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A kind of synthetic method of key mother core intermediate of baloxavir dipivoxil

A synthesis method and a technology for savidate are applied in the field of chemical synthesis of a new anti-influenza drug baloxavir dipivoxil core intermediate, which can solve the problems of low utilization rate of raw materials, low overall yield and high process cost, and achieves The effect of reducing the number of steps in the reaction route, high purity, and high overall yield

Active Publication Date: 2021-05-11
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Generally speaking, the overall yield of this route 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 key mother core intermediate of baloxavir dipivoxil
  • A kind of synthetic method of key mother core intermediate of baloxavir dipivoxil
  • A kind of synthetic method of key mother core intermediate of baloxavir dipivoxil

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029]

[0030] Add compound formula 1 (24.03g, 100mmol) and dichloromethane (120mL) into the three-necked flask, stir well, add triethylamine (20.24g, 200mmol), add EDCI (23.00g, 120mmol), and stir for 20 to 30 minutes A solution of 2-(2,2-dimethoxyethoxy)ethylamine compound formula 2 (16.41g, 110mmol) in dichloromethane (60mL) was added dropwise, and reacted at 25-30°C for 6-8 hours after the addition was completed. After the reaction, add water (240mL), separate the layers, extract the aqueous phase with dichloromethane (120mL) once, combine the organic phases, wash once with 2% dilute hydrochloric acid (120mL), wash once with saturated brine (120mL), anhydrous Dry over sodium sulfate, concentrate, beat with a mixed solvent of ethyl acetate and petroleum ether, filter, and dry to obtain product 3 (34.54g, 93.0%)

[0031] MS(ESI)m / z=372.2[M+H] + , 1 H NMR (400MHz, CDCl 3 )δ7.14(br,1H),7.82(d,J=6.0Hz,1H),6.48(d,J=5.6Hz,1H),4.40-4.55(m,1H),4.16-4.31(m,2H ), 3.45-3.60 (m...

Embodiment 2

[0034]

[0035] Add compound formula 3 (37.14g, 100mmol) and tetrahydrofuran (186mL) into the three-necked flask, add p-toluenesulfonic acid hydrate (3.80g, 20mmol), slowly add hydrazine hydrate (6.88g, 110mmol, 80%), after stirring Heat to 50-55°C and react for 4-6 hours. After the reaction was completed, slowly cool to room temperature, add 5% sodium bicarbonate solution (371mL) and stir, the aqueous phase was extracted twice with ethyl acetate (186mL), the combined organic phase was washed once with saturated brine (186mL), and dried over anhydrous sodium sulfate , filtered, concentrated and then slurried with a mixed solvent of ethyl acetate and petroleum ether, filtered and dried to obtain product 4 (32.25g, 91.0%).

[0036] The acid p-toluenesulfonic acid in embodiment 2 can be replaced by methanesulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid; the reaction solvent tetrahydrofuran can be dichloromethane, toluene, acetonitrile, 2-methyltetrahydrofu...

Embodiment 3

[0038]

[0039]Add (S)-tetrahydrofuran-2-carboxylic acid (13.93g, 120mmol) and dichloromethane (160mL) into a three-necked flask, stir well and add, add pivaloyl chloride (15.68g, 130mmol), stir for 1 to 2 hours, then drop Add triethylamine (30.36g, 300mmol), and then add compound 4 (32.14g, 100mmol), and react at 25-30°C for 4-6 hours. Add water (160mL) after the reaction, separate the layers, extract the water phase with dichloromethane (80mL) twice, combine the organic phases with 10% sodium bicarbonate solution (160mL) and wash once, then wash twice with saturated brine (160mL) , dried over anhydrous sodium sulfate, concentrated and then recrystallized with a mixed solvent of acetone and petroleum ether, filtered and dried to obtain product 5 (18.41g, 43.9%).

[0040] MS(ESI)m / z=420.2[M+H] + , 1 H NMR (400MHz, CDCl 3 )δ7.12(d, J=7.6Hz, 1H), 6.38(d, J=8.0Hz, 1H), 5.90(dd, J=9.6, 2.4Hz, 1H), 4.65(d, J=13.6Hz, 1H),4.60(br,1H),4.16-4.31(m,2H),4.09-4.15(m,1H),3.90(t,J=6....

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Abstract

The invention provides a method for synthesizing the key mother nucleus intermediate formula 6 of baloxavir dipivoxil, which uses compound formula 1 as the starting material, undergoes a condensation reaction with compound formula 2 to obtain the intermediate compound formula 3, and then directly reacts with hydrazine hydrate in one step Ring forming to obtain the racemic compound formula 4, followed by condensation with (S)-tetrahydrofuran-2-carboxylic acid, crystallization and resolution to obtain the intermediate compound formula 5, and finally removal of the chiral prosthetic group to obtain the target product compound formula 6. This route avoids unnecessary protection and replacement of substituents, combined with a one-step ring-forming reaction, greatly reduces the steps of the reaction route, improves the route efficiency and yield, and greatly reduces the cost. The route is as follows:

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a chemical synthesis method of a novel anti-influenza drug baloxavir dipivoxil intermediate. Background technique [0002] Baloxavir marboxil (trade name: Xofluza) is a new type of Cap-dependent endonuclease inhibitor anti-influenza drug discovered by Shionogi Pharmaceuticals of Japan and jointly developed with Roche of Switzerland. In March, the US Food and Drug Administration (FDA) announced the approval of the new anti-influenza drug baloxavir dipivoxil for the treatment of uncomplicated acute influenza patients aged 12 and over for no more than 48 hours. This is the first new anti-influenza drug with a new mechanism of action approved by the FDA in the past 20 years, which has great market prospects. [0003] The chemical name of baloxavir dipivoxil is: (((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepine-11-yl )-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/14
Inventor 郑旭春张一平吴怡华
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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