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Method for synthesizing novel anti-influenza drug

A synthetic method and suitable technology, applied in the field of medicine and chemical industry, can solve the problems of high preparation cost of key thiazem fragments, material waste of thiazem fragments, low utilization rate of raw materials, etc., achieve optimization of reagents and reaction conditions, easy purification and purification, and reduce The effect of amplifying difficulty

Active Publication Date: 2019-03-22
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has long steps, the preparation cost of the key thiazem fragment is high, and it needs to use the odorous and highly toxic reagent thiophenol, which makes industrial scale-up difficult; in addition, the key thiazem fragment is a racemate, and the subsequent docking reaction involves chiral Although the induction has a certain selectivity, not only part of the thiazem fragment material is wasted but also part of the optical isomer is generated, so the overall yield is low, the utilization rate of raw materials is not high, and the process cost is high

Method used

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  • Method for synthesizing novel anti-influenza drug
  • Method for synthesizing novel anti-influenza drug
  • Method for synthesizing novel anti-influenza drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038]

[0039] Add thiosalicylic acid (15.42g, 100mmol), 1-(chloromethyl)-2,3-difluorobenzene 2 (17.07g, 105mmol) and N,N-dimethylformamide (77mL ), add potassium carbonate (20.73g, 150mmol), stir evenly and then heat to 45-55°C for 10-16 hours. After the reaction was completed, water (154 mL) was added, and a large amount of solid precipitated out, which was filtered and dried to obtain compound 3 (26.06 g, yield 93%).

[0040]Here the solvent N,N-dimethylformamide can be replaced by dichloromethane, acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone or toluene; Potassium can be replaced by potassium bicarbonate, sodium bicarbonate, sodium carbonate, cesium carbonate inorganic base or triethylamine, diisopropylethylamine, pyridine, DMAP, DBU or DABCO.

Embodiment 2

[0042]

[0043] Add polyphosphoric acid (84mL) into the three-necked flask, heat up to 75-85°C and stir, add compound formula 3 (28.03g, 100mmol), after the addition, heat up to 100-110°C for 3-4 hours, and cool to 75°C after the reaction is complete. Slowly add water (280ml) dropwise at ~85°C to quench the reaction, cool to room temperature, add dichloromethane (140mL) and stir for 20 minutes, then separate the organic phase, extract the aqueous phase with dichloromethane (70mL) twice, and combine the organic phases Wash once with saturated sodium bicarbonate (140mL) solution, once with saturated brine (70mL), dry over sodium sulfate, concentrate, beat with petroleum ether, filter, and dry to obtain compound 4 (24.13g, yield 92%).

[0044] In this reaction step, solvents such as dichloromethane, 1,2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran or 1,4-dioxane can also be added as the reaction solvent.

Embodiment 3

[0046]

[0047] Add compound formula 3 (28.03g, 100mmol) and dichloromethane (140mL) into the three-necked flask, stir and dissolve, add thionyl chloride (17.85g, 150mmol) dropwise, heat and reflux for 4 to 6 hours, spin off after the reaction Most of the dichloromethane, then add dichloromethane (56mL) and swirl once, then add dichloromethane (140mL) and stir to dissolve, cool to 0-5°C, add aluminum trichloride (26.67g, 200mmol) in batches, After adding, it was warmed up to room temperature and reacted for 3 to 5 hours. After the reaction, water (280ml) was added dropwise to quench the reaction. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (70mL). The organic phase was combined with saturated sodium bicarbonate ( 140mL) solution, washed once with saturated brine (70mL), dried over sodium sulfate, concentrated and then slurried with petroleum ether, filtered, and dried to obtain compound formula 4 (24.13g, yield 87%).

[00...

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Abstract

The invention discloses a method for synthesizing a novel anti-influenza drug baloxavir marboxil. The method comprises the following steps: directly docking a thiosalicylic acid compound 1 and a 1-(halogenated methyl)-2,3-difluorobenzene compound 2 serving as initial raw materials so as to obtain a compound 3; performing PPA ring closure to obtain a 7,8-difluorodibenzo[b,e]thiozepine-11(6H)-one compound 4, and obtaining a key chiral thiazem intermediate compound 5 under catalysis of a chiral enzyme; directly condensating the compound 5 and a key chiral fragment compound 6 by virtue of a Mitsubobu reaction so as to obtain a compound 7; finally performing dealkylation protection, and condensating with ((methoxycarbonyl)oxo)4-methyl-toluenesulfonate, so as to obtain the final product compound9, namely the baloxavir marboxil. According to the synthetic route, the process operation magnification difficulty of the route is reduced, the production of by-products is reduced, the product purity is improved, and the cost of the route is reduced.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a chemical synthesis method for the key intermediate and raw material of the novel anti-influenza drug baloxavir dipivoxil. Background technique [0002] In February 2018, the new anti-influenza drug Baloxavir marboxil (trade name: Xofluza), developed by Shionogi in Japan and jointly researched with Roche in Switzerland, received accelerated approval in Japan and was approved for marketing. Baloxavir dipivoxil is an innovative Cap-dependent endonuclease inhibitor and one of the few new drugs in the world that can inhibit the proliferation of influenza virus. In June 2018, the U.S. Food and Drug Administration (FDA) accepted the new drug application for baloxavir dipivoxil and granted it a priority review qualification. If approved, baloxavir dipivoxil will become the first oral single-dose antiviral drug, and also the first anti-influenza drug with an in...

Claims

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Application Information

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IPC IPC(8): C12P17/00C07D498/14C07D337/12
CPCC07D337/12C07D498/14C12P17/00
Inventor 郑旭春张一平付晨晨吴怡华
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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