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A kind of extraction process of lovastatin

A technology for lovastatin and bacterial residues, which is applied in the field of separating or purifying lovastatin or its pharmaceutically acceptable salt, can solve the problems of high energy consumption, easily corroded equipment, large volume of fermentation liquid, etc. The effect of saving acid-base reagents and facilitating recovery

Active Publication Date: 2019-06-04
丽珠集团(宁夏)制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At the beginning of the extraction process, the fermented liquid is cyclized. The fermented liquid that needs to be heated is huge, almost at the largest stage of the overall extraction process, and the fermented liquid also contains strong oxidizing sulfuric acid, which consumes a lot of energy. And easy to corrode equipment

Method used

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  • A kind of extraction process of lovastatin
  • A kind of extraction process of lovastatin
  • A kind of extraction process of lovastatin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Experimental group 1 (refer to CN 102344426)

[0040] 1L of fermentation broth, adjusted to pH 1.5 with 5mol / L HCl, stirred and sedimented for 1 hour, filtered, collected the fungus residue, added 0.25L butyl ester to the fungus residue, stirred and extracted the fungus residue for 3 hours at a temperature of 55°C , separate, collect the extract, keep warm at 30°C, add 50ml 0.5mol / L NaOH, stir and wash for 30 minutes, let stand for 15 minutes to remove the water phase, add 50ml 0.5mol / L HCl to the organic phase, stir and wash for 30 minutes, let stand for 15 minutes Remove the water phase, add 50ml of deionized water to the organic phase, stir and wash for 30 minutes, let stand for 15 minutes to remove the water phase, and vacuum concentrate the organic phase (temperature 65-70°C, vacuum degree less than 0.08MPa) to a volume of about 30ml, and cool down to 12°C, keep warm for 3 hours, centrifuge and dry to obtain the crude product.

[0041] Experimental group 2 (refer ...

Embodiment 2

[0069] Take 1L of lovastatin fermentation broth, and slowly add concentrated sulfuric acid under stirring to adjust the pH of the fermentation broth to 3.5-4.0.

[0070] Filter and dry the bacteria residue.

[0071] Add ethyl acetate of 5.0 times of the weight of the bacterium to the bacterium residue and soak for 5 hours to filter, after the filtration is completed, add 1% NaHCO solution of 10% of the filtrate volume to the filtrate, leave the filtrate to stand for 1 hour and separate the water layer, Save the organic phase.

[0072] Concentrate the organic phase. When concentrating, the pressure is above -0.080Mpa. Concentrate at about 55°C for 10h, and concentrate to a volume 5 times smaller than that of the product. Then lower the temperature of the concentrated solution to 10°C, stir and keep warm for 6 hours, and the stirring speed is 150rpm, crystallization.

[0073] Filter, wash the crude product crystals with cold ethyl acetate at 15°C, and dry the crude wet product...

Embodiment 3

[0081] Take 1L of lovastatin fermentation broth, and slowly add concentrated sulfuric acid under stirring to adjust the pH of the fermentation broth to 3.5.

[0082] Filter and dry the fungus residue until the water content of the fungus residue reaches 40%.

[0083] Add ethyl acetate of 4.0 times the weight of the bacterium residue to the bacterium residue and soak for 5 hours to filter, after the filtration is completed, add 1% NaHCO with a volume of 10% of the filtrate to the filtrate 3 solution, the filtrate was allowed to stand for 1 hour, and the aqueous layer was separated, and the organic phase was retained.

[0084] The organic phase was concentrated, and the concentration was carried out at about 55 degrees under reduced pressure for 10 hours, and then the temperature of the concentrated solution was lowered to 5 degrees Celsius, and stirred and kept for 6 hours at a stirring speed of 150 rpm to crystallize.

[0085] Filter, wash the crude product crystals with cold...

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Abstract

The invention relates to a method for separating or purifying lovastatin or pharmaceutically acceptable salt thereof from fermentation liquid. The method comprises the following steps that 1, the lovastatin fermentation liquid is taken, and the pH of the fermentation liquid is regulated to be 1.0-5.0 by slowly adding concentrated sulfuric acid in a stirring state; 2, filtering is conducted, and mushroom dregs are blow-dried till the water content of the mushroom dregs reaches 10%-70%; 3, an organic solvent is added into the mushroom dregs, soaking and filtering are conducted, a 1.0%-5.0% NaHCO3 solution of which the volume accounts for 10% of that of filtrate is added into the filtrate, a water layer is separated out, and an organic layer is retained; 4, the organic layer is concentrated, concentrated liquid is cooled, stirred and crystallized, and a cyclization reaction of the lovastatin is conducted during concentration; 5, filtering is conducted, crude crystals obtained after filtering are washed with cold ethyl acetate at the temperature of 10%-20% and dried at the temperature about 40-50 DEG C, and then a crude lovastatin product is obtained. The method is high in yield, capable of saving energy and suitable for large-scale production.

Description

technical field [0001] The invention relates to a method for isolating or purifying lovastatin or a pharmaceutically acceptable salt thereof from microbial fermentation broth. Background technique [0002] Lovastatin (Lovastatin) is also called Electin, and its chemical name is chemical name: (S)-2-methylbutyric acid-(1S, 3S, 7S, 8S, 8aR) -1, 2, 3, 7, 8,8a-hexahydro-3,7-dimethyl-8-{2-[(2R,4R)-4-hydroxy-6-oxo-2-tetrahydro, the specific structural formula is as follows: [0003] [0004] Lovastatin is the first generation of statins, and now it is mostly used as the precursor of pravastatin, an active statin drug. Therefore, the yield and quality of lovastatin directly affect the cost and purity of pravastatin. [0005] The existing method for extracting and preparing lovastatin is mainly to heat the fermentation broth, alkalinize and filter, and then extract the filtrate or perform resin exchange extraction on the filtrate. The process of using macroporous resin adsorptio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D309/30
CPCC07D309/30
Inventor 郑滔张伟罗勇史顺智马宁
Owner 丽珠集团(宁夏)制药有限公司