Method for simultaneously preparing R-sinomenine and / or S-sinomenine

Abstract

The invention discloses a method for simultaneously preparing R-double sinomenine and / or S-double sinomenine, which comprises the following steps: mixing a sinomenine hydrochloride solution and a potassium ferricyanide solution, adding alkali and stirring to obtain a precipitate, washing the precipitate until the washing solution is neutral, adding a hydrochloric acid solution, stirring and reacting until the washing solution is acidic, slightly standing until the precipitate is separated out, and carrying out suction filtration to obtain the R-double sinomenine and / or S-double sinomenine. And finally, adding activated carbon into the solution, preserving heat, decolorizing, carrying out suction filtration, adding an alkali solution into the filtrate, precipitating to obtain R-sinomenine or a mixture of R-sinomenine and S-sinomenine, and adding acid to separate out and precipitate to obtain S-sinomenine. The invention provides a method for preparing a mixture of R-sinomenine and S-sinomenine or an R-, S-sinomenine monomer by regulating and controlling the proportion of the potassium ferricyanide solution, the reaction is controllable, and few byproducts are generated by synthesis.

Description

Technical Field

[0001] The present invention belongs to the technical field of compound preparation and separation, and in particular relates to a method for simultaneously preparing R-sinomenine and / or S-sinomenine. Background Art

[0002] Sinomenine hydrochloride is an alkaloid containing hydrochloride and is the main active substance extracted from Sinomenine. In 1929, GOTO K et al. discovered the bissinomenine molecule and inferred that there were two isomers, pointing out that their stereo configuration was limited rotation; Brossi et al. further found that steric hindrance and strong solvent effects led to the stereoisomerism of bissinomenine. Deng Zhangshuang et al. found that sinomenine can selectively synthesize stereoisomers of sinomenine dimers in KMnO4 aqueous solution by adjusting the pH value, and verified its structure using mass spectrometry, nuclear magnetic resonance analysis and X-ray diffraction. Li Jianxin et al. used sinomenine as the parent, and through biotransformation technology and chemical synthesis methods, generated bissinomenine derivatives through carbon-carbon connection at position 1. The bissinomenine product was obtained by adding manganese dioxide or potassium permanganate for oxidation reaction, extraction and drying, and column chromatography separation, but there is no method in the prior art that can simultaneously prepare R-bissinomenine and S-bissinomenine. Summary of the invention

[0003] In order to overcome the technical problems in the prior art, the present invention provides a method for simultaneously preparing R-sinomenine and S-sinomenine, by adding potassium ferrocyanide solution, R-sinomenine and S-sinomenine are simultaneously prepared, and a method for quickly preparing R-sinomenine or S-sinomenine monomers is provided.

[0004] In order to solve the above technical problems, the technical solutions proposed by the present invention are as follows:

[0005] The present invention provides a method for simultaneously preparing R-sinomenine and / or S-sinomenine, comprising the following steps:

[0006] S1, mixing the sinomenine hydrochloride solution with the potassium ferrocyanide solution, adding alkali and stirring to obtain a precipitate;

[0007] S2, washing the precipitate obtained in step S1 until the washing liquid is neutral, adding hydrochloric acid solution until it becomes acidic, leaving it for a while, and filtering it with suction;

[0008] S3, filtration to obtain a white solid, which is S-bisinomenine;

[0009] S4, the filtrate solution obtained in step S2 is added with activated carbon for heat preservation and decolorization according to the color of the solution, and then filtered, and the potassium ferrocyanide solution is different in proportion, and an alkali solution is added for precipitation to obtain a mixture of R-bisinomenine and S-bisinomenine, or R-bisinomenine monomer. .

[0010] In the present invention, sinomenine hydrochloride undergoes an oxidative polymerization reaction under the action of potassium ferricyanide. Under alkaline conditions, the sinomenine molecule loses a hydrogen ion and loses an electron under the oxidation of oxygen to obtain a resonant phenol free radical structure. The same resonant phenol free radical is coupled, and after passing through a diquinone structure intermediate state, it is finally converted into a stable phenol dimer. The potassium ferricyanide in the present invention is an instantaneous reaction. After mixing, alkali is added to immediately obtain disinomenine, which can completely consume sinomenine hydrochloride. In addition, different proportions of potassium ferricyanide can be added to control the ratio of the two disinomenines. In the prior art, adding hydrogen peroxide requires a long time of stirring reaction to obtain disinomenine, and the product is relatively fixed, and the reaction is incomplete, with a low yield.

[0011] The use of hydrochloric acid in step S2 is beneficial to acidify the alkali precipitate into salt and dissolve it in water. Only in the liquid state can it be decolorized by activated carbon adsorption to remove iron ions, thereby improving the purity of bisinomenine.

[0012] As an optional embodiment, in the preparation method provided by the present invention, in steps S1 and S4, the alkaline condition is to add a sodium carbonate solution, and the concentration of the sodium carbonate solution is 5-10%.

[0013] The sodium carbonate solution is alkaline as the control solution. Compared with sodium hydroxide, the reaction is easy to control and will not dissolve the sample.

[0014] As an optional embodiment, in the preparation method provided by the present invention, in step S1, the molar ratio of the sinomenine hydrochloride solution to the potassium ferrocyanide solution is 1:(0.4-1.2).

[0015] In the present invention, the ratio of R-disinoline and S-disinoline in the product can be adjusted by the amount of potassium ferrocyanide added. When the ratio is 1:1, a monomer mainly in R configuration is easily obtained, and the solubility of the salt is different, so S-disinoline monomer is obtained.

[0016] As an optional embodiment, in the preparation method provided by the present invention, in step S1, the reaction temperature is room temperature to 60°C.

[0017] In the present invention, the dissolution of sinomenine hydrochloride is related to temperature. When the temperature is increased, the solubility increases. The greater the solubility, the faster the reaction.

[0018] As an optional embodiment, in the preparation method provided by the present invention, in step S4, the insulation temperature after adding activated carbon is 50-80° C., and the insulation time is 10-40 min.

[0019] As an optional embodiment, in the preparation method provided by the present invention, the mixture of R-sinomenine and S-sinomenine obtained in step S4 is separated using a C18 chromatographic column or a silica gel column.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] The invention provides a method for simultaneously preparing R-disinoline and S-disinoline. The method comprises the following steps: adding a potassium ferrocyanide solution to simultaneously prepare R-disinoline and S-disinoline; adjusting the amount of potassium ferrocyanide added to change the conversion ratio of R-disinoline and S-disinoline to obtain an R-disinoline monomer; utilizing the difference in solubility of hydrochloride salts to separate S-disinoline; and subjecting the mixture to liquid phase or silica gel column chromatography to obtain S-disinoline or R-disinoline monomers. The method comprises the following steps: the reaction is controllable and the by-products generated by the synthesis are small. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0023] Figure 1 The liquid chromatography 262 nm spectrum of R-bisinomenine prepared in Example 1;

[0024] Figure 2 The liquid chromatography 262 nm spectrum of the precipitate prepared in Example 2;

[0025] Figure 3 Example 2 Preparation of S-sinomenine liquid chromatography 262nm spectrum;

[0026] Figure 4 The liquid chromatography 262 nm spectrum of the mixed precipitate prepared in Example 3;

[0027] Figure 5 This is the liquid chromatography 262nm spectrum of the mixed solution prepared in Comparative Example 1.

[0028] Figure 6 It is the liquid chromatography 262nm spectrum of Sinomenine hydrochloride;

[0029] Figure 7 The UV spectrum of R-bisinomenine prepared in Example 1;

[0030] Figure 8 This is the UV spectrum of S-bisinomenine prepared in Example 2;

[0031] Fig. 9 This is the UV spectrum of sinomenine hydrochloride. DETAILED DESCRIPTION

[0032] In order to facilitate the understanding of the present invention, the present invention will be described more comprehensively and meticulously below in combination with the specification and preferred embodiments, but the protection scope of the present invention is not limited to the following specific embodiments.

[0033] Unless otherwise defined, all professional terms used below have the same meanings as those generally understood by those skilled in the art. The professional terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of protection of the present invention.

[0034] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0035] Example 1

[0036] Take 0.1mol / L sinomenine hydrochloride solution and 0.1mol / L potassium ferrocyanide solution, mix them at 1:1 at 50℃, add 10% sodium carbonate solution to the mixture to make it alkaline until no more precipitation occurs, and collect the rich precipitate on the filter paper, rinse with water until the effluent is neutral, rinse the solid with purified water and transfer it to a clean beaker, add dilute hydrochloric acid to dissolve the solid completely. Add activated carbon to the acidified solution, keep it warm at 50-80 degrees for 30 minutes, filter it while it is hot, and add 10% sodium carbonate solution to the filtrate to obtain the nearly white R-sinomenine monomer.

[0037] Example 2

[0038] Take 0.1mol / L sinomenine hydrochloride solution and 0.1mol / L potassium ferrocyanide solution, mix them at 1:0.7 at 50℃, add 10% sodium carbonate solution to the mixture to make it alkaline until no precipitation occurs, and collect the rich precipitate on the filter paper, rinse with water until the effluent is neutral, rinse the solid with purified water and transfer it to a clean beaker, add dilute hydrochloric acid to make it acidic, and precipitate a white solid as S-sinomenine. Add 10% sodium carbonate solution to the filtrate to obtain a nearly white mixture of R- and S-sinomenine.

[0039] Example 3

[0040] Take 0.1mol / L sinomenine hydrochloride solution and 0.1mol / L potassium ferrocyanide solution, mix them at 1:0.5 at 50℃, add 10% sodium carbonate solution to the mixture to make it alkaline until no more precipitation occurs, and collect the rich precipitate on the filter paper, rinse with water until the effluent is neutral, rinse the solid with purified water and transfer it to a clean beaker, add dilute hydrochloric acid until it becomes acidic, and precipitate a white solid as S-sinomenine. Add 10% sodium carbonate solution to the filtrate to obtain a nearly white mixture of R-sinomenine and S-sinomenine.

[0041] Comparative Example 1

[0042] Take 0.1 mol / L sinomenine hydrochloride solution and 0.1 mol / L potassium ferrocyanide solution, mix them at a ratio of 1:0.3 at 50°C, add 10% sodium carbonate solution to the mixture to make it alkaline until no precipitation occurs, and collect the rich precipitate on filter paper, rinse with water until the effluent is neutral, and dry in an oven at 60°C to obtain a mixture of sinomenine and R-, S-bisinomenine.

[0043] The mixtures prepared in Examples 1-3 and Comparative Example 1 were subjected to liquid phase separation using a C18 chromatographic column under the following conditions:

[0044] Preparation and separation: Mobile phase A: 20 mmol / 1 disodium hydrogen phosphate. Adjust the pH to 8.0 with 20 mmol / l sodium dihydrogen phosphate, and then adjust the pH to 9.0 to 9.5 with 5% triethylamine. Mobile phase B: acetonitrile / methanol gradient elution A: 12-70% gradient elution.

[0045] The liquid phase 262nm spectra of each product in Examples 1-3 and Comparative Example 1 are as follows Figure 1-5 As shown, Figure 1 The liquid chromatography 262 nm spectrum of R-bisinomenine prepared in Example 1, Figure 2 The liquid chromatography 262 nm spectrum of the precipitate prepared in Example 2, Figure 3 Example 2 Preparation of S-sinomenine Liquid Chromatography 262nm Spectrum, Figure 4 The liquid chromatography 262 nm spectrum of the mixed precipitate prepared in Example 3, Figure 5 The liquid chromatography 262nm spectrum of the mixed solution prepared in Comparative Example 1. Figure 6 Comparison of the results of the 262nm spectrum of the liquid chromatography of Sinomenine hydrochloride shows that a mixture containing R-sinomenine and S-sinomenine is prepared simultaneously in the embodiment or R- and S-sinomenine monomers are prepared separately. The ratio of potassium ferrocyanide added in Comparative Example 1 is too low, and the reaction is incomplete, resulting in an incompletely consumed mixture of Sinomenine hydrochloride and the reaction product R- and S-sinomenine. This proves that excess potassium ferrocyanide is used to form R-sinomenine.

[0046] The UV spectra of R-bisinomenine prepared in Example 1 and S-bisinomenine prepared in Example 2 are as follows: Figure 7 and Figure 8 As shown, Fig. 9 The comparison of the UV spectrum of sinomenine hydrochloride proved that R-sinomenine and S-sinomenine were prepared.

[0047] The above contents are further detailed descriptions of the present invention in combination with specific preferred embodiments, and it cannot be determined that the specific implementation of the present invention is limited to these descriptions. For ordinary technicians in the field to which the present invention belongs, several simple deductions or substitutions can be made without departing from the concept of the present invention, which should be regarded as falling within the scope of protection of the present invention.

Claims

1. A method for simultaneously preparing R-sinomenine and / or S-sinomenine, characterized in that: The following steps are involved: S1, mixing the sinomenine hydrochloride solution with the potassium ferrocyanide solution, adding alkali and stirring to obtain a precipitate; S2, washing the precipitate obtained in step S1 until the washing liquid is neutral, adding hydrochloric acid solution until it becomes acidic, leaving it for a while, and filtering it with suction; S3, filtration to obtain a white solid, which is S-bisinomenine; S4. The filtrate solution obtained in step S2 is added with activated carbon according to the color of the solution, and then filtered after heat preservation and decolorization. The proportion of potassium ferrocyanide solution is different, and an alkaline solution is added for precipitation to obtain a mixture of R-disinoline and S-disinoline, or R-disinoline monomer.

2. The method for simultaneously preparing R-sinomenine and / or S-sinomenine according to claim 1, characterized in that: In steps S1 and S4, the alkaline condition is to add a sodium carbonate solution, and the concentration of the sodium carbonate solution is 5-10%.

3. The method for simultaneously preparing R-sinomenine and / or S-sinomenine according to claim 1, characterized in that: In step S1, the molar ratio of the sinomenine hydrochloride solution to the potassium ferrocyanide solution is 1:(0.4-1.2).

4. The method for simultaneously preparing R-sinomenine and / or S-sinomenine according to claim 1, characterized in that: In step S1, the reaction temperature is room temperature to 60°C.

5. The method for simultaneously preparing R-sinomenine and / or S-sinomenine according to claim 1, characterized in that: In step S4, the insulation temperature after adding the activated carbon is 50-80° C., and the insulation time is 10-40 min.

6. The method for simultaneously preparing R-sinomenine and / or S-sinomenine according to claim 1, characterized in that: The mixture of R-sinomenine and S-sinomenine obtained in step S4 is separated using a C18 chromatographic column or a silica gel column.

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