A method for preparing dehydroevodiamine and dehydroevodiamine salts

Abstract

This invention discloses a method for preparing dehydroevodiamine and its salt, relating to the field of organic synthesis technology. The method involves dissolving evodiamine in an organic solvent and subjecting it to a dehydrogenation reaction under light irradiation to obtain dehydroevodiamine; or dissolving evodiamine in an organic solvent and reacting it with an acid under the action of a catalyst to obtain dehydroevodiamine salt. This invention not only solves the problems of cumbersome processes, long cycles, low production efficiency, and poor environmental friendliness in the extraction and separation of dehydroevodiamine from plants, but also overcomes the defect of demethylation side reactions that easily occur during the synthesis of dehydroevodiamine, achieving efficient synthesis of dehydroevodiamine and its salt.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for preparing dehydroevodiamine and dehydroevodiamine salt. Background Technology

[0002] Dehydroevodiamine (DHED) is a natural indolequinazoline quaternary ammonium alkaloid from Evodia rutaecarpa. It is derived from the dried, nearly mature fruit of Evodia rutaecarpa, Evodia thunbergii, or Evodia rutaecarpa var. sparsely hairy, belonging to the natural indolequinazoline alkaloid class. It is a quaternary ammonium alkaloid with moderate polarity and a certain degree of alkalinity. Its pharmacological effects include anti-Alzheimer's disease, anti-arrhythmia, anti-tumor, antiviral, and anti-inflammatory effects, especially its significant effects on memory and cognitive impairments manifested in Alzheimer's disease.

[0003] Due to the unique physicochemical properties of dehydroevorutin and its tendency to undergo demethylation reactions on quaternary ammonium nitrogen, its extraction and separation processes differ from those of other components. One study optimized the extraction process of dehydroevorutin using ethanol solvent via response surface methodology. The optimized extraction conditions were: 90-mesh powder of Evodia rutaecarpa, 18.73 times the particle size of 65.22% ethanol solution, and 0.82 h of extraction, yielding an extraction rate of 6.97 mg / g. Another study used pH zone chromatography to separate and purify dehydroevorutin from Evodia rutaecarpa using an alkaline solution with added triethylamine as the mobile phase and hydrochloric acid as the stationary phase. The purity of dehydroevorutin obtained from 2 g of crude Evodia rutaecarpa alkaloid extract reached 93.1%, with an extraction rate of 152 mg / g. Based on the alkaline nature of dehydroevodiamine, some literature utilizes acidic solutions for extraction, combined with polyamide column chromatography, crystallization, and recrystallization, to purify dehydroevodiamine from Evodia rutaecarpa with a purity exceeding 98%, and an extraction rate of approximately 2.2 mg / g. Other literature, based on the moderate polarity of dehydroevodiamine, employs alcoholic solvent extraction, combined with adsorption column chromatography, decolorization, and recrystallization to purify it from Evodia rutaecarpa. The highest extraction rate of 2.2 mg / g was achieved when using AB-type macroporous resin as the adsorption column for separation, and dehydroevodiamine was found to have strong inhibitory activity against various agricultural pathogens. Schramm et al. developed a simple method for purifying gram-level dehydroevodiamine, achieving a purity exceeding 95% through cation exchange resin and preparative RP-HPLC (reversed-phase high-performance liquid chromatography). However, the extraction and separation process for preparing dehydroevodiamine is time-consuming, inefficient, and unsuitable for industrial production.

[0004] There are few reports on the synthesis of dehydroevodiamine and its derivatives, mainly because the demethylation side reaction easily occurs during the reaction, making it difficult to obtain the target product. Studies have found that dehydroevodiamine exists in a ring-opening dicarbonyl form under alkaline conditions.

[0005] A method for preparing dehydroevodiamine from evodiamine has been reported in the literature. When preparing dehydroevodiamine salt by reacting evodiamine with an acid, it was found that the solvent has a significant impact on the reaction. Dehydroevodiamine cannot be formed in methanol, ethanol, ethyl acetate, or acetonitrile; it can only be formed in acetone. This may be because acetone acts as a reducing agent, accepting hydrogen from evodiamine and promoting the reaction. Dehydroevodiamine hydrochloride undergoes ring-opening under alkaline conditions to form the free dehydroevodiamine base, which then undergoes ring-closure under acidic conditions to form the dehydroevodiamine salt. Furthermore, the ring-closure reaction of the free base was found to be difficult to carry out in solvents with high water content or in pure water. This may be because ring-closure generates water, and a high water content in the solution may, conversely, inhibit the reaction. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a method for preparing dehydroevodiamine and dehydroevodiamine salt. The preparation method is simple to operate, the reaction conditions are mild, and the product yield and purity are high, making it suitable for industrial production.

[0007] The technical problem to be solved by this invention is achieved by the following technical solution:

[0008] The first objective of this invention is to provide a method for preparing dehydroevodiamine, wherein evodiamine is dissolved in an organic solvent and undergoes a dehydrogenation reaction under light irradiation to obtain dehydroevodiamine.

[0009] Furthermore, 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 capable of dissolving evodiamine may be selected.

[0010] Furthermore, the wavelength of the illumination conditions is 210~700 nm, the power is 50~100 W, and the time is 1~24 h.

[0011] Furthermore, the illumination conditions also include the addition of a photosensitizer. Even 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's function is to improve light efficiency and shorten reaction time.

[0012] The second objective of this invention is to provide a method for preparing dehydroevodiamine salt, wherein evodiamine is dissolved in an organic solvent and reacted with an acid under the action of a catalyst to obtain dehydroevodiamine salt.

[0013] Furthermore, 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.

[0014] Furthermore, the acid is an inorganic acid or an organic acid such as hydrochloric acid, hydrobromic acid, acetic acid, or propionic acid.

[0015] Furthermore, the molar ratio of evodiamine to acid is 1:(1~3).

[0016] Furthermore, the catalyst includes, but is not limited to, one or more of ferric chloride, ferric bromide, and cerium ammonium nitrate.

[0017] Furthermore, the mass ratio of evodiamine to catalyst is 1:(0.01~0.5).

[0018] The beneficial effects of this invention are: this invention not only solves the problems of cumbersome process, long cycle, low production efficiency and poor environmental protection in the extraction, separation and preparation of dehydroevodiamine from plants; at the same time, it also solves the defect of demethylation side reaction that dehydroevodiamine is prone to occur in the synthesis reaction, and realizes the efficient synthesis of dehydroevodiamine and dehydroevodiamine salt. Attached Figure Description

[0019] Figure 1 The 1H NMR spectrum of dehydroevodiamine in Example 1;

[0020] Figure 2 for Figure 1 A magnified view of a portion of the image;

[0021] Figure 3 This is the mass spectrum of dehydroevodiamine in Example 1;

[0022] Figure 4 The 1H NMR spectrum of dehydroevodiamine hydrochloride in Example 7;

[0023] Figure 5 for Figure 4 A magnified view of a portion of the image;

[0024] Figure 6 The 1H NMR spectrum of dehydroevodiamine hydrochloride in Example 8;

[0025] Figure 7 for Figure 6 A magnified view of a portion of the image. Detailed Implementation

[0026] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below with reference to specific embodiments and illustrations.

[0027] Example 1

[0028] 1 g of evodiamine and 50 mL of ethyl acetate 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 50 W) for 24 h. After the reaction was completed, the reaction solution was distilled under reduced pressure to recover ethyl acetate, and the concentrate was purified by silica gel column chromatography (V... 二氯甲烷 :V 甲醇 (Gradient elution of 100:0~10:1) yielded dehydroevodiamine. Yield 62%, purity 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).

[0029] Example 2

[0030] 2 g of evodiamine and 50 mL of acetone 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 50 W) for 24 h. After the reaction was completed, the acetone was recovered by vacuum distillation, and the concentrate was purified by silica gel column chromatography (V... 二氯甲烷 :V 甲醇 (Gradient elution of 100:0~10:1) yielded dehydroevodiamine. Yield: 63%, purity: 99.6%.

[0031] Example 3

[0032] 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, and the concentrate was purified by silica gel column chromatography (V... 二氯甲烷 :V 甲醇 (Gradient elution of 100:0~10:1) yielded dehydroevodiamine. Yield: 65%, purity: 99.5%.

[0033] Example 4

[0034] 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%.

[0035] Example 5

[0036] 5 g of evodiamine and 500 mL of methanol 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 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%.

[0037] Example 6

[0038] 1 g of evodiamine and 100 mL of ethanol 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 12 h. 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%.

[0039] Example 7

[0040] 1 g of evodiamine and 100 mL of acetonitrile 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 12 h. 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%.

[0041] Example 8

[0042] 10 g of evodiamine, 500 mL of acetone, and 1 g of titanium dioxide were added to a 1000 mL round-bottom flask and reacted at room temperature under fluorescent light (500–700 nm, 50 W) with stirring for 8 h. After the reaction was complete, 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%.

[0043] Example 9

[0044] 0.5 g of evodiamine and 50 mL of acetone were added to a 100 mL round-bottom flask and reacted under natural light with stirring at room temperature for 8 h. After the reaction was completed, the acetone 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 63.1%, and the purity was 97.2%.

[0045] Comparative Example 1

[0046] 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.

[0047] Example 10

[0048] Evodiamine (1 g, 3.30 mmol), 20 mL acetone, acetic acid (0.3 mL, 5 mmol), and 1 g 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 crystallize, and the crystals were filtered to obtain dehydroevodiamine acetate. The yield was 53%, and the purity was 97.8%.

[0049] Example 11

[0050] 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%. 1 H-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=8.0Hz, 1H), 7.78-7.82 (dt, J=7.6 Hz, 1H), 7.72-7.74 (d,J=8.4Hz, 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).

[0051] Example 12

[0052] Evodiamine (0.5 g, 1.65 mmol), 20 mL acetone, 3 mol / L hydrochloric acid (1 mL, 3 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 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=8.0Hz, 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).

[0053] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing dehydroevodiamine salt, characterized in that: Evodiamine is dissolved in an organic solvent and reacted with an acid in the presence of a catalyst to obtain dehydroevodiamine salt. The organic solvent is acetonitrile; The acid is one of hydrochloric acid, hydrobromic acid, acetic acid, and propionic acid; The catalyst is one or more of ferric chloride and ferric bromide.

2. The method for preparing dehydroevodiamine salt according to claim 1, characterized in that: The molar ratio of evodiamine to acid is 1:(1~3).

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

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