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A method for detecting chiral isomers of key intermediates of avibactam sodium

A technology for avibactam sodium and chiral isomers, which is applied in the field of medicine and achieves the effects of strong practicability, convenient parameter adjustment and symmetrical peak shape

Inactive Publication Date: 2020-06-12
海南欣莱医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] At present, there is no documented method to effectively control the chiral isomers of (2S,5R)-5-(benzyloxyamino)-piperidine-2-carboxylic acid benzyl oxalate

Method used

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  • A method for detecting chiral isomers of key intermediates of avibactam sodium
  • A method for detecting chiral isomers of key intermediates of avibactam sodium
  • A method for detecting chiral isomers of key intermediates of avibactam sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] A sample of (2S,5R)-5-(benzyloxyamino)-piperidine-2-carboxylic acid benzyl oxalate whose batch number is 150804 is selected to detect the content of its chiral isomers, including the following steps:

[0053] S1, prepare the test solution:

[0054] Weigh 20mg of (2S,5R)-5-(benzyloxyamino)-piperidine-2-carboxylate benzyl oxalate sample, add 10mL of methanol, mix well, and prepare each 1mL containing (2S,5R)-5 -(Benzyloxyamino)-piperidine-2-carboxylic acid benzyl oxalate 2.0mg solution, as the test solution, stand-by.

[0055] S2. Prepare mixed control solution:

[0056] Weigh 2g (2S,5R)-5-(benzyloxyamino)-piperidine-2-carboxylic acid benzyl oxalate, 5mg (2S,5S)-5-(benzyloxyamino)-piperidine-2-carboxylic acid Benzyl ester oxalate, 5 mg (2R,5S)-5-(benzyloxyamino)-piperidine-2-carboxylic acid benzyl oxalate, and 5 mg (2R,5R)-5-(benzyloxyamino)-piperidine -2-benzyloxyamino)-piperidine-2-carboxylic acid benzyl oxalate, add 1000mL of methanol, mix well, and prepare each 1mL...

Embodiment 2

[0066] Choose the (2S,5R)-5-(benzyloxyamino)-piperidine-2-formic acid benzyl oxalate sample of the same batch as in Example 1, and detect the content of its chiral isomers. This implementation The difference between Example and Example 1 is only: the parameters of flow velocity in the chromatographic conditions are different, and other detection conditions are consistent with Example 1. In this embodiment, the assay conditions of high performance liquid chromatography include:

[0067] Chromatographic column: CHIRALPAK AD-H (model: length 250mm, inner diameter 4.6mm, amylose filler, filler particle size 5μm);

[0068] Detector: UV detector;

[0069] Detection wavelength: 280nm;

[0070] Column temperature: 30°C;

[0071] Flow rate: 0.8mL / min;

[0072] Mobile phase: calculated by volume ratio, n-hexane: isoamyl alcohol: ethanol: diethylamine=850:150:50:0.5.

[0073] Calculated by external standard method, in (2S,5S)-5-(benzyloxyamino)-piperidine-2-carboxylic acid benzyl ox...

Embodiment 3

[0075] Choose the (2S,5R)-5-(benzyloxyamino)-piperidine-2-formic acid benzyl oxalate sample of the same batch as in Example 1, and detect the content of its chiral isomers. This implementation The difference between Example and Example 1 is only: the parameters of flow velocity in the chromatographic conditions are different, and other detection conditions are consistent with Example 1. In this embodiment, the assay conditions of high performance liquid chromatography include:

[0076] Chromatographic column: CHIRALPAK AD-H (model: length 250mm, inner diameter 4.6mm, amylose filler, filler particle size 5μm);

[0077] Detector: UV detector;

[0078] Detection wavelength: 280nm;

[0079] Column temperature: 30°C;

[0080] Flow rate: 1.2mL / min;

[0081] Mobile phase: calculated by volume ratio, n-hexane: isoamyl alcohol: ethanol: diethylamine=850:150:50:0.5.

[0082]Calculated by external standard method, in (2S,5S)-5-(benzyloxyamino)-piperidine-2-carboxylic acid benzyl oxa...

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Abstract

The invention provides a method for detecting chiral isomers of a key intermediate of avibactam sodium. The method specifically comprises the following steps: detection of content of the chiral isomers in benzyl(2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate with high performance liquid chromatography; effective separation of main peak. Adopted chromatographic conditions are as follows: a CHIRALPAK AD-H chromatographic column is adopted, the column temperature is 25-40 DEG C, detection wavelength is 280 nm, a mobile phase is a mixture of n-hexane, isoamyl alcohol, ethyl alcohol and diethylamine, and the flow rate is 0.8-1.2 mL / min. In an actual detection process, the chiral isomers higher than 0.066% can be detected from the key intermediate when the limit of detection inthe method reaches 0.33 mu g / mL, the practicability is high, and the detection process is simple and fast.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a method for detecting chiral isomers of key intermediates of avibactam sodium, in particular to (2S,5R)-5-(benzyloxyamino)-piperidine-2 - High performance liquid phase detection method for chiral isomers of benzyl formate oxalate. Background technique [0002] Avibactam Sodium (NXL-104) is a diazabicyclooctone compound, jointly developed by ForestLab and AstraZeneca. In February 2014, Actavis acquired Forest Lab and obtained the right to develop it. In February 2015, it On March 25, the compound preparation of ceftazidime and avibactam sodium was approved for marketing in the United States under the trade name of AVYCAZ. Avibactam sodium is currently the most promising new β-lactamase inhibitor. Compared with the three marketed β-lactamase inhibitors, it has a long-acting and reversible covalent binding to the enzyme, and does not induce β-lactamase production. [0003] Ceftaz...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): G01N30/02G01N30/06
CPCG01N30/02G01N30/06
Inventor 邝少轶陈年根白秉信羊诚德
Owner 海南欣莱医药科技股份有限公司
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