Purification method for lipstatin

A purification method, lipox technology, applied in the field of liplastatin purification, can solve the problems of high labor intensity, easy blockage of filter cloth, degradation of liprestatin, etc., achieve low production cost, reduce pollution, and simple process Effect

Active Publication Date: 2013-03-27
鲁南新时代生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The current method for purifying liprestatin mainly has the following disadvantages: 1. Because the Streptomyces toxins fermented liquid has a large viscosity and contains a certain amount of oily substances, the pretreatment of the fermented liquid mostly adopts plate and frame filter press technology, and direct press filter often It is easy to block the filter cloth, so adding a large amount of filter aids such as diatomaceous earth, perlite, etc. Most of the organic solvents used in the extraction are acetone and ethanol. Due to the hydrophilicity and lipophilicity of these two solvents, the extracted riprestatin has more water-soluble impurities, which increases the difficulty of subsequent purification and easily causes lipostatin. Degradation of statin; 3. The types of solvents used are too many; 4. The purity and yield of riprestatin obtained by purification are low
[0005] If the purity of liprestatin is low, there will be many impurities in the hydrogenated orlistat, making it difficult to prepare high-purity orlistat that meets medical standards by existing methods

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Take 2.0L of fermentation broth (fermentation unit 6.6g / L), add 8.0L of ethyl acetate, and extract for 5h under stirring conditions. After standing for 1 h, the phases were separated, and the upper layer extract was concentrated to dryness under reduced pressure to obtain 66.2 g of a yellow-brown riprestatin crude product. Dissolve the crude yellow-brown riprestatin in 240 mL of heptane, filter it, and concentrate the filtrate under reduced pressure to a volume of 60.0 mL to obtain a concentrated solution.

[0026] The silica gel column uses 100-200 mesh silica gel as the filler, and after equilibrating with heptane, put the concentrated solution on the column. First wash with a mobile phase with a volume ratio of heptane to ethyl acetate of 95:5 for 3 column volumes, then elute with a mobile phase with a volume ratio of heptane to ethyl acetate of 70:30 at a flow rate of 0.5 column volumes Every hour, collect the eluate with liprestatin HPLC detection purity ≥ 94% (ca...

Embodiment 2

[0029] Take 2.0L of fermentation broth (fermentation unit 6.5g / L), add 4.0L of ethyl acetate, and extract for 4h under stirring conditions. After standing for 1 h, the phases were separated, and the upper layer extract was concentrated to dryness under reduced pressure to obtain 64.8 g of a yellow-brown riprestatin crude product. Dissolve the crude yellow-brown riprestatin in 350 mL of heptane, filter it, and concentrate the filtrate under reduced pressure to a volume of 64.0 mL to obtain a concentrated solution.

[0030] The silica gel column uses 200-300 mesh silica gel as the filler, and after equilibrating with heptane, put the concentrated solution on the column. First wash with a mobile phase with a volume ratio of heptane to ethyl acetate of 88:12 for 3 column volumes, then elute with a mobile phase with a volume ratio of heptane to ethyl acetate of 80:20 at a flow rate of 0.8 column volumes Every hour, collect the eluate with liprestatin HPLC detection purity ≥ 94% (c...

Embodiment 3

[0033] Take 2.0L of fermentation broth (fermentation unit 6.2g / L), add 6.0L of ethyl acetate, and extract for 2h under stirring conditions. After standing for 1 h, the phases were separated, and the upper layer extract was concentrated to dryness under reduced pressure to obtain 63.8 g of a yellow-brown riprestatin crude product. Dissolve the crude yellow-brown riprestatin in 460 mL of n-hexane, filter it, and concentrate the filtrate under reduced pressure to a volume of 76.0 mL to obtain a concentrated solution.

[0034]The silica gel column uses 300-400 mesh silica gel as the filler, and after equilibrating with heptane, put the concentrated solution on the column. First wash with a mobile phase with a volume ratio of heptane to ethyl acetate of 90:10 for 3 column volumes, then elute with a mobile phase with a volume ratio of heptane to ethyl acetate of 75:25 at a flow rate of 1.2 column volumes Every hour, collect the eluate with liprestatin HPLC detection purity ≥ 94% (c...

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Abstract

The invention belongs to the technical field of medicines and particularly relates to a purification method for lipstatin. The technical scheme is that the purification method mainly comprises the steps of fermentation liquid direct extraction concentration, organic solvent dissolving filtering, silica-gel column chromatography and crystallization and the like, lipstatin with the weight content of 75%-85% and the high performance liquid chromatography (HPLC) detection purity of no smaller than 97% is obtained, and the total yield is 72%. The purification method is simple in steps, short in period, high in product yield and good in quality, all solvents can be recycled, the production cost is greatly reduced, and pollution to the environment is reduced.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for purifying liprestatin. Background technique [0002] Lipstatin is a metabolite of Streptomyces toxytricini, which can selectively inhibit the activity of pancreatic lipase in the gastrointestinal tract, reduce the body's decomposition and absorption of fat in food, and thus achieve weight control. Purpose. Due to the unstable nature of lipostatin, it is easily oxidized in the air, while its tetrahydro derivative Orlistat (Orlistat) has relatively stable characteristics, and has been successfully developed by Roche as a weight-loss drug - Xenical, It is currently the only drug for the treatment of obesity marketed as a non-central nervous system effect. [0003] At present, the preparation of orlistat is mainly through two methods, one is the total synthesis method, and its cost is higher; the other is the semi-synthesis method, that is, the fermentatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/12
Inventor 赵志全梁红宝
Owner 鲁南新时代生物技术有限公司
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