CN111138428B - Preparation method of African tetrandrine and African tetrandrine - Google Patents

Preparation method of African tetrandrine and African tetrandrine Download PDF

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CN111138428B
CN111138428B CN201911367362.3A CN201911367362A CN111138428B CN 111138428 B CN111138428 B CN 111138428B CN 201911367362 A CN201911367362 A CN 201911367362A CN 111138428 B CN111138428 B CN 111138428B
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african tetrandrine
tetrandrine
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african
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CN111138428A (en
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吴正治
陶成
陈健
曾永长
刘洁人
李利民
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Wu Zhengzhi
Shenzhen Jintai Pharmaceutical Technology LP
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Shenzhen Institute of Gerontology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • 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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  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention discloses a preparation method of African tetrandrine and the African tetrandrine. The preparation method comprises the following steps: taking berberine hydrochloride, adding dimethylbenzene and trichloroacetic acid into the berberine hydrochloride, and reacting for a predetermined time at a first predetermined temperature to form a first reactant; adding water into the first reactant, standing for crystallization, converting into hydrochloride through strong base type anion exchange resin, and concentrating to obtain demethyleneberberine; taking out methylene berberine, and adding acetonitrile and potassium carbonate into the methylene berberine to form a mixture; dropwise adding methyl p-toluenesulfonate into the mixture at a second preset temperature, and cooling the mixture to room temperature after the raw materials are completely consumed to form a second reactant; and (3) concentrating the second reactant, adding potassium hydroxide into the concentrated solution, filtering to obtain a filtrate, adding hydrochloric acid into the filtrate until no precipitate is generated, recrystallizing by using methanol, and finally converting by using strong base type anion exchange resin to prepare the African tetrandrine.

Description

Preparation method of African tetrandrine and African tetrandrine
Technical Field
The invention relates to the technical field of material preparation, in particular to a preparation method of African tetrandrine, and the invention also relates to the African tetrandrine.
Background
The African tetrandrine belongs to berberine alkaloids, and has attracted more extensive attention and research since the self-separation. The research shows that the African tetrandrine has the effect of inhibiting the proliferation of metastatic osteosarcoma U-2OS cells and the formation of new vessels. In addition, the inventor of the invention found that the african tetrandrine has significant inhibitory activity (IC) to acetylcholinesterase through research in 201850Up to 0.01 μ g/mL), galantamine has a very high development value due to its availability as a marketing drug approved by the FDA.
However, because the content of the african tetrandrine in nature is relatively low and the existing separation and purification process is difficult, the large-scale synthesis and preparation are difficult, which also limits the research on the important natural products to a great extent.
In 1966, the synthesis of african tetrandrine was first completed by professor Cava. However, the overall yield of the synthesis is very low, and is only about 9% according to statistics. In addition, highly toxic agents such as dimethyl sulfate are used in the synthesis process, so that the method is not suitable for industrial mass production. In the subsequent studies for half a century, the synthesis process of african tetrandrine has not been a significant breakthrough. The chemical synthesis difficulty of the African tetrandrine is very high, and the reason for the chemical synthesis difficulty is that: on the one hand, the whole reaction condition is difficult to control and the yield is low for the conversion of berberine into demethyleneberberine. For the optimization of the transformation, the method reported by the Jinweiping (preparation method of palmatine CN100999622B) requires the use of a large amount of concentrated hydrochloric acid, has severe reaction conditions and poor controllability, and is not suitable for industrial production. On the other hand, for the conversion of demethyleneberberine to african tetrandrine, selective methylation needs to be realized, and the yield is low due to poor reaction selectivity. Jianjiadong (Berberberine analytes a Novel Class of the Low-sensitivity-Lipoprotein Receptor Up-Regulators: Synthesis, Structure-Activity Relationships, and Cholesterol-Power efficiency J.Med.Chem.2009, 52, 492-501) reported that selective methylation can be achieved by using methyl iodide, but because methyl iodide belongs to a highly toxic substance and is extremely volatile (the boiling point is 42 ℃), the methyl iodide is easy to explode, and the conversion cannot be applied to mass preparation and industrial production.
Because the synthesis of the African tetrandrine has not been good breakthrough all the time, the African tetrandrine sold in the market at present is mainly separated. Due to the high cost of synthesis, the market price of the african tetrandrine is very high, which limits the application of the african tetrandrine to a great extent.
Disclosure of Invention
The invention aims to provide a preparation method of African tetrandrine and a new technical scheme of the African tetrandrine, and solves the problem that the synthesis of the existing African tetrandrine is difficult.
According to a first aspect of the invention, a method for preparing african tetrandrine is provided. The preparation method comprises the following steps:
taking berberine hydrochloride, adding dimethylbenzene and trichloroacetic acid into the berberine hydrochloride, and reacting for a predetermined time at a first predetermined temperature to form a first reactant; adding water into the first reactant until no precipitate is generated, standing for crystallization, converting into hydrochloride through strong base type anion exchange resin, and concentrating to obtain demethyleneberberine;
taking out methylene berberine, and adding acetonitrile and potassium carbonate into the methylene berberine to form a mixture; dropwise adding methyl p-toluenesulfonate into the mixture at a second preset temperature, and cooling the mixture to room temperature after the raw materials are completely consumed to form a second reactant; and (3) concentrating the second reactant, adding potassium hydroxide into the concentrated solution, filtering to obtain a filtrate, adding hydrochloric acid into the filtrate until no precipitate is generated, recrystallizing by using methanol, and finally converting by using strong base type anion exchange resin to prepare the african alkaloid.
Optionally, the first predetermined temperature is room temperature.
Optionally, the predetermined time is 2.5h to 4.5 h.
Optionally, the molar ratio between the berberine hydrochloride, the xylene and the trichloroacetic acid is 0.6: 0.9: 0.7.
optionally, the second predetermined temperature is 55 ℃ to 65 ℃.
Optionally, the molar ratio between the demethyleneberberine, the acetonitrile, the potassium carbonate, the methyl p-toluenesulfonate, and the potassium hydroxide is 1: 2.3: 1: 1.1: 41.2.
optionally, in the process of dropwise adding methyl p-toluenesulfonate into the mixture, the dropwise adding of methyl p-toluenesulfonate is controlled to be finished within 5.5h to 6.5 h.
Optionally, the concentration of the hydrochloric acid is 0.5mol/L to 1.5 mol/L.
Optionally, a thin layer chromatograph is used to determine that the material is completely consumed.
According to a second aspect of the present invention there is provided a african tetrandrine. The African tetrandrine is prepared according to the preparation method of the African tetrandrine.
The preparation method of the African tetrandrine provided by the embodiment of the invention has the characteristics of short process route and high efficiency. In the preparation method, the preparation conditions are mild, the toxicity of the adopted raw materials is very low, and the price of the raw materials is also low, so that the production cost can be effectively reduced, the price of the African tetrandrine can be further reduced, and the application of the African tetrandrine can be expanded. In addition, the preparation method has the characteristic of high yield, and is very suitable for industrial mass production.
Other features of the present invention and its advantages will become apparent from the following detailed description of exemplary embodiments of the invention.
Detailed Description
Various exemplary embodiments of the present invention will now be described in detail. It should be noted that: the relative arrangement of the components and steps, the numerical expressions and numerical values set forth in these embodiments do not limit the scope of the present invention unless specifically stated otherwise.
The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses.
Techniques, methods, and apparatus known to those of ordinary skill in the relevant art may not be discussed in detail but are intended to be part of the specification where appropriate.
In all examples shown and discussed herein, any particular value should be construed as merely illustrative, and not limiting. Thus, other examples of the exemplary embodiments may have different values.
According to an embodiment of the invention, a preparation method of african tetrandrine is provided. The preparation method can be used for synthesizing the African tetrandrine, and effectively solves the problems of various defects in the existing synthesis process of the African tetrandrine. The preparation method provided by the invention can reduce the chemical synthesis difficulty and synthesis cost of the African tetrandrine. The preparation method provided by the invention is very suitable for industrial mass production of the African tetrandrine, and further the use of the African tetrandrine is enlarged.
The preparation method of the African tetrandrine provided by the embodiment of the invention at least comprises the following steps:
step S1, taking a proper amount of berberine hydrochloride, adding xylene and trichloroacetic acid into the berberine hydrochloride, and reacting for a predetermined time at a first predetermined temperature to form a first reactant; adding appropriate amount of water into the first reactant until no precipitate is generated, standing for crystallization, and passing through strong base type anion exchange resin (Cl)-Type) converting the crystallization product into hydrochloride, and concentrating to obtain the demethyleneberberine.
Step S2, taking a proper amount of demethyleneberberine, adding acetonitrile and potassium carbonate into the demethyleneberberine to form a mixture, dropwise adding methyl p-toluenesulfonate into the mixture at a second preset temperature, and cooling the mixture to room temperature after the raw materials are completely consumed to form a second reactant; concentrating the second reactant, adding potassium hydroxide into the concentrated solution, filtering to obtain filtrate, adding hydrochloric acid into the filtrate until no precipitate is generated, recrystallizing with methanol, and passing through strong base type anion exchange resin (Cl)-Type) is converted to the recrystallization product, and the African tetrandrine is finally prepared.
The preparation method of the African tetrandrine provided by the embodiment of the invention is specially designed for the characteristics of the African tetrandrine, the synthesis process route is simple and short and efficient, and the problem of large-scale synthesis and preparation of the African tetrandrine for half a century is solved. Particularly, compared with the prior preparation method, the preparation method provided by the invention has the advantages that the preparation conditions are milder, the toxicity of the adopted raw materials is very low, the price of the raw materials is low, and the production cost can be effectively reduced. In addition, the preparation method provided by the invention has the characteristic of high yield, and the yield can reach 60% or even higher according to statistics. This yield is significantly higher than in the prior art. The preparation method is very suitable for industrial mass production of the African tetrandrine.
In step S1 of the present invention, the first predetermined temperature is controlled to be room temperature, typically around 25 ℃. The preset time is controlled to be 2.5-4.5 h. And more preferably, the predetermined time is designed to be 3 h. At this predetermined time, the yield was the best, with less by-product and the highest purity of the product obtained.
In step S1 of the present invention, the ratio of the amounts of the raw materials should be reasonably controlled. Namely, the dosage ratio of berberine hydrochloride, xylene and trichloroacetic acid used in the preparation should be reasonably controlled. In one example of the present invention, the molar ratio between the berberine hydrochloride, the xylene and the trichloroacetic acid is 0.6: 0.9: 0.7. the ratio of the raw materials used may be appropriately adjusted by those skilled in the art according to the particular needs. The dosage ratio of the raw materials provided by the invention is preferable, and under the dosage ratio, the yield of the demethyleneberberine is improved, the generated by-products are less, and the purity of the obtained demethyleneberberine is highest.
In step S1 of the present invention, berberine hydrochloride, xylene and trichloroacetic acid are reacted to form a first reactant, and after the first reactant is formed, an appropriate amount of water is added to the first reactant. The added water may be deionized water, for example. And the purpose of adding water is: in order to better generate a precipitate. And when no more precipitate is produced, the addition of water is stopped. Standing for crystallizing, and separating with strong base type anion exchange resin (Cl)-Type) the product after standing crystallization is converted into hydrochloride. Finally, the demethyleneberberine is obtained by concentration treatment. Wherein, the yield of the prepared demethyleneberberine can reach 90 percent. The yield is much higher than that of the demethyleneberberine in the prior art. It can be seen thatThe method provided by the invention can obviously improve the yield of the demethyleneberberine.
The following are the nuclear magnetic spectrum, mass spectrum, hplc data of demethyleneberberine prepared according to step S1 of the present invention, as follows:
Rf＝0.4(DCM/MeOH，10：1)；mp：220-222℃；1H NMR(400MHz， DMSO-d6)δ10.04(s，1H，OH-2)，9.81(s，1H，H-8)，9.26(s，1H，OH-3)， 8.74(s，1H，H-13)，8.16(d，J＝9.1Hz，1H，H-11)，8.04(d，J＝9.1Hz， 1H，H-12)，7.50(s，1H，H-1)6.80(s，1H，H-4)，4.88(t，J＝6.3Hz， 2H，H-6)，4.08(s，3H，OCH3-10)，4.05(s，3H，OCH3-9)，3.11(t，J＝6.3 Hz，H，H-5)；13C NMR(100MHz，DMSO)δ150.0(C-10)，149.2(C-12)， 145.6(C-9)，145.1(C-3)，143.5(C-8)，138.3(C-13a)，133.3(C-12a)， 127.2(C-4a)，126.7(C-12)，123.5(C-11)，121.2(C-13b)，119.1(C-8a)， 117.8(C-13)，114.9(C-4)，112.7(C-1)，61.9(OCH3-10)57.1(C-6)，55.6 (OCH3-9)，25.8(C-5)；HRMS(ESI)：m/z calcd for C19H18NO4Cl[M-Cl]+: 324.1230, found: 324.1239. purity: 98.4 percent.
From the above data, it can be seen that the demethyleneberberine prepared by the present invention is indeed demethyleneberberine, and has high purity.
In addition, it can be seen from step S1 of the present invention that the overall reaction conditions are easier to control and the final yield is higher for the conversion of berberine hydrochloride to demethyleneberberine.
In step S2 of the present invention, the molar ratio between the demethyleneberberine, the acetonitrile, the potassium carbonate, the methyl p-toluenesulfonate, and the potassium hydroxide is 1: 2.3: 1: 1.1: 41.2. The ratio of the raw materials used may be appropriately adjusted by those skilled in the art according to the particular needs. The dosage ratio of the raw materials provided by the invention is more preferable, mainly aiming at improving the yield and obtaining higher-purity African tetrandrine.
In step S2 of the present invention, the second predetermined temperature may be controlled to be 55 to 65 ℃. In the present invention, it is preferable that the second predetermined temperature is set to 60 ℃. Under the temperature condition, the method is favorable for improving the yield of the final product of the African tetrandrine, and the obtained African tetrandrine has few by-products and higher purity.
In step S2 of the present invention, when methyl p-toluenesulfonate is added to a mixture of demethyleneberberine, acetonitrile and potassium carbonate, methyl p-toluenesulfonate may be added dropwise, for example. It should be noted that, when methyl p-toluenesulfonate is added dropwise to the mixture, the dropping speed should not be too fast, and should be controlled to be slow, so as to facilitate the reaction between the raw materials.
In an alternative embodiment of the invention, methyl p-toluenesulfonate is slowly added dropwise to the mix using an autosampler. Wherein, the dropping speed needs to be reasonably controlled, so that the dropping of the methyl p-toluenesulfonate is finished within 5.5 to 6.5 hours. More preferably, the dropping speed of the methyl p-toluenesulfonate is controlled so that the dropping of the methyl p-toluenesulfonate is completed within 6 hours, which enables a more sufficient reaction between the raw materials to consume the raw materials.
After the methyl p-toluenesulfonate is added dropwise into the mixture (formed by demethyleneberberine, acetonitrile and potassium carbonate), whether the raw materials are completely reacted and consumed needs to be further determined. During this process, the reaction can be checked, for example, using a thin layer chromatograph to confirm complete consumption of the starting material. And after the raw materials are completely consumed, the subsequent steps are carried out.
In step S2 of the present invention, an appropriate amount of hydrochloric acid is also added. The concentration of the hydrochloric acid may be, for example, 0.5 to 1.5 mol/L. Hydrochloric acid can be used for: the whole system is adjusted to be acidic, so that a product is precipitated. And more preferably, the concentration of the hydrochloric acid is 1 mol/L.
It should be noted that, besides hydrochloric acid, other acids, such as sulfuric acid, nitric acid, etc., can be used in the present invention, and those skilled in the art can flexibly select them according to the actual situation, and the present invention is not limited thereto.
The preparation method provided by the invention can prepare the high-purity African tetrandrine through two simple steps. Moreover, the yield of the prepared african tetrandrine can reach 60 percent, and even higher possibility exists. Compared with the prior art in which the yield is only 9%, the preparation method of the invention actually improves the chemical synthesis yield of the African tetrandrine and is beneficial to the popularization and application of the African tetrandrine.
The nuclear magnetic spectrum, mass spectrum and hplc data of the african tetrandrine prepared by the invention are as follows:
Rf＝0.6(DCM/MeOH，10：1)；mp：210-212℃；1H NMR(400MHz， DMSO-d6)δ9.88(s，1H，H-8)，9.48(s，1H，H-13)，8.81(s，1H，OH-2)， 8.19(d，J＝9.1Hz，1H，H-12)，8.07(d，J＝9.1Hz，1H，H-11)，7.58(s， 1H，H-1)，7.06(s，1H，H-4)，4.94(t，J＝6.1Hz，2H，H-6)，4.10(s， 3H，OCH3-10)，4.07(s，3H，OCH3-9)，3.89(s，3H，OCH3-3)，3.20(t， J＝6.1Hz，2H，H-5)；13C NMR(100MHz，DMSO)δ150.6(C-2)，150.2 (C-3)，146.4(C-9)，145.3(C-10)，143.5(C-8)137.8(C-4a)，133.1(C-8a)， 127.0(C-12)，126.7(C-11)，123.5(C-12a)，121.3(C-13a)，119.5(C-13)， 119.1(C-13b)，112.2(C-4)，111.4(C-1)，61.9(OCH3-10)，57.1(OCH3-9)， 55.9(OCH3-3)，55.5(C-6)，26.0(C-5)；HRMS(ESI)：m/z calcd for C20H20NO4Cl [M-Cl]+：338.1387，found：338.1377.
from the above data it can be seen that: the substance finally prepared by the invention is really the African tetrandrine.
The method for preparing African tetrandrine of the present invention is described in detail by the following specific examples.
Example 1
Step S1, taking 0.6mol berberine hydrochloride (about 200g), adding 0.9mol xylene (about 100mL) and 0.7mol trichloroacetic acid (about 70mL) into the berberine hydrochloride, and reacting at room temperature for 4h to form a first reactant;
adding appropriate amount of water into the first reactant until no precipitate is generated, standing for crystallization, and passing through strong base type anion exchange resin (Cl)-Type) converting the crystallization product into hydrochloride, and obtaining the demethyleneberberine after concentration treatment. Wherein, the prepared demethyleneberberine is about 175g, and the yield can reach 90%.
Step S2, after step S1 is completed, weighing 27.9mmol of demethyleneberberine (about 10g), adding 64.1mmol of acetonitrile (about 500mL) and 27.9mmol of potassium carbonate (about 3.84g) into the demethyleneberberine to form a mixed material, and dropwise adding 30.7mmol of methyl p-toluenesulfonate (about 4.6mL) into the mixed material at a second preset temperature, wherein the dropwise adding of the methyl p-toluenesulfonate is controlled within 6h, and after the raw material is completely consumed, the mixed material is cooled to room temperature to form a second reactant;
concentrating the second reactant, adding 1149.5mol potassium hydroxide (about 100mL) to the concentrated solution, filtering to obtain filtrate, adding hydrochloric acid (1 mol/L) to the filtrate until no precipitate is formed, recrystallizing with methanol, and passing through strong base anion exchange resin (Cl)-Type) is converted to the recrystallized product, and finally the African tetrandrine is prepared. Wherein the obtained African tetrandrine is about 6.2 g. The yield of the African tetrandrine can reach 60%.
For the above steps S1 and S2, reference may be made to the following formula (1):
Figure RE-GDA0002430736120000081
in table 1 below, the preparation method of african tetrandrine provided by the present invention is compared with the existing synthesis method of african tetrandrine (here, the method of the professor Cava is taken as an example).
TABLE 1 comparison of the Synthesis methods of African tetrandrine
Figure RE-GDA0002430736120000082
Figure RE-GDA0002430736120000091
As can be seen from Table 1, compared with the prior art, the preparation method of African tetrandrine provided by the invention has the characteristics of shorter synthetic process route, high efficiency and high yield, and the preparation conditions are very mild. The raw materials adopted by the method have very low toxicity and low price, and can effectively reduce the synthesis cost, thereby reducing the market selling price of the African tetrandrine and being very beneficial to the popularization of the African tetrandrine.
On the other hand, the embodiment of the invention also provides the African tetrandrine, and the African tetrandrine is prepared according to the preparation method of the African tetrandrine. The African tetrandrine has the characteristics of high purity and relatively low price.
The African tetrandrine provided by the invention can be applied to treatment of senile dementia, Parkinson's disease and other diseases, and has a high treatment effect.
Although some specific embodiments of the present invention have been described in detail by way of examples, it should be understood by those skilled in the art that the above examples are for illustrative purposes only and are not intended to limit the scope of the present invention. It will be appreciated by those skilled in the art that modifications may be made to the above embodiments without departing from the scope and spirit of the invention. The scope of the invention is defined by the appended claims.

Claims (9)

1. A preparation method of African tetrandrine is characterized by comprising the following steps: the preparation method comprises the following steps:
taking berberine hydrochloride, adding dimethylbenzene and trichloroacetic acid into the berberine hydrochloride, and reacting for a predetermined time at a first predetermined temperature to form a first reactant; adding water into the first reactant until no precipitate is generated, standing for crystallization, converting into hydrochloride through strong base type anion exchange resin, and concentrating to obtain demethyleneberberine;
taking out methylene berberine, and adding acetonitrile and potassium carbonate into the methylene berberine to form a mixture; dropwise adding methyl p-toluenesulfonate into the mixture at a second preset temperature, and cooling the mixture to room temperature after the raw materials are completely consumed to form a second reactant; and (3) concentrating the second reactant, adding potassium hydroxide into the concentrated solution, filtering to obtain a filtrate, adding hydrochloric acid into the filtrate until no precipitate is generated, recrystallizing by using methanol, and finally converting by using strong base type anion exchange resin to prepare the african alkaloid.
2. The method of preparing african tetrandrine according to claim 1, wherein: the first predetermined temperature is room temperature.
3. The method of preparing african tetrandrine according to claim 1, wherein: the preset time is 2.5-4.5 h.
4. The method of preparing african tetrandrine according to claim 1, wherein: the molar ratio of the berberine hydrochloride to the xylene to the trichloroacetic acid is 0.6: 0.9: 0.7.
5. the method of preparing african tetrandrine according to claim 1, wherein: the second predetermined temperature is 55-65 ℃.
6. The method of preparing african tetrandrine according to claim 1, wherein: the molar ratio of the demethyleneberberine to the acetonitrile to the potassium carbonate to the methyl p-toluenesulfonate to the potassium hydroxide is 1: 2.3: 1: 1.1: 41.2.
7. the method of preparing african tetrandrine according to claim 1, wherein: and in the process of dropwise adding the methyl p-toluenesulfonate into the mixture, controlling the methyl p-toluenesulfonate to be completely dropwise added within 5.5 to 6.5 hours.
8. The method of preparing african tetrandrine according to claim 1, wherein: the concentration of the hydrochloric acid is 0.5 mol/L-1.5 mol/L.
9. The method of preparing african tetrandrine according to claim 1, wherein: and detecting by using a thin layer chromatograph to determine that the raw materials are completely consumed.
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WO2014075309A1 (en) * 2012-11-19 2014-05-22 中国科学院大连化学物理研究所 Use and preparation method of berberine compounds

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CN103816152B (en) * 2012-11-19 2016-08-10 中国科学院大连化学物理研究所 The Use and preparation method of spectrum of berberine compounds

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WO2014075309A1 (en) * 2012-11-19 2014-05-22 中国科学院大连化学物理研究所 Use and preparation method of berberine compounds

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