CN110256389B - Preparation method of hyoscyamine - Google Patents
Preparation method of hyoscyamine Download PDFInfo
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- CN110256389B CN110256389B CN201910484452.4A CN201910484452A CN110256389B CN 110256389 B CN110256389 B CN 110256389B CN 201910484452 A CN201910484452 A CN 201910484452A CN 110256389 B CN110256389 B CN 110256389B
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
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Abstract
The invention discloses a preparation method of hyoscyamine, which comprises the steps of firstly, using 2, 4-dihydroxy-5-methoxybenzaldehyde as a starting material, adding a solvent and a catalyst, adding a malonic acid compound to perform heat preservation reaction at the reaction temperature of 0-300 ℃ to obtain a reaction solution, wherein the heat preservation reaction time is 2-10 h, and the dosage of the malonic acid compound is 1-10 equivalent; cooling the reaction liquid at the temperature of-10-35 ℃, separating out a large amount of solids after cooling the reaction liquid, and performing reduced pressure suction filtration on the reaction liquid with the separated out large amount of solids to obtain a scopoletin crude product and a filtrate; step three, recrystallizing the hyoscyamine crude product by using ethyl acetate to obtain a hyoscyamine pure product; the method has the advantages of high use yield, low cost and less pollution.
Description
Technical Field
The invention relates to the field of biochemistry and medicine, in particular to a preparation method of hyoscyamine.
Background
Hyoscyamine is coumarin compound, is phenolic substance widely existing in Solanaceae plants, and has wide distribution in plants, wherein the content in plant root such as Scopolia japonica (Scopolia japonica Maxim) root, belladonna (Herba Atropa Belladonnas) root and Angelica dahurica (Angelica Dahurica Fisch. Ex Hoffin) root of Solanaceae plants is high. The scopoletin can be extracted from plants such as artemisia annua and the like, has important medicinal value, and has various agricultural biological activities mainly including bacteriostatic activity, plant growth and development regulation, plant resistance induction and the like. Furthermore, scopoletin can also be used to detect the release of active oxygen during oxidative burst and as a peroxyscavenger and acetylcholinesterase inhibitor. Hyoscyamus has the functions of dispelling wind, resisting inflammation, relieving pain and eliminating phlegm in clinic.
The product is mostly prepared by a method for extracting from plant artemisia annua at present, the extraction process is complicated, the extraction efficiency is low, the product is expensive, and the market competitiveness is not realized. At present, the monopoly of international reagent industry such as merck, Sammerfo and the like is mainly used for carrying out monopoly operation on the product. In addition, the traditional production process of the product reported by foreign documents has the obvious defects of large pollution, large operation difficulty, low yield and the like, so that domestic companies have no capacity for realizing green production of the product in China for a while, and the rapid development of health of the biochemical diagnostic reagent industry and the plant immune inducer industry in China is hindered.
The existing production methods of hyoscyamine mainly comprise the following three methods: the first is directly extracted from artemisia annua, firstly preparing an artemisia annua acetone extract, then adding silica gel into the artemisia annua acetone extract for column chromatography separation, and eluting by using a petroleum ether-ethyl acetate mild solvent. The method can obtain pure scopoletin product 30-50 mg from 1 kg of Artemisia annua, has low extraction efficiency, and also generates a large amount of waste residue and liquid. The process does not meet the requirements of green synthesis.
The second method is that 2, 4-dihydroxy-5-methoxybenzaldehyde and malonic acid are used as raw materials and synthesized by a 2-step method, and pyridine and aniline are used as solvents and reaction reagents for ring closing of 2, 4-dihydroxy-5-methoxybenzaldehyde and malonic acid to obtain a carboxyl intermediate; decarboxylation of the carboxyl intermediate at high temperature gave hyoscyamine (Bioorganic & Medicinal Chemistry Letters,2016,26(23), 5732-;
the synthesis method is the most widely adopted method at present, the used raw materials are relatively cheap, and the operation controllability is good; however, the synthetic method has a relatively long route and requires 2 independent operations; the reaction time is relatively long, the reaction time in the step 1 needs 24 hours, the reaction time in the step 2 also needs 3.5 hours, and the total reaction time is 27.5 hours; and in both steps of reaction, a reproductive toxicity solvent pyridine with very big smell is needed, so that great hidden danger exists for the body health of operators, the green synthesis principle is not met, and the industrial mass production requirement is difficult to meet.
The third method is to synthesize the compound by using 2, 4-dihydroxy-5-methoxybenzaldehyde and (triphenylphosphine alkene) ethyl acetate as raw materials through a 1-step method: heating 2, 4-dihydroxy-5-methoxybenzaldehyde and ethyl (triphenylphosphine) acetate in N, N-diethylaniline for reaction to obtain hyoscyamine (Tetrahedron,2002,58(11), 2163-2166);
the synthetic method has short route and relatively simpler and more convenient operation; however, this route also has the obvious disadvantage that the conversion rate of the process is relatively low, and the yield is only 27%; the molecular weight of the ethyl (triphenylphosphine) acetate is 348.37, while the molecular weight of the acetic acid actually added to the molecule is only 60.05, the atom economy is extremely poor, and a large amount of by-product, namely, triclosan, is generated in the reaction process, so that great difficulty is caused in subsequent purification; the process method does not conform to the principle of green synthesis and is difficult to meet the requirement of industrial mass production.
Disclosure of Invention
In order to overcome the defects in the prior art, the embodiment of the invention provides a preparation method of hyoscyamine, which has the advantages of high use yield, low cost and less pollution.
In order to achieve the above object, the embodiment of the present application discloses a method for preparing hyoscyamine, comprising: the method comprises the following steps: using 2, 4-dihydroxy-5-methoxybenzaldehyde as a starting material, and adding a solvent and a catalyst, wherein the solvent is one or two of N, N-dimethylaniline and N, N-diethylaniline; the catalyst is one or two of N, N-dimethylaniline and N, N-diethylaniline; adding a malonic acid compound to perform heat preservation reaction at the reaction temperature of 0-300 ℃ to obtain a reaction solution, wherein the heat preservation reaction time is 2-16 h, and the dosage of the malonic acid compound is 1-10 equivalent; the malonic acid compound is one or more of malonic acid, monomethyl malonate, monoethyl malonate, monoisopropyl malonate, dimethyl malonate, diethyl malonate and diisopropyl malonate;
step two: cooling the reaction liquid at the temperature of-10-35 ℃, separating out a large amount of solids after cooling the reaction liquid, and performing reduced pressure suction filtration on the reaction liquid with the separated out large amount of solids to obtain a scopoletin crude product and a filtrate;
step three: and recrystallizing the crude scopoletin product by using ethyl acetate to obtain a pure scopoletin product.
Preferably, the filtrate can be repeatedly used as a solvent or subjected to distillation under reduced pressure to extract the solvent.
Preferably, the reaction temperature in the first step is 50-250 ℃.
Preferably, the cooling temperature in the second step is-5 ℃ to 10 ℃.
Preferably, the reaction time of the first step is 4-8 h.
Preferably, the reaction solution in the first step is subjected to TLC to monitor the reaction, so as to monitor the progress of the reaction.
The invention has the following beneficial effects:
1. the reaction steps are few, the operation is simple and convenient, and the method is suitable for industrial production;
2. the intermediate treatment link is saved, the reaction yield is improved, the cost of unit product is reduced, the cost is lower, the yield is high, and the method is suitable for production of most related enterprises;
3. the filtrate obtained in the second step contains a solvent, a small amount of excessive malonic acid compounds which are not completely reacted, a small amount of products which are not completely crystallized, and other impurities; the solvent and the malonic acid compound can be mechanically applied in the next reaction, so that the pollution is less, and the method is suitable for industrial production;
4. the reagent in the invention is also a catalyst, so that an additional catalyst is not required to be added, and the post-treatment operation is simplified.
In order to make the aforementioned and other objects, features and advantages of the invention comprehensible, preferred embodiments accompanied with figures are described in detail below.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a nuclear magnetic resonance spectrum of a pure scopoletin product in example 1 of the present invention;
FIG. 2 is an HPLC chromatogram of a pure scopoletin product in example 2 of the present invention;
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The following detailed description of implementations of the invention refers to the accompanying drawings.
Example 1, 336g of 2, 4-dihydroxy-5-methoxybenzaldehyde, 256g of monomethyl malonate, and 1.5L of N, N-dimethylaniline were sequentially charged into a 5L four-necked reaction flask with mechanical stirring to obtain a reaction solution; after heating the reaction solution to 180 ℃, the reaction solution was subjected to a heat-preserving reaction as shown in the following chemical formula 1 for 6 hours, and simultaneously, the reaction solution was subjected to TLC monitoring reaction, thereby monitoring the progress of the reaction and confirming whether the reaction was completed.
Chemical formula 1
After the heat preservation reaction for 6 hours, the temperature of the reaction liquid is reduced to 10 ℃, and a large amount of yellow-green solids are separated out from the reaction liquid. Carrying out vacuum filtration on the reaction liquid with the yellow-green solid separated out, and collecting a large amount of yellow-green scopoletin crude products and filtrate; the crude scopoletin product was recrystallized from ethyl acetate to yield 352g of a yellow-green solid scopoletin pure product.
It can be understood that the filtrate can be reused in the next reaction, and the N, N-dimethylaniline can also be recovered by reduced pressure distillation. The solvent can be recycled, the cost is low, and the pollution is small.
Referring to FIG. 1, the pure scopoletin product was examined by NMR, and as shown in FIG. 1, the NMR spectrum showed a total of 8 groups of H, 6 of which were scopoletin, and the remainder were H of water and deuterated solvent. Wherein, the yield of the pure product of hyoscyamine reaches 91.6 percent, the melting point is 200-204 ℃, and the HPLC purity is 99.23 percent. The hyoscyamine pure product has high use yield and less reaction steps.
In the embodiment, the N, N-dimethylaniline is used as both the solvent and the catalyst, so that an additional catalyst is not required, and the post-treatment operation is simplified.
Example 2 to a 5L four-necked reaction flask, 505g of 2, 4-dihydroxy-5-methoxybenzaldehyde, 400g of malonic acid and 2.5L of N, N-dimethylaniline were sequentially charged with mechanical stirring to obtain a reaction solution; heating the reaction solution to reflux reaction, performing heat preservation reaction on the reaction solution for 4 hours as shown in the following chemical formula 2, and simultaneously monitoring the reaction by TLC (thin layer chromatography) of the reaction solution subjected to the heat preservation reaction, thereby monitoring the reaction progress and confirming whether the reaction is finished.
Chemical formula 2
After the heat preservation reaction for 4 hours, the temperature of the reaction liquid is reduced to 5 ℃, and a large amount of yellow-green solids are separated out from the reaction liquid. And (3) carrying out reduced pressure suction filtration on the reaction liquid with the yellow-green solid separated out, collecting a large amount of yellow-green scopoletin crude products and filtrate, wherein the filtrate can be continuously used in the next reaction, and the N, N-dimethylaniline can also be recovered by reduced pressure distillation. The crude scopoletin product was recrystallized from ethyl acetate to yield 540g of a yellow-green scopoletin pure product.
It is understood that in this example, the N, N-xylidine is both a solvent and a catalyst, and additional catalyst may not be required, while simplifying work-up operations.
The yield of the pure product of hyoscyamine is 93.7%, and the melting point is 200-204 ℃. Referring to fig. 2, the purified scopoletin product was detected by high performance liquid chromatography, and as shown in fig. 2, the HPLC chromatogram showed that the peak area of the hetero peak in the purified scopoletin product was very small, the HPLC purity was 99.12%, the yield of the purified scopoletin product was high, and the number of reaction steps was small. The results of the analysis of the purified scopoletin are shown in table 1.
TABLE 1
Example 3 to a 5L four-necked reaction flask, 505g of 2, 4-dihydroxy-5-methoxybenzaldehyde, 620g of diethyl malonate, and 2LN, N-diethylaniline were sequentially charged with mechanical stirring to obtain a reaction solution; after the reaction solution was heated to 210 ℃ for reaction, the reaction solution was subjected to a heat-retaining reaction shown in the following chemical formula 3 for 8 hours, and simultaneously, the reaction solution was subjected to TLC monitoring reaction to monitor the progress of the reaction and confirm whether the reaction was completed.
Chemical formula 3
After the heat preservation reaction for 8 hours, the temperature of the reaction liquid is reduced to-5 ℃, and a large amount of yellow-green solid is separated out from the reaction liquid. Carrying out vacuum filtration on the reaction liquid from which the yellow-green solid is separated out, collecting a large amount of yellow-green scopoletin crude products and filtrate, wherein the filtrate can be continuously used in the next reaction, and can also be subjected to vacuum distillation to recover N, N-diethylaniline; recrystallizing the crude scopoletin product with ethyl acetate to obtain 510g of a yellow-green solid scopoletin pure product. At this time, the yield of the pure product of scopoletin is 88.5%, the melting point is 200-.
It is understood that in this example, the N, N-diethylaniline is both the solvent and the catalyst, and additional catalyst is not needed, and the post-treatment operation is simplified.
The principle and the implementation mode of the invention are explained by applying specific embodiments in the invention, and the description of the embodiments is only used for helping to understand the method and the core idea of the invention; meanwhile, for a person skilled in the art, according to the idea of the present invention, there may be variations in the specific embodiments and the application scope, and in summary, the content of the present specification should not be construed as a limitation to the present invention.
Claims (6)
1. A preparation method of a biochemical diagnostic reagent and a plant immunity inducer-hyoscyamine is characterized in that:
the method comprises the following steps: 2, 4-dihydroxy-5-methoxybenzaldehyde is used as a starting material, a solvent and a catalyst are added, wherein the solvent is one or two of N, N-dimethylaniline and N, N-diethylaniline; the catalyst is one or two of N, N-dimethylaniline and N, N-diethylaniline; adding a malonic acid compound to perform heat preservation reaction at the reaction temperature of 0-300 ℃ to obtain a reaction solution, wherein the heat preservation reaction time is 2-16 h, and the dosage of the malonic acid compound is 1-10 equivalent; the malonic acid compounds are one or more of malonic acid, monomethyl malonate, monoethyl malonate, monoisopropyl malonate, dimethyl malonate, diethyl malonate and diisopropyl malonate;
step two: cooling the reaction liquid at the temperature of-10-35 ℃, separating out a large amount of solids after cooling the reaction liquid, and performing reduced pressure suction filtration on the reaction liquid with the separated out large amount of solids to obtain a scopoletin crude product and a filtrate;
step three: and recrystallizing the crude scopoletin product by using ethyl acetate to obtain a pure scopoletin product.
2. The method of claim 1, wherein the filtrate is used repeatedly as a solvent or subjected to distillation under reduced pressure to extract the solvent.
3. The method of preparing scopoletin according to claim 1, wherein the reaction temperature in step one is from 50 ℃ to 250 ℃.
4. The method of preparing scopoletin according to claim 1, wherein the cooling temperature in step two is from-5 ℃ to 10 ℃.
5. The method of claim 1, wherein the incubation in step one is for a period of time ranging from 4 hours to 8 hours.
6. The method for producing scopoletin according to claim 1, wherein the reaction solution in the first step is subjected to TLC monitoring to monitor the progress of the reaction.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584762A (en) * | 2012-01-10 | 2012-07-18 | 中国药科大学 | Gelsemic acid derivative and preparation method and application thereof |
| CN103896895A (en) * | 2013-12-31 | 2014-07-02 | 浙江工业大学 | Method for preparing coumarin derivative |
| CN103965150A (en) * | 2014-05-28 | 2014-08-06 | 广州康臣药物研究有限公司 | Scopoletin derivative as well as preparation method and application thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584762A (en) * | 2012-01-10 | 2012-07-18 | 中国药科大学 | Gelsemic acid derivative and preparation method and application thereof |
| CN103896895A (en) * | 2013-12-31 | 2014-07-02 | 浙江工业大学 | Method for preparing coumarin derivative |
| CN103965150A (en) * | 2014-05-28 | 2014-08-06 | 广州康臣药物研究有限公司 | Scopoletin derivative as well as preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| Gastroprotective activity of synthetic coumarins: Role of endogenous prostaglandins, nitric oxide, non-protein sulfhydryls and vanilloid receptors;Beatriz Sepulveda et al.;《Bioorganic & Medicinal Chemistry Letters》;20161201;第26卷(第23期);第5732-5735页 * |
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