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

A technology of 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 enantiomeric crystals of levorotatory and dexketoprofen, and complete separation with a narrow operating interval. , affecting the separation efficiency of SMB, etc., to achieve the effect of simple and easy operation, high purity and recovery rate, and high recovery rate

Inactive Publication Date: 2014-04-09
WENZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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

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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 a separation technology of 2-ylpropionic acid non-steroidal anti-inflammatory drugs, in particular to a method for separation of ketoprofen enantiomers by temperature gradient simulated moving bed chromatography. Background technique [0002] Ketoprofen (also known as Euprofen, Ketoprofen, Ketoprofen, Ketoprofen) is an arylalkanoic acid compound with the chemical name of 2-(3-benzoylphenyl)propionic acid. It has two optical isomers, namely Levoketoprofen and Dexketoprofen, which have different pharmacological 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 racemate product. In a variety of biological models, dexketoprofen is superior to the ketoprofen racemate. At the same time, some st...

Claims

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Application Information

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Patent Type & Authority Patents(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 UNIV
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