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HPLC (High-Performance Liquid Chromatography) method for intermediate products of palonosetron hydrochloride synthesis

An analytical method and technology of dihydronaphthalene, applied in the field of drug analysis, can solve the problems of large damage to the chiral column, high cost, many process steps, etc., and achieve the effects of saving time, low cost and short analysis time.

Active Publication Date: 2017-10-24
方达医药技术(上海)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] There are many synthetic processes of palonosetron hydrochloride, but these processes have many steps and many by-products. Some steps have very harsh reaction conditions and require special reagents, which are not suitable for industrial production.
Zhu Yang etc. provide a kind of synthesis technique of palonosetron hydrochloride hydrochloride (the synthesis of palonosetron hydrochloride, Chinese Journal of Pharmaceutical Industry, 2009, 40), its reaction condition is gentle, without special reagent and equipment, But there are following two deficiencies: (1) yield is too low, and the total yield of palonosetron hydrochloride (being SS type) only has 12%; (2) by N-[(3,4-dihydronaphthalene -1-yl)methyl]-1-azabicyclo[2.2.2]-octane-3-amine dihydrochloride to prepare N-[(3,4-dihydronaphthalen-1-yl)methyl ]-(S)-1-Azabicyclo[2.2.2]octane-3-amine requires chiral resolution
However, the Daicel OD-H chiral column is expensive, and the column efficiency is extremely easy to reduce, and the intermediate reaction solution has many impurities, which will cause great damage to the chiral column, and the cost is too high

Method used

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  • HPLC (High-Performance Liquid Chromatography) method for intermediate products of palonosetron hydrochloride synthesis
  • HPLC (High-Performance Liquid Chromatography) method for intermediate products of palonosetron hydrochloride synthesis
  • HPLC (High-Performance Liquid Chromatography) method for intermediate products of palonosetron hydrochloride synthesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 N-[(3,4-dihydronaphthalene-1-yl)methyl]-(S)-1-azabicyclo[2.2.2]octane-3-amine and its R-type isomer separate

[0037] 1. Experimental materials

[0038] Shimadzu LC-20A high performance liquid chromatography;

[0039] CPA225D electronic balance (Beijing Sartorius Instrument System Co., Ltd.);

[0040] Chromatographic column: ZORBAX Extend-C18 column (Agilent);

[0041] N-[(3,4-dihydronaphthalen-1-yl)methyl]-(S)-1-azabicyclo[2.2.2]octane-3-amine (S-type isomer) and its The R-isomer is self-made, the chemical structure and configuration have been confirmed, and the chemical structural formula is as follows figure 1 shown;

[0042] Isophorone diamine is a commercially available cis-trans isomer mixture (CAS: 2855-13-2, the total purity of cis-trans isomers > 99%), purchased from Bailingwei Technology Co., Ltd.;

[0043] Acetonitrile was chromatographically pure, water was deionized water, and other reagents were analytically pure.

[0044] 2. Experimental ...

Embodiment 2

[0071] Embodiment 2 comparative example, does not add isophorone diamine in the sample diluent

[0072] 1. Experimental materials

[0073] Shimadzu LC-20A high performance liquid chromatography;

[0074] CPA225D electronic balance (Beijing Sartorius Instrument System Co., Ltd.);

[0075] Chromatographic column: ZORBAX Extend-C18 column (Agilent);

[0076] N-[(3,4-dihydronaphthalen-1-yl)methyl]-(S)-1-azabicyclo[2.2.2]octane-3-amine (S-type isomer) and its The R-isomer is self-made, the chemical structure and configuration have been confirmed, and the chemical structural formula is as follows figure 1 shown;

[0077] Acetonitrile was chromatographically pure, water was deionized water, and other reagents were analytically pure.

[0078] 2. Experimental methods and results

[0079] 1. Solution preparation

[0080] Sample diluent: 20% acetonitrile water solution by volume.

[0081] Mixed reference substance solution: weigh 10 mg of the S-isomer and 1 mg of the R-isomer ref...

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Abstract

The invention discloses an HPLC (High-Performance Liquid Chromatography) method for intermediate products of palonosetron hydrochloride synthesis. The method comprises the steps of taking octadecylsilane chemically-bonded silica as a fixed phase, taking acetonitrile-water as a moving phase, adding an effective amount of isophorondiamine into a control solution or test solution containing N-[(3,4-dihydronaphth-1-yl)methyl]-(S)-1-azabicyclo[2.2.2]octan-3-amine and R-type isomers thereof, carrying out uniform shaking, then, carrying out standing for at least 30 minutes, and then, injecting the mixture into a liquid chromatograph for analysis, wherein the isophorondiamine is a cis and trans isomer mixture. According to the HPLC method provided by the invention, the effective separation of N-[(3,4-dihydronaphth-1-yl)methyl]-(S)-1-azabicyclo[2.2.2]octan-3-amine and R-type isomers thereof can be achieved by only using ordinary C18 chromatographic columns and the ordinary acetonitrile-water mixed solvent, so that the cost is low, the operation is simple and convenient, and the analysis time is short.

Description

technical field [0001] The invention belongs to the field of drug analysis and relates to the reaction monitoring of drug intermediates, in particular to N-[(3,4-dihydronaphthalen-1-yl)methyl]-(S)-1-azabicyclo[2.2. 2] HPLC analysis method of octane-3-amine and its isomers. Background technique [0002] Palonosetron hydrochloride is a highly efficient and highly selective 5-HT3 receptor antagonist developed by MGI Pharma and Helsinn Healthcare in Switzerland. It was first approved for marketing in the United States in July 2003 and is used clinically for radiotherapy and chemotherapy. Acute and delayed nausea and vomiting. It has attracted much attention because of its high curative effect, low toxicity and side effects, long half-life, and small dosage (Palonosetron for the prevention of chemotherapy-induced nausea and vomiting: approval and efficacy, Cancer Manag Res, 2009). [0003] There are many synthesis techniques of palonosetron hydrochloride, but these techniques h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/02
Inventor 陈云陈昊王斌
Owner 方达医药技术(上海)有限公司