Synthetic method of alpha-asarone

Abstract

A synthesis method of alpha-asarone comprises the following steps: 1, 2, 4-trimethoxybenzene is sequentially subjected to an acylation reaction, a reduction reaction and a dehydration reaction, and a product is obtained; the acylation reaction comprises the following steps: reacting 1, 2, 4-trimethoxybenzene with an acylating agent to generate 2, 4, 5-trimethoxypropiophenone by using Lewis acid as a catalyst; the reduction reaction comprises the following steps: reacting 2, 4, 5-trimethoxy propiophenone with a reducing agent to generate 2, 4, 5-trimethoxy phenylpropanol; the dehydration reaction comprises the following step: under a catalytic condition, enabling 2, 4, 5-trimethoxy phenylpropanol and anhydride to generate alpha-asarone. The obtained alpha-asarone product is high in purity and low in impurity content; after the conventional intermediate purification operation is simplified, a qualified product can still be obtained, and the production efficiency can be obviously improved; the method is simple to operate, low in risk and suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a synthesis process of alpha-asarone. Background Art

[0002] α-Asarone is mainly found in the volatile oils of natural products such as Acorus calamus, and its chemical name is 2,4,5-trimethoxy-1-propenylbenzene. Since the 1960s, the pharmacology, toxicology and clinical application of α-asarone have been extensively studied at home and abroad, and significant progress has been made. Studies have shown that it has antitussive, expectorant, antiasthmatic, sedative, antispasmodic and anticonvulsant effects, and also has different degrees of inhibitory effects on the growth of Pneumococcus, Staphylococcus aureus and Escherichia coli. At present, asarone injection has been widely used in clinical practice and has good clinical effects.

[0003] At present, the synthesis of α-asarone mainly includes the following methods:

[0004] Method 1: Wang Zhicai et al. proposed in "Synthesis of Z- and E-asarone", Organic Chemistry, 1990, 10(4): 350-352, that 2,4,5-trimethoxybenzaldehyde is used as a raw material, and two isomers of asarone are prepared by Grignard reaction, dehydration reaction or Wittig reaction, and then α-asarone is separated and purified. This method has poor stereoselectivity, and β-asarone has great toxicity. The product needs to be separated and purified, and the yield is low.

[0005] Method 2: Liu Bochun's patent (publication number CN1511817A) reports that 1,2,4-trimethoxybenzene is used as a raw material to obtain 2,4,5-trimethoxybenzaldehyde through Vilsmeier reaction, and then propionic anhydride, sodium propionate and other materials are added to prepare the product through ethylene reaction and recrystallization. The α-asarone synthesized by this method has good selectivity, but the reaction conversion rate is low, and each step of the product needs to be recrystallized, dried and purified, resulting in a low yield.

[0006] Method 3, Yu Aihe et al. reported in "Selection of dehydrating agent for the synthesis of α-asarone", Synthetic Chemistry, 2006, 14(5): 500-502, that 2,4,5-trimethoxybenzaldehyde was used as the raw material, 2,4,5-trimethoxyphenylpropanol was prepared by Grignard reaction, and then copper sulfate was used as a catalyst to azeotropically dehydrate toluene to obtain the target product. This method has a good yield, but the entire reaction process requires strict anhydrous operation, which is very demanding.

[0007] Method 4: Chen Yiping's patent (publication number CN101195562A) reports that 1,2,4-trimethoxybenzene is used as a raw material and acylated with propionic acid, reduced, and dehydrated to obtain a product. The acylation yield of this method is low, and secondary purification by recrystallization is required. The subsequent use of high-boiling acid anhydride as a dehydration solvent requires high-temperature distillation to remove, which is not conducive to industrial production.

[0008] Method 5, Huang Zhengliang et al. patent (publication number CN108727168A) reported that 2,4,5-trimethoxyphenylpropanol was used as raw material, and after dehydration with propionic anhydride / propionic acid mixed solution, high temperature concentration, n-hexane extraction, pH adjustment, concentration crystallization, and recrystallization were used to obtain the product. The α-asarone synthesized by this method has high purity and good selectivity, but high temperature concentration is not conducive to product stability, and a large amount of solvent extraction and acid-base adjustment are required during the purification process, which is a relatively cumbersome process. Summary of the invention

[0009] The technical problem to be solved by the present invention is to overcome the above-mentioned defects of the prior art and provide a method for synthesizing α-asarone with high production efficiency.

[0010] The technical solution adopted by the present invention to solve the technical problem is as follows: a method for synthesizing α-asarone, using 1,2,4-trimethoxybenzene to sequentially undergo acylation reaction, reduction reaction, and dehydration reaction to obtain an α-asarone product;

[0011] The acylation reaction comprises: 1,2,4-trimethoxybenzene reacts with an acylating agent in a solvent under the condition of Lewis acid as a catalyst to generate 2,4,5-trimethoxyphenylacetophenone; the temperature of the acylation reaction is 0 to 10°C;

[0012] The reduction reaction comprises: 2,4,5-trimethoxyphenylpropiotone reacts with a reducing agent in a solvent to generate 2,4,5-trimethoxyphenylpropanol;

[0013] The dehydration reaction comprises: under the catalytic condition of a catalyst, 2,4,5-trimethoxyphenylpropanol reacts with an acid anhydride to prepare α-asarone.

[0014] Preferably, in the acylation reaction, the molar ratio of 1,2,4-trimethoxybenzene to the acylating agent is 1:1-2.

[0015] Preferably, in the acylation reaction, the molar ratio of 1,2,4-trimethoxybenzene to the catalyst is 1:1-5.

[0016] Preferably, in the acylation reaction, the volume ratio of 1,2,4-trimethoxybenzene to the solvent is 1:5-20.

[0017] Preferably, in the acylation reaction, the acylating agent used is one or more of propionic acid, propionic anhydride and propionyl chloride.

[0018] Preferably, in the acylation reaction, the catalyst used is one or more of aluminum trichloride, zinc chloride, tin tetrachloride and tin dichloride.

[0019] Preferably, in the acylation reaction, the solvent used is dichloromethane and / or chloroform.

[0020] Preferably, the temperature of the acylation reaction is 2-8°C.

[0021] Preferably, the acylation reaction time is 1 to 5 hours.

[0022] Preferably, in the reduction reaction, the molar ratio of 2,4,5-trimethoxypropiophenone to the reducing agent is 1:0.6-2.

[0023] Preferably, in the reduction reaction, the volume ratio of 2,4,5-trimethoxypropiophenone to the solvent is 1:3-10.

[0024] Preferably, in the reduction reaction, the reducing agent used is one or more of lithium aluminum hydride, sodium borohydride and potassium borohydride.

[0025] Preferably, in the reduction reaction, the solvent used is anhydrous ethanol.

[0026] Preferably, the temperature of the reduction reaction is 20-50°C.

[0027] More preferably, the temperature of the reduction reaction is 30-45°C.

[0028] Preferably, in the dehydration reaction, the molar ratio of 2,4,5-trimethoxyphenylpropanol to the catalyst is 1:0.1-2.

[0029] Preferably, in the dehydration reaction, the volume ratio of 2,4,5-trimethoxyphenylpropanol to acid anhydride is 1:3-10.

[0030] Preferably, in the dehydration reaction, the catalyst used is one or more of potassium acetate, sodium acetate, copper acetate, magnesium acetate, and copper sulfate.

[0031] Preferably, in the dehydration reaction, the acid anhydride used is acetic anhydride.

[0032] Preferably, the temperature of the dehydration reaction is 120-170°C.

[0033] More preferably, the temperature of the dehydration reaction is 130-145°C.

[0034] Preferably, after the acylation reaction is completed, water is added to quench the reaction, an organic solvent is used to extract and neutralize the Lewis acid in the organic phase, and the organic phase is concentrated to remove the solvent and then directly used in the reduction reaction.

[0035] Preferably, after the reduction reaction is completed, the solvent is concentrated to remove it, water is added to dissolve the excess reducing agent, and the organic solvent is used for extraction. The organic phase is concentrated to remove the solvent and then directly used for the dehydration reaction.

[0036] More preferably, after the reduction reaction is completed and the solvent is concentrated and removed, the molar ratio of the amount of water added to the amount of the reducing agent used in the reduction reaction is 150 to 60:1.

[0037] Preferably, after the dehydration reaction is completed, the reaction solution is crystallized in cold water or ice water, and the obtained crystals are recrystallized in an alcohol aqueous solution to obtain an α-asarone product.

[0038] More preferably, the volume content of alcohol in the alcohol aqueous solution is 60%-100%.

[0039] More preferably, in the alcohol aqueous solution, the type of alcohol is one or more of methanol, ethanol, propanol, isopropanol and butanol.

[0040] More preferably, the temperature of the cold water or ice water is -3°C to 5°C.

[0041] More preferably, the recrystallization temperature is -5 to 0°C.

[0042] Preferably, TLC is used to monitor the progress of the reaction.

[0043] The present invention has the following beneficial effects:

[0044] (1) The α-asarone product obtained by the present invention has high purity and low impurity content;

[0045] (2) After simplifying the conventional intermediate purification operation, qualified α-asarone products can still be obtained, which can significantly improve production efficiency;

[0046] (3) The present invention is easy to operate, has low risk, and is suitable for industrial production.

[0047] In addition to the above-described purposes, features and advantages, the present invention has other purposes, features and advantages. The present invention will be further described in detail below with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] The drawings constituting a part of this application are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0049] Figure 1 This is a HPLC test chart of the condensation liquid obtained by the acylation reaction in Example 1 of the present invention;

[0050] Figure 2 This is the HPLC detection chart of the α-asarone product obtained in Example 1 of the present invention;

[0051] Figure 3This is a graph showing the absorbance measurement results of blue fluorescent impurities of α-asarone products obtained in Examples 1 to 3 of the present invention;

[0052] Figure 4 This is a graph showing the results of content detection of the α-asarone product obtained in Example 1 of the present invention;

[0053] Figure 5 It is the HPLC detection chart of the condensation liquid obtained by the comparative acylation reaction;

[0054] Figure 6 This is the HPLC test chart of the α-asarone product obtained in the comparative example;

[0055] Figure 7 This is a graph showing the absorbance measurement result of the blue fluorescent impurity of the α-asarone product obtained in the comparative example;

[0056] Figure 8 This is a graph showing the results of content detection of the α-asarone product obtained in the comparative example. DETAILED DESCRIPTION

[0057] In order to make the purpose, scheme and beneficial technology of the present invention clearer, the present invention is further described in detail below in conjunction with the embodiments and drawings. It should be pointed out that the embodiments described in this specification are only for explaining the present invention, not for limiting the present invention.

[0058] For simplicity, only some numerical ranges are explicitly disclosed herein. However, any lower limit can be combined with any upper limit to form an unambiguous range; and any lower limit can be combined with other lower limits to form an unambiguous range, and any upper limit can be combined with any other upper limit to form an unambiguous range. In addition, although not explicitly stated, each point or single value between the range endpoints is included in the range. Thus, each point or single value can be combined with any other point or single value as its own lower limit or upper limit or with other lower limits or upper limits to form an unambiguous range.

[0059] In the description of this article, it should be noted that, unless otherwise specified, “above” and “below” are inclusive of the number, and the “multiple” in “one or more” means two or more, and the “multiple” in “one or more” means two or more.

[0060] The embodiment of the present invention provides a method for synthesizing α-asarone, which uses 1,2,4-trimethoxybenzene to sequentially undergo acylation reaction, reduction reaction, and dehydration reaction to obtain an α-asarone product;

[0061] The acylation reaction comprises: under the condition of Lewis acid as catalyst, 1,2,4-trimethoxybenzene reacts with an acylating agent in a solvent to generate 2,4,5-trimethoxyphenylacetophenone; the temperature of the acylation reaction is 0 to 10°C (specifically, it can be 0°C, 0.5°C, 1°C, 1.5°C, 2°C, 2.5°C, 3°C, 3.5°C, 4°C, 4.5°C, 5°C, 5.5°C, 6°C, 6.5°C, 7°C, 7.5°C, 8°C, 8.5°C, 9°C, 9.5°C, 10°C);

[0062] The reduction reaction comprises: 2,4,5-trimethoxyphenylpropiotone reacts with a reducing agent in a solvent to generate 2,4,5-trimethoxyphenylpropanol;

[0063] The dehydration reaction comprises: under the catalytic condition of a catalyst, 2,4,5-trimethoxyphenylpropanol reacts with an acid anhydride to prepare α-asarone.

[0064] The α-asarone synthesis process of the invention comprises the following steps: using 1,2,4-trimethoxybenzene as a raw material and reacting with Lewis acid aluminum chloride, zinc chloride and other catalysts to prepare 2,4,5-trimethoxyphenylpropiotone through Friedel-Crafts reaction; then reacting with lithium aluminum hydride and other reducing agents to obtain 2,4,5-trimethoxyphenylpropanol; and finally reacting with an acid anhydride for dehydration to obtain the product.

[0065] The synthetic route of the present invention is as follows:

[0066]

[0067] The reported α-asarone synthesis routes each have their own advantages and disadvantages, but usually after each step of the intermediate reaction is completed, complex operations such as extraction, recrystallization separation, and drying are performed, which greatly affects the production efficiency. Moreover, it has been found through research that these purification operations cannot be further simplified, otherwise the product quality will be unqualified. After in-depth research, the inventors of the present invention have found that under specific reaction conditions, α-asarone with higher purity and lower impurity content can be obtained, and after simplifying the treatment after the intermediate reaction is completed, a qualified product can still be obtained, and even the intermediate does not need to be separated, and it can be synthesized by a one-pot method, which greatly improves the yield and production efficiency.

[0068] The synthesis method of α-asarone provided in the embodiment of the present invention has the following advantages:

[0069] (1) The obtained α-asarone product has high purity and low impurity content;

[0070] (2) After simplifying the conventional intermediate purification operation, qualified α-asarone products can still be obtained, which can significantly improve production efficiency;

[0071] (3) Easy to operate, low risk, suitable for industrial production.

[0072] In an embodiment of the present invention, in the acylation reaction, the molar ratio of 1,2,4-trimethoxybenzene to the acylating agent is 1:1-2.

[0073] In an embodiment of the present invention, in the acylation reaction, the molar ratio of 1,2,4-trimethoxybenzene to the catalyst is 1:1-5.

[0074] In an embodiment of the present invention, in the acylation reaction, the volume ratio of 1,2,4-trimethoxybenzene to the solvent is 1:5-20.

[0075] In an embodiment of the present invention, in the acylation reaction, the acylating agent used is one or more of propionic acid, propionic anhydride and propionyl chloride.

[0076] In some embodiments of the present invention, in the acylation reaction, the catalyst used is one or more of aluminum trichloride, zinc chloride, tin tetrachloride, and tin dichloride.

[0077] In an embodiment of the present invention, in the acylation reaction, the solvent used is dichloromethane and / or chloroform.

[0078] In some embodiments of the present invention, the temperature of the acylation reaction is 2-8°C (specifically, it can be 2°C, 2.5°C, 3°C, 3.5°C, 4°C, 4.5°C, 5°C, 5.5°C, 6°C, 6.5°C, 7°C, 7.5°C, 8°C); this temperature range has the advantages of both higher product purity and faster reaction rate.

[0079] In an embodiment of the present invention, the acylation reaction time is 1 to 5 hours.

[0080] In an embodiment of the present invention, in the reduction reaction, the molar ratio of 2,4,5-trimethoxypropiophenone to the reducing agent is 1:0.6-2.

[0081] In an embodiment of the present invention, in the reduction reaction, the volume ratio of 2,4,5-trimethoxypropiophenone to the solvent is 1:3-10.

[0082] In some embodiments of the present invention, in the reduction reaction, the reducing agent used is one or more of lithium aluminum hydride, sodium borohydride, and potassium borohydride.

[0083] In some embodiments of the present invention, in the reduction reaction, the solvent used is anhydrous ethanol.

[0084] In an embodiment of the present invention, the temperature of the reduction reaction is 20-50°C.

[0085] In some embodiments of the present invention, the temperature of the reduction reaction is 30-45°C.

[0086] In an embodiment of the present invention, in the dehydration reaction, the molar ratio of 2,4,5-trimethoxyphenylpropanol to the catalyst is 1:0.1-2.

[0087] In an embodiment of the present invention, in the dehydration reaction, the volume ratio of 2,4,5-trimethoxyphenylpropanol to acid anhydride is 1:3-10.

[0088] In some embodiments of the present invention, in the dehydration reaction, the catalyst used is one or more of potassium acetate, sodium acetate, copper acetate, magnesium acetate, and copper sulfate.

[0089] In some embodiments of the present invention, in the dehydration reaction, the catalyst used is one or more of anhydrous potassium acetate, anhydrous sodium acetate, anhydrous copper acetate, anhydrous magnesium acetate, and anhydrous copper sulfate. The use of anhydrous catalysts can reduce the consumption caused by the hydrolysis of acid anhydrides.

[0090] In some embodiments of the present invention, in the dehydration reaction, the acid anhydride used is acetic anhydride.

[0091] In an embodiment of the present invention, the temperature of the dehydration reaction is 120-170°C.

[0092] In some embodiments of the present invention, the temperature of the dehydration reaction is 130-145°C.

[0093] In the embodiment of the present invention, after the acylation reaction is completed, water is added to quench, an organic solvent is used to extract and neutralize the Lewis acid in the organic phase, and the organic phase is concentrated to remove the solvent and directly used for the reduction reaction. This treatment method avoids complex operations such as recrystallization and drying, and significantly improves the yield and production efficiency.

[0094] In the embodiment of the present invention, after the reduction reaction is completed, the solvent is concentrated to remove the solvent, water is added to dissolve the excess reducing agent, and the organic solvent is used for extraction. The organic phase is concentrated to remove the solvent and then directly used for the dehydration reaction. This treatment method avoids complex operations such as recrystallization and drying, and significantly improves the synthesis efficiency.

[0095] In some embodiments of the present invention, after the reduction reaction is completed and the solvent is concentrated and removed, the molar ratio of the amount of water added to the amount of the reducing agent used in the reduction reaction is 150-60:1.

[0096] In an embodiment of the present invention, after the dehydration reaction is completed, the reaction solution is crystallized in cold water or ice water, and the obtained crystals are recrystallized in an alcohol aqueous solution to obtain an α-asarone product. After the dehydration reaction is completed, cold water or ice water is added for crystallization, which avoids product degradation and yield reduction caused by high-temperature concentration and organic solvent extraction, and reduces production costs. It is found through experiments that the post-treatment method has a high yield and is suitable for industrial production.

[0097] In some embodiments of the present invention, the volume content of alcohol in the alcohol aqueous solution is 60%-100%. The alcohol aqueous solution serves as a solvent for recrystallization, and other alcohol aqueous solutions with similar physical and chemical properties can also be used.

[0098] In some embodiments of the present invention, the alcohol in the alcohol aqueous solution is one or more of methanol, ethanol, propanol, isopropanol, and butanol. The alcohol aqueous solution serves as a solvent for recrystallization, and other alcohol aqueous solutions with similar physical and chemical properties can also be used.

[0099] In some embodiments of the present invention, the temperature of the cold water or ice water is -3°C to 5°C.

[0100] In some embodiments of the present invention, the recrystallization temperature is -5 to 0°C.

[0101] When the above-mentioned treatment method after the acylation reaction, the treatment method after the reduction reaction, and the treatment method after the dehydration reaction are simultaneously used in the process, there is no need to separate the intermediate product during the synthesis process, and the acylation, reduction, and dehydration can be synthesized by a one-pot method.

[0102] In some embodiments of the present invention, TLC is used to monitor the reaction progress. TLC (Thin Layer Chromatography) is a widely used experimental technique, commonly used in drug testing, impurity testing, tracking chemical reaction progress, etc.

[0103] Example

[0104] The following examples describe the disclosure of the present invention in more detail, and these examples are intended for illustrative purposes only, as it will be apparent to those skilled in the art that various modifications and variations will be made within the scope of the disclosure of the present invention. Unless otherwise stated, all parts, percentages, and ratios reported in the following examples are by weight. Unless otherwise stated, all reagents used in the examples are available through conventional commercial sources or are synthesized according to conventional methods and can be used directly without further processing. Unless otherwise stated, the instruments used in the examples are available through conventional commercial sources.

[0105] Example 1

[0106] Synthesis of condensation products (acylation reaction) - Preparation of 2,4,5-trimethoxypropiophenone:

[0107] Add 600.0g of dichloromethane, 100.0g of 1,2,4-trimethoxybenzene, and 83.30g of aluminum chloride to a dry reaction bottle. After the addition, control the temperature at 2°C and add 57.80g of propionyl chloride. After the addition, keep the temperature at 2°C for 3h. After TLC confirms that the reaction is complete, add 300g of water to quench. After quenching, stand and separate the liquids. Wash the aqueous phase with dichloromethane (150.0g×2 times) and combine the organic phases. Add 250g of 10% sodium hydroxide solution to the organic phase, stir and neutralize for 1h, stand and separate the layers. Wash the organic phase with 500.0g of water, add 20.0g of anhydrous sodium sulfate to dry, filter and concentrate to obtain the condensation liquid, which is code-named XXN-l-23053101.

[0108] The obtained condensation liquid was detected by high performance liquid chromatography (Thermo Fisher brand, model U3000), with a chromatographic column (Xtimate C18 4.6mm×250mm, 5μm) filled with octadecylsilane bonded silica gel; the chromatographic conditions were: methanol-water (70:30) as the mobile phase; the detection wavelength was 258nm, the column temperature was 30℃; the injection volume was 20μl; the flow rate was 1.0ml / min. Preparation of the test solution: take 1 drop of sample into a 25ml volumetric flask, add 70% methanol to dilute to the scale, shake well, and use it as the test solution. The HPLC detection results of the obtained condensation solution are as follows Figure 1 shown.

[0109] Depend on Figure 1 It can be seen that the purity of the condensation liquid obtained in this embodiment reaches 99.37%, indicating that impurities are effectively controlled, and the purity is increased by 2.03% compared with the comparative example. The condensate obtained by the present invention can be used for subsequent reactions without further recrystallization and purification, which reduces the product loss caused by the refining operation and greatly improves the production efficiency.

[0110] Synthesis of reduced product (reduction reaction) - Preparation of 2,4,5-trimethoxyphenylpropanol:

[0111] At room temperature, add 300 g of anhydrous ethanol and 13.15 g of sodium borohydride to the condensation liquid in the previous step, keep warm at 38°C for reaction, and confirm that the raw material reaction is complete by TLC. Concentrate until no liquid evaporates, slowly add 600 g of water under stirring, continue stirring for 2 hours, add dichloromethane for extraction, add 20.0 g of anhydrous sodium sulfate to dry the organic layer, filter the organic phase, and evaporate to dryness under reduced pressure at 40°C to obtain 122.31 g of 2,4,5-trimethoxyphenylpropanol with a purity of 99.27%.

[0112] Synthesis of α-asarone (dehydration reaction) - Preparation of 2,4,5-trimethoxy-1-propenylbenzene:

[0113] Mix 436.0g of acetic anhydride, 22.0g of anhydrous potassium acetate and 110.0g of the product of the previous step, heat to 138°C for reflux reaction, and detect the end point of the reaction by TLC. After the reaction is completed, the temperature is controlled at 2°C and the reaction solution is added to 1000g of ice water. After the addition, the mixture is kept warm and beaten for 1 hour, filtered, and the filter cake is rinsed with 327mL of ice water. Collect the wet product and add 350g of 70% ethanol, dissolve and stir for 0.5h, cool to 0°C for crystallization, filter and dry to obtain 75.53g of asarone finished product, which is code-named XXN-23102401.

[0114] The obtained asarone product was tested by high performance liquid chromatography (Thermo Fisher brand, model U3000), using a chromatographic column (Xtimate C18 4.6mm×250mm, 5μm) filled with octadecylsilane bonded silica gel, and the chromatographic conditions were: methanol-water (70:30) as the mobile phase; the detection wavelength was 258nm, the column temperature was 30°C; the injection volume was 20μl; the flow rate was 1.0ml / min. The preparation method of the test solution was as follows: take 10mg of the sample into a 50ml volumetric flask, add an appropriate amount of methanol (about 5ml) and ultrasonically dissolve it, then dilute it to the scale with 70% methanol and shake it well. The HPLC detection results of the obtained α-asarone product are as follows Figure 2 shown.

[0115] The blue fluorescent impurities are a type of oxidative impurities of asarone, which are promoted under acidic and high temperature conditions and are difficult to remove. The Chinese Pharmacopoeia stipulates that its absorbance shall not be greater than 0.20. In this embodiment, the obtained asarone finished product is detected by ultraviolet absorbance method (Shimadzu brand, model UV-2600): take an appropriate amount of sample and accurately weigh it, add ethyl acetate to make a solution containing 200 mg per 1 ml, and test it according to the thin layer chromatography method. 50 μl is absorbed and spotted on a silica gel G thin layer plate, and petroleum ether (60-90° C.)-ethyl acetate (6:4) is used as a developing agent. After development, it is taken out and dried, and the silica gel that shows a blue fluorescent spot (Rf value of about 0.3-0.5) under an ultraviolet lamp (365nm) is scraped and placed in a 10ml volumetric flask. In addition, silica gel of the same size as this spot is scraped from a blank area and placed in a 10ml volumetric flask as a blank control. Add an appropriate amount of ethanol, shake it thoroughly, and after elution, add ethanol to dilute to the scale, shake well, centrifuge and take the supernatant, and measure the absorbance at a wavelength of 278nm according to the ultraviolet-visible spectrophotometry method. The absorbance measurement results of the blue fluorescent substance of the obtained α-asarone product are as follows: Figure 3 shown.

[0116] Depend on Figure 2 It can be seen that the purity of α-asarone prepared in this example reaches 99.94%, the maximum single impurity is only 0.02%, and the impurity content is far lower than the statutory standard that the single impurity shall not exceed 0.5%, and the total impurity shall not exceed 1.0%. Figure 3It can be seen that the absorbance of the blue fluorescent impurity of α-asarone obtained in this example is only 0.015, which is far lower than the legal standard of not more than 0.2. It shows that under the operating conditions shown in the present invention, even if the intermediate is not separated and purified, a liquid phase purity qualified product can still be obtained by a one-pot method.

[0117] The content of the obtained α-asarone product is calculated as shown in Figure 4 .Depend on Figure 4 It can be seen that the content of α-asarone prepared in this embodiment is 99.278%, which meets the statutory standard that the content should not be less than 98.0%.

[0118] The final test results: purity 99.94%, content 99.278%, blue fluorescent substance absorbance 0.015, yield 74.6%. The above results all show that under the conditions shown in the present invention, even if the post-processing process of each intermediate is simplified, or even without separating the intermediate for recrystallization and purification, a qualified product can still be obtained by a one-pot method.

[0119] Example 2

[0120] Synthesis of condensation products (acylation reaction) - Preparation of 2,4,5-trimethoxypropiophenone:

[0121] Add 600.0g of dichloromethane, 100.0g of 1,2,4-trimethoxybenzene, and 83.30g of aluminum chloride to a dry reaction bottle. After the addition, add 57.80g of propionyl chloride at 5°C. After the addition, keep the temperature at 5°C for 3h. After TLC confirms that the reaction is complete, add 300g of water to quench. After quenching, let stand and separate. Wash the aqueous phase with dichloromethane (150.0g×2 times) and combine the organic phases. Add 250g of 10% sodium hydroxide solution to the organic phase, stir and neutralize for 1h, let stand and separate. Wash the organic phase with 500.0g of water, add 20.0g of anhydrous sodium sulfate to dry, filter and concentrate to obtain the condensation liquid.

[0122] Synthesis of reduced product (reduction reaction) - Preparation of 2,4,5-trimethoxyphenylpropanol:

[0123] At room temperature, 300 g of anhydrous ethanol and 13.15 g of sodium borohydride were added to the condensation liquid in the previous step. After the addition, the mixture was kept at 40°C for reaction. TLC confirmed that the reaction of the raw materials was complete. The mixture was concentrated until no liquid was evaporated. 600 g of water was slowly added under stirring. The stirring was continued for 2 hours. Dichloromethane was added for extraction. 20.0 g of anhydrous sodium sulfate was added to the organic layer for drying. After filtering, the organic phase was evaporated to dryness under reduced pressure at 40°C to obtain 119.37 g of 2,4,5-trimethoxyphenylpropanol with a purity of 99.37% and a two-step yield of 88.7%.

[0124] Synthesis of α-asarone (dehydration reaction) - Preparation of 2,4,5-trimethoxy-1-propenylbenzene:

[0125] Mix 436.0g of acetic anhydride, 22.0g of anhydrous potassium acetate and 110.0g of the product of the previous step, heat to 135°C for reflux reaction, and detect the end point of the reaction by TLC. After the reaction is completed, the reaction solution is added to 1000g of ice water at 3°C, and the mixture is kept warm and beaten for 1 hour, filtered, and the filter cake is rinsed with 327mL of ice water. Collect the wet product and add 350g of 70% ethanol, dissolve and stir for 1h, cool to 0°C for crystallization, filter and dry to obtain 72.74g of asarone finished product, which is code-named XXN-23102501.

[0126] The product was tested by high performance liquid chromatography and ultraviolet absorbance method; the results of the blue fluorescent substance absorbance determination are shown in Figure 3 The obtained product had a purity of 99.97%, a content of 99.258%, an absorbance of 0.011 for the blue fluorescent substance, and a yield of 69.7%.

[0127] Example 3

[0128] Synthesis of condensation products (acylation reaction) - Preparation of 2,4,5-trimethoxypropiophenone:

[0129] Add 600.0g of dichloromethane, 100.0g of 1,2,4-trimethoxybenzene, and 83.30g of aluminum chloride to a dry reaction bottle. After the addition, add 57.80g of propionyl chloride at 8℃. After the addition, keep the temperature at 8℃ for 3h. After TLC confirms that the reaction is complete, add 300g of water to quench. After quenching, let stand and separate. Wash the aqueous phase with dichloromethane (150.0g×2 times) and combine the organic phases. Add 250g of 10% sodium hydroxide solution to the organic phase, stir and neutralize for 1h, let stand and separate. Wash the organic phase with 500.0g of water, add 20.0g of anhydrous sodium sulfate to dry, filter and concentrate to obtain the condensation liquid.

[0130] Synthesis of reduced product (reduction reaction) - Preparation of 2,4,5-trimethoxyphenylpropanol:

[0131] At room temperature, 300 g of anhydrous ethanol and 14.15 g of sodium borohydride were added to the condensation liquid in the previous step. After the addition, the mixture was kept at 45°C for reaction. TLC confirmed that the reaction of the raw materials was complete. The mixture was concentrated until no liquid was evaporated. 600 g of water was slowly added under stirring. The stirring was continued for 2 hours. Dichloromethane was added for extraction. 20.0 g of anhydrous sodium sulfate was added to the organic layer for drying. After filtration, the organic phase was evaporated to dryness under reduced pressure at 40°C to obtain 120.15 g of 2,4,5-trimethoxyphenylpropanol with a purity of 100% and a two-step yield of 89.3%.

[0132] Synthesis of α-asarone (dehydration reaction) - Preparation of 2,4,5-trimethoxy-1-propenylbenzene:

[0133] Mix 436.0g of acetic anhydride, 22.0g of anhydrous potassium acetate and 110.0g of the product of the previous process, heat to 143°C for reflux reaction, and detect the end point of the reaction by TLC. After the reaction is completed, the reaction solution is added to 1000g of ice water at 5°C, and the mixture is kept warm and beaten for 1 hour, filtered, and the filter cake is rinsed with 327mL of ice water. Collect the wet product and add 350g of 70% ethanol, dissolve and stir for 40min, cool to -5°C for crystallization, filter and dry to obtain 77.86g of asarone finished product, which is code-named XXN-23102301.

[0134] The product was tested by high performance liquid chromatography and ultraviolet absorbance method; the results of the blue fluorescent substance absorbance determination are shown in Figure 3 After testing, the purity of the obtained product was 99.97%, the content was 99.044%, the absorbance of the blue fluorescent substance was 0.047, and the yield was 73.3%.

[0135] Comparative Example

[0136] In order to ensure a high reaction rate, the prior art often carries out the acylation reaction at a slightly higher temperature. The inventors of the present invention have found through research that such a synthesis process will cause excessive impurities in the product. If the intermediate is not separated and purified by methods such as crystallization, a qualified product cannot be obtained, which reduces the overall synthesis efficiency. Herein, a case of carrying out the acylation reaction at 20°C is provided as a comparative example.

[0137] Synthesis of condensation products (acylation reaction) - Preparation of 2,4,5-trimethoxypropiophenone:

[0138] Add 600.0g of dichloromethane, 100.0g of 1,2,4-trimethoxybenzene, and 83.30g of aluminum chloride to a dry reaction bottle. After the addition, control the temperature at 20°C and add 57.80g of propionyl chloride. After the addition, keep the temperature at 20°C for 3h. After TLC confirms that the reaction is complete, add 300g of water to quench. After quenching, stand and separate the liquids. Wash the aqueous phase with dichloromethane (150.0g×2 times) and combine the organic phases. Add 250g of 10% sodium hydroxide solution to the organic phase, stir and neutralize for 1h, stand and separate, wash the organic phase with 500.0g of water, add 20.0g of anhydrous sodium sulfate, dry, filter and concentrate to obtain the condensation liquid, which is code-named XXN-l-23052501.

[0139] The obtained condensation liquid was detected by high performance liquid chromatography (Thermo Fisher brand, model U3000), with a chromatographic column (Xtimate C18 4.6mm×250mm, 5μm) filled with octadecylsilane bonded silica gel; the chromatographic conditions were: methanol-water (70:30) as the mobile phase; the detection wavelength was 258nm, the column temperature was 30℃; the injection volume was 20μl; the flow rate was 1.0ml / min. Preparation of the test solution: take 1 drop of sample into a 25ml volumetric flask, add 70% methanol to dilute to the scale, shake well, and use it as the test solution. The HPLC detection results of the obtained condensation solution are as follows Figure 5 shown.

[0140] Depend on Figure 5 It can be seen that, based on Example 1, after the acylation reaction temperature is increased, the maximum single impurity is 2.13% and the purity is 97.34%, while the maximum single impurity result shown in Example 1 of the present invention is only 0.23%. The results show that after the acylation temperature is increased, the impurities increase significantly, and secondary purification by recrystallization is required before it can be used in production, which greatly increases the complexity of the operation, and further refining will also lead to material loss, affecting the yield.

[0141] Synthesis of reduced product (reduction reaction) - Preparation of 2,4,5-trimethoxyphenylpropanol:

[0142] This step of this comparative example is consistent with the operation of Example 1.

[0143] Synthesis of α-asarone (dehydration reaction) - Preparation of 2,4,5-trimethoxy-1-propenylbenzene:

[0144] 436.0g of acetic anhydride, 22.0g of anhydrous potassium acetate and 110.0g of the product of the previous step were mixed, heated to 138°C for reflux reaction, and the reaction endpoint was detected by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure and concentrated, and the residue was extracted three times with petroleum ether, and the organic phases were combined. The organic phase was concentrated to obtain an oily substance, 350g of 70% ethanol was added, and the solution was stirred for 0.5h, cooled to 0°C for crystallization, and filtered and dried to obtain 64.89g of asarone finished product, which was coded as XXN-23080101.

[0145] The obtained asarone product was tested by high performance liquid chromatography (Thermo Fisher brand, model U3000), using a chromatographic column (Xtimate C18 4.6mm×250mm, 5μm) filled with octadecylsilane bonded silica gel, and the chromatographic conditions were: methanol-water (70:30) as the mobile phase; the detection wavelength was 258nm, the column temperature was 30°C; the injection volume was 20μl; the flow rate was 1.0ml / min. The preparation method of the test solution was as follows: take 10mg of the sample into a 50ml volumetric flask, add an appropriate amount of methanol (about 5ml) and ultrasonically dissolve it, then dilute it to the scale with 70% methanol and shake it well. The HPLC detection results of the obtained α-asarone product are as follows Figure 6 shown.

[0146] The obtained asarone finished product was tested by ultraviolet absorbance method (Shimadzu brand, model UV-2600): take an appropriate amount of sample and weigh it accurately, add ethyl acetate to make a solution containing 200 mg per 1 ml, test it according to the thin layer chromatography method, absorb 50 μl and spot it on the silica gel G thin layer plate, use petroleum ether (60-90°C)-ethyl acetate (6:4) as the developing agent, after development, take it out and dry it, scrape the silica gel that shows a blue fluorescent spot (Rf value is about 0.3-0.5) under ultraviolet light (365nm) and place it in a 10ml volumetric flask, and scrape the silica gel of the same size as this spot in the blank area and place it in a 10ml volumetric flask as a blank control, add an appropriate amount of ethanol, shake it thoroughly, after elution, add ethanol to dilute to the scale, shake well, centrifuge and take the supernatant, and measure the absorbance at a wavelength of 278nm according to the ultraviolet-visible spectrophotometry method. The absorbance measurement results of the blue fluorescent substance of the obtained α-asarone product are as follows Figure 7 As shown (sample 1 in the figure).

[0147] Depend on Figure 6 It can be seen that the purity of α-asarone obtained in the comparative example reaches 99.90%, and the maximum single impurity is 0.05%. Figure 7 It can be seen that the absorbance of the blue fluorescent substance of the product shown in the comparative example is 0.245, which is not more than 0.2 as stipulated in the legal standard, and the measurement result is unqualified. Although the liquid phase purity of the product in the comparative example meets the legal standard, the other items do not meet the regulations. It is speculated that this may be because the acylated impurities in the condensate are converted into substances that cannot be detected in the liquid phase conditions, such as blue fluorescent impurities, etc. through subsequent reactions.

[0148] The content of the obtained α-asarone product is calculated as shown in Figure 8 .Depend on Figure 8 It can be seen that although the liquid phase purity of the comparative example is as high as 99.90%, the product content is only 97.242%, which does not meet the statutory standard of not less than 98.0%. It is speculated that it is due to the further conversion of acylated impurities that lead to the generation of impurities that cannot be detected under liquid phase conditions.

[0149] The final test results: purity 99.90%, content 97.242%, blue fluorescent substance absorbance 0.245, yield 64.1%, the product is unqualified. The post-treatment of the comparative example using reduced pressure concentration, extraction and other means has a good purification effect on α-asarone, but the product obtained in the comparative example still has excessive impurities; it is speculated that this is because the impurities generated in the acylation reaction were not removed in time, resulting in interference in the subsequent synthesis process, further promoting the formation of new impurities, and after multiple accumulations, the impurity content in the reaction solution is too high, and qualified products cannot be extracted by conventional post-treatment methods.

Claims

1. A method for synthesizing α-asarone, characterized in that: 1,2,4-Trimethoxybenzene undergoes acylation, reduction, and dehydration reactions in sequence to obtain α-asarone product; The acylation reaction comprises: 1,2,4-trimethoxybenzene reacts with an acylating agent in a solvent under the condition of Lewis acid as a catalyst to generate 2,4,5-trimethoxyphenylacetophenone; the temperature of the acylation reaction is 0 to 10°C; The reduction reaction comprises: 2,4,5-trimethoxyphenylpropiotone reacts with a reducing agent in a solvent to generate 2,4,5-trimethoxyphenylpropanol; The dehydration reaction comprises: under the catalytic condition of a catalyst, 2,4,5-trimethoxyphenylpropanol reacts with an acid anhydride to prepare α-asarone.

2. The method for synthesizing α-asarone according to claim 1, characterized in that: In the acylation reaction, the molar ratio of 1,2,4-trimethoxybenzene to the acylating agent is 1:1-2; in the acylation reaction, the molar ratio of 1,2,4-trimethoxybenzene to the catalyst is 1:1-5; in the acylation reaction, the volume ratio of 1,2,4-trimethoxybenzene to the solvent is 1:5-20; in the acylation reaction, the acylating agent used is one or more of propionic acid, propionic anhydride, and propionyl chloride; in the acylation reaction, the catalyst used is one or more of aluminum chloride, zinc chloride, tin tetrachloride, and tin dichloride; in the acylation reaction, the solvent used is dichloromethane and / or chloroform; the temperature of the acylation reaction is 2-8°C; and the time of the acylation reaction is 1-5h.

3. The method for synthesizing α-asarone according to claim 1 or 2, characterized in that: In the reduction reaction, the molar ratio of 2,4,5-trimethoxypropiophenone to the reducing agent is 1:0.6-2; in the reduction reaction, the volume ratio of 2,4,5-trimethoxypropiophenone to the solvent is 1:3-10; in the reduction reaction, the reducing agent used is one or more of lithium aluminum hydride, sodium borohydride, and potassium borohydride; in the reduction reaction, the solvent used is anhydrous ethanol; the temperature of the reduction reaction is 20-50°C, preferably 30-45°C.

4. The method for synthesizing α-asarone according to any one of claims 1 to 3, characterized in that: In the dehydration reaction, the molar ratio of 2,4,5-trimethoxyphenylpropanol to the catalyst is 1:0.1-2; in the dehydration reaction, the volume ratio of 2,4,5-trimethoxyphenylpropanol to the acid anhydride is 1:3-10; in the dehydration reaction, the catalyst used is one or more of potassium acetate, sodium acetate, copper acetate, magnesium acetate, and copper sulfate; in the dehydration reaction, the acid anhydride used is acetic anhydride; the temperature of the dehydration reaction is 120-170°C, preferably 130-145°C.

5. The method for synthesizing α-asarone according to any one of claims 1 to 4, characterized in that: After the acylation reaction is completed, water is added to quench the reaction, an organic solvent is used to extract and neutralize the Lewis acid in the organic phase, and the organic phase is concentrated to remove the solvent and then directly used in the reduction reaction.

6. The method for synthesizing α-asarone according to any one of claims 1 to 5, characterized in that: After the reduction reaction is completed, the solvent is concentrated to remove the solvent, water is added to dissolve the excess reducing agent, and the organic phase is extracted with an organic solvent. The organic phase is concentrated to remove the solvent and then directly used in the dehydration reaction.

7. The method for synthesizing α-asarone according to claim 6, characterized in that: After the reduction reaction is completed and the solvent is concentrated and removed, the molar ratio of the amount of water added to the amount of the reducing agent used in the reduction reaction is 150-60:

1.

8. The method for synthesizing α-asarone according to any one of claims 1 to 7, characterized in that: After the dehydration reaction is completed, the reaction solution is crystallized in cold water or ice water, and the obtained crystals are recrystallized in an alcohol aqueous solution to obtain an α-asarone product.

9. The method for synthesizing α-asarone according to claim 8, characterized in that: The volume content of alcohol in the alcohol aqueous solution is 60%-100%; the type of alcohol in the alcohol aqueous solution is one or more of methanol, ethanol, propanol, isopropanol, and butanol; the temperature of the cold water or ice water is -3°C to 5°C; the temperature of the recrystallization is -5 to 0°C.

10. The method for synthesizing α-asarone according to any one of claims 1 to 4, characterized in that: The progress of the reaction was monitored by TLC.

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