Avibactam intermediate, and preparation method and application of avibactam intermediate

An intermediate and alkyl technology, applied in the field of pharmaceutical synthesis, can solve the problems of salt formation, complicated operation, low yield, etc., and achieve the effects of simple post-processing, lowering production pressure, and avoiding residues

Active Publication Date: 2019-08-02
JIANGXI FUSHINE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 o

Method used

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  • Avibactam intermediate, and preparation method and application of avibactam intermediate
  • Avibactam intermediate, and preparation method and application of avibactam intermediate
  • Avibactam intermediate, and preparation method and application of avibactam intermediate

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0045] Example 1:

[0046] Put compound I ((1R, 2S, 5R)-6-benzyloxy-7-oxo-1,6-diaza [3.2.1]octane-2-carboxamide) 5g (18mmol) into the reaction flask ), acetone 50ml, palladium charcoal 0.5g, replace with nitrogen at least 3 times, replace with hydrogen 3 times, at 25~35℃, pass hydrogen and keep for 3h, TLC check the reaction is complete, replace with nitrogen 3 times, filter with The filter cake was rinsed with acetonitrile, the temperature of the filtrate was cooled to 0°C, 9.7g (72mmol) of benzyldimethylamine was added, and 4.2g (36mmol) of chlorosulfonic acid was added dropwise. Incubate for 2h, the reaction is complete, the reaction solution is reduced to dryness, 50ml of dichloromethane, 30ml of pure water are added, the phases are separated, the aqueous phase is extracted once with 20ml of dichloromethane, the organic phases are combined, reduced to dryness, and 20ml of isopropyl ether is added , A solid precipitated, filtered with suction, rinsed with isopropyl ether, and...

Example Embodiment

[0048] Example 2:

[0049] Put 5g (18mmol) of compound I, 50ml of acetone, 0.5g of palladium on carbon into the reaction flask, replace with nitrogen at least 3 times, and replace 3 times with hydrogen. At 25~35℃, let in hydrogen and keep it for 3h. TLC detects that the reaction is complete. Replace with nitrogen 3 times, filter with suction, rinse the filter cake with acetone, cool the filtrate to 0°C, add 9.7 g (72 mmol) of benzyl dimethylamine, and add 3.5 g (36 mmol) of sulfuric acid dropwise. Incubate for 2h, and the reaction is complete. The reaction solution was depressurized to dryness, 50ml of dichloromethane and 30ml of pure water were added, and the phases were separated. The aqueous phase was extracted once with 20ml of dichloromethane. The organic phases were combined, decompressed to dryness, and 20ml of isopropyl ether was added. A solid precipitated out. After filtering, rinsing with isopropyl ether, and drying the material at 35°C, 5.9 g of compound III was obta...

Example Embodiment

[0051] Example 3:

[0052] Put 5g (18mmol) of Compound I, 50ml of acetone, 0.5g of palladium on carbon into the reaction flask, replace it with nitrogen at least 3 times, and replace 3 times with hydrogen. At 25-35℃, let hydrogen gas and keep for 5h. TLC detects that the reaction is complete. Replace with nitrogen 3 times, filter with suction, rinse the filter cake with acetone, cool the filtrate to 0°C, add 9.7 g (72 mmol) of benzyl dimethylamine, and add 3.5 g (36 mmol) of sulfuric acid dropwise. Incubate for 2h, and the reaction is complete. The reaction solution was decompressed to dryness, 50ml of dichloromethane and 30ml of pure water were added, and the phases were separated. The aqueous phase was extracted once with 20ml of dichloromethane. The organic phases were combined and decompressed to dryness. 25ml of ethanol was added and dissolved at 20-35°C. Add dropwise sodium isocaprylate solution in ethanol, and solids will precipitate out, keep at 20~35℃ for 2h, filter wit...

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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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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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