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Preparation method of avibactam intermediate

A technology for intermediates and compounds, applied in the field of pharmaceutical synthesis, can solve the problems of weak carbonate alkalinity, high preparation cost, long reaction time, etc., and achieves the effects of mild reaction conditions, avoiding potential safety hazards and fewer reaction impurities

Inactive Publication Date: 2019-12-20
JIANGXI FUSHINE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The publication number is CN 108822014 A patent document, a synthetic method of avibactam intermediate, which adopts carbonate as base for reaction, but because carbonate is weakly basic, its reaction time is longer, and the base The dosage is higher, the post-processing is complicated, and the preparation cost is higher
In addition, when carbonate is used as the base for the reaction, it is easy to produce bubbles that are difficult to control when carrying out industrial scale-up experiments, which reduces the safety of the industrial process and increases the difficulty of post-processing

Method used

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  • Preparation method of avibactam intermediate
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  • Preparation method of avibactam intermediate

Examples

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Effect test

Embodiment 1

[0021] A preparation method of an avibactam intermediate, compound I and trimethylsulfoxide iodide are reacted in a solvent in the presence of a base to prepare compound II, and the reaction is as follows:

[0022]

[0023] The operation is as follows:

[0024] Put 25g (78mmol) of Compound I, 100ml of dimethyl sulfoxide, 21.1g (96mmol) of trimethylsulfoxide iodide, 2.5g (104mmol) of lithium hydroxide into the reaction bottle, and keep warm at 30°C until the reaction is complete (about 2 hours ), add 20ml of pure water, 60ml of saturated ammonium chloride, 200ml of EA, separate the phases, extract the aqueous phase once with 50ml of EA, combine the organic phases, wash twice with saturated brine, reduce the pressure to dryness, crystallize with isopropyl ether, pump Filter and dry to obtain 30.9g of compound II, yield: 96%, content: 97%.

Embodiment 2

[0026] A preparation method of an avibactam intermediate, compound I and trimethylsulfoxide iodide are reacted in a solvent in the presence of a base to prepare compound II, and the reaction is as follows:

[0027]

[0028] The operation is as follows:

[0029] Put 20.4g (78mmol) of Compound I, 100ml of dimethyl sulfoxide, 21.1g (96mmol) of trimethylsulfoxide iodide, 2.5g (104mmol) of lithium hydroxide into the reaction bottle, and keep warm at 30°C until the reaction is complete (about 1.5 hours), add 20ml of pure water, 60ml of saturated ammonium chloride, 100ml of EA, separate the phases, extract the aqueous phase once with 50ml of EA, combine the organic phases, wash twice with saturated brine, reduce the pressure to dryness, and crystallize with isopropyl ether, Suction filtration and drying gave Compound II 26.1g, yield: 94%, content: 97%.

Embodiment 3

[0031] A preparation method of an avibactam intermediate, compound I and trimethylsulfoxide iodide are reacted in a solvent in the presence of a base to prepare compound II, and the reaction is as follows:

[0032]

[0033] The operation is as follows:

[0034] Put 100ml of dimethylsulfoxide, 21.1g (96mmol) of trimethylsulfoxide iodide, 25g (78mmol) of compound I, 5.0g (85.8mmol) of magnesium hydroxide into the reaction bottle, and keep warm at 30°C until the reaction is complete (about 2.5 hours), add 20ml of pure water, 60ml of saturated ammonium chloride, and 100ml of EA, separate the phases, extract the water phase once with 50ml of EA, combine the organic phases, wash twice with saturated brine, depressurize to dryness, crystallize with isopropyl ether, pump Filter and dry to obtain 31.2g of compound II, content: 96%, yield: 97%.

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Abstract

The invention discloses a preparation method of an avibactam intermediate. The method comprises the following step: performing a reaction on a compound I and trimethylsulfoxonium iodide in the presence of a base to prepare a compound II, wherein the structures of the compound I and the compound II are shown in the specification, R is one selected from the group consisting of methyl, ethyl, benzyl,tert-butyl and allyl, and the base is one or more selected from the group consisting of magnesium hydroxide, lithium hydroxide and calcium hydroxide. According to the preparation method of the avibactam intermediate, the method uses pyroglutamate with double protection as a raw material, the pyroglutamate reacts with the trimethylsulfoxonium iodide in the presence of the base to obtain the avibactam intermediate, and the method provided by the invention avoids the defects of potential safety hazard of a strong base, severe reaction condition requirements and strict process control requirements in the prior art, and has the advantages of mild reaction conditions, simple operation, high safety, and less reaction impurities.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of an avibactam intermediate. 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 skeleton, which is different from the structure of classic β-lactamase inhibitors. Its own structure can be ...

Claims

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Application Information

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IPC IPC(8): C07C315/04C07C315/06C07C317/50
CPCC07C315/04C07C315/06C07C317/50
Inventor 龚杰谢永居张应军周忠波余翔曹敏张惠芝
Owner JIANGXI FUSHINE PHARMA CO LTD
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