CN1324026C

CN1324026C - Process for preparing berberine sulphate

Info

Publication number: CN1324026C
Application number: CNB021330018A
Authority: CN
Inventors: 安晓霞; 刘九知; 宁娟; 王虹; 朱树森
Original assignee: DONGBEI PHARMACEUTICAL FACTORY
Current assignee: Northeast Pharmaceutical Group Co., Ltd.
Priority date: 2002-09-23
Filing date: 2002-09-23
Publication date: 2007-07-04
Anticipated expiration: 2022-09-23
Also published as: CN1485326A

Abstract

The present invention relates to a process for preparing berberine sulphate, which is characterized in that an intermediate body of complete synthesis berberine-crude product berberine is used as raw materials. The present invention comprises the following steps: A, crude product berberine is used as raw materials; water is added; at the temperature of 80 to 95DEG C, activated carbon is completely dissolved and filtered by agitation, and accordingly, refined berberine solution (a) is obtained; B, after the solution (a) is agitated, dilute sulphuric acid solution is added; at the temperature of 70 to 95DEG C, reaction is carried out for 3 to 5 hours by agitation, and after cooling, filtration, washing and drying, hydrogen sulfate berberine (b) is obtained. C, (b) and distilled water are placed into a reaction bottle; 10% of NaOH solution is dripped to the full dissolution of (b) by agitation; the pH is regulated to 7 to 8; pressure reduction and water removal are carried out to dryness; then, 80 to 90% of alcohol is added; after heating and back flow are carried out for 30 minutes, filtration, liquid filtration, cooling and devitrification are carried out for more than 4 hours; the mixture is filter, and a filter cake is recrystallized by 80 to 90% of alcohol for obtaining the berberine sulfate finished product, and the quality of the berberine sulfate finished product conforms to standard requirements. The new method for preparing the berberine sulfate can overcome the disadvantages of a plurality of the existing preparation methods of low yield, high cost, difficult assurance of quality, etc.

Description

Preparation method of berberine sulfate

Technical Field

The invention relates to a preparation method of broad-spectrum berberine sulfate, namely berberine sulfate, belonging to the field of drug synthesis.

Background

Berberine, also known as berberine, is a traditional medicine for treating enteritis and bacillary dysentery. Has long history and definite curative effect. At present, the clinical treatment range is gradually expanded, so that the development of berberine has wide market prospect. The berberine clinically applied has medicinal forms such as hydrochloride, bisulfate, sulfate and the like. Compared with berberine hydrochloride, the berberine sulfate has the characteristic of high water solubility, for example, the solubility of the berberine sulfate in water at room temperature is 100 times of that of the berberine hydrochloride, so the berberine sulfate not only can be prepared into tablets, but also can be prepared into injections for patients who are inconvenient to take orally and need treatment urgently, and can also be provided for veterinary use, thereby greatly widening the medication route and the application range of the berberine.

Berberine sulfate, english name: berberfine Sulfate

The molecular formula is as follows: c₄₀H₃₆N₂O₁₂S.3H₂O

The preparation methods of berberine sulfate are mostly plant extraction methods, and two preparation methods of berberine sulfate are introduced in journal of Chinese herbal medicine, 11 vol.4 in 1980, and 159-160 pages.

1. Acetone berberine conversion method

2. Method for converting berberine hydrogen sulfate

Starting materials for the above two preparation methodsAll berberine hydrochloride is extracted from plants. And thus resources are limited. In addition, in the method 1, when the acetone berberine is converted into the berberine sulfate, the disadvantage of incomplete conversion exists, and the unconverted acetone berberine is required to be recycled and reused, so the operation is troublesome; in addition, acetone is used as solvent in this method, which results in a higher cost. In the method 2, although an organic solvent is not used, the use amount of sodium sulfate and sulfuric acid is large, the cost is high, the treatment amount of three wastes is large, in addition, the yield is only 65 percent lower due to the primary crystallization of the berberine bisulfate, and secondary recovery needs to be increased; furthermore, the initial raw material berberine hydrochloride contains a large amount of cl^-Ions, which must be pre-treated before berberine sulphate preparation, otherwise cl^-Ion will shadowQuality of berberine sulphoxylate. Practice proves that the method 1 and the method 2 can increase cl in berberine hydrochloride^-The pretreatment step of the ions sometimes also has difficulty in ensuring the product quality and yield of berberine sulfate. Chinese patent CN1312250A reports a preparation method of berberine sulfate, which comprises the following steps: the method has the advantages that the process is simple, the raw material source is not limited by natural resources, the prepared berberine sulfate has low purity and contains a small amount of berberine bisulfate, so that the water solubility of the product is influenced, the quality requirement of preparing berberine sulfate injection cannot be met, and the small amount of berberine bisulfate is difficult to remove from the finished product. Further, CN1312250A reports a method for producing berberine bisulfate, in which the reaction is incomplete due to the short reaction time of the heat preservation, and berberine sulfate and sulphur are produced simultaneously. The berberine sulfate has high water solubility, can be washed away by water when the berberine bisulfate is filtered, does not influence the quality of the berberine bisulfate, but can influence the yield of the berberine bisulfate due to incomplete reaction of the berberine bisulfate.

Disclosure of Invention

The invention aims to provide a novel method for preparing berberine sulfate by taking a totally synthesized berberine intermediate, namely crude berberine as a raw material, so as to overcome the defects of low yield, high cost, difficult quality guarantee and the like of the preparation methods.

The preparation method of the berberine sulfate comprises the following steps: A. taking crude berberine as raw material, adding water and active carbon, stirring at 80-95 deg.C to dissolve completely, filtering to obtain refined berberine solution (a); wherein the crude berberine, water and active carbon are calculated according to the weight ratio: 1: 8-15: 0.02-0.05; B. adding dilute sulfuric acid solution into the solution (a) while stirring, stirring and reacting for 3-5 hours at 70-95 ℃, cooling, filtering, washing and drying to obtain berberine hydrogen sulfate (b); (a) the ratio of the liquid to the dilute sulfuric acid is 30: 1-15: 1 by volume ratio, and the concentration of the dilute sulfuric acid is 30-45% (v/v); C. adding the (b) and distilled water into a reaction bottle, dropwise adding 10% (w/v) NaOH solution while stirring until the (b) is completely dissolved, adjusting the pH to 7-8, decompressing, removing water until the (b) is dry, adding 80-90% ethanol, heating, refluxing for 30 minutes, filtering, cooling filtrate, crystallizing for 4-5 hours, filtering, recrystallizing filter cakes with 80-90% ethanol to obtain a finished berberine sulfate product, wherein the quality meets the standard requirement; (b) the proportion of the alcohol, distilled water, ethanol and 10 percent NaOH is 1: 8-14: 12-16: 1.0-1.1 according to the weight to volume ratio; the ethanol used for recrystallization accounts for 42-45% of the total ethanol.

The process route of the invention can be simplified as follows:

the berberine sulfate prepared by the method has high purity, completely meets the quality requirement of injection preparation, and has the advantages of simple and convenient operation, high product yield and low cost.

Detailed Description

Example 1: a, refining of crude berberine:

adding 92g (containing 42% of berberine and 43% of water) of crude berberine into 2000ml beaker, adding 800ml of distilled water and 3g of active carbon, heating to 85-90 ℃ under stirring for complete dissolution, filtering, washing filter cake with 100ml of hot water, and combining washing filtrates to obtain refined berberine solution (a).

B. Preparation of berberine hydrogen sulfate

Heating 900ml of the solution (a) to 85-90 ℃, adding 30ml of 45% (v/v) sulfuric acid while stirring, preserving the heat at 85-90 ℃ for reaction for 3 hours, cooling to room temperature, then carrying out 4 hours, filtering, washing a filter cake with a small amount of water, and drying the filter cake to obtain 44.5g of the berberis bisulfate (b), with the content of 81.1%, the water content of 13.2% and the yield of 93.3%.

Preparation of C berberine sulfate

Putting 45g of berberine hydrogen sulfate (b) into a 1000ml four-necked bottle, adding 450ml of distilled water, dropwise adding 49.5ml of 10% (w/v) NaOH solution while stirring, adjusting the pH value to 7.7-8.0, then distilling under reduced pressure to remove water, adding 325ml of 85% ethanol, heating and refluxing for 30 minutes, filtering, adding 245ml of 85% ethanol into a filter cake for recrystallization, and obtaining 38.2g of fine berberine sulfate with the content of 87.1%, the water content of 13.2% and the weight yield of 84.9% in one step, wherein the fine berberine sulfate is qualified after total inspection.

Example 2

A, refining of crude berberine:

the refining method of the crude berberine product in the embodiment is basically the same as that in the embodiment 1, except that the using amount of the active carbon is 2.0g, the total using amount of the distilled water is 1380ml, and the reaction temperature is 80-85 ℃;

b the preparation method of berberine hydrogen sulfate is basically the same as that of example 1, except that 30% (v/v) of sulfuric acid is selected, the dosage is 60ml, the reaction temperature is 87-93 ℃, the reaction time is 4 hours, the amount of berberine hydrogen sulfate (B) is 43g, the content is 82%, the water content is 13.7%, and the yield is 91.25%;

preparation of C berberine sulfate

The preparation method of berberine sulfate in this example is substantially the same as that of example 1, except that 630ml of distilled water is used, 90% of ethanol is used, 720ml of ethanol is used, wherein 42% of ethanol is used for recrystallization, 302ml of ethanol is used, 39g of berberine sulfate is obtained, 86.8% of berberine sulfate is used, 13.7% of water is used, and the weight yield is 86.7%.

Example 3

Refining of crude berberine

The refining method of the crude berberine product in the embodiment is basically the same as that in the embodiment 1, except that the using amount of the active carbon is 4.6g, the using amount of the distilled water is 736ml, and the reaction temperature is 90-95 ℃;

b preparation of berberine hydrogen sulfate

The preparation method of the berberine bisulfate in the embodiment is basically the same as that of the embodiment 1, except that the reaction temperature is 70-80 ℃, the reaction time is 5 hours, the sulfuric acid content is 35% (v/v), the dosage is 45ml, the yield of the berberine bisulfate (b) is 42.5g, the content is 82.5%, the water content is 13.5%, and the yield is 90.74%;

preparation of C berberine sulfate

The preparation method of berberine sulfate in this example is substantiallythe same as that of example 1, except that the amount of distilled water is 360ml, the amount of 10% NaOH is 45ml, the pH is adjusted to 7.0-7.2, the concentration of ethanol is 80%, and the amount of ethanol is 540ml, wherein the amount of ethanol used for recrystallization is 45%, 243ml, the amount of berberine sulfate is 38g, the content is 87.2%, the water content is 12.2%, and the weight yield is 84.4%.

Claims

1. The preparation method of the berberine sulfate comprises the following steps, and is characterized in that: A. taking crude berberine as raw material, adding water and active carbon, stirring at 80-95 deg.C to dissolve completely, filtering to obtain refined berberine solution (a); wherein the crude berberine, water and active carbon are calculated according to the weight ratio: 1: 8-15: 0.02-0.05; B. adding dilute sulfuric acid solution into the solution (a) while stirring, stirring and reacting for 3-5 hours at 70-95 ℃, cooling, filtering, washing and drying to obtain berberine hydrogen sulfate (b); (a) the ratio of the liquid to the dilute sulfuric acid is 30: 1-15: 1 by volume ratio, and the concentration of the dilute sulfuric acid is 30-45% (v/v); C. adding the (b) and distilled water into a reaction bottle, dropwise adding 10% (w/v) NaOH solution while stirring until the (b) is completely dissolved, adjusting the pH to 7-8, decompressing, removing water until the (b) is dry, adding 80-90% ethanol, heating, refluxing for 30 minutes, filtering, cooling filtrate, crystallizing for 4-5 hours, filtering, recrystallizing filter cakes with 80-90% ethanol to obtain a finished berberine sulfate product, wherein the quality meets the standard requirement; (b) the proportion of the alcohol, distilled water, ethanol and 10 percent NaOH is 1: 8-14: 12-16: 1.0-1.1 according to the weight to volume ratio; the ethanol used for recrystallization accounts for 42-45%of the total ethanol.

2. The method for preparing berberine sulfate according to claim 1, wherein the material ratio and reaction conditions in each step can be as follows: A. refining the crude berberine: adding 92g of crude berberine containing 42% of berberine and 43% of water into 2000ml of a beaker, adding 800ml of distilled water and 3g of activated carbon, heating to 85-90 ℃ under stirring for complete dissolution, filtering, washing a filter cake with 100ml of hot water, and combining washing filtrates to obtain the refined berberine solution (a);

B. preparation of berberine hydrogen sulfate

Heating 900ml of the solution (a) to 85-90 ℃, adding 30ml of 45% (v/v) sulfuric acid while stirring, preserving the heat at 85-90 ℃ for reaction for 3 hours, cooling to room temperature, then carrying out 4 hours, filtering, washing a filter cake with a small amount of water, and drying the filter cake to obtain 44.5g of berberine hydrogen sulfate (b), wherein the content of berberine hydrogen sulfate (b) is 81.1%, the water content of berberine hydrogen sulfate is 13.2%, and the yield of berberine hydrogen sulfate (b) is 93.3%;

preparation of C berberine sulfate