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Preparation method of relebactam

A technology for relebactam and intermediates, applied in the production of bulk chemicals, organic chemistry, etc., can solve problems such as high-pressure catalytic hydrogenation, and achieve the effects of safe and environmentally friendly synthesis processes, reduced process operations, and high yields

Active Publication Date: 2020-11-17
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

[0020] This method has been improved on the starting materials, but it is similar to the method mentioned in the patent document WO2009091856. In the process of converting intermediate IV to intermediate V, the operation of high-pressure catalytic hydrogenation is not removed, which has certain safety risks.

Method used

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  • Preparation method of relebactam
  • Preparation method of relebactam
  • Preparation method of relebactam

Examples

Experimental program
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Effect test

Embodiment 1

[0058] (1) Intermediate 3: ethyl (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3,2,1]octane-2-carboxylate

[0059] Add 100ml of ethyl acetate and 10.0g of compound 2 into the reaction flask, and start stirring. Slowly add 5% sodium carbonate solution at room temperature until the solid basically disappears, stir for 30-40 minutes, let stand to separate layers; keep the organic layer, add anhydrous sodium sulfate to dry for 1-2 hours. Filter and concentrate to half volume. Add 8.2 g of triethylamine; control the temperature at 5±5° C., and add dropwise 8.1 g of triphosgene in ethyl acetate (20 ml of ethyl acetate). After the dropwise addition, control the temperature at 5±5°C, stir and react for 1 hour, add 100ml of purified water, control the reaction temperature at 25±5°C, stir and react for 0.5 to 1 hour, and then stand to separate layers. The organic layer was retained and concentrated under reduced pressure; 8.1 g of a reddish-brown solid was obtained, namely intermediate...

Embodiment 2

[0069] (1) Intermediate 3: ethyl (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3,2,1]octane-2-carboxylate

[0070] Add 100ml of dichloromethane and 10.0g of compound 2 into the reaction flask, and start stirring. Slowly add 5% sodium carbonate solution at room temperature until the solid basically disappears, stir for 30-40 minutes, let stand to separate layers; keep the organic layer, add anhydrous sodium sulfate to dry for 1-2 hours. Filter and concentrate to half volume. Add 8.2 g of triethylamine; control the temperature at 5±5° C., and add 7.2 g of triphosgene in dichloromethane solution (20 ml of dichloromethane) dropwise. After the dropwise addition, control the temperature at 5±5°C, stir and react for 1 hour, add 100ml of purified water, control the reaction temperature at 25±5°C, stir and react for 0.5 to 1 hour, and then stand to separate layers. The organic layer was retained and concentrated under reduced pressure; 8.0 g of a reddish-brown solid was obtained, name...

Embodiment 3

[0080] (1) Intermediate 3: ethyl (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3,2,1]octane-2-carboxylate

[0081] Add 1000ml of dichloromethane and 100.0g of compound 2 into the reaction flask, and start stirring. Slowly add 5% sodium carbonate solution at room temperature until the solid basically disappears, stir for 30-40 minutes, let stand to separate layers; keep the organic layer, add anhydrous sodium sulfate to dry for 1-2 hours. Filter and concentrate to half volume. Add 82.3g of triethylamine; control the temperature at 5±5°C, and add 72.1g of triphosgene in dichloromethane solution (200ml of dichloromethane) dropwise. After the dropwise addition, control the temperature at 5±5°C, stir and react for 1 hour, add 1000ml of purified water, control the reaction temperature at 25±5°C, stir and react for 0.5 to 1 hour, and then stand to separate layers. The organic layer was retained and concentrated under reduced pressure; 80.5 g of a reddish-brown solid was obtained, na...

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Abstract

The invention discloses a preparation method of relebactam. The method specifically comprises the following steps: removing oxalic acid under the action of weak base to obtain free alkali, and reacting the free alkali with an acylation reagent to obtain an intermediate 3; hydrolyzing the intermediate 3 under the action of an alkaline reagent to obtain an intermediate 4; reacting the intermediate 4with N-Boc-4-aminopiperidine under the action of a coupling reagent to obtain an intermediate 5; carrying out one-pot reaction on the intermediate 5, conducting debenzylating by using a catalyst, conducting sulfonating by using a sulfonating reagent, and then forming ammonium salt to obtain an intermediate 6; and removing the protecting group on the piperidine ring from the intermediate 6 under the action of a hydrolysis reagent to obtain the final product relebactam. The preparation method has the advantages of simple operation, short production period, simple post-treatment, less generationof three wastes, abandonment of catalytic hydrogenation operation, reduction of danger, and high yield, good purity and low cost of the obtained product, and is more suitable for industrial large-scale production.

Description

technical field [0001] The invention relates to a preparation method of relebactam, which belongs to the technical field of medicine and chemical industry. Background technique [0002] Relebactam (English name: Relebactam), molecular formula: C 12 h 20 N 4 o 6 S, molecular weight: 348.37, CAS number: 1174018-99-5, structural formula as follows: [0003] [0004] Relebactam, also known as MK-7655, is a β-lactamase inhibitor of a new type of diazabicyclooctone compound developed by Merck in the United States. Its structure is similar to that of avibactam and can inhibit pneumonia. Hydrolytic activity of KPC-2 β-lactamase from Klebsiella and AmpC β-lactamase from Pseudomonas aeruginosa on nitroceftin. The combination therapy of relebactam and imipenem-cilastatin, the pivotal phase III study has achieved positive trial data, compared with the imipenem-cilastatin regimen, relebactam and imipenem The combination of penem-cilastatin can effectively treat imipenem-sensitiv...

Claims

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Application Information

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IPC IPC(8): C07D471/08
CPCC07D471/08Y02P20/55
Inventor 彭坤朱晓斐杨庆坤侯传山李卓华颜连忠
Owner 山东安信制药有限公司