CN115124530A - Preparation method of evodiamine - Google Patents
Preparation method of evodiamine Download PDFInfo
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- CN115124530A CN115124530A CN202210750885.1A CN202210750885A CN115124530A CN 115124530 A CN115124530 A CN 115124530A CN 202210750885 A CN202210750885 A CN 202210750885A CN 115124530 A CN115124530 A CN 115124530A
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- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract
The invention relates to a method for preparing evodiamine, which is characterized by comprising the following steps: the 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; and then, adding tert-butyl hydroperoxide, tryptamine, methyl trifluoromethanesulfonate and hexamethylphosphoric triamide to perform one-pot cyclization reaction to obtain the evodiamine. The method adopts a two-step one-pot method, has novel synthesis means, simple and convenient process route, environmental protection, low price of raw materials, simplicity, easy obtaining, mild reaction conditions, no metal or harmful reagent participating in the reaction, less pollution, total yield of 38.2-47.4 percent and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of organic chemistry, in particular to a method for preparing evodiamine.
Background
Evodiamine, known in english as evodamine. The fructus evodiae is one of old traditional Chinese medicine plants, tender fruits are soaked and dried to be the traditional Chinese medicine fructus evodiae, is a bitter stomach strengthening agent and an analgesic, is also used as an ascarid, can be used for treating diseases such as hypertension, diarrhea, gastric ulcer, headache and the like, and simultaneously has the effect of an oxytocic on uterine atony and bleeding conditions of a lying-in woman. Evodiamine is one of main natural alkaloid components of traditional Chinese medicine evodia rutaecarpa, belongs to tryptamine indole alkaloids, and is used for treating gastrointestinal tract diseases, amenorrhea, postpartum hemorrhage, antithrombotic activity, anticancer activity and vasodilatation activity in traditional Chinese medicines for a long time, and has the effect of regulating cardiovascular and endocrine systems.
In 1915, Asahina firstly separated the effective natural bioactive molecule evodiamine from the evodia fruit. In 1928, evodiamine was synthesized for the first time by Asahina and Ohta. In the next decades, various synthetic methods of evodiamine and analogues thereof have been reported through research at home and abroad. Mhaske and the like adopt isatoic anhydride and tryptamine to prepare evodiamine through acylation and methyl introduction by multi-step reaction, and the reaction route is as many as 6 steps. In 2007, Kitajima et al reported a synthetic route starting from N-methylanthranilic acid and tryptamine with intermediate formation of evodiamine by mercury acetate mediated cyclization, using expensive and environmentally unfriendly reagents such as triphenylphosphine and mercury acetate. In 2013, Richard et al react with tryptamine and ethyl formate to perform imine acylation to synthesize evodiamine, and adopt a toxic oxidant to participate in the reaction in the process to obtain a key imine intermediate dihydrocarboline. Wu-Anxin and Qing mu Sheng et al synthesized evodiamine by a known and conventional condensation reaction method using tryptamine and N-methylisatoic anhydride (Wu-Anshi, a method for producing evodiamine, CN: 201910028395.9). Bear yoga et al take tryptamine and N-methyl anthranilic acid as initial raw materials, according to a Diels-Alder reaction mechanism, N-methyliminoketene is taken as a key intermediate to react with a 3, 4-dihydro-beta-carboline compound, the yield of the generated evodiamine can reach 50.4%, and a method for preparing the evodiamine and derivatives thereof with potential industrial advantages is provided. Wuyonglong and Lohai Bin, etc. take indole acetonitrile as raw material, palladium carbon catalytic hydrogenation prepares tryptamine, then mix with ethyl formate to get solution and take formylation reaction, dissolve reactant in dichloromethane solution, add trifluoroacetic acid to take cyclization reaction, then prepare another intermediate by N-methyl anthranilic acid and excessive ethyl chloroformate under the reflux state, finally take condensation reaction of two intermediates under the non-polar solvent system. The invention has the advantages of rich raw material sources, low price, improved yield through the optimization of reaction conditions, realization of the purpose of reducing production cost, environmental friendliness and suitability for large-scale industrial production (Wu Yonglong, Xuzhuqing, Cheng Rong, Xuwei, a synthetic method of evodiamine, ZL:201010265405. X; Rohaibin, spring, Liangwei, Cheng Jianwen, Zhang Tianhua, a class of evodiamine compounds and a preparation method and application thereof, CN: 201710245872.8; Rohaibin, Wu De Yan, Yuxinying, Huang Yiyu has, a evodiamine compound and a preparation method and application thereof, and CN: 202111316255.5). Tryptamine is adopted as a raw material by Pengzhi et al, and three steps of formylation, cyclization, condensation and ring closure are carried out to obtain the evodiamine, so that phosgene and ethyl chloroformate are avoided in the whole process, the safety risk in the production process is reduced, and the reaction steps are greatly simplified. Meanwhile, the invention realizes the recycling process of the solvent in the production, greatly reduces the production cost and has industrial popularization value (Pengzhitong, Zhang Mei, Zhao jin zhao, a production process of evodiamine and a method for recycling the solvent in the production, CN 202011281682. X). And Fanhua et al, which uses N, N-dimethylaniline as a reaction raw material to obtain N-methyl isatoic anhydride through oxidative carbonylation, then obtains N- (2-indolylethyl) -2- (methylamino) benzamide through aminolysis, and finally synthesizes evodiamine through three steps of cyclization (Zhaohua, Wangcheng, a method for synthesizing evodiamine by using carbonylation three steps, ZL: 201710893048.3).
Several methods have been used to synthesize evodiamine based on its structural composition. However, some synthetic methods have complex routes and low total yield. Therefore, it is necessary to develop a simple and rapid synthesis method. Although the method can successfully synthesize the evodiamine, some toxic reagents are often needed in the process, the synthesis route is complicated, and the generated by-products not only bring great pressure to environmental protection, but also cause great waste. Under the background, the invention provides a novel method for constructing the evodiamine by using 2-aminobenzaldehyde as a raw material and performing cyclization reaction by a two-step one-pot method, and the method has the advantages of mild reaction process conditions, simple and easily obtained raw materials, no metal participation, less pollution and environmental protection.
Disclosure of Invention
The invention aims to provide a green and environment-friendly method for synthesizing evodiamine.
The invention relates to a preparation method for synthesizing evodiamine, which adopts 2-aminobenzaldehyde as a raw material to react with hydroxylamine hydrochloride to obtain 2-aminobenzaldehyde oxime, and then triethyl orthoformate is added to carry 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 ethanol solution of 2-aminobenzaldehyde, stirring for dissolving, continuously adding hydroxylamine hydrochloride at 0 ℃, after stirring and reacting completely, slowly adding triethyl orthoformate into the reaction liquid, mixing uniformly, then dropwise adding glacial acetic acid, heating the reaction system to 80 ℃ for reflux reaction completely, and then 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 the triethyl orthoformate, the 2-aminobenzaldehyde, the potassium carbonate and the 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 continuing to stir at 120 ℃ to react completely; the product was cooled to room temperature and saturated NaHCO was used 3 Quenching the solution, extracting with ethyl acetate and 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 hexamethylphosphoric triamide is 1: 3: 2: 10.
The specification of the tert-butyl hydroperoxide is 5.5M in decane solution.
The reagents adopted for purification by silica gel flash chromatography are petroleum ether and ethyl acetate.
The reaction equation is as follows:
the invention has the beneficial effects that: the method adopts a two-step one-pot method, has novel synthesis means, simple and convenient process route, environmental protection, low price of raw materials, simplicity, easy obtainment, mild reaction conditions, no metal or harmful reagent participating in the reaction, less pollution, total yield up to 38.2-47.4 percent and suitability for industrial production.
Detailed Description
Example 1
The weighed 2-aminobenzaldehyde (1.21g, 10.0mmol) was added to a round bottom flask (100mL equipped with magnetons), 30mL of an ethanol solution was poured, followed by addition and dissolution of potassium carbonate (1.38g, 10.0mmol) in the flask, the flask was placed in a ice salt bath, hydroxylamine hydrochloride (0.83g, 12.0mmol) was added to the flask at 0 ℃, stirring was conducted uniformly, the reaction was carried out for 10 hours, TLC monitoring was carried out until the reaction of the raw materials was completed, triethyl orthoformate (6.7mL,40mmol) was slowly added to the reaction solution and mixed uniformly, glacial acetic acid (10 mol%) was slowly added dropwise, after completion of the dropwise addition, the reaction was heated to about 80 ℃ for 30 minutes under reflux, TLC monitoring was carried out until the reaction was completed, and the reaction was stopped and cooled to room temperature. Adding a certain amount of saturated NaHCO into the mixed solution 3 After the solution was dissolved, a solid was precipitated and washed with dehydrated ether under stirring to obtain a crude product of the 3-oxo-quinazoline compound, which was recrystallized from ethyl acetate to obtain 1.08g of the 3-oxo-quinazoline compound as a white solid with a yield of 79%.
A mixture of the 3-oxo-quinazoline compound (58.4mg, 0.4mmol), tryptamine (192mg, 1.2mmol) and t-butyl hydroperoxide (218. mu.L, 5.5M in decane solution, 1.2mmol) was added to a dry sealed tube (10mL with magnetons) in air, followed by 1, 4-dioxane (8mL) solvent. The tube was stirred at 60 ℃ for 44 hours and TLC monitored to completion. Methyl trifluoromethanesulfonate (43.8. mu.L, 0.4mmol) was then added, and after stirring the reaction mixture at room temperature for 1 hour, hexamethylphosphoric triamide (0.35mL,2mmol) was added. The reaction mixture was then stirred at 120 ℃ for 12 hours, monitored by TLC plates to completion, stopped and cooled to room temperature. With saturated NaHCO 3 Quench the reaction with aqueous Ether (3X 10 mL)) And (4) extracting. The organic layers were combined and washed with anhydrous Na 2 SO 4 Drying, followed by suction filtration, purified the crude product by flash chromatography on silica gel to give pure evodiamine as a white solid 36.4mg, 60% yield.
Example 2
Adding weighed 2-aminobenzaldehyde (4.84g, 40.0mmol) into a round-bottom flask (250mL containing magnetons), pouring 80mL of ethanol solution, adding potassium carbonate (5.52g, 40.0mmol) into the flask and dissolving, putting the flask into a glacial salt bath, adding hydroxylamine hydrochloride (3.32g, 48.0mmol) into the flask at 0 ℃, uniformly stirring, reacting for 12 hours, monitoring by TLC until the raw materials are completely reacted, slowly adding triethyl orthoformate (26.6mL,160mmol) into the reaction solution, uniformly mixing, slowly adding glacial acetic acid (10 mol%), after adding, heating the reaction to about 80 ℃, refluxing for 40 minutes by TLC until the raw materials are completely reacted, stopping the reaction, cooling to room temperature, adding a certain amount of saturated NaHCO into the mixed solution 3 In the solution, a solid is precipitated and is stirred and washed by using anhydrous ether, the obtained solid is a crude product of the 3-oxo-quinazoline compound, and the 3-oxo-quinazoline compound is obtained by recrystallization from ethyl acetate, wherein the yield is 72 percent, and the white solid is 3.74 g.
A mixture of 3-oxo-quinazoline compound (292mg, 2mmol), tryptamine (960mg, 6mmol) and tert-butyl hydroperoxide (1.09mL, 5.5M in decane solution, 6mmol) was added to a dry round bottom flask in air, followed by 1, 4-dioxane (40mL) solvent. The flask was stirred at 60 ℃ for 48 hours and monitored by TLC to completion of the reaction. Methyl trifluoromethanesulfonate (219. mu.L, 2mmol) was then added, and after stirring the reaction mixture at room temperature for 1.5 hours, hexamethylphosphoric triamide (1.75mL,20mmol) was added. The reaction mixture was then stirred at 120 ℃ for 14 h, monitored by TLC plates to completion, stopped and cooled to room temperature. With saturated NaHCO 3 The reaction was quenched with aqueous solution and extracted with ethyl acetate (3X 30 mL). The organic layers were combined and washed with anhydrous Na 2 SO 4 Drying followed by suction filtration and purification of the crude product by flash chromatography on silica gel gave pure evodiamine as a white solid 160.6mg, 53% yield.
Intermediate 3-oxo-quinazoline compound: yellow solid, Mp:155-, 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.
the 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 ethanol solution of 2-aminobenzaldehyde, stirring for dissolving, continuously adding hydroxylamine hydrochloride at 0 ℃, after stirring and reacting completely, slowly adding triethyl orthoformate into the reaction liquid, mixing uniformly, then dropwise adding glacial acetic acid, heating the reaction system to 80 ℃ for reflux reaction completely, and then adding saturated NaHCO 3 Cooling the solution and product to room temperature, washing the separated solid with anhydrous etherRecrystallizing with ethyl acetate to obtain 3-oxy-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 solution, extracting with ethyl acetate and 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.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080096902A1 (en) * | 2004-08-19 | 2008-04-24 | Applied Genetics Incorporated Dermatics | Biomimetic Of Evodia Rutaecarpa Fruit Extract For Amelioration Of Inflammation |
| CN101941971A (en) * | 2010-08-25 | 2011-01-12 | 杭州福斯特药业有限公司 | Method for synthesizing evodiamine |
| CN107629051A (en) * | 2017-09-27 | 2018-01-26 | 桂林理工大学 | A kind of method that rutaecarpin is synthesized using carbonylation three-step approach |
| CN110453242A (en) * | 2019-09-17 | 2019-11-15 | 广西师范大学 | A kind of method of electrochemistry formated Rutaecarpine |
| CN113683615A (en) * | 2021-09-27 | 2021-11-23 | 南华大学 | Evodiamine derivative and preparation and application thereof |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080096902A1 (en) * | 2004-08-19 | 2008-04-24 | Applied Genetics Incorporated Dermatics | Biomimetic Of Evodia Rutaecarpa Fruit Extract For Amelioration Of Inflammation |
| CN101941971A (en) * | 2010-08-25 | 2011-01-12 | 杭州福斯特药业有限公司 | Method for synthesizing evodiamine |
| CN107629051A (en) * | 2017-09-27 | 2018-01-26 | 桂林理工大学 | A kind of method that rutaecarpin is synthesized using carbonylation three-step approach |
| CN110453242A (en) * | 2019-09-17 | 2019-11-15 | 广西师范大学 | A kind of method of electrochemistry formated Rutaecarpine |
| CN113683615A (en) * | 2021-09-27 | 2021-11-23 | 南华大学 | Evodiamine derivative and preparation and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 王翠玲等: "吴茱萸次碱的合成进展" * |
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