react until the reaction is complete. Nitrogen protection cools to below 30°C.

[0059] Add 27kgTEA under the protection of nitrogen, and react in the dark below 30°C (generally, the reaction is at room temperature, when the room temperature is higher than 30°C, properly lower the temperature) until the reaction is complete, add 200kg of 5% (W) hydrochloric acid, and stir for 5 minutes. The layers were allowed to stand, and the water layer was transferred to an extraction kettle. 250 kg of dichloromethane was added to the water layer and stirred for 5 minutes. Stand to separate layers, discard the water lay...

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Abstract

The invention discloses an intermediate isomer for preparing cefovecin by taking penicillin potassium salt as a raw material and a preparation method therefor. An intermediate ring-opening rearrangement material is used as a raw material to perform isomerization reaction to obtain the intermediate isomer; the method specifically comprises the following steps: adding a dehydrated reaction organic solvent into a reaction container, then adding intermediate oxides, regulating temperature to 90-100 DEG C, stirring until the solution is clear, adding trimethyl phosphite, adjusting the vacuum degree, controlling the reaction temperature to be 90-100 DEG C, reacting until the reaction is complete, cooling to 30 DEG C or lower under the protection of nitrogen, adding organic alkali into the reaction container, and reacting in a dark place at the temperature of 30 DEG C or below under the protection of nitrogen until the reaction is complete to obtain the intermediate isomer. Compared with theprior art, when the intermediate is synthesized, a one-pot method is adopted for preparation, and the operation difficulty is reduced. Because the stability of the cephalosporin mother nucleus is poorer, the reaction selectivity is improved by strictly controlling the reaction conditions, and finally, the reaction yield is high and the product quality is good.

Description

technical field [0001] The invention relates to a pharmaceutical intermediate, in particular to an intermediate isomer for preparing cefotaxime by using penicillin potassium salt as a raw material and a preparation method thereof. Background technique [0002] Cefotaxime is a third-generation cephalosporin drug, its molecular structure is: [0003] [0004] Cefotaxime was successfully synthesized by Smithkline Beecham Company for the first time in 1994, but the synthesis cost was relatively high. It was later developed by Pfizer as a pet drug. It was first allowed in the European Union in 2006 for the treatment of skin infections in cats and dogs. It was not until 2008 in the United States. It is allowed to be used for the treatment of skin and soft tissue infections in cats and dogs. Compared with the three cephalosporins (cephradine, cefpodoxime axetil, and ceftiofur) that have been used, cefotaxime has better antibacterial activity and is more High bioavailability and...

Claims

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Application Information

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IPC IPC(8): C07D507/00C07D499/04C07D499/46
CPCC07D507/00C07D499/04C07D499/46
Inventor 郭胜超王光明何东贤邵倩李艳刘艳余佳
Owner CHONGQING MEDICAL & PHARMA COLLEGE
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