A kind of synthetic method of anti-influenza drug

A synthetic method and suitable technology, applied in the field of medicine and chemical industry, can solve the problems of long steps, high process cost and low overall yield

Active Publication Date: 2021-07-09
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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  • A kind of synthetic method of anti-influenza drug
  • A kind of synthetic method of anti-influenza drug
  • A kind of synthetic method of 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, 150 mmol), stir well 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 synthesis method of a novel anti-influenza drug baloxavir dipivoxil, which uses thiosalicylic acid compound 1 and 1-(halomethyl)-2,3-difluorobenzene compound 2 as starting materials Direct docking to obtain compound 3, and then use PPA ring closure to obtain 7,8-difluorodibenzo[b,e]thiapine-11(6H)-one compound 4, and then obtain the key compound 4 under the catalysis of chiral enzyme Chiral Thiazem Intermediate Compound 5. Then compound 5 is directly condensed with the key chiral fragment compound 6 by Mitsubobu reaction to obtain compound 7, and finally removes the alkyl protection and condenses with ((methoxycarbonyl) oxygen) 4-toluenesulfonic acid methyl ester to obtain the final product compound 9 bar loxavir dipivoxil. This synthetic route reduces the difficulty of enlarging the process operation of the route, reduces the generation of by-products, improves the product purity, and reduces the cost of the route. The specific route:

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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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/14
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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