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A kind of synthetic method of avibactam sodium

A technology for the synthesis of avibactam sodium and its synthesis method, which is applied in the field of synthesis of avibactam sodium, can solve the problems of long time, weak sulfonation performance, price increase and cost, etc., and achieve simplification of reaction operation, reduction of production cost, shortening The effect of reaction time

Active Publication Date: 2020-04-28
JIANGXI FUSHINE PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In the process of synthesizing the urea ring, this method first selects the methoxycarbonyl group as the protecting group to protect the nitrogen atom on the piperidine ring, and then utilizes carbonyldiimidazole to construct the urea ring, although this method makes the reaction yield of this step There has been a certain improvement, but the price of fluorenyl methaneoxycarbonyl chloride is expensive, which is not conducive to large-scale application
Simultaneously, when this method carries out sulfonation reaction, the sulfonation reagent selected is sulfur trioxide trimethylamine complex, and its weaker sulfonation performance makes reaction need longer time, and its higher price is also certain. increased cost
Then use highly toxic 4-methyl-2-pentanone in the process of synthesizing quaternary ammonium salt with tetrabutylammonium salt as ammonium reagent, and its higher boiling point (115.8 ℃) is unfavorable for removing completely, thus directly Affect the quality of the final product in the next step

Method used

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  • A kind of synthetic method of avibactam sodium
  • A kind of synthetic method of avibactam sodium
  • A kind of synthetic method of avibactam sodium

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] A kind of synthetic method of Avibactam sodium comprises the following steps:

[0038](1) Measure acetonitrile (100mL) into the reaction flask, add (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxamide (10g), and control the temperature at 5-8°C , 20mL (3eq) N,N-diisopropylethylamine was added to the system, and then 6.4mL (1.3eq) dimethyldichlorosilane was added dropwise, and the reaction was complete as detected by TLC. Add 8.5g CDI (1.3eq) to the system, raise the temperature to 45°C and stir. After the reaction is complete as detected by TLC, add 9.2mL (3eq) isopropanol, and continue stirring at 45°C. Cool to room temperature, add 50mL toluene to the system, then add 140mL 2mol / L HCl solution, after the system is separated, collect the organic phase, concentrate to obtain a light yellow solid, wash with methyl tert-butyl ether to obtain (2S, 5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (9.8 g, yield 90%).

[0039] (2) Measure 50 mL each of is...

Embodiment 2

[0044] A kind of synthetic method of Avibactam sodium comprises the following steps:

[0045] (1) Measure acetonitrile (100mL) into the reaction flask, add (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxamide (10g), and control the temperature at 5-8°C , 20mL (3eq) N,N-diisopropylethylamine was added to the system, and then 6.4mL (1.3eq) dimethyldichlorosilane was added dropwise, and the reaction was complete as detected by TLC. Add 8.5g CDI (1.3eq) to the system, raise the temperature to 45°C and stir. After the reaction is complete as detected by TLC, add 9.2mL (3eq) isopropanol, and continue stirring at 45°C. Cool to room temperature, add 50mL toluene to the system, then add 140mL 2mol / L HCl solution, after the system is separated, collect the organic phase, concentrate to obtain a light yellow solid, wash with methyl tert-butyl ether to obtain (2S, 5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (9.8 g, yield 90%).

[0046] (2) Measure 50 mL each of i...

Embodiment 3

[0051] A kind of synthetic method of Avibactam sodium comprises the following steps:

[0052] (1) Measure acetonitrile (100mL) into the reaction flask, add (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxamide (10g), and control the temperature at 5-8°C , 20mL (3eq) N,N-diisopropylethylamine was added to the system, and then 6.4mL (1.3eq) dimethyldichlorosilane was added dropwise, and the reaction was complete as detected by TLC. Add 8.5g CDI (1.3eq) to the system, raise the temperature to 45°C and stir. After the reaction is complete as detected by TLC, add 9.2mL (3eq) isopropanol, and continue stirring at 45°C. Cool to room temperature, add 50mL toluene to the system, then add 140mL 2mol / L HCl solution, after the system is separated, collect the organic phase, concentrate to obtain a light yellow solid, wash with methyl tert-butyl ether to obtain (2S, 5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (9.8 g, yield 90%).

[0053] (2) Measure 50 mL each of i...

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Abstract

The invention discloses a synthetic method for avibactam sodium salt. The method comprises the following steps: taking (2S, 5R)-5-[(benzyl oxyl) amino] piperidine-2-formamide as a starting material; constructing a urea ring by carbonyl diimidazole under the effect of dimethyldichlorosilance to obtain (2S, 5R)-6-(benzyl oxyl)-7-oxo-1,6-diazabicyclo [3.2.1] octane-2-formamide; then carrying out hydrogenation to remove benzyl; carrying out sulfonation reaction on the compound and a sulfonated reagent; synthesizing into a quaternary ammonium salt intermediate by using quaternary ammonium salt; and finally carrying out ion exchange to obtain the avibactam sodium salt. The improved process is low in cost, simple and convenient to operate, good in product quality and suitable for industrial production. In a process of synthesizing the intermediate (2S, 5R)-6-(benzyl oxyl)-7-oxo-1,6-diazabicyclo [3.2.1] octane-2-formamide, dimethyldichlorosilance which is low in price is used, and therefore, the production cost is greatly reduced.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry synthesis, and in particular relates to a synthesis method of avibactam sodium. Background technique [0002] Avibactam, a new type of β-lactamase inhibitor developed by Novexel, is comparable to three β-lactamase inhibitors (sulbactam, tazobactam, and clavulanic acid) that have been marketed. Compared with it, it has the advantages of long-acting and reversible covalent binding with the enzyme, and will not induce the production of β-lactamase. When used in combination with various cephalosporins and carbapenem antibiotics, it has broad-spectrum antibacterial activity, especially against Escherichia coli and Klebsiella pneumoniae containing extended-spectrum β-lactamases, Escherichia coli containing excessive AmpC enzymes And the activity of Escherichia coli containing both AmpC and extended-spectrum β-lactamases is remarkable. In 2012, Dubreui et al. found that the three-drug combination of ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/08
CPCC07D471/08
Inventor 乔仁忠周航陈照行赵静李超
Owner JIANGXI FUSHINE PHARMA CO LTD
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