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A new method for the synthesis of baloxavir intermediates

A technology of intermediates and new methods, applied in the field of synthesis of organic compounds, can solve the problems of high cost, expensive raw materials and catalysts, and unsuitability for industrial production, and achieve the effects of low cost, high product yield, and mild conditions

Active Publication Date: 2022-03-04
南京安淮创新药物研究院有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] This method requires column chromatography, the raw materials and catalysts used are expensive, and the key step requires special equipment for hydrogenation reaction, which is costly and not suitable for industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Preparation of compound 3:

[0035] In a 2000ml four-necked flask, add 100.0g morpholine, 348.45g triethylamine and 700ml tetrahydrofuran, drop the temperature to 0°C and add 207.53g allyl chloroformate dropwise, and react overnight at 25°C after dropping, the GC control reaction is completed, Concentrate and recover tetrahydrofuran, add 800ml ethyl acetate, wash twice with 400ml 5% dilute hydrochloric acid, dry ethyl acetate with anhydrous sodium sulfate and concentrate to obtain compound 3, a light yellow oily liquid, with a yield of 94%.

Embodiment 2

[0037] Preparation of Compound 4:

[0038] In a 5000ml four-neck flask, add 1900ml of methanol, 100ml of formic acid, 100.00g of compound 3, heat the system to reflux, then add 124.76g of NBS in 5 times within 5 hours, continue to reflux for 3h after the addition, and the GC control material disappears , the system cooled down, concentrated to recover methanol, added 1000ml 5% sodium hydroxide solution, then extracted three times with dichloromethane (1000mlx3), combined dichloromethane, dried with anhydrous sodium sulfate, concentrated and recovered dichloromethane, and then distilled under reduced pressure Fractions were collected (top temperature 165°C, 2mmHg), yield 61.6%.

Embodiment 3

[0040] Preparation of Compound 5:

[0041] Under nitrogen protection, 80.01g of compound 4 was dissolved in 600ml of acetonitrile, 105.05g of Boc hydrazine was added, the system was cooled to -25°C with a dry ice ethanol bath, 51.80g of tin tetrachloride was slowly added dropwise, and stirred at -25°C for 90 minutes. After the central control reaction is completed, the reaction solution is poured into ice aqueous sodium bicarbonate solution for quenching and quenching, then 400ml of dichloromethane is added, stirred at room temperature, paved with diatomaceous earth and filtered, the filtrate is layered, and then the water phase is used dichloromethane extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and dichloromethane was recovered by distillation under reduced pressure to obtain the crude compound 5, which was recrystallized with 300ml tert-butyl methyl ether to obtain the pure product as a light yellow solid with a yield o...

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PUM

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Abstract

The invention relates to the technical field of synthesis of organic compounds, in particular to a method for synthesizing a baloxavir intermediate, comprising the following steps: taking cheap and easy-to-obtain morpholine and allyl chloroformate as starting materials, Condensation under the action of compound 3 is obtained, and compound 3 reacts with formic acid and methanol in the presence of NBS catalyst to obtain compound 4, and then obtains compound 5 with Boc hydrazine under heating conditions; compound 5 is resolved to obtain target compound 6, and finally with Compound 7 is reacted to obtain the target product; the method has simple reaction, short route, early resolution, less waste, and is environmentally friendly, and the yield of each step is high, and the waste of raw materials and reagents is small.

Description

technical field [0001] The invention relates to the technical field of synthesis of organic compounds, in particular to a novel synthesis method of a baloxavir intermediate. Background technique [0002] Baloxavir is a new type of Cap-dependent endonuclease inhibitor anti-influenza drug discovered by Shionogi Pharmaceutical in Japan and jointly developed with Roche in Switzerland. It has been developed for the treatment of influenza A or B. Unlike neuraminidase inhibitors, which inhibit virus release from infected host cells, baloxavir blocks influenza virus proliferation by inhibiting the initiation of mRNA synthesis. In November 2018, the U.S. Food and Drug Administration (FDA) announced the approval of a 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 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/12
CPCC07D413/12Y02P20/55
Inventor 陈桂平
Owner 南京安淮创新药物研究院有限公司