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Avibactam sodium synthesis method

A technology of avibactam sodium and a synthesis method, which is applied in the field of medicinal chemistry synthesis, can solve the problems of limited industrialization potential, expensive reaction reagents, harsh reaction step conditions, etc., and achieves reduction of synthesis difficulty and reduction of high-risk and high-toxicity reagents. Use and reaction conditions are mild and easy to control the effect

Active Publication Date: 2018-07-03
ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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  • Abstract
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Problems solved by technology

This route also has some harsh reaction steps, difficult operation, expensive raw materials, expensive reaction reagents, high toxicity of by-products, and environmental unfriendliness, which also limits its industrial potential.

Method used

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  • Avibactam sodium synthesis method
  • Avibactam sodium synthesis method
  • Avibactam sodium synthesis method

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Embodiment Construction

[0043] The present invention will be further described in conjunction with specific examples, but the content of the present invention is not limited by the examples.

[0044] One, the preparation of ethyl 5-hydroxy-2-piperidinecarboxylate (2)

[0045]

[0046] Add ethyl 5-hydroxy-2-pyridinecarboxylate (1) (25g, 149.6mmol), rhodium carbon (2.5g, 10%Rh / C) and ethanol (150ml) into the hydrogenation kettle and stir to dissolve, pressurize the hydrogen to 200psi Reaction 12h. The solvent was removed by rotary evaporation to obtain a crude product (25.3 g) of ethyl 5-hydroxy-2-piperidinecarboxylate (2), which was directly subjected to the next reaction without purification.

[0047] Two, the preparation of (2S,5S)-5-hydroxyl-2-piperidinecarboxylic acid ethyl ester (3)

[0048]

[0049] Add crude 5-hydroxy-2-piperidinecarboxylate ethyl ester (2) (25.3 g, 146 mmol) and potassium phosphate buffer solution (2.53 L, 0.1 M, pH=8) into a 5 L single-necked flask to adjust the pH va...

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Abstract

The invention discloses an avibactam sodium synthesis method. In the existing synthesis method, the production cost is high, the selectivity of the intermediate is low during the reducing so as to cause the reduced yield, and the large-scale production is limited by the high toxicity of the side-product generated in the reaction, no environment protection and other factors. According to the present invention, 5-hydroxy-2-pyridine ethyl formate is used as a starting raw material, and 11 steps such as reduction hydrogenation, biological lipase resolution, electrophilic addition, nucleophilic substitution, Boc removing, aminolysis, intramolecular urealysis, debenzylation, sulfonic acid esterification, salt formation and cation exchange are performed to obtain avibactam sodium; and the synthesis method has advantages of high yield, short route, mild reaction conditions, low environmental pollution, easy large-scale preparation and the like.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, in particular to a synthesis method of avibactam sodium. Background technique [0002] Avibactam sodium (NXL104, AVE1330A), patented in 2011, is a non-β-lactam β-lactamase inhibitor. On February 25, 2015, the U.S. FDA approved the marketing of Avycaz (ceftazidime-avibactam sodium, ceftazidime-avibactam sodium), a new compound antibiotic drug jointly developed by Actavis (Actavis) and AstraZeneca (AZN) in the U.S. It is mainly used for the treatment of complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI) in adults, and is suitable for patients with kidney infection (pyelonephritis) with limited or no alternative treatment options. Currently, avibactam sodium The compound preparation combined with other antibiotics is still in the stage of clinical research. [0003] The principle of avibactam sodium is basically the same as that of the exist...

Claims

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Application Information

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IPC IPC(8): C07D471/08
CPCC07D471/08
Inventor 王涛应晓宁杜良栋陈新志吴国锋
Owner ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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