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Full-synthetic method of racemic tetrandrine

A technology for total synthesis of tetrandrine, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of short supply, high pressure on environmental protection, low production efficiency, etc.

Active Publication Date: 2019-06-28
ZHEJIANG JINHUA CONBA BIO PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the production of tetrandrine by the method of extracting from the roots of tetrandrine has the following disadvantages: 1, the plant resources of tetrandrine are gradually scarce, and the supply exceeds the demand
2. The production efficiency is low, and the extraction process is complicated; 3. The amount of three wastes in the production process is large, and the pressure on environmental protection is high
[0008] This method has lengthy route, cumbersome operation, low resolution efficiency, and the total yield is only about 1%, making it difficult to realize industrial production

Method used

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  • Full-synthetic method of racemic tetrandrine
  • Full-synthetic method of racemic tetrandrine
  • Full-synthetic method of racemic tetrandrine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] (1) Preparation of Compound 2

[0075] Add 100 g of 5-bromovanillin and 1000 g of dichloromethane into a 3 L three-necked flask, stir at room temperature to dissolve and clarify. Add 200 g of 20% NaOH solution, and react at room temperature for 1 hour. Then add 100 g of methyl iodide, and heat to reflux for 10 hours, and the reaction of the raw materials is complete. The reaction solution was lowered to room temperature, left standing for liquid separation, and the aqueous phase was extracted twice with 200 g of dichloromethane. The dichloromethane phases were combined, washed once with 500 g of saturated brine and 500 g of water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain 90.3 g of a yellow solid, namely Compound 2, with a yield of 85.1%.

[0076] (2) Preparation of Compound 3

[0077] Add 100 g of compound 2, 62 g of triethylamine, 125 g of nitromethane and 500 g of absolute ...

Embodiment 2

[0113] (1) Preparation of Compound 2

[0114]Add 115 g of 5-bromovanillin and 1150 g of chloroform into a 3 L three-necked flask, stir at room temperature to dissolve and clarify. Add 200 g of 20% NaOH solution, and react at room temperature for 1 hour. Add 130 g iodomethane again, heat to reflux reaction for 10 hours, the reaction of raw materials is complete. The reaction solution was lowered to room temperature, left standing for liquid separation, and the aqueous phase was extracted twice with 200 g of chloroform. The chloroform phases were combined, washed once with 500 g of saturated brine and 500 g of water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain 95.2 g of a yellow solid, namely Compound 2, with a yield of 78.0%.

[0115] (2) Preparation of compound 3

[0116] 131 g of compound 2, 62 g of potassium carbonate, 98 g of nitromethane and 500 g of acetic acid were added into a 2...

Embodiment 3

[0152] (1) Preparation of Compound 2

[0153] Add 50 g of 5-bromovanillin and 500 g of toluene into a 1 L three-necked flask, stir at room temperature to dissolve and clarify. Add 59 g of potassium carbonate and cool down to 0~5 oC. Slowly add 41 g of dimethyl sulfate, after the addition is complete, heat to 40 °C for 14 hours, and the reaction of the raw materials is complete. The reaction solution was concentrated to dryness under reduced pressure, 200 g of water was added, and extracted twice with 500 g of dichloromethane. The dichloromethane phases were combined, washed once with 200 g of saturated brine and 200 g of water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain 43.1 g of a yellow solid, namely Compound 2, with a yield of 81.2%.

[0154] (2) Preparation of Compound 3

[0155] 24.5 g of compound 2, 8.2 g of ammonium acetate, 20 g of nitromethane and 125 g of isopropanol were ad...

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Abstract

The invention discloses a full-synthetic method of racemic tetrandrine, and belongs to the technical field of drug synthesis. The full-synthetic method of the racemic tetrandrine comprises the steps that a synthetic route adopts a convergence synthesis method, a 5-bromovanillin, namely a compound 1 and 3-hydroxy-4-methoxyphenylacetic acid, namely a compound 5 are taken as starting materials to obtain a compound 4 and a compound 6 respectively, then the compound 4 and the compound 6 are taken as raw materials to synthesize a compound 11, a compound 19 is synthesized from the compound 11, and finally, the compound 11 reacts with the compound 19. The full-synthetic method of the racemic tetrandrine has the advantages that the synthetic efficiency is higher, the yield is higher, and the cost is lower; the reaction conditions are milder, the operation is simple and convenient, the industrial value is higher, and a reference is provided for the full-synthetic method of optical voidness tetrandrine.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a total synthesis method of racemic tetrandrine. Background technique [0002] Tetrandrine, also known as tetrandrine or tetrandrine, is a class of alkaloids present in the root of Fangjiaceae plant, which has anti-myocardial ischemia, inhibition of platelet aggregation, antispasmodic, analgesic, sedative, anti Inflammation, anti-ulcer, liver protection, immune regulation and hypoxia resistance. Tetrandrine is a drug that has been marketed for the treatment of hypertension, rheumatic pain, arthralgia, neuralgia and other diseases. It can be used in the treatment of lung cancer in combination with low-dose radiation agent, and can also be used in the treatment of simple silicosis I, II, III and various stages of coal silicosis. [0003] [0004] Industrially, tetrandrine is produced by extracting and separating the roots of tetrandrine. However, the total alkaloid con...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/18
CPCY02P20/55
Inventor 金庆平余斌葛真真戴艳群陈宇金岩周鸣强袁伟成
Owner ZHEJIANG JINHUA CONBA BIO PHARM CO LTD
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