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A kind of preparation method of relebactam

A technology for reilobactam and intermediates, which is applied in the production of organic chemistry and bulk chemicals, can solve the problem of not getting rid of high-pressure catalytic hydrogenation, etc., and achieve the effects of safety and environmental protection in the synthesis process, reduction of process operations, and high yield.

Active Publication Date: 2022-03-29
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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  • A kind of preparation method of relebactam
  • A kind of preparation method of relebactam
  • A kind of preparation method of relebactam

Examples

Experimental program
Comparison scheme
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 is specifically as follows: oxalic acid is removed under the action of a weak base to obtain a free base, and the free base is reacted with an acylating reagent to obtain an intermediate 3; the intermediate 3 is hydrolyzed under the action of an alkaline reagent to obtain an intermediate 4; Under the action of a coupling reagent, react with N-Boc-4-aminopiperidine to obtain intermediate 5; intermediate 5 is reacted in a "one-pot method", the catalyst is debenzylated, the sulfonating reagent is sulfonated, and then ammonium salt is obtained Intermediate 6; Intermediate 6 removes the protecting group on the piperidine ring under the action of a hydrolysis reagent to obtain the final product relebactam. The preparation method is simple in operation, short in production cycle, simple in post-treatment, produces less three wastes, abandons catalytic hydrogenation operation, reduces risk, and the obtained product has high yield, good purity and low cost, and is more suitable for large-scale industrial 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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Patent Type & Authority Patents(China)
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
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