Preparation method of dehydroevodiamine and dehydroevodiamine salt

Abstract

The invention discloses a preparation method of dehydroevodiamine and a dehydroevodiamine salt, and relates to the technical field of organic synthesis.The preparation method comprises the steps that evodiamine is dissolved in an organic solvent, a dehydrogenation reaction is conducted under the illumination condition, and dehydroevodiamine is obtained; evodiamine is dissolved in an organic solvent and reacts with acid under the action of a catalyst, and the dehydroevodiamine salt is obtained. According to the method, the problems that the process is tedious, the period is long, the production efficiency is low, the environmental protection property is poor and the like when the dehydroevodiamine is extracted, separated and prepared from plants are solved; meanwhile, the defect that demethylation side reaction easily occurs in the synthesis reaction process of the dehydroevodiamine is overcome, and efficient synthesis of the dehydroevodiamine and the dehydroevodiamine salt is achieved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a preparation method of dehydroevodiamine and dehydroevodiamine salt. BACKGROUND

[0002] Dehydroevodiamine (DHED) is a natural indole quinazoline quaternary amine alkaloid in evodia, which is derived from the dried nearly mature fruits of evodia, stone tiger or sparsiflora evodia, belongs to natural indole quinazoline alkaloid, and is a quaternary amine alkaloid with moderate polarity and certain alkalinity. Its pharmacological effects include anti-Alzheimer's disease, anti-arrhythmia, anti-tumor, anti-virus, anti-inflammatory and the like, and it has a significant effect on memory dysfunction and cognitive dysfunction of Alzheimer's disease.

[0003]

[0004] Due to the particularity of the physicochemical properties of dehydroevodiamine and the easy demethylation reaction on the quaternary amine nitrogen, the extraction and separation process is different from other components. Some documents optimize the ethanol solvent method for extracting dehydroevodiamine by response surface analysis method, and the optimized extraction process conditions are that the evodia medicinal material is crushed to 90 meshes, 18.73 times of 65.22% ethanol solution is extracted for 0.82h, and the extraction rate is 6.97mg / g. Some documents purify dehydroevodiamine from traditional Chinese medicine evodia by pH zone chromatography, add triethylamine alkaline solution as the mobile phase, add hydrochloric acid solution as the stationary phase, purify dehydroevodiamine from 2g evodia alkaloid crude extract, and the purity of dehydroevodiamine is 93.1%, and the extraction rate is 152mg / g. Some documents extract dehydroevodiamine from evodia medicinal material by using acid solution according to the alkaline property of dehydroevodiamine, and combine polyamide column chromatography, crystallization and recrystallization and the like to purify dehydroevodiamine, and the purity of dehydroevodiamine is more than 98%, and the extraction rate is about 2.2mg / g. Some documents extract and purify dehydroevodiamine from evodia by using alcohol solvent according to the moderate polarity of dehydroevodiamine, and combine adsorption column chromatography, decolorization and recrystallization and the like, and when AB type macroporous resin is used as the adsorption column chromatography for separation, the extraction rate is the highest, which is 2.2mg / g, and it is found that dehydroevodiamine has strong inhibitory activity on various agricultural pathogenic bacteria. Schramm et al. develop a simple method for purifying gram-level dehydroevodiamine, and the purity of dehydroevodiamine purified by cation exchange resin and preparative RP-HPLC (reverse phase high performance liquid chromatography) is more than 95%.

[0005] At present, the synthesis of dehydroevodiamine and its derivatives is rarely reported, and the main reason is that the demethylation side reaction is easy to occur in the reaction process, which makes it difficult to obtain the target product. It is found that dehydroevodiamine exists in the form of open ring dicarbonyl under alkaline conditions.

[0006]

[0007] A method for preparing dehydroevodiamine from evodiamine is reported in the literature. When evodiamine is reacted with acid to prepare dehydroevodiamine salt, it is found that the solvent has a great influence on the reaction. Dehydroevodiamine cannot be generated in methanol, ethanol, ethyl acetate and acetonitrile, and only in acetone. The reason may be that acetone as a reducing agent can accept hydrogen from evodiamine, promoting the reaction. Hydrochloric acid dehydroevodiamine will open ring under alkaline conditions to form dehydroevodiamine free base, and the free base will close ring to form dehydroevodiamine salt under acidic conditions. In addition, it is found in the test process that the free base ring closing reaction is difficult to carry out in the solvent with high water content or pure water, and the reason may be that the ring closing reaction generates water, and if the water content in the solution is high, it may in turn inhibit the reaction. SUMMARY

[0008] The technical problem to be solved by the present application is to provide a preparation method of dehydroevodiamine and dehydroevodiamine salt, which is simple in operation, mild in reaction conditions, high in product yield and purity, and suitable for industrial production.

[0009] The technical problem to be solved by the present application is solved by the following technical scheme:

[0010] The first object of the present application is to provide a preparation method of dehydroevodiamine, which dissolves evodiamine in an organic solvent and dehydrogenates under light conditions to obtain dehydroevodiamine.

[0011]

[0012] Further, the organic solvent includes but is not limited to one or more of dichloromethane, ethyl acetate, chloroform, tetrahydrofuran, acetonitrile, methanol, ethanol and acetone, and any organic solvent that can dissolve evodiamine can be selected.

[0013] Further, the wavelength of the light condition is 210-700 nm, the power is 50-100 W, and the time is 1-24 h.

[0014] Further, the light condition further includes adding a photosensitizer. Further, the photosensitizer includes but is not limited to one or more of titanium dioxide, cerium oxide, zinc oxide, silicon dioxide, ferric oxide and aluminum oxide. The photosensitizer can improve the light efficiency and shorten the reaction time.

[0015] The second object of the present application is to provide a preparation method of dehydroevodiamine salt, which dissolves evodiamine in an organic solvent and reacts with an acid under the action of a catalyst to obtain dehydroevodiamine salt.

[0016] Further, the organic solvent includes but is not limited to one or more of tetrahydrofuran, acetonitrile, methanol, ethanol, and acetone, and any organic solvent that is miscible with water and can dissolve evodiamine can be selected.

[0017] Further, the acid is hydrochloric acid, hydrobromic acid, acetic acid, propionic acid, or other inorganic or organic acid.

[0018] Further, the molar ratio of evodiamine to the acid is 1:(1-3).

[0019] Further, the catalyst includes but is not limited to one or more of ferric chloride, ferric bromide, and cerium ammonium nitrate.

[0020] Further, the mass ratio of evodiamine to the catalyst is 1:(0.01-0.5).

[0021] The present application has the following beneficial effects: the present application not only solves the problems of complicated process, long period, low production efficiency, and poor environmental protection in the extraction and separation of dehydroevodiamine from plants, but also solves the defect that dehydroevodiamine is prone to demethylation side reactions in the synthesis reaction process, and realizes the efficient synthesis of dehydroevodiamine and dehydroevodiamine salt. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 is the nuclear magnetic hydrogen spectrum of dehydroevodiamine in Example 1;

[0023] Figure 2 is a partial enlarged view of Figure 1 ;

[0024] Figure 3 is the mass spectrum of dehydroevodiamine in Example 1;

[0025] Figure 4 is the nuclear magnetic hydrogen spectrum of dehydroevodiamine hydrochloride in Example 7;

[0026] Figure 5 is a partial enlarged view of Figure 4 ;

[0027] Figure 6 is the nuclear magnetic hydrogen spectrum of dehydroevodiamine hydrochloride in Example 8;

[0028] Figure 7 is a partial enlarged view of Figure 6 . DETAILED DESCRIPTION

[0029] In order to make the technical means, creative features, purposes and effects of the present application easy to understand, the present application is further described below in combination with specific examples and drawings.

[0030] Example 1

[0031] 1 g evodiamine and 50 mL ethyl acetate were added into a 100 mL round-bottom flask, and the reaction was stirred at room temperature under blue light irradiation (wavelength of 400-500 nm, power of 50 W) for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to recover the ethyl acetate, and the concentrate was separated and purified by a silica gel column (V 二氯甲烷 :V 甲醇 = 100:0-10:1, gradient elution), to obtain dehydroevodiamine. The yield was 62%, and the purity was 99.4%. ESI-MS (m / z): Chemical Formula: C 19 H 16 N3O + , Exact Mass: 302.1, [M+] + = 302.2. 1 H-NMR (400 MHz, D2O) δ: 8.22-8.24 (dd, J = 5.2 1.2 Hz, 1H), 7.93-7.96 (dt, J = 5.2 Hz, 1H), 7.81-7.82 (d, J = 5.6 Hz, 1H), 7.70-7.72 (d, J = 5.6 Hz, 1H), 7.61-7.64 (t, J = 5.2 Hz, 1H), 7.48-7.50 (d, J = 5.6 Hz, 1H), 7.38-7.40 (t, J = 5.2 Hz, 1H), 7.13-7.16 (t, J = 5.2 Hz, 1H), 4.43-4.40 (t, J = 4.8 Hz, CH2, 2H), 4.27 (d, CH3, 3H), 3.21-3.23 (t, J = 4.8 Hz, CH2, 2H).

[0032] Example 2

[0033] 2 g evodiamine and 50 mL acetone were added into a 100 mL round-bottom flask, and the reaction was stirred at room temperature under blue light irradiation (wavelength of 400-500 nm, power of 50 W) for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to recover the acetone, and the concentrate was separated and purified by a silica gel column (V 二氯甲烷 :V 甲醇 = 100:0-10:1, gradient elution), to obtain dehydroevodiamine. The yield was 63%, and the purity was 99.6%.

[0034] Example 3

[0035] 2 g of evodiamine and 50 mL of dichloromethane were added to a 100 mL round-bottom flask and reacted at room temperature with stirring under blue light irradiation (wavelength 400–500 nm, power 100 W) for 24 h. After the reaction was completed, the dichloromethane was recovered by vacuum distillation of the reaction solution, and the concentrate was purified by silica gel column chromatography (V... 二氯甲烷 :V 甲醇 The solution was eluted using a gradient ratio of 100:0 to 10:1 to obtain dehydroevodiamine. Yield: 65%, purity: 99.5%.

[0036] Example 4

[0037] 10 g of evodiamine and 500 mL of dichloromethane were added to a 1000 mL round-bottom flask and reacted at room temperature with stirring under blue light irradiation (wavelength 400–500 nm, power 50 W) for 24 h. After the reaction was completed, the dichloromethane was recovered by vacuum distillation of the reaction solution, and the concentrate was recrystallized (V... 乙酸乙酯 :V 正己烷 The ratio of 5:1 was used to obtain dehydroevodiamine. The yield was 72.3%, and the purity was 98.6%.

[0038] Example 5

[0039] 5g of evodiamine and 500mL of methanol were added to a 1000mL round-bottom flask and reacted at room temperature with stirring under blue light irradiation (wavelength 400-500nm, power 50W) for 24h. After the reaction was completed, the methanol was recovered by vacuum distillation, and the concentrate was recrystallized (V... 乙酸乙酯 :V 正己烷 The ratio of 5:1 was used to obtain dehydroevodiamine. The yield was 68.6%, and the purity was 98.1%.

[0040] Example 6

[0041] 1 g of evodiamine and 100 mL of ethanol were added to a 1000 mL round-bottom flask and stirred at room temperature for 12 h under blue light irradiation (wavelength 400–500 nm, power 50 W). After the reaction was completed, the ethanol was recovered by vacuum distillation, and the concentrate was recrystallized (V... 乙酸乙酯 :V 正己烷 The ratio of 5:1 was used to obtain dehydroevodiamine. The yield was 69.8%, and the purity was 98.4%.

[0042] Example 7

[0043] 1 g of evodiamine and 100 mL of acetonitrile were added to a 1000 mL round-bottom flask and stirred at room temperature for 12 h under blue light irradiation (wavelength 400–500 nm, power 50 W). After the reaction was completed, the acetonitrile was recovered by vacuum distillation, and the concentrate was recrystallized (V... 乙酸乙酯 :V 正己烷The ratio of 5:1 was used to obtain dehydroevodiamine. The yield was 70.6%, and the purity was 97.9%.

[0044] Example 8

[0045] 10g of evodiamine, 500mL of acetone, and 1g of titanium dioxide were added to a 1000mL round-bottom flask and reacted at room temperature under fluorescent light (500-700nm, 50W) with stirring for 8 hours. After the reaction was completed, the reaction solution was filtered, and acetone was recovered by vacuum distillation. The concentrate was recrystallized (V... 乙酸乙酯 :V 正己烷 The ratio of 5:1 was used to obtain dehydroevodiamine. The yield was 78.4%, and the purity was 98.9%.

[0046] Example 9

[0047] 0.5 g of evodiamine and 50 mL of acetone were added to a 100 mL round-bottom flask and stirred under natural light at room temperature for 8 hours. After the reaction was completed, the acetone was recovered by vacuum distillation, and the concentrate was recrystallized (V... 乙酸乙酯 The mixture was prepared by reacting hexane (V:V = 5:1) to yield dehydroevodiamine. The yield was 63.1%, and the purity was 97.2%.

[0048] Comparative Example 1

[0049] 1 g of evodiamine and 50 mL of dichloromethane were added to a 100 mL round-bottom flask and left in the dark for 24 hours. Almost no reaction occurred.

[0050] Example 6

[0051] Evodiamine (1 g, 3.30 mmol), 20 mL of acetone, 0.3 mL of acetic acid (5 mmol), and 1 g of ferric chloride were added to a 100 mL round-bottom flask, and the mixture was heated to 50 °C and stirred for 1 h. After the reaction was complete, the reaction solution was poured into ice water to allow crystallization. The crystals were then filtered to obtain dehydroevodiamine acetate. The yield was 53%, and the purity was 97.8%.

[0052] Example 7

[0053] Evodiamine (0.5 g, 1.65 mmol), 20 mL acetonitrile, 4 mol / L hydrochloric acid (1 mL, 4 mmol), and 5 mL ferric chloride aqueous solution (10 wt%) were added to a 100 mL round-bottom flask and stirred at room temperature for 2 h. After the reaction was complete, the reaction solution was poured into ice water to crystallize, and the crystals were filtered to obtain dehydroevodiamine hydrochloride. The yield was 59%, and the purity was 98.3%. 1H-NMR (400 MHz, DMSO-d6) δ: 12.78 (s, 1H), 8.34-8.36 (dd, J = 8.0 1.2 Hz, 1H), 8.13-8.20 (m, 2H), 7.87-7.89 (d, J = 8.0 Hz, 1H), 7.78-7.82 (dt, J = 7.6 Hz, 1H), 7.72-7.74 (d, J = 8.4 Hz, 1H), 7.50-7.54 (dt, J = 8.0 Hz, 1H), 7.25-7.29 (dt, J = 8.0 Hz, 1H), 4.45-4.49 (t, J = 7.2 Hz, CH2, 2H), 4.40 (d, CH3, 3H), 3.31-3.34 (t, J = 7.2 Hz, CH2, 2H).

[0054] Example 8

[0055] Evodiamine (0.5 g, 1.65 mmol), 20 mL acetone, 3 mol / L hydrochloric acid (1 mL, 3 mmol) and 5 mL aqueous ferric chloride solution (10 wt%) were added into a 100 mL round-bottom flask, and the reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was poured into ice water, and crystals were precipitated. Filtration was performed to obtain hydrochloric acid dehydroevodiamine. The yield was 71%, and the purity was 98.7%. 1 H-NMR (400 MHz, CD3OD) δ: 8.42-8.44 (dd, J = 8.0 Hz, 1H), 8.09-8.15 (m, 2H), 7.86-7.88 (d, J = 8.0 Hz, 1H), 7.78-7.82 (t, J = 7.2 Hz, 1H), 7.69-7.71 (d, J = 8.0 Hz, 1H), 7.53-7.56 (t, J = 8.0 Hz, 1H), 7.29-7.33 (t, J = 8.0 Hz, 1H), 4.59-4.62 (t, J = 7.2 Hz, CH2, 2H), 4.48 (d, CH3, 3H), 3.40-3.44 (t, J = 7.2 Hz, CH2, 2H).

[0056] The above shows and describes the basic principles and main features of the present application and the advantages of the present application. It should be understood by those skilled in the art that the present application is not limited by the above examples, and the above examples and descriptions in the specification are only illustrative of the principles of the present application. Without departing from the spirit and scope of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of the claimed present application. The scope of protection of the present application is defined by the appended claims and their equivalents.

Claims

1. A process for the preparation of dehydroevodamine, characterized in that: Evodiamine is dissolved in an organic solvent to undergo a dehydrogenation reaction under light conditions to obtain dehydroevodiamine.

2. The process for preparing dehydroevodiamine according to claim 1, characterized in that: The organic solvent is one or more of dichloromethane, ethyl acetate, chloroform, tetrahydrofuran, acetonitrile, methanol, ethanol, and acetone.

3. The process for preparing dehydroevodamine according to claim 1, characterized in that: The wavelength of the light condition is 210-700 nm, the power is 50-100 W, and the time is 1-24 h.

4. The process for preparing dehydroevodamine according to claim 1, characterized in that: The light condition further comprises adding a photosensitizer. Preferably, the photosensitizer is one or more of titanium dioxide, cerium oxide, zinc oxide, silicon dioxide, diiron trioxide, and aluminum trioxide.

5. A process for the preparation of a dehydroevodiamine salt, characterized in that: Evodiamine is dissolved in an organic solvent to react with an acid under the action of a catalyst to obtain a dehydroevodiamine salt.

6. The process for preparing a dehydroevodiamine salt according to claim 5, characterized in that: The organic solvent is one or more of tetrahydrofuran, acetonitrile, methanol, ethanol, and acetone.

7. The method of claim 5, wherein the dehydroevodiamine salt is prepared by the process comprising: (a) dissolving dehydroevodiamine in a solvent; (b) adding a base to the solution of step (a); and (c) isolating the dehydroevodiamine salt. The acid is one of hydrochloric acid, hydrobromic acid, acetic acid, and propionic acid.

8. The method of claim 5, wherein the dehydroevodiamine salt is prepared by the process comprising: (a) dissolving dehydroevodiamine in a solvent; (b) adding a base to the solution of step (a); and (c) isolating the dehydroevodiamine salt. The molar ratio of evodiamine to the acid is 1:(1-3).

9. The method of claim 5, wherein the dehydroevodiamine salt is prepared by the process comprising: (a) dissolving dehydroevodiamine in a solvent; (b) adding a base to the solution of step (a); and (c) isolating the dehydroevodiamine salt. The catalyst is one or more of ferric chloride, ferric bromide, and cerium ammonium nitrate.

10. The method for preparing dehydroevodiamine salt according to claim 5, characterized in that: The mass ratio of evodiamine to the catalyst is 1:(0.01-0.5).

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