A method for preparing evodiamine

Abstract

The invention discloses a method for preparing evodiamine, comprising the following steps: S1, performing a mitsunobu reaction on a tryptamine alcohol, dialkyl azodicarboxylate, triphenylphosphine and diphenylphosphoryl azide in a first reaction solvent to prepare a tryptamine alkyl azide derivative intermediate; S2, performing an intermolecular Mukaiyama-Michael addition reaction on the tryptamine alkyl azide derivative intermediate obtained in step S1 and N-methyl-3-OTMS indole in a second reaction solvent through Lewis acid catalysis, and obtaining evodiamine by an intramolecular Boyer-Schmidt-Aube rearrangement one-pot method. The invention provides a new process and new ideas for synthesizing evodiamine, and the process route of the invention is simple and not redundant, and the reaction yield is high, which has great innovation, enriches the synthesis method of evodiamine, and has good potential for large-scale industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing evodiamine. Background Art

[0002] Evodiamine is an alkaloid isolated from the fruit of Evodia rutaecarpa, which has multiple biological activities, such as anti-inflammatory, anti-obesity and anti-tumor. In terms of anti-inflammatory, evodiamine can inhibit the expression of cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) in a dose-dependent manner, reduce the release of prostaglandins (E2), block hypoxia-induced phosphorylation of AKt, 70kDa ribosomal protein S6 kinase (p70S6K) and 4E binding protein (4E-BP), regulate the translation process of hypoxia-inducible factor (HIF-1alpha), and have no effect on mRNA levels and protein degradation rates. Evodiamine mainly inhibits hypoxia-induced COX-2 expression by mediating the dephosphorylation of Akt and p70S6K, and then exerts analgesic effects through sensory nerve desensitization. It is particularly important to note that evodiamine, as a new natural anticancer drug, can inhibit the proliferation of various tumor cells, including cervical cancer, colon cancer, lung cancer, melanoma, T lymphocyte leukemia, prostate cancer and breast cancer. In addition, it also has other biological activities, such as regulating body temperature, anti-hypoxia, dermatological applications, bronchial contraction and hormone secretion regulation. In addition, evodiamine has a good binding ability to a variety of proteins, so it can be used as a multi-target compound to exert a variety of biological activities. Therefore, evodiamine has broad application prospects in the prevention and treatment of many diseases.

[0003] In the prior art, the synthesis of evodiamine mainly includes the following methods:

[0004] Patent JP2019131483A discloses a method for obtaining evodiamine from tryptamine and methyl isatoic anhydride as basic raw materials, through condensation, and then cyclization catalyzed by trimethyl orthoformate, as shown below:

[0005] .

[0006] Patent US20240140949A1 discloses a method for obtaining dihydroisoquinoline from N-formyltryptamine by Bischler–Napieralski reaction, and then in situ decarboxylation 4+2 cycloaddition with methyl isatoic anhydride to obtain evodiamine, as shown below:

[0007] .

[0008] Patent CN115124530A discloses a method of reacting o-aminobenzaldehyde with hydroxylamine hydrochloride, followed by the addition of triethyl orthoformate, and a one-pot cyclization to obtain 3-oxoquinazoline, followed by the addition of tert-butyl hydroperoxide, tryptamine, and methyl trifluoromethanesulfonate, and a one-pot cyclization reaction to obtain evodiamine, as shown below:

[0009] .

[0010] In view of the application potential of evodiamine in the prevention and treatment of many diseases, it is necessary to study the synthesis process of evodiamine in order to enrich its preparation methods and provide more options and ideas for its large-scale industrial production. Summary of the invention

[0011] The technical problem to be solved by the present invention is to provide a method for preparing evodiamine in view of the deficiencies in the above-mentioned prior art.

[0012] In order to solve the above technical problems, the technical solution adopted by the present invention is: a method for preparing evodiamine, comprising the following steps:

[0013] S1, performing a Mitsunobu reaction on tryptophol, dialkyl azodicarboxylate, triphenylphosphine and diphenylphosphoryl azide in a first reaction solvent to prepare a tryptamine alkyl azide derivative intermediate;

[0014] S2. The tryptamine alkyl azide derivative intermediate obtained in step S1 is reacted with N-methyl-3-OTMS indole in a second reaction solvent by Lewis acid catalysis to undergo an intermolecular Mukaiyama-Michael addition reaction, and evodiamine is obtained by an intramolecular Boyer-Schmidt-Aube rearrangement in one pot.

[0015] The reaction route of this method is as follows:

[0016]

[0017] Preferably, the dialkyl azodicarboxylate in step S1 is selected from one or both of diethyl azodicarboxylate and diisopropyl azodicarboxylate, and diisopropyl azodicarboxylate is most preferred.

[0018] Preferably, the reaction time in step S1 can be 6-12 h, for example, 6, 8, 10, 12 h or any value therebetween, and most preferably 8 h.

[0019] Preferably, the reaction temperature in step S1 may be 5-15°C, for example, 5°C, 10°C, 15°C or any value therebetween, most preferably 10°C.

[0020] Preferably, in step S1, the molar ratio of dialkyl azodicarboxylate to tryptophan is 1.5:1-1.1:1, for example, 1.5:1, 1.3:1, 1.2:1, 1.1:1 or any value between them, and most preferably 1.2:1.

[0021] Preferably, the molar ratio of triphenylphosphine to tryptophan is 1.5:1 to 1.1:1, for example, 1.5:1, 1.3:1, 1.2:1, 1.1:1 or any value between them, and most preferably 1.2:1.

[0022] Preferably, the molar ratio of diphenylphosphoryl azide to tryptol is 1.5:1 to 1.1:1, for example, 1.5:1, 1.3:1, 1.2:1, 1.1:1 or any value between them, and most preferably 1.2:1.

[0023] Preferably, the first reaction solvent is selected from at least one of toluene, tetrahydrofuran and dichloromethane, and most preferably tetrahydrofuran.

[0024] Preferably, with volume in mL and weight in g, in step S1, the volume of the first reaction solvent is 8 to 15 times the weight of the tryptophan, for example, 8, 10, 12, 13, 15 times or any value between them, most preferably 12 times.

[0025] Preferably, the reaction time in step S2 can be 12-24 hours, for example, 12, 15, 20, 24 or any value therebetween, and most preferably 15 hours.

[0026] Preferably, the reaction temperature in step S2 may be 30-50°C, for example, 30°C, 40°C, 45°C, 50°C or any value between them, most preferably 40°C;

[0027] Preferably, the Lewis acid in step S2 is selected from at least one of titanium tetrachloride, boron trifluoride etherate, and tin tetrachloride, and most preferably titanium tetrachloride.

[0028] Preferably, in step S2, the molar ratio of N-methyl-3-OTMS indole to the tryptamine alkyl azide derivative intermediate is 2.5:1 to 1.0:1, for example, it can be 2.5:1, 2.0:1, 1.5:1, 1.0:1 or any value between them, and most preferably is 2.0:1.

[0029] Preferably, the molar ratio of Lewis acid to tryptamine alkyl azide derivative intermediate is 5.0:1-2.5:1, for example, 5.0:1, 4.0:1, 3.0:1, 2.5:1 or any value between them, and most preferably 4.0:1.

[0030] Preferably, the second reaction solvent is selected from at least one of toluene, ethylene dichloride and dichloromethane, and most preferably dichloromethane.

[0031] Preferably, with the unit of volume being mL and the unit of weight being g, in step S1, the volume of the second reaction solvent is 15 to 25 times the weight of the tryptamine alkyl azide derivative intermediate, for example, 15, 20, 25 times or any value between them, most preferably 20 times.

[0032] Preferably, the preparation method of evodiamine comprises the following steps:

[0033] S1, adding tryptol, triphenylphosphine and diphenylphosphoryl azide into the first reaction solvent, introducing nitrogen, then adding dialkyl azodicarboxylate dropwise, reacting at 5-15° C. for 6-12 hours, concentrating after the reaction, and separating by column chromatography to obtain a tryptamine alkyl azide derivative intermediate;

[0034] S2. Add the tryptamine alkyl azide derivative intermediate and N-methyl-3-OTMS indole obtained in step S1 to the second reaction solvent, introduce nitrogen, then add Lewis acid dropwise, react at 30-50° C. for 12-24 hours, pour the product into hydrochloric acid to quench the reaction after completion, adjust the pH value to 8-9, filter, rinse the filter cake with the second reaction solvent, collect the eluent, extract with dichloromethane, let stand and separate, wash the dichloromethane layer with saturated sodium chloride, dry and concentrate with anhydrous sodium sulfate, add the obtained crude product into methanol, heat and recrystallize to obtain evodiamine.

[0035] Preferably, the preparation method of evodiamine comprises the following steps:

[0036] S1, adding tryptol, triphenylphosphine and diphenylphosphoryl azide to the first reaction solvent, introducing nitrogen into the obtained mixture, cooling the mixture to below 5°C and then adding dialkyl azodicarboxylate dropwise, controlling the temperature of the reaction system not to exceed 10°C during the addition, reacting at 5-15°C for 6-12h after the addition, concentrating after the reaction, and separating by column chromatography to obtain a tryptamine alkyl azide derivative intermediate;

[0037] S2. Add the tryptamine alkyl azide derivative intermediate and N-methyl-3-OTMS indole obtained in step S1 to the second reaction solvent, introduce nitrogen to reduce the temperature of the reaction system to below 5°C, then add Lewis acid dropwise, control the temperature of the reaction system not to exceed 10°C during the addition, react at 30-50°C for 12-24h after the addition, pour the product into 0.5-2mol / L hydrochloric acid to quench after the reaction is complete, then adjust the pH value to 8-9 with 0.5-2mol / L sodium hydroxide, filter with diatomaceous earth, rinse the filter cake with the second reaction solvent, collect the elution, extract with dichloromethane, let stand and separate, wash the dichloromethane layer with saturated sodium chloride, dry and concentrate with anhydrous sodium sulfate, add methanol to the obtained crude product, heat and recrystallize to obtain evodiamine.

[0038] The beneficial effects of the present invention are:

[0039] The invention provides a new process and new idea for synthesizing evodiamine. The invention uses tryptophan as a raw material, adopts Mitsunobu reaction to prepare alkyl azide, and then reacts with 3-OTMS indole to undergo intermolecular Mukaiyama Michael addition reaction under Lewis acid catalysis, and obtains evodiamine through intramolecular Boyer-Schmidt-Aube rearrangement in one pot. The process route of the invention is simple and not complicated, and the reaction yield is high, the invention has great innovation, enriches the synthesis method of evodiamine, and has good potential for industrial mass production. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 The NMR spectrum of the intermediate prepared in Example 1;

[0041] Figure 2 This is the NMR spectrum of evodiamine prepared in Example 1. DETAILED DESCRIPTION

[0042] The present invention is further described in detail below in conjunction with embodiments so that those skilled in the art can implement the invention with reference to the description.

[0043] It should be understood that the terms such as “having”, “including” and “comprising” used herein do not exclude the existence or addition of one or more other elements or combinations thereof.

[0044] The test methods used in the following examples are conventional methods unless otherwise specified. The materials and reagents used in the following examples are all commercially available unless otherwise specified. In the following examples, if no specific conditions are specified, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used, if the manufacturer is not specified, are all conventional products that can be purchased commercially. Example 1

[0045] S1. Preparation of tryptamine alkyl azide derivative intermediates

[0046]

[0047] Add 38 mL of anhydrous tetrahydrofuran into a 100 mL three-necked flask, then add tryptone (3.22 g, 0.020 mol), triphenylphosphine (6.30 g, 0.024 mol), diphenylphosphoryl azide (6.60 g, 0.024 mol), and after replacing nitrogen three times, cool the temperature to below 5°C, and then slowly add diisopropyl azodicarboxylate (4.85 g, 0.024 mol) dropwise. During the addition, pay attention to control the temperature not to exceed 10°C. After the addition, keep the temperature at 10°C and react for 8 hours. After the reaction is completed as monitored by TLC, the reaction solution is directly concentrated to dryness, and then separated by column chromatography to obtain 3.18 g of tryptophan alkyl azide derivative intermediate with a yield of 85.38%.

[0048] The NMR spectrum of the intermediate is Figure 1 As shown, the NMR data are as follows:

[0049] 1 H-NMR(400MHz,CDCl3)δ8.03 (br s, 1H), 7.60 (d, J=7.9 Hz, 1H),7.38 (d,J=8.1Hz, 1H), 7.24-7.20 (m, 1H), 7.17-7.13 (m, 1H),7.09 (d, J=0.6 Hz, 1H), 3.58 (t, J=7.2Hz, 1H), 3.08 (t, J=7.2 Hz, 1H).

[0050] S2. Preparation of Evodiamine

[0051]

[0052] Add 64 mL of dried dichloromethane into a 100 mL three-necked flask, then add tryptamine alkyl azide derivative intermediate (3.18 g, 0.017 mol) and N-methyl-3-OTMS indole (7.5 g, 0.034 mol). After replacing nitrogen three times, cool the temperature to below 5°C, and then slowly add titanium tetrachloride (12.90 g, 0.068 mol). During the addition, pay attention to control the temperature not to exceed 10°C. After the addition, heat to 40°C and reflux for 24 hours. After the reaction was completed as monitored by TLC, the reaction solution was poured into 1 mol / L dilute hydrochloric acid at about 5°C for quenching, and then the pH was adjusted to 9 with 1 mol / L sodium hydroxide, filtered through diatomaceous earth, the filter cake was rinsed 3 times with dichloromethane, extracted with dichloromethane and allowed to stand for stratification, the dichloromethane layer was washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated to dryness, the obtained crude product was added to methanol, heated to 60°C for recrystallization, and 3.85 g of evodiamine was obtained with a yield of 74.63%.

[0053] The NMR spectrum of evodiamine is as follows Figure 2 As shown, the NMR data are as follows:

[0054] 1 H-NMR(400MHz,DMSO-d6)δ11.09(s,1H),7.81(d,J=7.6Hz,1H),

[0055] 7.48(d,J=7.6Hz,2H),7.38(d,J=8.4Hz,1H),7.04(tt,J=25.8,7.4Hz,4H),

[0056] 6.13(s,1H),4.65(dd,J=13.2,5.6Hz,1H),3.19(d,J=12.6Hz,1H),

[0057] 2.89(s,3H),2.79(d,J=15.6Hz,2H). Example 2

[0058] S1. Preparation of tryptamine alkyl azide derivative intermediates

[0059]

[0060] Add 48 ml of anhydrous toluene to a 100 ml three-necked flask, then add tryptone (3.22 g, 0.020 mol), triphenylphosphine (7.87 g, 0.030 mol), diphenylphosphinothionate (8.26 g, 0.030 mol), and cool to below 5°C after nitrogen is replaced three times. Then slowly drop diisopropyl azodicarboxylate (6.07 g, 0.030 mol). During the dropwise addition, pay attention to control the temperature not to exceed 10°C. After adding, keep the temperature at 10°C and react for 8 hours. After the reaction is complete as monitored by TLC, the reaction solution is directly concentrated to dryness, and then separated by column chromatography to obtain 3.01 g of tryptophan alkyl azide derivative intermediate, with a yield of 80.82%.

[0061] S2. Preparation of Evodiamine

[0062]

[0063] Add 75 ml of dry toluene into a 100 ml three-necked flask, then add tryptamine alkyl azide derivative intermediate (3.01 g, 0.016 mol) and N-methyl-3-OTMS indole (8.86 g, 0.040 mol). After replacing nitrogen three times, cool the temperature to below 5°C, and then slowly add tin tetrachloride (20.84 g, 0.080 mol). During the addition, pay attention to control the temperature not to exceed 10°C. After the addition, heat to 50°C and react for 24 hours. After the reaction was completed as monitored by TLC, the reaction solution was poured into 1 mol / L dilute hydrochloric acid at about 5°C for quenching, and then the pH was adjusted to 9 with 1 mol / L sodium hydroxide, filtered through a pad of diatomaceous earth, the filter cake was rinsed 3 times with dichloromethane, extracted with dichloromethane, and allowed to stand for stratification. The dichloromethane layer was washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was added to methanol, heated to 60°C for recrystallization, and 3.39 g of evodiamine was obtained with a yield of 69.88%.

[0064] Although the embodiments of the present invention have been disclosed as above, they are not limited to the applications listed in the specification and the implementation modes. They can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to specific details.

Claims

1. A method for preparing evodiamine, It is characterized in that The following steps are involved: S1, performing a mitsunobu reaction on a tryptol, a dialkyl azodicarboxylate, triphenylphosphine, and diphenylphosphoryl azide in a first reaction solvent to prepare a tryptamine alkyl azide derivative intermediate; Among them, the structural formula of the tryptamine alkyl azide derivative intermediate is as follows: ； S2, subjecting the tryptamine alkyl azide derivative intermediate obtained in step S1 to an intermolecular Michael addition reaction with N-methyl-3-OTMS indole in a second reaction solvent under the catalysis of a Lewis acid, and obtaining evodiamine through an intramolecular Boyer-Schmidt-Aub rearrangement in one pot; The dialkyl azodicarboxylate in step S1 is selected from diisopropyl azodicarboxylate; In step S1, the molar ratio of dialkyl azodicarboxylate to tryptophan is 1.5:1-1.1:1, the molar ratio of triphenylphosphine to tryptophan is 1.5:1-1.1:1, and the molar ratio of diphenylphosphinate to tryptophan is 1.5:1-1.1:1; The first reaction solvent is selected from one of toluene and tetrahydrofuran; In terms of volume in mL and weight in g, in step S1, the volume of the first reaction solvent is 8 to 15 times the weight of the tryptophan; The Lewis acid in step S2 is selected from titanium tetrachloride; In step S2, the molar ratio of N-methyl-3-OTMS indole to the intermediate of tryptamine alkyl azide derivative is 2.5:1-1.0:1, and the molar ratio of Lewis acid to the intermediate of tryptamine alkyl azide derivative is 5.0:1-2.5:1; The second reaction solvent is selected from one of toluene and dichloromethane; In step S1, the volume of the second reaction solvent is 15 to 25 times the weight of the tryptamine alkyl azide derivative intermediate, with the unit of volume being mL and the unit of weight being g; The preparation method of evodiamine specifically comprises the following steps: S1, adding tryptol, triphenylphosphine and diphenylphosphoryl azide to the first reaction solvent, introducing nitrogen into the obtained mixture, cooling the mixture to below 5°C and then adding dialkyl azodicarboxylate dropwise, controlling the temperature of the reaction system not to exceed 10°C during the addition, reacting at 5-15°C for 6-12h after the addition, concentrating after the reaction, and separating by column chromatography to obtain a tryptamine alkyl azide derivative intermediate; S2. Add the tryptamine alkyl azide derivative intermediate and N-methyl-3-OTMS indole obtained in step S1 to the second reaction solvent, introduce nitrogen to reduce the temperature of the reaction system to below 5°C, then add Lewis acid dropwise, control the temperature of the reaction system not to exceed 10°C during the addition, react at 30-50°C for 12-24h after the addition, pour the product into 0.5-2mol / L hydrochloric acid to quench after the reaction is complete, then adjust the pH value to 8-9 with 0.5-2mol / L sodium hydroxide, filter with diatomaceous earth, rinse the filter cake with the second reaction solvent, collect the elution, extract with dichloromethane, let stand and separate, wash the dichloromethane layer with saturated sodium chloride, dry and concentrate with anhydrous sodium sulfate, add methanol to the obtained crude product, heat and recrystallize to obtain evodiamine.

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