CN115124530B - Preparation method of evodiamine - Google Patents
Preparation method of evodiamine Download PDFInfo
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- CN115124530B CN115124530B CN202210750885.1A CN202210750885A CN115124530B CN 115124530 B CN115124530 B CN 115124530B CN 202210750885 A CN202210750885 A CN 202210750885A CN 115124530 B CN115124530 B CN 115124530B
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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, the tender fruit is the traditional Chinese medicine fructus evodiae after being soaked and dried, is a bitter stomachic and analgesic, is also used as a 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 for puerpera uterine arrays and bleeding conditions. Evodiamine is one of the main natural alkaloid components of the traditional Chinese medicine evodia rutaecarpa, belongs to tryptamine indole alkaloids, and is used for treating gastrointestinal diseases, amenorrhea, postpartum hemorrhage, antithrombotic, anticancer and vasodilatation activities and has the effect of regulating cardiovascular and endocrine systems for a long time in the traditional Chinese medicine.
In 1915, asahina firstly separated the effective natural bioactive molecule evodiamine from fructus evodiae 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 using tryptamine and N-methylisatoic anhydride through a known and conventional condensation reaction method (Wu' anxin, a method for preparing 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 Rohaibin, etc. take indole acetonitrile as raw material, palladium carbon is catalyzed and hydrogenated to prepare tryptamine, then the tryptamine is mixed with ethyl formate to form a solution for formylation, then reactants are dissolved in dichloromethane solution, trifluoroacetic acid is added for cyclization, N-methyl anthranilic acid and excessive ethyl chloroformate are used for preparing another intermediate under reflux state, and finally the two intermediates are condensed and reacted under a 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 aim of reducing production cost, environmental friendliness and suitability for large-scale industrial production (Wuyonglong, xuzhuqing, chenghongrong, xuwei, a synthetic method of evodiamine, ZL:201010265405.X, louisanling, spring, lijiawei, chenjianwen, zhang Tianhua, a class of evodiamine compounds and a preparation method and application thereof, CN:201710245872.8, louisaibin, wudelphin, yuyingying, huangyixu, an evodiamine compound and a preparation method and application thereof, CN: 202111623155.5). Penstodong and the like adopt tryptamine as a raw material and obtain the evodiamine through three steps of formylation, cyclization and condensation ring closing reaction, the whole process avoids the use of phosgene and ethyl chloroformate, reduces the safety risk in the production process and greatly simplifies the reaction steps. Meanwhile, the invention realizes the application process of the solvent in the production, greatly reduces the production cost and has industrial popularization value (Pengzhong, 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 use N, N-dimethylaniline as a reaction raw material to obtain N-methyl isatoic anhydride through oxidative carbonylation, then obtain N- (2-indolylethyl) -2- (methylamino) benzamide through aminolysis, and finally synthesize the evodiamine compound through three steps of cyclization reaction (Fanhua, wangzhao, a method for synthesizing evodiamine by using carbonylation reaction 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 solution and the product to room temperature, washing the separated solid with anhydrous ether, and recrystallizing with ethyl acetate to obtain 3-oxo-quinazol(ii) an alkyl; wherein the mol ratio of the triethyl orthoformate to the 2-aminobenzaldehyde to the potassium carbonate to 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 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.
The specification of the tert-butyl hydroperoxide is 5.5M in decane solution.
The silica gel flash chromatography adopts petroleum ether and ethyl acetate as the reagents for purification.
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
Adding weighed 2-aminobenzaldehyde (1.21g, 10.0mmol) into a round-bottom flask (100 mL is provided with magnetons), pouring 30mL of ethanol solution, then adding potassium carbonate (1.38g, 10.0mmol) into the flask and dissolving, placing the flask into an ice salt bath, adding hydroxylamine hydrochloride (0.83g, 12.0mmol) into the flask at 0 ℃, uniformly stirring, reacting for 10 hours, monitoring by TLC until the raw materials are completely reacted, and adding the orthoformate into the flaskEthyl ester (6.7mL, 40mmol) was slowly added to the reaction mixture and mixed well, glacial acetic acid (10 mol%) was slowly added dropwise, after the addition was complete, the reaction was heated to about 80 ℃ and refluxed for 30 minutes, TLC monitored until the reaction was complete, 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 (58.4 mg,0.4 mmol), 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 (10 mL with magnetite) in air, followed by 1, 4-dioxane (8 mL) solvent. The tube was stirred at 60 ℃ for 44 hours and TLC monitored to completion. Methyl trifluoromethanesulfonate (43.8. Mu.L, 0.4 mmol) 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 The reaction was quenched with aqueous solution and extracted with ethyl acetate (3X 10 mL). 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, 40.0 mmol) into a round-bottom flask (250 mL with magnetons), pouring 80mL of ethanol solution, then adding potassium carbonate (5.52g, 40.0 mmol) into the flask and dissolving, putting the flask into a glacial salt bath, adding hydroxylamine hydrochloride (3.32g, 48.0 mmol) 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 liquid, uniformly mixing, slowly dropwise adding glacial acetic acid (10 mol%), after dropwise adding, heating to 80 ℃ for about refluxing for 40 minutes, monitoring by TLC until the raw materials are completely reacted, stopping the reaction, cooling to the temperature of 80 ℃Adding a certain amount of saturated NaHCO into the mixed solution at room temperature 3 After the solution was dissolved, a solid was precipitated and washed with anhydrous ether under stirring to obtain a solid, i.e., a crude product of the 3-oxo-quinazoline compound, which was recrystallized from ethyl acetate to obtain a 3-oxo-quinazoline compound as a white solid (3.74 g), in a yield of 72%.
A mixture of 3-oxo-quinazoline compound (292mg, 2mmol), tryptamine (960 mg, 6mmol) and t-butyl hydroperoxide (1.09 mL, 5.5M,6mmol in decane solution) was added to a dry round bottom flask in air, followed by 1, 4-dioxane (40 mL) solvent. The flask was stirred at 60 ℃ for 48 hours and monitored by TLC to completion of the reaction. Methyl trifluoromethanesulfonate (219. Mu.L, 2 mmol) 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:155-156 deg.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.
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 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.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| CN101005856A (en) * | 2004-08-19 | 2007-07-25 | 皮肤应用遗传学股份有限公司 | Biomimetic of evodia rutaecarpa fruit extract for amelioration of inflammation |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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| 王翠玲等.吴茱萸次碱的合成进展.有机化学.2006,第26卷(第26期),第1437-1443页. * |
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