CN115124530B - A kind of preparation method of evodiamine - Google Patents

Abstract

A kind of preparation method of evodiamine of the present invention is characterized in that: described method adopts 2-aminobenzaldehyde as raw material and reacts with hydroxylamine hydrochloride to obtain 2-aminobenzaldehyde oxime, then adds triethyl orthoformate, and connects one pot method Cyclization reaction obtains 3-oxygen-quinazoline; Thereafter, add tert-butyl hydroperoxide, tryptamine, methyl trifluoromethanesulfonate and hexamethylphosphoric triamide to carry out one-pot cyclization reaction, Evodiamine was obtained. The method of the present invention adopts a two-step one-pot method, novel synthesis means, simple and convenient process route, green environmental protection, low price of raw materials, simple and easy to obtain, mild reaction conditions, no metal and harmful reagents participating in the reaction, less pollution, and a total yield of 38.2%. ~47.4%, suitable for industrial production.

Description

A kind of preparation method of evodiamine

technical field

The invention relates to the technical field of organic chemistry, in particular to a preparation method of evodiamine.

Background technique

Evodiamine, the English name is Evodiamine. Evodia rutaecarpa is one of the ancient traditional Chinese medicine plants. After soaking and drying the tender fruit, it is the traditional Chinese medicine Evodia rutaecarpa. Stomach ulcers, headaches and other diseases, and at the same time act as an oxytocic agent for maternal uterine weakness and bleeding. Evodiamine is one of the main natural alkaloid components of the traditional Chinese medicine Evodia rutaecarpa, belonging to the tryptamine-indole alkaloids, which have long been used in traditional Chinese medicine for the treatment of gastrointestinal diseases, amenorrhea, postpartum hemorrhage, antithrombotic, anticancer and vasodilatory activities , and regulate the cardiovascular and endocrine systems.

In 1915, Asahina isolated the effective natural bioactive molecule evodiamine from the fruit of Evodia rutaecarpa for the first time. In 1928, Asahina and Ohta synthesized evodiamine for the first time. In the following decades, various synthetic methods of evodiamine and its analogues have been reported at home and abroad. Mhaske et al. used isatoic anhydride and tryptamine to acylate, introduced a methyl group, and prepared evodiamine in a multi-step reaction, with a reaction route of up to 6 steps. In 2007, Kitajima et al. reported a synthetic route starting from N-methylanthranilic acid and tryptamine, in which evodiamine was mediated by mercury acetate-mediated cyclization. This reaction used triphenylphosphine and mercury acetate expensive and environmentally unfriendly reagents. In 2013, Richard et al. used tryptamine and ethyl formate to react imide acylation to synthesize evodiamine. On the way, toxic oxidants were used to participate in the reaction to obtain the key imine intermediate dihydrocarboline. Wu Anxin, Aoki Katsuyuki and others used tryptamine and N-methylisatoic anhydride to synthesize evodiamine using a well-known and commonly used condensation reaction method (Aoki Katsuyuki, the production method of evodiamine, CN: 201910028395.9). Xiong Yu et al. used tryptamine and N-methylanthranilic acid as starting materials, and according to the Diels-Alder reaction mechanism, used N-methyliminoketene as the key intermediate and 3,4-dihydro-β -carboline compound is reacted, and the yield of evodiamine generated can reach 50.4%, which provides a method with potential industrial advantages for preparing evodiamine and its derivatives. Wu Yonglong, Luo Haibin and others used indole acetonitrile as raw material, palladium carbon catalytic hydrogenation to prepare tryptamine, then mixed with ethyl formate into a solution for formylation reaction, then dissolved the reactant in dichloromethane solution, added trifluoromethane Acetic acid undergoes cyclization reaction, and another intermediate is prepared from N-methylanthranilic acid and excess ethyl chloroformate under reflux, and finally the two intermediates are condensed in a non-polar solvent system. The present invention has the advantages of abundant sources of raw materials, low price, and by optimizing the reaction conditions, the yield is improved, the purpose of reducing production costs is achieved, the environment is friendly, and it is suitable for large-scale industrial production (Wu Yonglong, Xu Zhuqing, Chen Changrong, Xu Wei, A Synthetic Method of Evodiamine, ZL: 201010265405.X; Luo Haibin, Sheng Chunquan, Lai Zengwei, Chen Jianwen, Zhang Tianhua, A Class of Evodiamine Compounds and Their Preparation and Application, CN: 201710245872.8; Luo Haibin, Wu Deyan, Yuan Suying, Huang Yiyou, an evodiamine compound and its preparation method and use, CN: 202111316255.5). Peng Xuedong and others used tryptamine as a raw material to obtain evodiamine through a three-step reaction of formylation, cyclization, and condensation ring closure. The whole process avoided the use of phosgene and ethyl chloroformate, reducing the safety risk in the production process. The reaction steps are greatly simplified. At the same time, the invention realizes the mechanical application process of solvents in production, greatly reduces the production cost, and has the value of industrialization promotion (Peng Xuedong, Zhang Mei, Zhao Jinzhao, A production process of evodiamine and a method for recovering mechanical solvents in production, CN: 202011281682. X). and Fang Hua et al. used N,N-dimethylaniline as the reaction raw material to obtain N-methyl isatoic anhydride through oxidative carbonylation reaction, and then obtained N-(2-indoleethyl)-2- (Methylamino) benzamide, and finally synthesize evodiamine compound by three-step cyclization reaction (and Fang Hua, Wang Shoucai, a method for synthesizing evodiamine by three-step carbonylation reaction, ZL: 201710893048.3).

According to the structural composition of evodiamine, there have been several methods to synthesize it. However, some synthetic methods have complex routes and low overall yields. Therefore, it is necessary to develop simple and rapid synthetic methods. Although the above method can successfully synthesize evodiamine, some toxic reagents are often used in the process and the synthesis route is cumbersome, and the generated by-products not only bring great pressure to environmental protection, but also cause a lot of waste. Under such a background, the present invention proposes a new method for constructing evodiamine by using 2-aminobenzaldehyde as a raw material through two-step one-pot reaction cyclization. Less and go green.

Contents of the invention

The object of the present invention is to provide a kind of method of synthesizing evodiamine that is green and environment-friendly.

A preparation method for synthesizing evodiamine of the present invention uses 2-aminobenzaldehyde as a raw material to react with hydroxylamine hydrochloride to obtain 2-aminobenzaldehyde oxime, then adds triethyl orthoformate, and performs a one-pot cyclization reaction in series to obtain 3-oxo- Quinazoline; thereafter, adding tert-butyl hydroperoxide, tryptamine, methyl trifluoromethanesulfonate and hexamethylphosphoric triamide to carry out a one-pot cyclization reaction to obtain evodiamine;

The specific process is:

Step 1: Synthesis of 3-oxo-quinazoline

Add potassium carbonate to the ethanol solution of 2-aminobenzaldehyde and stir to dissolve, continue to add hydroxylamine hydrochloride at 0°C, after the stirring reaction is complete, slowly add triethyl orthoformate to the reaction solution, mix well and then add dropwise Glacial acetic acid, then heat the reaction system to 80°C for reflux. After the reaction is complete, add saturated NaHCO ₃ solution, and cool the product to room temperature. The precipitated solid is washed with anhydrous ether and recrystallized from ethyl acetate to obtain 3-oxo-quinone Azoline; Wherein, the mol ratio of triethyl orthoformate, 2-aminobenzaldehyde, potassium carbonate, hydroxylamine hydrochloride is 5: 1: 1: 1.2.

Step 2: Synthesis of Evodiamine

Add the mixture of 3-oxo-quinazoline, tryptamine and tert-butyl hydroperoxide into 1,4-dioxane solvent, heat to 60°C and stir to complete the reaction, then add hexamethylphosphoric triamide, And continue stirring at 120°C to complete the reaction; the product is cooled to room temperature, quenched with saturated NaHCO ₃ solution, extracted with ethyl acetate, dried with anhydrous Na ₂ SO ₄ , suction filtered and purified by silica gel flash chromatography to obtain evodiamine ; The mol ratio of the 3-oxo-quinazoline, tryptamine, tert-butyl hydroperoxide, methyl trifluoromethanesulfonate and hexamethylphosphoric triamide is 1: 3: 3: 2: 10 .

The specification of the tert-butyl hydroperoxide is 5.5M in decane solution.

The reagents used in the silica gel flash chromatography purification are petroleum ether and ethyl acetate.

The reaction equation is as follows:

Beneficial effects of the present invention: the method of the present invention adopts a two-step one-pot method, novel synthesis means, simple and convenient process route, green and environmental protection, low price of raw materials, simple and easy to obtain, mild reaction conditions, no metal and harmful reagents participating in the reaction, and less pollution , and the total yield reaches 38.2%-47.4%, which is suitable for industrial production.

Detailed ways

Example 1

Add the weighed 2-aminobenzaldehyde (1.21g, 10.0mmol) into a round bottom flask (100mL with a magnet), pour 30mL of ethanol solution, and then add potassium carbonate (1.38g, 10.0mmol) in the flask and dissolved, put the flask into an ice-salt bath, add hydroxylamine hydrochloride (0.83g, 12.0mmol) to the flask at 0°C, stir evenly, react for 10 hours, monitor by TLC until the raw material has reacted completely, and triethyl orthoformate (6.7mL, 40mmol) was slowly added to the reaction solution, and mixed evenly, slowly added dropwise glacial acetic acid (10mol%), after the dropwise addition was completed, the reaction was heated to reflux at about 80°C for 30 minutes, monitored by TLC until the reaction was complete, stop The reaction was cooled to room temperature. Add a certain amount of saturated NaHCO solution in the mixed solution, there will be solid precipitation, then stir and wash with anhydrous ether, the gained solid is the crude product of ₃ -oxo-quinazoline compound, which can be obtained by recrystallization through ethyl acetate The 3-oxo-quinazoline compound was obtained as a white solid, 1.08 g, with a yield of 79%.

A mixture of 3-oxo-quinazoline compound (58.4 mg, 0.4 mmol), tryptamine (192 mg, 1.2 mmol) and tert-butyl hydroperoxide (218 μL, 5.5 M in decane, 1.2 mmol) was dissolved in air was added to a dry sealed tube (10 mL with a magnet), and then 1,4-dioxane (8 mL) was added as a solvent. The sealed tube was stirred at 60° C. for 44 hours, monitored by TLC until the reaction was complete. Methyl trifluoromethanesulfonate (43.8 μL, 0.4 mmol) was then added, and after the reaction mixture was stirred at room temperature for 1 hour, hexamethylphosphoric triamide (0.35 mL, 2 mmol) was added. Then the reaction mixture was stirred at 120° C. for 12 hours, monitored by TLC plate until the reaction was complete, stopped the reaction and cooled to room temperature. The reaction was quenched with saturated aqueous NaHCO ₃ and extracted with ethyl acetate (3×10 mL). The organic layers were combined and dried over anhydrous Na ₂ SO ₄ , followed by suction filtration, and the crude product was purified by silica gel flash chromatography to obtain pure evodiamine as a white solid, 36.4 mg, with a yield of 60%.

Example 2

Add the weighed 2-aminobenzaldehyde (4.84g, 40.0mmol) into a round-bottomed flask (250mL is equipped with a magnet), pour 80mL of ethanol solution, and then add potassium carbonate (5.52g, 40.0mmol) in the flask and dissolved, the flask was put into an ice-salt bath, and hydroxylamine hydrochloride (3.32g, 48.0mmol) was added to the flask at 0°C, stirred evenly, and reacted for 12 hours, monitored by TLC until the reaction of the raw materials was complete, and triethyl orthoformate (26.6mL, 160mmol) was slowly added to the reaction solution, and mixed evenly, and glacial acetic acid (10mol%) was slowly added dropwise. After the dropwise addition, the reaction was heated to about 80°C and refluxed for 40 minutes, monitored by TLC until the raw materials were completely reacted. Stop the reaction, cool to room temperature, add a certain amount of saturated NaHCO solution in the mixed solution, there will be solid precipitation, then stir and wash with anhydrous ether, _the gained solid is the crude product of 3-oxo-quinazoline compound, passed Recrystallization from ethyl acetate gave 3-oxo-quinazoline compound as 3.74 g of white solid with a yield of 72%.

A mixture of 3-oxo-quinazoline compound (292mg, 2mmol), tryptamine (960mg, 6mmol) and tert-butyl hydroperoxide (1.09mL, 5.5M in decane, 6mmol) was added in air to In the dry round bottom flask, 1,4-dioxane (40 mL) solvent was added. The flask was stirred at 60 °C for 48 hours, monitored by TLC until the reaction was complete. Methyl trifluoromethanesulfonate (219 μL, 2 mmol) was then added, and after the reaction mixture was stirred at room temperature for 1.5 hours, hexamethylphosphoric triamide (1.75 mL, 20 mmol) was added. Then the reaction mixture was stirred at 120° C. for 14 hours, monitored by TLC plate until the reaction was complete, stopped the reaction and cooled to room temperature. The reaction was quenched with saturated aqueous NaHCO ₃ and extracted with ethyl acetate (3×30 mL). The organic layers were combined and dried over anhydrous Na ₂ SO ₄ , followed by suction filtration, and the crude product was purified by silica gel flash chromatography to obtain pure evodiamine as a white solid 160.6 mg, yield 53%.

Intermediate 3-oxo-quinazoline compound: yellow solid, Mp: 155-156°C, yield 72%, ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 7.66-7.76 (m, 2H), 7.85-7.91 (m,2H),9.01(s,1H); ¹³ C NMR(100MHz,CDCl ₃ )δ124.5,125.5,129.0,130.4,131.4,131.6,139.8,140.0,149.9;IR(KBr,υ/cm-1) :1861,1703,1567,1331,1193,995; HRMS(EI) calcd for C ₈ H ₇ N ₂ O(M+H)+: 147.0558; found: 147.0561.

Product Evodiamine: White solid, Mp: 244～245℃, yield 53%; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.09(s, 1H), 7.81(d, J=7.6Hz, 1H), 7.48(d,J=7.6Hz,2H),7.38(d,J=8.4Hz,1H),7.04(tt,J=25.8,7.4Hz,4H),6.13(s,1H),4.65(dd,J =13.2, 5.6Hz, 1H), 3.19(d, J=12.6Hz, 1H), 2.89(s, 3H), 2.79(d, J=15.6Hz, 2H). ¹³ C NMR (100MHz, DMSO-d ₆ )δ164.7, 149.2, 136.9, 133.9, 131.1, 128.5, 126.4, 122.3, 120.7, 119.7, 119.4, 118.7, 117.9, 112.1, 112.0, 70.2, 41.4, 36.9, 19.9. HRMS (ESI) calcd for C ₁₉ H ₁₇ N ₃ O[M+H] ⁺ :304.1445,found:304.1447.

Claims (3)

1. a preparation method of evodiamine is characterized by comprising the following steps: the preparation method comprises the steps of reacting 2-aminobenzaldehyde serving as a raw material with hydroxylamine hydrochloride to obtain 2-aminobenzaldehyde oxime, adding triethyl orthoformate, and carrying out a series one-pot cyclization reaction to obtain 3-oxo-quinazoline; then, adding tert-butyl hydroperoxide, tryptamine, methyl trifluoromethanesulfonate and hexamethylphosphoric triamide to perform one-pot cyclization reaction to prepare evodiamine;

the specific process is as follows:

step 1: synthesis of 3-oxo-quinazolines

Adding potassium carbonate into an ethanol solution of 2-aminobenzaldehyde, stirring for dissolving, continuously adding hydroxylamine hydrochloride at 0 ℃, after stirring and reacting completely, slowly adding triethyl orthoformate into a reaction solution, mixing uniformly, then dropwise adding glacial acetic acid, heating a reaction system to 80 ℃, performing reflux reaction completely, adding saturated NaHCO ₃ Cooling the product to room temperature, washing the separated solid with anhydrous ether, and recrystallizing with ethyl acetate to obtain 3-oxo-quinazoline; wherein the mol ratio of triethyl orthoformate, 2-aminobenzaldehyde, potassium carbonate and hydroxylamine hydrochloride is 5: 1: 1.2;

step 2: synthesis of Evodiamine

Adding a mixture of 3-oxo-quinazoline, tryptamine and tert-butyl hydroperoxide into a 1, 4-dioxane solvent, heating to 60 ℃, stirring to react completely, adding hexamethyl phosphoric triamide, and continuously stirring at 120 ℃ to react completely; the product was cooled to room temperature and saturated NaHCO was used ₃ Quenching the reaction solution, extracting with ethyl acetate, and extracting with anhydrous Na ₂ SO ₄ Drying, filtering and purifying by silica gel flash chromatography to obtain evodiamine; the mol ratio of the 3-oxy-quinazoline, the tryptamine, the tert-butyl hydroperoxide, the methyl trifluoromethanesulfonate and the hexamethyl phosphoric triamide is 1: 3: 2: 10.

2. The method for preparing evodiamine according to claim 1, wherein the method comprises the following steps: the specification of the tert-butyl hydroperoxide is 5.5M in decane solution.

3. The method for preparing evodiamine according to claim 1, wherein the method comprises the following steps: the reagents adopted for purification by silica gel flash chromatography are petroleum ether and ethyl acetate.