Total synthesis method of optically pure tetrandrine

A total synthesis technology of tetrandrine, which is applied in the field of total synthesis of optically pure tetrandrine, can solve the problems of low biological activity of racemic tetrandrine, limited production, high pressure on environmental protection, etc., and achieve optimal synthesis Effects of process parameters, reduction of synthesis steps, reduction of reaction steps

Active Publication Date: 2020-08-11
ZHEJIANG JINHUA CONBA BIO PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, the production of tetrandrine by extracting from the roots of tetrandrine has the following disadvantages: 1. The demand for the raw material tetrandrine is large and the production is limited, resulting in a shortage of supply in the market; 2. The extraction process is complicated, the production efficiency is low and the cost is low. 3. The amount of production waste is large and the pressure o

Method used

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  • Total synthesis method of optically pure tetrandrine
  • Total synthesis method of optically pure tetrandrine
  • Total synthesis method of optically pure tetrandrine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] (1) Preparation of compound 3

[0054] Add 4.2g of compound 1, 4.6g of compound 2, 0.36g of cuprous bromide, 9.8g of potassium carbonate and 84g of toluene into a 250mL three-necked flask, heat to 100°C for 48 hours under the protection of nitrogen, and the reaction of the raw materials is complete; the reaction solution is concentrated under reduced pressure To dryness, add 42g of water, adjust pH=3 or so with 10% dilute hydrochloric acid, and then extract twice with 82g of dichloromethane; combine the dichloromethane phases, wash twice with 82g of water, and dry over anhydrous sodium sulfate; Concentrate under pressure to dryness to obtain a brown solid, which is purified by column chromatography to obtain 5.5 g of a light yellow solid, which is compound 3, with a yield of 69.7%, and an ee value of 99.2%. The chromatographic conditions for detecting its optical purity by HPLC are: mobile phase Ratio: 0.1% diethylamine-n-hexane: ethanol = 80:20; flow rate: 1.0mL / min; c...

Embodiment 2

[0062] (1) Preparation of Compound 3

[0063] Add 4.8g of compound 1, 4.0g of compound 2, 1.8g of cuprous bromide dimethyl sulfide mixture, 8.4g of cesium carbonate and 80g of o-xylene into a 250mL three-necked flask, heat to reflux for 48 hours under the protection of nitrogen, and the raw materials are completely reacted . The reaction solution was concentrated to dryness under reduced pressure, 50 g of water was added, the pH was adjusted to about 3 with 10% dilute hydrochloric acid, and extracted twice with 100 g of dichloromethane. The dichloromethane phases were combined, washed twice with 100 g of water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain a brown solid, which was purified by column chromatography to obtain 5.1 g of a light yellow solid, namely compound 3, with a yield of 56.9% and an ee value of 99.3%;

[0064] (2) Preparation of Compound 4

[0065] Add 3.0 g of compound...

Embodiment 3

[0070] (1) Preparation of compound 3

[0071] Add 4.8g of compound 1, 4.0g of compound 2, 0.3g of cuprous chloride, 2.0g of sodium hydroxide and 80g of toluene into a 250mL three-neck flask, and heat to reflux for 60 hours under the protection of nitrogen to react the raw materials completely. The reaction solution was concentrated to dryness under reduced pressure, 50 g of water was added, the pH was adjusted to about 3 with 10% dilute hydrochloric acid, and extracted twice with 100 g of dichloromethane. The dichloromethane phases were combined, washed twice with 100 g of water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain a brown solid, which was purified by column chromatography to obtain 4.9 g of a light yellow solid, namely compound 3, with a yield of 54.1% and an ee value of 98.6%.

[0072] (2) Preparation of Compound 4

[0073] Add 3.0 g of compound 3, 60 g of hydrochloric acid and...

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Abstract

The invention discloses a total synthesis method of optically pure tetrandrine, and belongs to the technical field of drug synthesis. The method comprises the following steps: (1) under the action ofa catalyst (1), carrying out intermolecular Ullmann reaction on a compound (1) and a compound (2) under alkaline and high-temperature conditions to synthesize a compound 3; (2) removing a hydroxyl protecting group from the compound (3) under an acidic condition to synthesize a compound (4); (3) carrying out intramolecular Ullmann reaction on the compound (4) under the action of a catalyst (2) under alkaline and high-temperature conditions to synthesize a compound (5), namely the optically pure tetrandrine. A convergent synthesis strategy is adopted, and only three steps are needed from the compound (1) to the synthesis of optically pure tetrandrine so that the reaction steps are greatly reduced, and the time and the material cost are saved; the yield can be as high as 28.7%-38.9%, and theyield is increased by dozens of times; the target product can be obtained on the gram scale, 1.3 g-1. 5 g of final optically pure product is synthesized, and the method has better industrialization potential.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a total synthesis method of optically pure tetrandrine. Background technique [0002] Tetrandrine is an alkaloid extracted from the root of Tetrandrine, a plant of the family Tetrandrine. Its structure is as follows, [0003] [0004] It has many pharmacological effects, such as antipyretic, analgesic, anti-inflammatory, diuretic, antihypertensive, etc. Many literatures have reported that tetrandrine also has inhibitory activity on various tumor cells, such as liver cancer, lung cancer, gastric cancer, prostate cancer, breast cancer and so on. [0005] At present, tetrandrine is generally produced by extracting and separating the roots of tetrandrine. However, the total alkaloid content in tetrandrine root is 1.5-2.3%, while the content of tetrandrine is about 1%. Therefore, the production of tetrandrine by extracting from the root of tetrandrine has the following di...

Claims

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Application Information

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IPC IPC(8): C07D491/18
CPCC07D491/18C07B2200/07Y02P20/55Y02P20/582
Inventor 袁伟成周鸣强金庆平陈宇葛真真戴艳群金岩郑宁川
Owner ZHEJIANG JINHUA CONBA BIO PHARM CO LTD
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