Method for splitting ketoprofen enantiomer by temperature gradient simulated moving bed chromatogram

A technology for simulating moving bed and temperature gradient, applied in organic chemistry methods, chemical instruments and methods, separation of optically active compounds, etc., can solve the problem of not preparing L- and D-ketoprofen enantiomer crystals, complete separation and narrow operating range , affecting SMB separation efficiency and other issues, to achieve the effect of simple and easy operation, high purity and recovery rate, and high recovery rate

Inactive Publication Date: 2012-06-27
WENZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still several problems in this method: 1) the closed-loop process is adopted, and the operation flexibility is small, and the disturbance of each pump flow rate and feed concentration will seriously affect the separation efficiency of SMB; 2) the isothermal operation is used, and the low selectivity of the chiral separation system Resulting in a narrow operating range for complete separation, restricting output, and requiring a large amount of solvent consumption, these problems will become more prominent due to the nonlinearity of adsorption equilibrium in the industrial production process; 3) The obtained product is a solution, and no levorotatory and dexketoprofen enantiomer crystals, unable to face the market directly

Method used

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  • Method for splitting ketoprofen enantiomer by temperature gradient simulated moving bed chromatogram
  • Method for splitting ketoprofen enantiomer by temperature gradient simulated moving bed chromatogram

Examples

Experimental program
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Effect test

Embodiment 1

[0035] 1. Preprocessing

[0036] Using a Chiralpak AD chromatographic column, mix chromatographically pure n-hexane, ethanol, and trifluoroacetic acid in a volume ratio of 80: 20: 0.01 to form a mobile phase, and filter it with a 0.22 μm solvent filter membrane. Ultrasonic treatment for 20min was used as the eluent; then the mobile phase was used as the solvent to accurately prepare a ketoprofen racemate solution with a total concentration of 1g / L, which was used as the feed solution.

[0037] 2. Simulated moving bed (SMB) separation

[0038] The operating conditions are as follows:

[0039] Mobile phase: normal hexane: ethanol: trifluoroacetic acid=80: 20: 0.01

[0040] Injection concentration: C F =1.0g / L;

[0041] Number of chromatographic columns: 8 ( , 2 / 2 / 2 / 2 distribution);

[0042] Eluent flow rate: Q D =10.0mL / min;

[0043] Extraction flow: Q E =2.9 mL / min;

[0044] Feed liquid flow rate: Q F =0.4mL / min;

[0045] Raffinate flow rate: Q R =2.1 mL / min; ...

Embodiment 2

[0077] 1. Preprocessing

[0078] Using a Chiralpak AD chromatographic column, mix chromatographically pure n-hexane, ethanol, and trifluoroacetic acid in a volume ratio of 100: 0: 0.03 to form a mobile phase, and filter it with a 0.22 μm solvent filter membrane. Ultrasonic treatment for 20min was used as an eluent; then the mobile phase was used as a solvent to accurately prepare a ketoprofen racemate solution with a total concentration of 40g / L, which was used as a feed solution.

[0079] 2. Simulated moving bed (SMB) separation

[0080] The operating conditions are as follows:

[0081] Mobile phase composition: normal hexane: ethanol: trifluoroacetic acid=100: 0: 0.03;

[0082] Injection concentration: C F =40.0g / L;

[0083] Number of chromatographic columns: 8 ( , 2 / 2 / 2 / 2 distribution);

[0084] Eluent flow rate: Q D =20.0 mL / min;

[0085] Extraction flow: Q E =9.2 mL / min;

[0086] Feed liquid flow rate: Q F =0.4 mL / min;

[0087] Raffinate flow rate: Q R =2.5 ...

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Abstract

The invention discloses a method for splitting ketoprofen enantiomer by temperature gradient simulated moving bed chromatogram. The method comprises the following steps of: preparing a mobile phase as an eluate; using the eluate as a solvent to prepare a ketoprofen racemate solution as a charging liquid; introducing the charging liquid and the eluate with a temperature difference or with a same temperature into an open-loop simulated moving bed chromatogram to split the ketoprofen racemate and obtain levorotatory ketoprofen solution with a purity higher than 98% and a dextrorotatory ketoprofen solution; collecting the obtained levorotatory ketoprofen solution and the dextrorotatory ketoprofen solution; and carrying out distillation, recrystallization and drying respectively to obtain levorotatory ketoprofen enantiomer crystal and dextrorotatory ketoprofen enantiomer crystal with purity higher than 98%. The method has advantages of high separation efficiency, small solvent amount, continuous production and large operation elasticity, and has good commercialized application prospect.

Description

technical field [0001] The invention relates to the resolution technology of 2-ylpropionic acid non-steroidal anti-inflammatory drugs, in particular to a method for separating ketoprofen enantiomers by temperature gradient simulated moving bed chromatography. Background technique [0002] Ketoprofen (also known as Youprofen, Ketoprofen, Ketoprofen, Ketoprofen) is an aryl alkanoic acid compound with a chemical name of 2-(3-benzoylphenyl)propionic acid. It has two optical isomers, namely levoketoprofen and dexketoprofen, which have different pharmaceutical activities. Dexketoprofen has analgesic, anti-inflammatory and antipyretic effects, and is mainly used for the treatment of rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and gout. On the market, ketoprofen as an anti-inflammatory drug mainly appears as a racemic product. In a variety of biological models, dexketoprofen is superior to ketoprofen racemate, and at the same time, some studi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/84C07C51/47C07B57/00
Inventor 余卫芳徐进朱磊刘玉明孙玉高周慧君
Owner WENZHOU UNIVERSITY
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