CN111205285A - Purification method and crystal form of berberine or berberine salt - Google Patents
Purification method and crystal form of berberine or berberine salt Download PDFInfo
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- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
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Abstract
The invention discloses a method for purifying berberine or berberine salt, which comprises the following steps: converting raw materials mainly containing berberine or berberine salt I into acetone adduct of berberine, and converting acetone adduct of berberine into berberine salt II to obtain berberine salt II or berberine. The invention also discloses a crystal form of the acetone adduct of berberine. By adopting the purification method, the raw material containing the berberine or the berberine salt is converted into the berberine acetone adduct, and then the berberine acetone adduct is converted into the final product berberine or the berberine salt, so that the high-purity berberine or the berberine salt can be obtained, the total impurity content is lower than 0.2%, the single impurity content is lower than 0.1%, and the safety of the medicine is ensured.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a purification method and a crystal form of berberine or a salt thereof.
Background
Berberine is an important alkaloid and is a Chinese medicament which is used for a long time in China. Can be extracted from Coptidis rhizoma, cortex Phellodendri, and radix Berberidis. It has obvious bacteriostasis. The berberine hydrochloride is also called berberine hydrochloride, and has a chemical structure shown in formula I, and can also exist in the form of sulfate. The berberine can inhibit pathogenic microorganism, and has inhibitory effect on various bacteria such as Bacillus dysenteriae, Bacillus tuberculosis, pneumococcus, Salmonella typhi and Corynebacterium diphtheriae, wherein the berberine has strongest effect on Bacillus dysenteriae, and can be used for treating digestive tract diseases such as bacterial gastroenteritis and dysentery. The traditional Chinese medicine composition is mainly used for treating bacillary dysentery and gastroenteritis in clinic, and has small side effect.
The structural formula of the berberine hydrochloride is shown as a formula I:
the pharmaceutical impurities are closely related to the quality, safety and efficacy of the medicine, and the importance of impurity control in the development and research of the medicine is more and more emphasized. The prior solvent recrystallization method of berberine hydrochloride has the defects that: 1) low efficiency and multiple recrystallization. 2) Poor reproducibility, strongly correlated with the source and purity of the starting material. 3) The success rate is low, and the crude product containing various impurities can not reach the standard in many times.
The current Chinese pharmacopoeia has a total impurity requirement of less than 4% for berberine hydrochloride. In the process of evaluating the consistency of the medicine, the structure of impurities more than 0.1 percent needs to be identified, and corresponding toxicological studies are carried out to determine the safety influence of the impurities on human bodies. In order to improve the safety of the medicine and reduce the cost of the medicine, the method is an ideal method for directly preparing the product with the single impurity content of less than 0.1 percent, however, no purification method or preparation method capable of preparing the product with the single impurity content of less than 0.1 percent is reported at home and abroad at present.
Disclosure of Invention
The invention provides a method for synthesizing high-quality berberine, berberine hydrochloride and other salts.
A method for purifying berberine or a salt thereof, comprising: converting raw materials mainly comprising berberine or berberine salt I into acetone adduct of berberine, and converting the acetone adduct of berberine into berberine salt II to obtain berberine salt II; or further processing to obtain berberine.
The invention uses berberine hydrochloride or berberine sulfate or other crude or purer salt as initial material, to convert them into acetone adduct, and then convert the acetone adduct into berberine hydrochloride or berberine sulfate or other salt, or further obtain berberine product. Almost all impurities of raw materials of which the main components are berberine or berberine salt I are removed through a salt-acetone adduct-salt conversion process.
A method for purifying berberine or a salt thereof, comprising the steps of:
(1) adding a raw material of which the main component contains berberine salt I (including the condition that the main component is the berberine salt I or the main component is the berberine and the berberine salt I) into a solvent A, and adding alkali to dissociate the berberine salt I;
(2) adding acetone, crystallizing, and performing solid-liquid separation to obtain berberine acetone adduct;
(3) reacting the berberine acetone adduct with the acid solution corresponding to the salt II, crystallizing to obtain berberine salt II, and optionally dissociating to obtain berberine.
Alternatively, a method for purifying berberine or a salt thereof, comprising the steps of:
(1) adding raw materials of which the main components are berberine into a solvent A;
(2) adding acetone, crystallizing, and performing solid-liquid separation to obtain berberine acetone adduct;
(3) reacting the berberine acetone adduct with the acid solution corresponding to the salt II, crystallizing to obtain berberine salt II, and optionally dissociating to obtain berberine.
Alternatively, a method for purifying berberine or a salt thereof, comprising the steps of:
(1) mixing raw materials mainly comprising berberine with acetone, crystallizing, and performing solid-liquid separation to obtain berberine acetone adduct;
(2) reacting the berberine acetone adduct with the acid solution corresponding to the salt II, crystallizing to obtain berberine salt II, and optionally dissociating to obtain berberine.
The structure of the berberine acetone adduct is as follows:
step (1) may be performed at room temperature. Alternatively, heating may be carried out to dissolve the raw material mainly containing berberine salt I in the solvent A, and the heating temperature may be 10-100 deg.C. Then, a base is added to the reaction solution for dissociation.
In the step (1), the alkali can be selected from various common organic bases or inorganic bases, for example, the common selectable alkali includes one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like. The adding amount of the alkali is based on berberine salt I capable of being neutralized, and the mol ratio of the alkali to the berberine salt I is (1-10): 1, more preferably (1-5): 1, more preferably (1-2): 1.
in the step (1), the mass-to-volume ratio of the berberine salt I to the solvent A is 5-100 (g/L), and more preferably 10-40 (g/L).
The acid solution corresponding to the salt II is an aqueous solution of the acid corresponding to the salt II.
In the step (1), after neutralization by adding a base, filtration may be optionally carried out as required, but the filtration step itself is not essential.
After the neutralization in the step (1) is finished, directly entering the step (2) without any post-treatment;
in the step (2), the molar amount of the acetone added is (1-100) times, more preferably (1-80) times, and still more preferably (1-50) times of the molar amount of the berberine salt I.
In the current processes reported at home and abroad, the obtained berberine or berberine salt product or crude product contains impurities which are difficult to remove, and most or almost all of the impurities can not react with acetone. The invention removes almost all impurities by reacting raw materials with berberine as the main component or crude product obtained by dissociating berberine salt I with acetone to obtain acetone adduct. After the reaction is finished, the acetone adduct obtained by the invention is separated out, impurities are kept in the solution, and the impurities and the acetone adduct obtained by the invention can be easily separated.
In the step (2), acetone may be added dropwise, as an option.
Optionally, the crystallization temperature in the step (2) is 0-30 ℃, and more preferably 0-20 ℃; the crystallization time is 1 to 10 hours, and more preferably 1 to 5 hours.
In the step (2), the solid-liquid separation can be realized by filtration, or centrifugal separation, or can be realized by other known methods.
After the reaction in the step (2) is finished and solid-liquid separation is carried out, the solid can be directly processed in the step (3) without any other post-treatment.
In the step (3), the reaction solvent may be water. In the step (3), the adding amount of water is calculated according to the mass of the berberine salt I in the step (1), and the volume of the water required to be added in the step (3) is 10-100 mL per 1g of the berberine salt I. Of course, the reaction can also be carried out directly in an alcoholic or aqueous acid solution.
In the step (3), the acid corresponding to the salt II can be hydrochloric acid, sulfuric acid, acetic acid, citric acid, succinic acid, capric acid, saccharin, acesulfame potassium or tannic acid, etc. Preferably, the acid corresponding to the salt II can be hydrochloric acid or sulfuric acid. Preferably, the acid corresponding to the salt II is 0.1-5N hydrochloric acid; the addition amount of HCl is 2-200 times of the molar amount of berberine converted in the starting materials. More preferably 10 to 100 times.
The crystallization temperature in the step (3) is 0-30 ℃, and the crystallization time is 1-10 h.
In the present invention, stirring operations such as magnetic stirring and mechanical stirring may be added as necessary, or microwaves and the like may be used to assist the reaction.
Preferably, the berberine salt I or the berberine salt II are respectively and independently selected from one or more of berberine hydrochloride, berberine sulfate, berberine hydrogen sulfate, berberine acetate, berberine citrate, berberine succinate, berberine caprate, berberine saccharinate, berberine acesulfame and berberine tannate.
Preferably, the berberine salt I or the berberine salt II is respectively and independently selected from one or more of berberine hydrochloride and berberine sulfate.
Preferably, the solvent A is selected from water or alcohol solvent, wherein the alcohol solvent comprises one or more of methanol, ethanol, isopropanol, tert-butanol and n-butanol.
Further preferably, the solvent a is selected from water or methanol. In this case, as a further preference, the berberine salt I or the berberine salt II is independently selected from one or more of berberine hydrochloride and berberine sulfate.
Preferably, the berberine salt I is berberine hydrochloride or berberine sulfate; the berberine salt II is berberine hydrochloride.
Preferably, the berberine salt I is berberine hydrochloride; the berberine salt II is berberine hydrochloride, and the reaction route is as follows:
a method for purifying berberine hydrochloride (or berberine hydrochloride) comprises the following steps:
(a) adding initial raw materials of berberine hydrochloride or berberine sulfate into a reaction bottle by using water or alcohol as a solvent, and slowly heating to a certain range for dissolving;
(b) adding sodium hydroxide aqueous solution into the dissolved solution (or suspension), stirring for a period of time, adding a certain amount of acetone, after crystals are separated out, continuing to crystallize and stir for a period of time, and filtering to obtain acetone adduct;
(c) suspending the acetone adduct in water, adding hydrochloric acid aqueous solution with certain concentration dropwise, separating out yellow crystal, stirring for a while, filtering, and oven drying to obtain berberine hydrochloride.
In the step (a), the temperature rise range is 50-100 ℃. Of course, step (a) may also be carried out at room temperature, depending on the solvent chosen.
In the step (b), the concentration of the sodium hydroxide is 0.1N to 6N.
In the step (b), the structural formula of the obtained acetone adduct crystal single crystal is shown in figure 1.
In the step (c), the hydrochloric acid is 0.1-5N hydrochloric acid; the addition amount of HCl is 2-200 times of the molar amount of berberine in the starting raw materials. More preferably 2 to 100 times.
A berberine acetone adduct crystal form is provided, and characteristic peaks exist at positions of 7.97 degrees +/-0.2 degrees, 10.16 degrees +/-0.2 degrees, 16.08 degrees +/-0.2 degrees, 17.47 degrees +/-0.2 degrees, 19.59 degrees +/-0.2 degrees, 20.69 degrees +/-0.2 degrees, 22.52 degrees +/-0.2 degrees and 24.85 degrees +/-0.2 degrees in an X-ray powder diffraction pattern expressed by a 2 theta angle.
A berberine acetone adduct crystal form is obtained, and has characteristic peaks at 7.96 degrees +/-0.2 degrees, 10.16 degrees +/-0.2 degrees, 12.76 degrees +/-0.2 degrees, 13.35 degrees +/-0.2 degrees, 14.99 degrees +/-0.2 degrees, 15.57 degrees +/-0.2 degrees, 15.83 degrees +/-0.2 degrees, 16.08 degrees +/-0.2 degrees, 17.47 degrees +/-0.2 degrees, 19.59 degrees +/-0.2 degrees, 20.30 degrees +/-0.2 degrees, 20.69 degrees +/-0.2 degrees, 22.52 degrees +/-0.2 degrees, 23.78 degrees +/-0.2 degrees and 24.85 degrees +/-0.2 degrees in an X-ray powder diffraction pattern expressed by a 2 theta angle.
A crystal form of berberine acetone adduct is provided, and the obtained X-ray powder diffraction pattern expressed by 2 theta angle is shown in figure 2.
A preparation method of a crystal form of a berberine acetone adduct comprises the following steps:
(1) adding a raw material mainly containing berberine salt I into a solvent A, and adding alkali to free berberine in the solvent A;
(2) adding acetone, crystallizing, and performing solid-liquid separation to obtain berberine acetone adduct;
preferably, the berberine salt I is selected from one or more of berberine hydrochloride, berberine sulfate, berberine hydrogen sulfate, berberine acetate, berberine citrate, berberine succinate, berberine caprate, berberine saccharinate, berberine acesulfame and berberine tannate.
Preferably, the berberine salt I is selected from one or more of berberine hydrochloride and berberine sulfate.
Preferably, the solvent A is selected from water or alcohol solvent, wherein the alcohol solvent comprises one or more of methanol, ethanol, isopropanol, tert-butanol and n-butanol.
Further preferably, the solvent a is selected from water or methanol. In this case, as a further preference, the berberine salt I or the berberine salt II is independently selected from one or more of berberine hydrochloride and berberine sulfate.
In the step (1), the alkali can be selected from various common organic bases or inorganic bases, for example, the common selectable alkali includes one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like. The adding amount of the alkali is based on berberine salt I capable of being neutralized, and the mol ratio of the alkali to the berberine salt I is (1-10): 1, more preferably (1-5): 1, more preferably (1-2): 1.
in the step (1), after neutralization by adding a base, filtration may be optionally carried out as required, but the filtration step itself is not essential.
After the neutralization in the step (1) is finished, directly entering the step (2) without any post-treatment;
in the step (2), the molar amount of the acetone added is (1-100) times, more preferably (1-80) times, and still more preferably (1-50) times of the molar amount of the berberine salt I.
In the step (2), acetone may be added dropwise, as an option.
Optionally, the crystallization temperature in the step (2) is 0-30 ℃, and more preferably 0-20 ℃; the crystallization time is 1 to 10 hours, and more preferably 1 to 5 hours.
A preparation method of a crystal form of a berberine acetone adduct comprises the following steps:
dissolving berberine sulfate or berberine hydrochloride in water to obtain brown solution, and adding sodium hydroxide aqueous solution at room temperature; stirring at room temperature and adding acetone dropwise. And (3) after the light yellow crystals are separated out, continuously stirring for 1-3 hours, and filtering to obtain light yellow berberine acetone adduct crystals.
In the present invention, unless otherwise specified, the reaction is carried out at room temperature.
Compared with the prior art, the preparation method of berberine hydrochloride has the advantages of simple and convenient operation and mild reaction conditions, and can obtain high-purity berberine hydrochloride.
By adopting the purification method, the raw material containing the berberine or the berberine salt is converted into the berberine acetone adduct, and then the berberine acetone adduct is converted into the final product berberine or the berberine salt, so that the high-purity berberine or the berberine salt can be obtained, the total impurity content is lower than 0.2%, the single impurity content is lower than 0.1%, and the safety of the medicine is ensured.
Drawings
FIG. 1 is a single crystal structure of berberine acetone adduct crystal.
FIG. 2 is an XRD diffraction pattern of berberine acetone adduct crystal.
Fig. 3a and 3b are HPLC spectra corresponding to example 1.
Detailed Description
Example 1
38.3 g of berberine sulfate (0.10 mmol, 87% purity) was dissolved in 2.0 l of water to give a brown solution, and 0.10 l of 1N aqueous sodium hydroxide solution was added at room temperature. After stirring at room temperature, 0.01 l (small amount) of acetone was added dropwise. After light yellow crystals precipitated, stirring was continued for 2 hours, and filtration gave a pale yellow berberine acetone adduct. The single crystal structure of the acetone adduct obtained is shown in FIG. 1 (single crystal analysis using Bruker Apex diffractometer, available from Bruker AXS Inc)TM(Madison, Wisconsin). Diffraction data were collected at 23 ℃ using a Mo source). The XRD diffraction pattern of the acetone adduct obtained is shown in FIG. 2 (carried out using a Bruker D8 diffractometer, available from Bruker AXS IncTM(Madison, Wisconsin) under the following detection conditions: the sample (about 10 mg) is mounted on a single crystal silicon wafer holder (e.g., cloth)Ruksi zero background X-ray diffraction sample holder) and spread the sample into a thin layer with the aid of a microscope slide; the sample was rotated at 30 revolutions per minute (to improve counting statistics) and irradiated with X-rays generated by a copper long thin focusing tube operating at 40kV and 40mA and having a wavelength of 1.5406 angstroms (i.e., about 1.54 angstroms). In the theta illumination mode, the exposure is for 1 second every 0.02, 2. increment (continuous scan mode) in the range of 20 under 5 to 40. The run time of D8 was 15 min. ).
Peak data are shown in the following table:
TABLE 1
Suspending berberine acetone adduct in 2.0L water, slowly adding 0.10L 1N hydrochloride aqueous solution dropwise at room temperature to precipitate yellow crystal, stirring for 2 hr, filtering, oven drying to obtain yellow berberine hydrochloride dihydrate crystal, and HPLC detection result is shown in figure 3a and figure 3b with yield of 90%.
The nuclear magnetic data of the berberine acetone adduct is as follows:
1H-NMR，DMSO，400MHZ，δ2.05[s,3H],2.31[dd,1H,J＝16Hz,4Hz],2.72-2.82[m,2H],2.93[dd,1H,J＝16Hz,4Hz],3.19-3.25[m,1H],3.28-3.32[m,1H],3.79[s,6H],5.22-5.25[t,1H,J＝6Hz],6.02[s,2H],6.03[s,1H],6.73[s,1H],6.75[s,1H],6.77[s,1H],7.27[s,1H]。
the nuclear magnetic data for berberine hydrochloride is as follows:
1H-NMR，CD3OD，400MHZ，δ3.28-3.31[m,2H],δ4.12[s,3H],δ4.23[s,3H],δ4.97-4.99[m,2H],δ6.14[s,2H]，δ6.98[s,1H]，δ7.62[s,1H]，δ8.0[d,1H,J＝12Hz]，δ8.11[d,1H,J＝8Hz],δ8.66[s,1H]，δ9.79[s,1H]。
example 2
32g berberine hydrochloride (90% pure) and 1280ml methanol, 428ml NaOH 0.2N was added dropwise starting at about 20 ℃ to give a brown clear liquid. After dropping, stirring for 10min, filtering, and dropping 172ml acetone into the filtrate. After the dripping is finished, cooling to 10-15 ℃, stirring for 2h, filtering, and drying at room temperature to obtain the berberine acetone complex, wherein XRD data are basically consistent with figure 2. The whole batch of wet product and 1600ml of water are put into a 2000ml bottle, and 160ml of 1mol/L hydrochloric acid is added dropwise. After dripping, the temperature is raised to 80-100 ℃ to obtain yellow liquid, and the temperature is kept for 10 min. After the temperature is preserved, the temperature is reduced to below 30 ℃ to obtain yellow needle-shaped or yellow fibrous solid, the berberine hydrochloride is filtered, rinsed with water and dried to obtain 27.2g of berberine hydrochloride, and the berberine hydrochloride is dried to obtain 27.2g of product with 85 percent of yield, 99.86 percent of purity and less than 0.1 percent of single impurity content.
Example 3
The same reaction was carried out using berberine acetate with a purity of 86% instead of "38.3 g berberine sulphate" in example 1, with the same molar mass, to finally obtain berberine hydrochloride with a yield of 85% with a purity of 99.85% and a single impurity content of less than 0.1%.
Example 4
The same reaction was carried out using berberine citrate with 90% purity instead of "38.3 g berberine sulphate" in example 1, with the same molar weight, to finally obtain berberine hydrochloride with 86% purity of 99.84% and single impurity content of less than 0.1%.
Example 5
The same reaction was carried out using berberine citrate with 90% purity instead of "2 g berberine hydrochloride" in example 2, with the same molar amount, to finally obtain berberine hydrochloride with 87% purity of 99.85% and less than 0.1% of single impurity content.
Example 6
The same reaction was carried out using berberine saccharinate with a purity of 90% instead of "38.3 g berberine sulphate" in example 1, with the same molar mass, to finally obtain berberine hydrochloride with a yield of 88% and a purity of 99.84%, with a single impurity content of less than 0.1%.
Example 7
The same reaction was carried out using berberine citrate with 96% purity in place of "38.3 g berberine sulphate" in example 1, in the same molar amount, and the molar ratio of acetone to berberine citrate was 50:1, resulting in a berberine hydrochloride yield of 89% with 99.84% purity and less than 0.1% single impurities.
Claims (10)
1. A method for purifying berberine or a salt thereof, comprising: converting raw materials mainly comprising berberine or/and berberine salt I into acetone adduct of berberine, and converting the acetone adduct of berberine into berberine salt II to obtain berberine salt II.
2. The method for purifying berberine or a salt thereof according to claim 1, comprising the steps of:
(1) adding the raw material containing berberine salt I in the main component into a solvent A, and adding alkali to free the berberine salt I;
(2) adding acetone, crystallizing, and performing solid-liquid separation to obtain berberine acetone adduct;
(3) reacting the berberine acetone adduct with the acid solution corresponding to the salt II, and crystallizing to obtain berberine salt II;
the step (1) can be replaced by the following steps:
(1) dissolving the raw material with the main component of berberine in a solvent A;
alternatively, the first and second electrodes may be,
the step (1) and the step (2) are replaced by:
mixing acetone with the raw material mainly containing berberine to obtain berberine acetone adduct.
3. The method for purifying berberine or a salt thereof according to claim 1 or 2, wherein the berberine salt I or the berberine salt II is independently selected from one or more of berberine hydrochloride, berberine sulfate, berberine hydrogen sulfate, berberine acetate, berberine citrate, berberine succinate, berberine caprate, berberine saccharinate, berberine acesulfame, and berberine tannate.
4. The method for purifying berberine or a salt thereof according to claim 3, wherein the berberine salt I or the berberine salt II is/are independently selected from one or two of berberine hydrochloride and berberine sulfate.
5. The method for purifying berberine or a salt thereof according to claim 2, wherein the solvent A is selected from water or an alcoholic solvent, wherein the alcoholic solvent comprises one or more of methanol, ethanol, isopropanol, tert-butanol, and n-butanol.
6. The method for purifying berberine or a salt thereof according to claim 5, wherein the solvent A is selected from water or methanol.
7. The method for purifying berberine or a salt thereof according to claim 2, wherein the crystallization temperature in the step (2) is 0-20 degrees and the crystallization time is 1-10 hours.
8. The method for purifying berberine or a salt thereof according to claim 2, wherein the crystallization temperature in the step (3) is 0-30 degrees and the crystallization time is 1-10 hours.
9. The method for purifying berberine or a salt thereof according to claim 1, wherein the berberine salt I is berberine hydrochloride, berberine sulphate; the berberine salt II is berberine hydrochloride.
10. A berberine acetone adduct crystal form is characterized in that characteristic peaks exist at positions of 7.97 degrees +/-0.2 degrees, 10.16 degrees +/-0.2 degrees, 16.08 degrees +/-0.2 degrees, 17.47 degrees +/-0.2 degrees, 19.59 degrees +/-0.2 degrees, 20.69 degrees +/-0.2 degrees, 22.52 degrees +/-0.2 degrees and 24.85 degrees +/-0.2 degrees in an X-ray powder diffraction pattern expressed by a 2 theta angle.
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| US11345697B1 (en) | 2020-12-10 | 2022-05-31 | Beiture LLC | Crystalline berberine ascorbate salt, methods of preparation and applications thereof |
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