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Method for large-scale synthesis of tetrodotoxin

A tetrodotoxin and compound technology, applied in the field of artificial synthesis of tetrodotoxin, can solve problems such as lack of credibility, lack of value for large-scale synthesis and preparation of tetrodotoxin, and inability to produce tetrodotoxin on a large scale

Pending Publication Date: 2022-01-21
SHANGHAI SHENGPING MEDICAL EQUIP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the steps of the synthetic method reported in related work are lengthy (generally greater than 30 steps), and the synthetic efficiency is very low. Generally, only 1-5 mg of sample can be obtained, and the yield report is not credible in consideration of the measurement method and the systematic error of the measurement equipment. degree, the significance of academic exploration of related work is greater than its practical application value, and it does not have the value of large-scale synthesis of tetrodotoxin and preparation of pharmaceutical raw materials
For example, the synthetic route reported by Fukuyama's research group (Angew.Chem.Int.Ed.2017,56,1549–1552) is as long as 31 steps, especially the last six steps use more highly toxic chemicals and expensive chemical reagents , the purification process of related reactions is cumbersome, and it is impossible to prepare tetrodotoxin on a scale above the gram level of the c-GMP standard

Method used

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  • Method for large-scale synthesis of tetrodotoxin
  • Method for large-scale synthesis of tetrodotoxin
  • Method for large-scale synthesis of tetrodotoxin

Examples

Experimental program
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preparation example Construction

[0080] The technical problem to be solved by the present invention is to provide a method for artificially large-scale synthesis of tetrodotoxin that does not rely on natural sources such as puffer fish, that is, a chemical method for gram-scale synthesis of tetrodotoxin. Compared with the method reported in the prior art, the advantage of the chemical synthesis method of the present invention is that the improvement of the synthesis method and the purification method enables the present invention to have the ability to produce tetrodotoxin and its derivatives on a large scale according to the c-GMP standard above the gram level, It is possible to carry out clinical trials of tetrodotoxin as a candidate drug that meets regulatory specifications, and it has laid a solid API foundation for tetrodotoxin to become an important member of the field of human analgesia and detoxification drugs, including:

[0081] (1) Only one step of intramolecular transesterification reaction is need...

Embodiment 1

[0095] Example 1 : the preparation of formula III compound

[0096]

[0097] At room temperature, 12 g of compound II and 6 g of potassium carbonate were dispersed in 300 ml of methanol, stirred at room temperature for 18 hours, HPLC detected that the raw materials disappeared, and the precipitate was removed by filtration, and most of the methanol was removed by rotary evaporation of the filtrate at room temperature. Then add 300 ml of water, extract the reaction solution three times with 300 ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter and spin dry, and use ethyl acetate-petroleum ether (1:3) silica gel column chromatography to obtain white Foamy solid compound III (7.3 g, yield 75%). 1H NMR (CDCl 3 ,400MHz):δ5.16(s,1H),5.02(d,J=6.9Hz,1H),5.01(s,1H),4.42(s,1H),4.41(d,J=6.9Hz,1H) ,4.37(d,J=10.1Hz,1H),4.32(s,1H),4.25(d,J=10.1Hz,1H),3.48(br s,1H),3.44(s,3H),1.46(s ,9H), 1.43(s,3H), 1.38(s,3H), 1.29(s,3H).

Embodiment 2

[0098] Example 2 : the preparation of formula IV compound

[0099]

[0100] Under ice bath, add 180 ml of freshly prepared TMSI solution (0.32M) to 6.9 g of compound III in 240 ml of anhydrous acetonitrile solution, react at room temperature for 15 minutes, add 450 ml of sodium thiosulfate solution to quench the reaction, and use chloroform- Methanol (9:1) was extracted three times with 450 ml of mixed solvent, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude compound IV (5.4 g), which was directly put into the next reaction without purification. 1 H NMR (CDCl 3 ,400MHz):δ6.34(br,2H),5.32(d,J=7.2Hz,1H),5.30(s,1H),4.79(d,J=1.2Hz,1H),4.42(d,J= 7.6Hz, 1H), 4.39(s, 1H), 4.38(d, J=10.0Hz, 1H), 4.28(d, J=10.4Hz, 1H), 3.57(s, 3H), 3.36(t, J= 2.0Hz, 1H), 2.03(d, J=8.0Hz, 1H), 1.46(s, 3H), 1.44(s, 6H), 1.38(s, 3H), 1.36(s, 3H).

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Abstract

The invention provides a biological and chemical combined method for synthesis of tetrodotoxin, which specifically comprises the following steps: by taking benzyl acetate which is cheap and easy to obtain as a raw material, carrying out biological fermentation to obtain an optically pure intermediate ((5S, 6R)-5, 6-dihydroxycyclohexa-1, 3-dienyl) meta-acetate (formula I), performing a series of chemical conversions on the intermediate, and obtaining tetrodotoxin with the purity of more than 95% without purification of the final product. The method has the potential of large-scale production, and is an excellent substitute for the existing method for extracting from globefish.

Description

technical field [0001] The invention belongs to the fields of medicine and organic synthesis, in particular to a method for artificially synthesizing tetrodotoxin (TTX). Background technique [0002] Tetrodotoxin (TTX) is an amino perhydroquinazoline compound with a cage-type orthoester internal salt structure, as shown below: [0003] [0004] Tetrodotoxin is a white crystal, odorless and tasteless, slightly soluble in water, soluble in acetic acid solution in water, insoluble in organic solvents; its molecular structure is very special, and it exists in the form of inner salt. Tetrodotoxin is a typical sodium ion channel blocker. It can selectively bind to sodium ion channel receptors on the cell membrane surface of muscle and nerve cells. It has the effects of detoxification and analgesia without addiction. Local anesthesia and tumor suppression. In clinical application, the single-use dose of tetrodotoxin is extremely low, in the range of micrograms, so the preparat...

Claims

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Application Information

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IPC IPC(8): C07D491/22
CPCC07D491/22C07D491/18Y02P20/55
Inventor 王广印李晓明王成喜黄平白骅赖亮郭朋姜标朱文峰
Owner SHANGHAI SHENGPING MEDICAL EQUIP CO LTD
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