CN110105361B - Preparation method of Evodikine and derivative thereof - Google Patents

Abstract

The invention belongs to the technical field of medicines, and relates to a preparation method of an evodiamine alkaloid Evodiakine and a derivative thereof. A large amount of screening is carried out on reaction conditions, and the evodiamine and the derivatives thereof can be synthesized into the evodiamine alkaloid Evodiakine and the derivatives thereof in one step in an oxygen environment. The reaction has the advantages of simple operation, good atom economy and the like.

Description

Preparation method of Evodikine and derivative thereof

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of an evodiamine alkaloid Evodiakine and a derivative thereof.

Background

The evodiamine alkaloid is an alkaloid with various pharmacological activities, and particularly has good inhibition effect on tumors. A large amount of reaction conditions are screened, and the evodiamine can be used for synthesizing the evodiamine alkaloid Evodiakine and the derivative thereof in one step in an oxygen environment. The reaction has the advantages of simple operation, good atom economy and the like.

The method comprises the steps of taking evodiamine and derivatives thereof as initial raw materials, dissolving the raw materials in a solvent, and adding copper bromide dimethyl sulfide and 4-dimethylaminopyridine which are also dissolved in the solvent in an oxygen environment. The reaction is stirred at room temperature under the condition, and after the monitoring reaction is finished, the solvent is separated and purified, so that the target product Evodiakine and the derivative thereof can be obtained.

Disclosure of Invention

The invention aims to provide a preparation method of an evodiamine alkaloid Evodiakine and a derivative thereof, which has the advantages of simple preparation method, mild experimental conditions, no requirement of harsh conditions such as high temperature, high pressure, strong acid, strong base and the like, and higher reaction yield.

In order to achieve the purpose, the invention adopts the following technical scheme:

an evodiamine alkaloid derivative has a structural general formula as follows:

；

wherein R is¹is-OMe or-H; r²is-CH₃or-CH₂CH₃。

The preparation method of the rutaecarpine alkaloid derivative comprises the following steps:

(1) dissolving copper bromide dimethyl sulfide in a solvent to prepare a copper bromide dimethyl sulfide solution;

(2) dissolving 4-dimethylaminopyridine in a solvent to prepare a 4-dimethylaminopyridine solution;

(3) dissolving the evodiamine derivative in a solvent in an oxygen environment, adding the copper bromide dimethyl sulfide solution prepared in the step (1) and the 4-dimethylaminopyridine solution prepared in the step (2), stirring for reaction, and after the reaction is monitored, separating and purifying the solvent to obtain the evodiamine alkaloid derivative.

The evodiamine derivative has the following structure:

；

wherein R is¹is-OMe or-H, R²is-CH₃or-CH₂CH₃。

The solvent comprises chloroform.

The reaction condition is room temperature reaction under the protection of oxygen.

The invention has the following remarkable advantages:

(1) the synthesis method is simple, and the target product can be obtained through reaction of common reagents; the experimental conditions are mild, and harsh conditions such as high temperature, high pressure, strong acid and strong alkali are not required; the yield can reach 46 percent.

(2) The compound is synthesized for the first time in one step, has effects on cardiovascular system, central nervous system and digestive system, and is expected to be developed into medicines for treating antithrombotic, postpartum hemorrhage, antibacterial, anti-inflammatory, analgesic, antitumor and the like.

Drawings

FIG. 1 shows the Evodiankine of example 1¹H nuclear magnetic resonance image; wherein (A) is CDCl₃As solvent, and DMSO as solvent.

FIG. 2 shows Evodiankine in example 1¹³C nuclear magnetic resonance image; wherein (A) is CDCl₃As solvent, and DMSO as solvent.

FIG. 3 is a photograph of the compound of example 2¹H nuclear magnetic resonance image.

FIG. 4 is a photograph of the compound of example 2¹³C nuclear magnetic resonance image.

FIG. 5 is a photograph of a compound of example 3¹H nuclear magnetic resonance image.

FIG. 6 shows preparation of compound of example 3¹³C nuclear magnetic resonance image.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

Example 1: preparation of Compound 1 (Evodikine)

(1) 41.2 mg of copper bromide dimethylsulfide (0.2 mmol) was dissolved in 10 mL of CHCl₃Preparing a copper bromide dimethyl sulfide solution;

(2) 48.9 mg of 4-dimethylaminopyridine (0.4 mmol) were dissolved in 10 mL of CHCl₃Preparing a 4-dimethylaminopyridine solution;

(3) evodiamine (606.8 mg, 2.0 mmol) was dissolved in 10 mL CHCl in an oxygen atmosphere₃Adding the copper bromide dimethyl sulfide solution and the 4-dimethylaminopyridine solution which are prepared in the steps (1) and (2); the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was diluted with 20 mL of ethyl acetate, and then 20 mL of a saturated aqueous ammonium chloride solution was added, and finally a saturated saline solution (20 mL) was added to extract the mixture 3 times. The organic phase was dried over anhydrous sodium sulfate, filtered and spin dried. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate =2:1, volume ratio) to give 310 mg of the product, yield 46%. The product was a white solid at room temperature.

The physical state is white solid;

melting point: 240.9-241.7^oC；

TLC: Rf = 0.30 (PE/EtOAc = 2:1)；

¹H NMR (400 MHz, CDCl₃) 7.89 (d,J= 7.7 Hz, 1H), 7.68 (t,J= 7.7Hz, 1H), 7.43 (t,J= 7.6 Hz, 1H), 7.37 (d,J= 8.3 Hz, 2H), 7.11 (t,J= 7.6Hz, 1H), 6.90 (t,J= 7.4 Hz, 1H), 6.50 (s, 1H), 6.40 (d,J= 7.8 Hz, 1H),4.10 – 4.03 (m, 1H), 3.96 (s, 1H), 3.48 (s, 3H), 3.36 – 3.29 (m, 1H), 2.75 –2.68 (m, 1H), 2.58 – 2.49 (m, 1H)；

¹H NMR (400 MHz, DMSO-d ₆) 7.71 (t,J= 7.2 Hz, 2H), 7.55 (d,J= 8.2Hz, 1H), 7.40 (t,J= 7.5 Hz, 1H), 7.31 (d,J= 7.3 Hz, 1H), 7.06 (t,J= 7.5Hz, 1H), 6.79 (t,J= 7.3 Hz, 1H), 6.54 (d,J= 7.8 Hz, 1H), 6.46 (s, 1H),5.93 (s, 1H), 3.91 – 3.81 (m, 1H), 3.42 (s, 3H), 3.15 – 3.06 (m, 1H), 2.68 –2.59 (m, 1H), 2.38 – 2.29 (m, 1H)；

¹³C NMR (101 MHz, CDCl₃) 168.82, 164.45, 146.91, 138.29, 133.10,131.11, 130.24, 128.97, 128.66, 126.82, 123.39, 122.49, 121.29, 111.00,91.13, 79.06, 46.27, 36.40, 33.98；

¹³C NMR (101 MHz, DMSO-d ₆) 169.04, 164.65, 148.54, 138.69, 133.19,130.55, 130.49, 130.16, 128.37, 126.52, 123.67, 123.54, 120.26, 112.22,91.59, 79.41, 46.20, 36.77, 33.61；

HRMS (ESI): calcd for C₁₉H₁₆N₃O₃[M + H]⁺ m/z334.1197, found 334.1151。

Example 2; preparation of Compound 2

(1) 6.1 mg of copper bromide dimethylsulfide (0.03 mmol) was dissolved in 3 mL of CHCl₃Preparing a copper bromide dimethyl sulfide solution;

(2) 7.3 mg of 4-dimethylaminopyridine (0.06 mmol) were dissolved in 3 mL of CHCl₃Preparing a 4-dimethylaminopyridine solution;

(3) N-Ethylevodiamine derivative (95 mg, 0.3 mmol) was dissolved in 3 mL of CHCl in an oxygen atmosphere₃Adding the copper bromide dimethyl sulfide solution and the 4-dimethylaminopyridine solution which are prepared in the step (1) and the step (2); the reaction was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was diluted with 20 mL of ethyl acetate, and then 20 mL of a saturated aqueous ammonium chloride solution was added, followed by extraction with saturated brine (20 mL) 3 times. The organic phase was dried over anhydrous sodium sulfate, filtered and spin dried. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate =2:1, volume ratio) to give 36 mg of product in 34% yield. The product was a pale yellow solid at room temperature.

The physical state is light yellow solid;

melting point: 106.4-107.2^oC；

TLC: R_f= 0.32 (PE/EtOAc = 2:1)；

¹H NMR (400 MHz, CDCl₃) 7.89 (d,J= 7.8 Hz, 1H), 7.68 (t,J= 7.8Hz, 1H), 7.45 (d,J= 10.2 Hz, 1H), 7.37 (d,J= 7.5 Hz, 1H), 7.11 (t,J=7.7 Hz, 1H), 6.90 (t,J= 7.3 Hz, 1H), 6.45 (s, 1H), 6.40 (d,J= 7.9 Hz,1H), 4.15 – 4.03 (m, 3H), 3.97 – 3.89 (m, 2H), 3.31 – 3.21 (m, 1H), 2.80 –2.68 (m, 1H), 2.61 – 2.50 (m, 1H), 1.30 (t,J= 6.3 Hz, 3H)；

¹³C NMR (101 MHz, CDCl₃) 167.89, 164.39, 147.05, 137.41, 133.13,131.26, 130.28, 129.51, 128.78, 127.02, 123.48, 122.62, 121.26, 110.96,90.93, 79.09, 46.10, 44.80, 33.96, 13.31；

HRMS (ESI): calcd for C₂₀H₁₉N₃O₃[M + H]⁺ m/z350.1499, found 350.1500。

Example 3; preparation of Compound 3

(1) 20.6 mg of copper bromide dimethylsulfide (0.10 mmol) was dissolved in 7.5 mL of CHCl₃Preparing a copper bromide dimethyl sulfide solution;

(2) 24.5 mg of 4-dimethylaminopyridine (0.20 mmol) were dissolved in 7.5 mL of CHCl₃Preparing a 4-dimethylaminopyridine solution;

(3) dissolving 5-methoxy evodiamine derivative (333 mg,1.0 mmol) in 7.5 mL of HCl under oxygen atmosphere₃Adding the copper bromide dimethyl sulfide solution and the 4-dimethylaminopyridine solution which are prepared in the step (1) and the step (2); the reaction was stirred at room temperature for 1 hour under the same conditions. After the reaction was completed, the solvent was dried, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate =2:1, volume ratio) to obtain 133 mg of a product with a yield of 37%. The product was a pale yellow solid at room temperature.

The physical state is light yellow solid;

melting point: 194.5 –195.6^oC；

TLC: R_f= 0.45 (PE/EtOAc = 1:1)；

¹H NMR (400 MHz, CDCl₃) 7.89 (d,J= 7.7 Hz, 1H), 7.67 (t,J= 7.6Hz, 1H), 7.42 (t,J= 7.4 Hz, 1H), 7.36 (d,J= 8.1 Hz, 1H), 6.95 (s, 1H),6.68 (d,J= 8.5 Hz, 1H), 6.53 (s, 1H), 6.35 (d,J= 8.5 Hz, 1H), 4.11 – 4.03(m, 1H), 3.76 (s, 3H), 3.48 (s, 3H), 3.38 – 3.30 (m, 1H), 2.71 – 2.63 (m,1H), 2.56 – 2.47 (m, 1H)；

¹³C NMR (101 MHz, CDCl₃) 168.97, 164.47, 155.08, 140.49, 138.32,133.05, 131.07, 130.24, 128.62, 126.77, 122.43, 116.19, 112.04, 109.02,91.35, 79.74, 55.95, 46.15, 36.41, 34.00；

HRMS (ESI): calcd for C₂₀H₁₉N₃O₄[M + H]⁺ m/z366.1448, found 366.1449。

the above description is only a preferred embodiment of the present invention, and all equivalent changes and modifications made in accordance with the claims of the present invention should be covered by the present invention.

Claims (3)

1. A preparation method of evodiamine alkaloid Evodia kinene is characterized by comprising the following steps: the method comprises the following steps:

(1) dissolving copper bromide dimethyl sulfide in a solvent to prepare a copper bromide dimethyl sulfide solution;

(2) dissolving 4-dimethylaminopyridine in a solvent to prepare a 4-dimethylaminopyridine solution;

(3) dissolving evodiamine in a solvent in an oxygen environment, adding the copper bromide dimethyl sulfide solution prepared in the step (1) and the 4-dimethylaminopyridine solution prepared in the step (2), stirring for reaction, and after the reaction is monitored, separating and purifying the solvent to obtain the evodiamine alkaloid Evodia kinene, wherein the structural general formula of the evodiamine alkaloid Evodia kinene is as follows:

；

wherein R is¹is-H; r²is-CH₃；

The evodiamine in the step (3) has the following structure:

；

wherein R is¹is-H, R²is-CH₃。

2. The method of claim 1, wherein: the solvent is chloroform.

3. The method of claim 1, wherein: the reaction condition is room temperature reaction under the protection of oxygen.

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