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A kind of preparation method of 6α-bromopenicillane-3α-carboxylate diphenylmethyl ester-1β-oxide

A technology of diphenylmethyl carboxylate and bromopenem, applied in the field of medicine, can solve problems such as poor product quality and low yield, and achieve the effects of improved safety, high yield, safe and environmentally friendly use

Active Publication Date: 2019-03-22
山东安信制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] (2) the preparation of peracetic acid needs acetic acid, also produces acetic acid in the preparation process, contains carboxyl group in acetic acid, and the diphenyldiazomethane of generation can react with the carboxyl group of acetic acid, generates a large amount of by-products (as shown in reaction equation 3), Cause poor product quality and low yield (detected by TLC during the reaction process, a relatively large impurity is produced, which is determined to be produced by the reaction of diphenyldiazomethane and acetic acid through verification)

Method used

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  • A kind of preparation method of 6α-bromopenicillane-3α-carboxylate diphenylmethyl ester-1β-oxide
  • A kind of preparation method of 6α-bromopenicillane-3α-carboxylate diphenylmethyl ester-1β-oxide
  • A kind of preparation method of 6α-bromopenicillane-3α-carboxylate diphenylmethyl ester-1β-oxide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] (1) Preparation of diphenyldiazomethane

[0030] Dissolve 32g of benzophenone hydrazone in 100ml of dichloromethane, add 40ml of water and 40ml of acetone, cool down to -2~2°C, slowly add 10ml of concentrated nitric acid (concentration 65%), continue to cool down to -2~2°C, Add 55 g of potassium permanganate in batches within 35 min, and keep warm for 1.5 h after the addition is complete. After the reaction was completed, suction filtered, and the filter cake was rinsed with 50 ml of dichloromethane. Stand to separate layers, discard the water layer, add 400ml saturated sodium bicarbonate solution to the organic layer to wash, then add 400ml saturated sodium bicarbonate solution to wash the layers, separate layers, and then add 400ml water to wash. Store at -5~5℃ for later use (brown red). Sampling was compared with diphenyldiazomethane standard substance for TLC comparison, and the results showed that the positions were consistent and there was only one spot. (Based...

Embodiment 2

[0034] (1) Preparation of diphenyldiazomethane

[0035] Dissolve 32g of benzophenone hydrazone in 100ml of dichloromethane, add 40ml of water and 40ml of acetone, cool down to -2~2°C, slowly add 10ml of concentrated nitric acid (concentration 65%), continue to cool down to -2~2°C, Add 60g of potassium permanganate in batches within 40min, after the addition is complete, keep it warm for 2h, filter with suction, and rinse the filter cake with 50ml of dichloromethane. Stand to separate layers, discard the water layer, add 400ml saturated sodium bicarbonate solution to the organic layer to wash, then add 400ml saturated sodium bicarbonate solution to wash the layers, separate layers, and then add 400ml water to wash. Store at -5~5℃ for later use (brown red). Sampling was compared with diphenyldiazomethane standard substance for TLC comparison, and the results showed that the positions were consistent and there was only one spot. (Based on content ≥ 99%).

[0036] (2) Preparati...

Embodiment 3

[0039] (1) Preparation of diphenyldiazomethane

[0040] Dissolve 33g of benzophenone hydrazone in 100ml of dichloromethane, add 40ml of water and 40ml of acetone, cool down to -2~2°C, slowly add 11ml of concentrated nitric acid (concentration 65%), continue to cool down to -2~2°C, Add 60g of potassium permanganate in batches within 35min, after the addition is complete, keep it warm for 2h, filter with suction, and rinse the filter cake with 50ml of dichloromethane. Stand to separate layers, discard the water layer, add 400ml saturated sodium bicarbonate solution to the organic layer to wash, then add 400ml saturated sodium bicarbonate solution to wash the layers, separate layers, and then add 400ml water to wash. Store at -5~5℃ for later use (brown red). Sampling was compared with diphenyldiazomethane standard substance for TLC comparison, and the results showed that the positions were consistent and there was only one spot. (Based on content ≥ 99%).

[0041] (2) Preparati...

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Abstract

The invention discloses a preparation method of 6alpha-bromopenicillanic-3alpha-carboxylic di-methylphenyl-1beta-oxide. According to the method, acetone is used as a catalyst; benzophenone hydrazone takes an oxidation reaction with KMnO4 under the acid condition to generate diazodiphenylmethane reaction liquid; then, the reaction liquid is dripped into the 6alpha-bromopenicillanic-3alpha-carboxylic di-methylphenyl-1beta-oxide to obtain a product. The method has the advantages that the method is simple; the use is safe; the environment-friendly effect is achieved; the product purity is high; the yield is high, and the like. The reaction equation is shown as the accompanying drawing.

Description

technical field [0001] The invention relates to a preparation method of a tazobactam intermediate - 6α-bromopenicillane-3α-carboxylate-1β-oxide, which belongs to the technical field of medicine. Background technique [0002] Tazobactam is a new type of penicillane sulfone β-lactamase inhibitor developed by Dapeng Pharmaceutical Company in Japan. It is one of the best β-lactamase inhibitors in clinical application at present, with high stability and activity Low, low toxicity, strong enzyme inhibitory activity and so on. In 1992, the compound drug tazobactam / piperacillin (1:8) of tazobactam was first launched in France for the treatment of various bacterial infections. [0003] At present, the synthesis method of tazobactam, most manufacturers use 6-APA as raw material, successively undergoes bromination, oxidation, carboxyl protection, reduction, thermal cracking, chloromethylation, azidation, double oxidation, cycloaddition , deprotection and other steps to prepare tazoba...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D499/865C07D499/87C07C245/16
CPCC07C245/16C07D499/865C07D499/87
Inventor 苏法鄂德林孙政军贾建朱立强张挺进郝春波李保勇樊长莹
Owner 山东安信制药有限公司