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Preparation method of avibactam sodium

A technology of avibactam sodium and compounds, applied in the direction of organic chemistry, can solve the problems of uncompetitive production cost, long validity period, and affecting the overall yield, and achieve shortened preparation cycle, mild process conditions, and simple operation Effect

Pending Publication Date: 2022-07-01
BEIJING JIMEITANG MEDICINE RES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The problem is that when the French Avantis Pharmaceutical Company published the compound patent, its core focus was on the protection of medicinal compounds, and the preparation method was not fully studied, and the yield of the preparation method was low, about 30%. In the context of the current centralized drug procurement , its production cost is not competitive
[0009] 2. The preparation method of AstraZeneca (Sweden) Co., Ltd. has a high yield (~64%), and its process cost and industrial transformation have competitive advantages, but the patent for its preparation method is valid until June 14, 2032, and the validity period is relatively long
After constructing the diazacyclization, compound 7 has an azabicyclic [3.2.1] structure, and the carbonyl linking the two rings is subject to a large twisting tension, which is easily attacked by nucleophiles in the subsequent hydrolysis and condensation processes. Side reactions leading to ring-opening decarbonylation
Therefore, affecting the overall yield

Method used

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  • Preparation method of avibactam sodium
  • Preparation method of avibactam sodium
  • Preparation method of avibactam sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1 Preparation of compound V

[0043]

[0044] Process 1:

[0045] Compound I (3.68kg, 10.0mol, 1.0eq.) was added to 30L of dichloromethane, sodium carbonate aqueous solution (sodium carbonate: 2.12kg, 20.0mol, 2.0eq.; water: 20L) was added under stirring, and the salt was dissolved with stirring , the liquids were separated, the aqueous phase was extracted with 10 L of dichloromethane, the combined dichloromethane phases were dried over anhydrous sodium sulfate, and filtered. The filtrate was added to the reaction kettle, and triethylamine (2.53kg, 25.0mol, 2.5eq.) was added, and under nitrogen protection, the temperature was lowered to 0-10°C, and trifluoroacetic anhydride (4.62kg, 22.0mol, 2.2eq.) was added dropwise. , after the reaction for 5 hours, the temperature was raised to 20-30 °C for 1 hour, and the reaction was completed by TLC monitoring. The salt was removed by filtration, and the dichloromethane phase was concentrated to obtain the intermedia...

Embodiment 2

[0055] Example 2 Preparation of compound VI

[0056]

[0057] Compound V (3.66kg, 7.2mol, 1.0eq.) was dissolved in a mixed solution of ethanol and water (ethanol: 12.5L; water: 250mL), and ethanol solution of sodium isooctanoate (sodium isooctanoate: 2.36 mL) was added dropwise at 20 to 30°C. kg, 14.4.2mol, 2.0eq.; ethanol: 10L), reacted for 3 hours, filtered to obtain avibactam sodium VI 1.95kg (theoretical value was 2.07kg) as white crystals, and the yield was 94%.

[0058] 1 H NMR (DMSO-d 6 ,400MHz)δ7.42(s,1H),7.27(s,1H),3.96-3.98(m,1H),3.67-3.69(d,1H, J=6.6Hz), 3.03-3.08(m,1H) ,2.90-3.00(m,1H),2.04-2.09(m,1H),1.75-1.83(m,1H),1.59-1.65(m,2H);

[0059] 13 C NMR (DMSO-d 6 ,100MHz)δ171.6,166.1,59.6,57.6,46.9,20.5,18.1;

[0060] ESI-MS[M] - m / z 264.

Embodiment 3

[0061] Example 3 Preparation of Compound V

[0062] Process 1:

[0063] Compound I (368.4g, 1.0mol, 1.0eq.) was added to 3L of dichloromethane, potassium carbonate aqueous solution (potassium carbonate: 276.4g, 2.0mol, 2.0eq.; water: 2L) was added with stirring, and the salt was dissolved with stirring , the liquids were separated, the aqueous phase was extracted with 1 L of dichloromethane, the combined dichloromethane phases were dried over anhydrous sodium sulfate, and filtered. The filtrate was added to the reaction kettle, triethylamine (253.9g, 2.5mol, 2.5eq.) was added, and under nitrogen protection, the temperature was lowered to 0-10°C, and trifluoroacetic anhydride (462.1g, 2.2mol, 2.2eq.) was added dropwise. , after the reaction for 5 hours, the temperature was raised to 20-30 °C for 1 hour, and the reaction was completed by TLC monitoring. The salt was removed by filtration, and the dichloromethane phase was concentrated to obtain the intermediate compound II as ...

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Abstract

The invention provides a novel preparation method of (2S, 5R)-2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2. 1]-octane-6-yl] sodium sulfate, and belongs to the technical field of chemical drug synthesis. In the construction process of avibactam sodium molecules, the mode of firstly introducing sulfonic groups, then carrying out aminolysis and then constructing diazo heterocyclic ring is adopted for the first time, and the construction thought is essentially different from original research and other preparation method patents. The initial raw material used in the method is a chemical product easily obtained in the market, and guarantees are provided for process production conversion. The novel preparation process is mild in condition, simple to operate, high in total yield, short in construction period and suitable for commercial production of the avibactam sodium bulk drug. An original preparation route is successfully avoided, so that the limitation of the protection period of an original preparation method patent is overcome, and the problem of medication accessibility of the medicine in China can be solved quickly.

Description

technical field [0001] The invention relates to the field of medicine, and relates to a raw material drug avibactam sodium ((2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]-octane -6-yl] sodium sulfate) preparation method. Background technique [0002] Avibactam is a non-beta-lactam inhibitor of diazabicyclooctanone compounds. Avibactam itself has no obvious antibacterial activity, but can inhibit type A (including ESBL and KPC) and type C β-Lactamase, Avibactam has broad-spectrum antibacterial activity when used in combination with various cephalosporins and carbapenem antibiotics, especially against Escherichia coli and Klebsiella pneumoniae containing extended-spectrum β-lactamases Bacillus, E. coli containing excess AmpC enzyme, and E. coli containing both AmpC and extended-spectrum β-lactamase showed significant activity. Avibactam and a variety of drugs can form compound preparations, such as: Avibactam + Ceftazidime, Avibactam + Ceftaroline, Avibactam + Aztreonam, ...

Claims

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Application Information

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IPC IPC(8): C07D471/08
CPCC07D471/08
Inventor 王辉李培
Owner BEIJING JIMEITANG MEDICINE RES CO LTD
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