CN1763021B - Method for purifying orlistat - Google Patents

Abstract

The present invention discloses orlistat purifying method, which includes dissolving coarse orlistate product in medium polarity solvent, filtering, eliminating impurity, crystallization, dissolving in non-polar solvent, recrystallization, and repeating some steps until reaching the medicinal purity standard. The said method is suitable for purifying coarse orlistate product with purity of 50-85 %, and has the advantages of high yield, short purification period, simple purification process and being suitable for industrial production.

Description

A method for purifying orlistat

technical field

The invention relates to a method for purifying an organic compound, in particular, the invention relates to a method for preparing high-purity orlistat.

Background technique

Orlistat (Orlistat), is a hydrogenated derivative of the natural product lipstatin (nibostatin) of the genus Streptomyces, and its chemical name is (S)-2-formylamino-4-methyl-pentanoate ( S)-1-[[(2S,3S,)-3-hexyl-4-oxo-2-oxetanyl]-methyl]-dodecyl ester. Orlistat is a specific gastrointestinal lipase inhibitor used in the prevention and treatment of obesity-related diseases.

The Chinese patent "A Purification Method for Trylipatin" (publication number: CN1266058A, published on September 13, 2000) discloses a purification method for orlistat, that is, the lipatatin produced after fermentation of Streptomyces is treated with heptane Double-stream extraction with aqueous acetic acid, hydrogenation and crystallization with hexane or heptane. U.S. Patent leucine derivatives (Patent No. US4598089, published in July 1986) discloses a method for obtaining orlistat by concentration and purification by chromatographic methods, that is: soaking and concentrating the fermented product lipstatin for column elution, concentration, and hydrogenation After crystallization with heptane. Although the method for purifying orlistat disclosed by these techniques is relatively simple, and can also obtain orlistat meeting pharmaceutical standards, these techniques have very high requirements for the purity of lipstatin in the fermented liquid, and require orlistat after hydrogenation The purity of the lixistat sample itself is relatively high. For example, the purification process disclosed in the CN1266058A patent requires high purity of the intermediate lipstain in the fermentation broth: the weight content is as high as 90%, otherwise it is impossible to purify orlistat with a purity that can be used for medicine. However, the purification or crystallization with heptane mentioned in US4598089 also has the defects that impurities cannot be completely and effectively removed, and the solvent consumption is relatively large. Concentrating and purifying by chromatography also has the following defects: low yield, long cycle time, difficult preservation of intermediate Lipstatin, easy oxidation and other defects.

At present, the production of domestic fermentation medium is still in its infancy, and it is impossible to provide medium raw materials for industrial use that are of comparable quality to foreign countries. For example, the content of linoleic acid used in the fermentation process of orlistat is only 54% in the best domestic products, while the foreign standard is 60%. Because of the difference between domestic fermentation medium raw materials and foreign countries and other reasons, the purity of lipstatin after fermentation will be very low in actual production, and the weight content is only about 20-45%. At the same time, because of the non-localization of the culture medium, the price of the imported culture medium is very high. From the perspective of production cost, it cannot be applied to industrial production at all.

Because of the low purity of lipstatin, the hydrogenated orlistat sample also contains other impurities besides orlistat, and the content of orlistat is very low, only 50-70% by weight. There are many impurities, and the composition of the impurities is also different from that disclosed in the prior art. In this actual situation, it is impossible to use the prior art for purification treatment. If the prior art is used for purification, the resulting finished product is far from the pharmaceutical Purity requirements used.

Contents of the invention

The invention overcomes the defect that the low-purity orlistat cannot be purified in the prior art, and provides a purification method that can purify the low-purity orlistat to meet the pharmaceutical standard and be suitable for industrial application.

The purpose of the present invention is to overcome the technical problem that it is difficult to purify low-purity orlistat in the prior art, and provide a kind of purified orlistat that can effectively remove impurities, has high yield, short cycle and is suitable for industrial production. craft.

After research, it was found that medium-polarity solvents have strong solubility selectivity, and orlistat is easily dissolved in medium-polarity solvents, but the impurities contained in orlistat samples are not soluble in medium-polarity solvents Among the non-polar solvents such as heptane, the solubility of more impurities in the orlistat sample is relatively high, and the impurities cannot be removed. The purpose of removing impurities can be achieved only by repeatedly dissolving and crystallizing several solvents. Thereby obtain the method for high-purity orlistat. The inventor utilizes this characteristic, by dissolving the orlistat sample in a medium polar solvent, such as ethanol, acetonitrile, acetone, isopropanol, methyl ethyl ketone, butanol, etc., orlistat is dissolved in the solvent , while impurities are insoluble to effectively remove impurities.

The invention provides a method for purifying orlistat, which can effectively remove impurities and obtain a product meeting pharmaceutical standards.

After the fermented liquid is extracted and concentrated, hydrogenated, and crystallized from heptane to obtain the orlistat sample according to the conventional process, the content of orlistat measured by HPLC is very low, and the content is only about 50-85% (weight/weight), or even Lower, far from the 98% medicinal standard.

The invention discloses a method for purifying orlistat, comprising the following steps:

1) Dissolution and crystallization: dissolve the orlistat sample with a medium-polarity solvent, the ratio of the amount of the solvent added to the orlistat sample is 2-5:1 in terms of weight to volume ratio, filter to remove impurities, Add medium-polarity solvent to the obtained filtrate to 10-15:1, crystallize, and obtain crystal sample;

2) Redissolution and recrystallization: Dissolve the crystalline sample obtained in 1) with a non-polar solvent. The ratio of the amount of the non-polar solvent added to the crystalline sample is 15-25:1 by weight to volume, and then filter. Remove impurities; add non-polar solvent to the obtained filtrate to 2545:1, and crystallize.

The weight content of the orlistat sample is about 50-85% or less. If the orlistat sample whose content is higher than 85% or even as high as 90% can be purified by the process of the prior art. Compared with the prior art, the purification process of the present invention is not very significant in terms of purifying orlistat higher than 85%. And for the orlistat sample whose content is lower than 50%, the present invention can also be purified, just need to repeat many times in the purification process, and this can prolong production cycle, and increase production cost greatly, from industrial point of view, Purification from less than 50% orlistat samples to a pure product meeting pharmaceutical standards does not meet the requirements of industrial production.

Wherein in step 1), the weight-to-volume ratio of the amount of solvent added to the orlistat sample during dissolution is 2-5:1, preferably 3-4:1. If the amount of solvent added is too small, the solution viscosity is too high, orlistat cannot be completely dissolved in the solvent, and it is difficult to filter. If the amount of the solvent added is too much, the impurities will also be dissolved into the solvent and mixed with orlistat, which cannot remove the impurities. During crystallization, the addition amount of medium polar solvent is also very important, preferably about 10:1. If too little is added, the crystallization speed will be too fast, and impurities will also be bound together; if too much is added, orlistat will dissolve too much in the solvent, the crystallization will not be good, and the yield will be too low.

Wherein in said step 2), when redissolving, the added amount of the non-polar solvent is preferably about 20:1 in terms of weight to volume ratio. In recrystallization, the amount of non-polar solvent added is also very important, and the amount of 25-45:1 can be selected, but when the amount of 30-40:1 is selected, the crystallization of orlistat is relatively complete, and the crystal form is relatively good.

In the step 1) described therein, the medium polar solvent is ethanol, acetonitrile, acetone, propylene glycol, isopropanol, butanone, butanol, etc., preferably acetonitrile.

Wherein described step 2) in, non-polar solvent is heptane, hexane, carbon tetrachloride, chloroform or sherwood oil etc., preferably heptane, because not only can remove the impurity after main peak with heptane, and The weight content of orlistat can be increased.

In the purification process of orlistat, after the crystallization step, the crystallization sample is subjected to high performance liquid chromatography (HPLC) detection, depending on the specific situation of impurities, repeating step 1) or step 2) or repeating step 1) and 2), and carry out HPLC detection to it, until the purity meeting pharmaceutical standards.

In the purification process of orlistat, the solvent used can be recovered or applied mechanically by industrial conventional methods, such as a rotary evaporator. On the one hand, the production cost is saved, and on the other hand, it will not cause industrial pollution. Suitable for industrialized mass production.

Throughout the purification process, the pore size of the filter membrane used for filtration can be selected from 0.8 μm, 0.45 μm, and 0.22 μm. Considering the flow rate and impurity removal effect, 0.45 μm is preferred.

The method for purifying orlistat disclosed in the present invention does not have high requirements for the purity of the lipstatin extracted and concentrated from the fermentation broth, which is about 20-45%. And the lipstatin purity in the patent CN1266058A is 90%. Therefore, the present invention mainly provides a method for purifying low-purity orlistat (important content 50-85%, or even lower) obtained after hydrogenating the lower-purity intermediate lipstatin to obtain a qualified product.

After the purification process disclosed in the present invention, the content of orlistat is determined by high-performance liquid chromatography, and the weight content of orlistat can reach more than 98%, which meets the pharmaceutical standard.

The process for purifying orlistat disclosed by the invention is simple and convenient, has low production cost and is suitable for industrialization.

Detailed ways

Below by example the present invention will be further described.

Example 1

Fermentation extract concentrate contains lipstatin 30% (weight/weight) 120ml, the sample obtained after hydrogenation contains 46g of orlistat sample, the content is 52%, the sample color is about gray, add 150ml of acetone to dissolve, filter, add acetone to 600ml, Crystallized and suction filtered to obtain 30 g of off-white crystals with a content of 96% (W/W) detected by HPLC and a maximum impurity of 0.52%. Add 120ml of acetone, dissolve, filter, add acetone to 400ml, crystallize at low temperature, and filter with suction to obtain 25g of crystals, off-white, detected by HPLC, the content is 97%, and the largest impurity is 0.4%. Add 500ml of heptane to re-dissolve, filter, add heptane to 900ml, and crystallize to obtain 20g of pure orlistat with a content of 98.8% and a maximum impurity of 0.4%.

Example 2

The purity of Lipstatin in the concentrated solution of fermentation extract was 40% (weight/weight) 90ml, and the purity of HPLC was 74% (calculated according to the peak area normalization method). Dissolve 110ml of ethanol, filter, add ethanol to 530ml, and crystallize to obtain 35g of orlistat sample with a purity of 83.1% and a maximum impurity of 0.9%. Add 550ml of heptane to re-dissolve, filter, add heptane to 1300ml, and crystallize to obtain 34g of orlistat sample with a purity of 88.1% and a maximum impurity of 0.9%. Add 700ml of heptane to re-dissolve, filter, add heptane to 1000ml, and crystallize to obtain 14g of pure orlistat with a purity of 98.5% and a maximum impurity of less than 0.5%.

Example 3

Fermentation extract concentrate contains lipstatin 35% (weight/weight) 100ml, HPLC purity 71% (according to peak area normalization method calculation), after hydrogenation obtains orlistat sample about 51g, content 70%, sample color gray, add Dissolve in 150ml of acetonitrile, filter, add acetonitrile to 750ml, and crystallize to obtain 32g of orlistat sample, off-white, purity 91.1%, maximum impurity 0.92%; add 750ml of hexane to re-dissolve, filter, add hexane to 1400ml, Crystallized to obtain 31 g of orlistat sample with a purity of 93.5% and a maximum impurity of 0.92%. Add acetonitrile 65mi to dissolve, filter, add acetonitrile to 310mi, crystallize, and obtain orlistat sample 18g, off-white, purity 95.1%, maximum impurity 0.53%; add 270ml of hexane to re-dissolve, filter, add hexane to 420ml , crystallized to obtain 16g of pure orlistat with a purity of 98.6% and a maximum impurity of less than 0.5%.

Claims (2)

1. the method for a purifying orlistat comprises following step:

1) dissolving, crystallization: with the orlistat sample with the dissolving of the solvent of middle polarity, weight ratio meter by volume, the add-on of solvent is 2-5 with the ratio of orlistat sample: 1, filter, decon, the solvent of adding middle polarity in the filtrate of gained are to 10-15: 1, crystallization gets crystallized sample;

2) dissolving, recrystallization: with 1) crystallized sample of gained dissolves with nonpolar solvent, weight ratio meter by volume, the add-on of nonpolar solvent is 15-25 with the ratio of crystallized sample: 1, filtration, decon; In the filtrate of gained, add nonpolar solvent, to 25-45: 1, crystallization;

Wherein, the weight content of described orlistat sample is 50-85%; Described middle polarity solvent is ethanol, acetonitrile, acetone; Described nonpolar solvent is heptane, hexane or sherwood oil.

2. the method for purifying orlistat according to claim 1 is characterized in that repeating a wherein any step or two steps, up to the purity that meets medicinal standard.