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Novel total synthesis method of racemic tetrandrine

A total synthesis technology of tetrandrine, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of risk, high synthesis cost, short route, etc., and achieve the effect of improved synthesis efficiency, low cost and easy operation

Active Publication Date: 2021-06-29
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

[0007] Org.Biomol.Chem., 2020, 18, 3047-3068 Construct tetrahydroisoquinoline ring by Pictet-Spengler reaction. According to the sequence of Ullmann reaction and cyclization reaction, four tetrandrine and its The synthetic route of the isomer still adopts the linear synthesis strategy, using 3-bromo-4,5-dimethoxybenzaldehyde and 3-methoxytyramine as starting materials, and synthesizes tetrandrine through 10 steps of reaction This method has a short route, but the starting materials are expensive, and dangerous reagents such as lithium diisopropylamide and lithium aluminum hydride need to be used in the reaction process, which is only suitable for academic research, and there are many problems in industrial production. Big risk, low feasibility;
[0008] The Chinese patent application CN109942593A was invented by the inventor of the present application. It adopts a convergent synthesis strategy and uses the chemical products vanillin and 5-bromovanillin as starting materials to synthesize two tetrahydroisoquinoline intermediates respectively. Two-step Ullmann reaction is used to synthesize racemic tetrandrine. The main raw materials of this method are cheap and easy to obtain, the reaction conditions are mild, and the synthesis efficiency is high. The synthesis cost is higher

Method used

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  • Novel total synthesis method of racemic tetrandrine
  • Novel total synthesis method of racemic tetrandrine
  • Novel total synthesis method of racemic tetrandrine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] (1) Preparation of compound 2

[0073] Add 100g of 5-bromovanillin, 8g of potassium iodide, 30g of sodium hydroxide and 800g of dichloromethane into a 2L three-necked flask, and add 96g of benzyl bromide dropwise at room temperature. After dropping, heat to reflux for 3 hours, and the reaction of the raw materials is complete. Cool down to room temperature, filter, and wash the filtrate twice with 800 g of 5% sodium hydroxide solution, once with 400 g of water, and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain a yellow oil, which was crystallized by 400 g of petroleum ether to obtain 124 g of a white solid, which was compound 2, with a yield of 89.2%;

[0074] (2) Preparation of compound 3

[0075] Add 100g of compound 2, 36g of triethylamine, 57g of nitromethane and 500g of ethanol into a 2L three-neck flask, heat to reflux for 12 hours, and the reaction of the raw materials is complete....

Embodiment 2

[0106] (1) Preparation of compound 2

[0107] 120g of 5-bromovanillin, 12g of potassium iodide, 72g of potassium carbonate and 800g of ethanol were added to a 2L three-necked flask, and 115g of p-methoxybenzyl bromide was added dropwise at room temperature. After dropping, heat to reflux for 6 hours, and the reaction of raw materials is complete. Cool down to room temperature, filter, and concentrate the filtrate to dryness under reduced pressure, add 600g of dichloromethane to dissolve, wash the organic phase twice with 800g of 5% sodium hydroxide solution, once with 400g of water, and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain a yellow oil, which was crystallized from 480 g of petroleum ether to obtain 150 g of a white solid, namely compound 2, with a yield of 82.1%;

[0108] (2) Preparation of compound 3

[0109] 110g of compound 2, 67g of ammonium acetate and 330g of nitromethane were add...

Embodiment 3

[0139] (1) Preparation of compound 2

[0140] Add 115g of 5-bromovanillin, 75g of triethylamine and 675g of acetonitrile into a 2L three-necked flask, cool down to 0-5°C, and add 95g of p-toluenesulfonyl chloride in batches. After the addition was completed, the insulation reaction was carried out for 3 hours, and the reaction of the raw materials was complete. The reaction solution was concentrated to dryness under reduced pressure, 300 g of water and 300 g of dichloromethane were added, the pH was adjusted to about 3 with 12% hydrochloric acid, the liquid was separated after standing, the organic phase was washed twice with 600 g of water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and after purification by 675 g of ethanol, 168 g of an off-white solid was obtained, which was compound 2, with a yield of 87.4%;

[0141] (2) Preparation of compound 3

[0142] Add 96g of compound 2, 12g of sodium...

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Abstract

The invention discloses a novel total synthesis method of racemic tetrandrine, and belongs to the technical field of pharmaceutical chemical synthesis. 5-bromovanillin and 4-hydroxyphenylacetic acid which are low in price and easy to obtain are respectively used as starting materials to synthesize a compound 10, the compound 10 is used for synthesizing a compound 12 and a compound 14 through a simple route, and the two compounds are subjected to intermolecular and intramolecular Ullmann reaction to synthesize the racemic tetrandrine A. The key intermediates 12 and 14 are synthesized through the compound 10, the synthesis efficiency is greatly improved, the raw materials are utilized to the maximum extent, and the method is a racemic tetrandrine total synthesis route which is simplest in operation and lowest in cost so far.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a new method for the total synthesis of racemic tetrandrine. Background technique [0002] Tetrandrine, also known as tetrandrine, is an alkaloid extracted from the tuber root of Stephamia tetrandra S. The main active ingredient of Fangji. It has anti-inflammatory, analgesic, antihypertensive, anti-silicosis, hypoglycemic, anti-free radical damage, anti-hepatic fibrosis and other anti-tumor pharmacological effects. It is clinically used for simple silicosis and coal silicosis, and also for early stage Mild hypertension, rheumatic pain, arthralgia, neuralgia, etc. It is also used in the treatment of liver cancer, lung cancer, colon cancer, bladder cancer and leukemia. The structure is as follows: [0003] [0004] In industry, tetrandrine is mainly separated by plant extraction, but the content of tetrandrine in the root of tetrandrine is only about...

Claims

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Application Information

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