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A kind of avibactam intermediate, preparation method and application thereof

An intermediate and reaction technology, applied in the field of drug synthesis, can solve the problems of low yield, salt formation, cumbersome operation, etc.

Active Publication Date: 2020-10-23
JIANGXI FUSHINE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the generated sulfonic acid compound cannot directly form a salt with tetrabutylammonium salt. It needs to be converted into ammonium salt by using ammonium bicarbonate and other reagents first, so that the obtained ammonium salt can react with tetrabutylammonium salt, which requires a two-step reaction. , the operation is cumbersome and the yield is low

Method used

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  • A kind of avibactam intermediate, preparation method and application thereof
  • A kind of avibactam intermediate, preparation method and application thereof
  • A kind of avibactam intermediate, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] 5g (18mmol ), acetone 50ml, palladium carbon 0.5g, replaced with nitrogen at least 3 times, replaced with hydrogen 3 times, at 25 ~ 35 ℃, passed through hydrogen for 3 hours, TLC detected that the reaction was complete, replaced 3 times with nitrogen, filtered with The filter cake was rinsed with acetonitrile, the temperature of the filtrate was cooled to 0°C, 9.7 g (72 mmol) of benzyldimethylamine was added, and 4.2 g (36 mmol) of chlorosulfonic acid was added dropwise. Insulate for 2 hours, the reaction is complete, the reaction solution is decompressed to dryness, add 50ml of dichloromethane, 30ml of pure water, separate the phases, extract the water phase with 20ml of dichloromethane once, combine the organic phases, depressurize to dryness, add 20ml of isopropyl ether , a solid precipitated, suction filtered, rinsed with isopropyl ether, and dried at 35°C to obtain compound III ([(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-di Azabicyclo[3.2.1]oct-6-yl]benzyldimethylamm...

Embodiment 2

[0050] Put 5g (18mmol) of compound I, 50ml acetone, and 0.5g palladium carbon into the reaction bottle, replace with nitrogen for at least 3 times, and replace with hydrogen for 3 times. Replaced with nitrogen 3 times, filtered with suction, washed the filter cake with acetone, cooled the filtrate to 0°C, added 9.7g (72mmol) of benzyldimethylamine, and added 3.5g (36mmol) of sulfuric acid dropwise. Keep warm for 2 hours, and the reaction is complete. The reaction solution was decompressed to dryness, added 50ml of dichloromethane, 30ml of pure water, separated the phases, extracted the aqueous phase once with 20ml of dichloromethane, combined the organic phases, decompressed to dryness, added 20ml of isopropyl ether, a solid precipitated, pumped Filter, rinse with isopropyl ether, and dry at 35°C to obtain 5.9g of compound III, with a yield of 83% and a content of >99%.

[0051] Put 5.0g of compound III into the reaction bottle, add 25ml of ethanol at 20-35°C, dissolve at 20-...

Embodiment 3

[0053] Put 5g (18mmol) of compound I, 50ml acetone, and 0.5g palladium carbon into the reaction bottle, replace with nitrogen for at least 3 times, and replace with hydrogen for 3 times. Replaced with nitrogen 3 times, filtered with suction, washed the filter cake with acetone, cooled the filtrate to 0°C, added 9.7g (72mmol) of benzyldimethylamine, and added 3.5g (36mmol) of sulfuric acid dropwise. Keep warm for 2 hours, and the reaction is complete. The reaction solution was decompressed to dryness, added 50ml of dichloromethane, 30ml of pure water, separated the phases, extracted the aqueous phase once with 20ml of dichloromethane, combined the organic phases, decompressed to dryness, added 25ml of ethanol, dissolved at 20-35°C, Add sodium isooctanoate ethanol solution dropwise, solids precipitate out, keep warm at 20-35°C for 2 hours, filter with suction, rinse with absolute ethanol, and dry. 4.0 g of compound IV was obtained with a yield of 77% and a content of 99%.

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Abstract

The invention discloses an avibactam intermediate, and a preparation method of the avibactam intermediate. The preparation method comprises the steps of allowing a compound II to react with a sulfonation reagent in the presence of an alkaline agent and then react with the alkaline agent to form the avibactam intermediate, wherein the alkaline agent is trialkylamine, pyridine, alkylpyridine, N-alkylpiperidine, dialkyl phenylamine or dialkyl benzylamine; alkyl in trialkyl amine is C5-8 alkyl; alkyl in alkyl pyridine in C1-4 alkyl; alkyl in N-alkylpiperidine is C1-4 alkyl; alkyl in dialkyl phenylamine is C1-4 alkyl; and alkyl in dialkyl benzylamine is C1-4 alkyl. Compared with the traditional method, the method adopts the alkaline agent with appropriate alkalinity to substitute the traditional alkaline agent; the alkaline agent can react with the compound II in a step directly with the sulfonation reagent; the post-treatment is simple; and the method is more suitable for industrial mass production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to an avibactam intermediate [(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1 ]oct-6-yl]ammonium sulfate, preparation method and application thereof. Background technique [0002] Avibactam (avibactam) is a new type of non-β-lactam structure β-lactamase inhibitor, combined with broad-spectrum cephalosporin ceftazidime (ceftazidime) for the treatment of complicated intra-abdominal infection (cIAI) and Complicated urinary tract infection (cUTI), the drug combination has been approved by the FDA, and the trade name is Avycaz. Combination with other antibiotics (such as ceftaroline axetil, thiazoxime, etc.) is in clinical research. Avibactam has a stronger effect and a wider range than the three previously listed β-lactamase inhibitors - clavulanic acid, sulbactam, and tazobactam. - Lactamase inhibition is significant. [0003] Avibactam has a diazabicyclooctane s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/08
CPCC07D471/08
Inventor 龚杰谢永居张应军李振业周忠波余翔杨玉平
Owner JIANGXI FUSHINE PHARMA CO LTD
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