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Preparation method of baloxavir key intermediate and intermediate thereof

An intermediate and key technology, applied in the field of medicine, can solve problems such as limiting the expansion of reaction substrates and high safety risks

Active Publication Date: 2020-10-23
CHINA PHARM UNIV
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Problems solved by technology

This route requires the use of foul-smelling and highly toxic thiophenol, which has a high safety risk. Not only that, but in the currently published synthesis patents or literature, the preparation methods and intermediates are similar to those of the original research patents, and the synthesis of the final product is difficult. It needs to be realized by Friedel-Crafts acylation, which requires not only highly polluting strong acid catalysts, such as Lewis acid, PPA, P 2 o 5 etc., which brings some inconvenience to the post-processing, and more importantly, it limits the expansion of the reaction substrate: Friedel-Crafts reaction requires a higher electron cloud density on the aromatic ring, that is, electron-withdrawing (EWG) replaces the aromatic ring Unable to react, which means that if baloxavir needs to be modified and modified later, this route will no longer be applicable

Method used

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  • Preparation method of baloxavir key intermediate and intermediate thereof
  • Preparation method of baloxavir key intermediate and intermediate thereof
  • Preparation method of baloxavir key intermediate and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Add 3,4-difluoro-2-methylbenzaldehyde (10g, 64mmol), N-bromosuccinimide (NBS) (14.68g, 76.9mmol), azobisiso Butyronitrile (AIBN) (1.05g, 6.4mmol), 100mL carbon tetrachloride, argon protection, stirred at 60°C for 10h, and monitored the reaction by TLC. After the reaction was completed, add 100 mL of water, extract with dichloromethane (50 mL×3), combine the dichloromethane phases, wash with saturated brine (10 mL×3), dry over anhydrous sodium sulfate, remove the organic phase by distillation under reduced pressure, and perform silica gel column chromatography Afterwards, 14.2 g of intermediate II was obtained, with a yield of 94.3%.

[0041] 1 H NMR (300MHz, Chloroform-d) δ10.36(s, 1H), 7.63(d, J=8.2Hz, 1H), 7.43(d, J=8.2Hz, 1H), 4.54(s, 2H)

[0042] Add 2-bromothiophenol (9.65g, 51.06mmol), sodium hydride (5.11g, 127.64mmol), 100mL N,N-dimethylformamide into a 250mL two-neck flask, add intermediate Ⅱ3 under argon protection , 4-difluoro-2-bromomethylbenzaldehyde (10...

Embodiment 2

[0047] In a 250mL round bottom flask, add 3,4-difluoro-2-methylbenzaldehyde (10g, 64mmol), liquid bromine (12.28g, 76.9mmol), benzoyl peroxide (BPO) (1.55g, 6.4mmol ), 100mL N,N-dimethylformamide, under argon protection, stirred at 60°C for 12h, and monitored the reaction by TLC. After the reaction was completed, 100 mL of water was added, extracted with ethyl acetate (50 mL×3), the ethyl acetate phases were combined, washed with water (50 mL×3), washed with saturated brine (10 mL×3), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove organic After column chromatography, 13.6 g of intermediate II was obtained, with a yield of 90.4%.

[0048] 1 H NMR (300MHz, Chloroform-d) δ: 10.36(s,1H), 7.63(d,J=8.2,1H), 7.43(d,J=8.2,1H), 4.54(s,2H)

[0049] Add intermediate II 3,4-difluoro-2-bromomethylbenzaldehyde (10g, 42.55mmol), anhydrous potassium carbonate (17.64g, 127.64mmol), 100mL anhydrous acetonitrile, and argon protection in a 250mL two-necked ...

Embodiment 3

[0054] The preparation method of embodiment 3 is the same as that of embodiment 1, except that bromine is montmorillonite in step (1), solvent A is dimethyl sulfoxide, and formula (I) 3,4-difluoro-2-methano The molar ratio of base benzaldehyde and bromine feeding is 1:2, and the molar ratio of feeding with initiator is 1:0.3. The temperature of the heating and stirring reaction was 80° C., and the time was 8 hours.

[0055] In the step (2), the alkali is anhydrous sodium bicarbonate, and the solvent B is acetone; the mol ratio of the intermediate II described in the step (2) and 2-bromothiophenol is 1:1.5, and the molar ratio of the alkali is 1:1.5. The ratio is 1:5. The reaction temperature of heating and stirring overnight was 65°C.

[0056] In step (3), the base is phenyllithium, and the solvent C is anhydrous 1,4-dioxane; the molar ratio of intermediate III to the base is 1:1.2. The reaction temperature at low temperature is -40°C, and the time is 0.5h.

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Abstract

The invention discloses a preparation method of a baloxavir key intermediate and the intermediate thereof. The method includes subjecting 3,4-difluoro-2-methyl benzaldehyde shown as a formula (I) as araw material to a bromination reaction to obtain 3,4-difluoro-2-bromomethyl benzaldehyde shown in a formula (II), carrying out a substitution reaction to obtain 3,4-difluoro-2-(((2-bromophenyl) thio)methyl)-benzaldehyde shown in a formula (III), and finally, carrying out a nucleophilic addition reaction to synthesize a target product, namely 7,8-difluorodibenzo[b, e]thiepin-11(6H)-ol shown in aformula (IV). The specific reaction process is shown in the specification. According to the method, 2-bromothiophenol is used for replacing foul and virulent thiophenol, the reaction steps are reducedto three steps, and the preparation method is high in yield, low in cost, environmentally friendly and easy to operate.

Description

technical field [0001] The invention belongs to the field of medicine and the technical field of drug synthesis, in particular to a method for preparing a key intermediate of baloxavir, 7,8-difluorodibenzo[b,e]thiaheptane-11(6H)-ol and its intermediates. Background technique [0002] Influenza (hereinafter referred to as influenza) is an acute respiratory disease that seriously endangers human health. It is highly contagious, spreads quickly, and has a high prevalence rate. About 20% of children and 5% of adults suffer from it every year. Influenza A or B with clinical symptoms. At present, the drugs used for influenza treatment mainly include M2 ​​ion channel inhibitors (amantadine hydrochloride, rimantadine) and neuraminidase inhibitors (oseltamivir, zanamivir). However, with the increasing frequency of drug use, influenza viruses have developed some resistance to these two types of drugs, especially M2 ion channel inhibitors. Second, these two classes of drugs are not ...

Claims

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Application Information

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IPC IPC(8): C07D337/12C07C47/55C07C323/22
CPCC07D337/12C07C47/55C07C323/22Y02P20/55
Inventor 徐进宜杨立媚徐盛涛徐飞杰姚鸿倪翔
Owner CHINA PHARM UNIV
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