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One-pot method for preparing pyrrolo[2,1-F][1,2,4]triazin-4-amine

A pyrrole and hydroxylamine technology, applied in the direction of organic chemistry, can solve the problems of not being suitable for industrial scale-up production, long reaction steps, cumbersome operation, etc., and achieve the effect of small quantity, environmentally friendly reaction system and high purity

Active Publication Date: 2020-08-14
SHANGHAI LINKCHEM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] This route has long reaction steps, harsh conditions, cumbersome operation, more three wastes, low total yield, and is not suitable for industrial scale-up production.

Method used

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  • One-pot method for preparing pyrrolo[2,1-F][1,2,4]triazin-4-amine
  • One-pot method for preparing pyrrolo[2,1-F][1,2,4]triazin-4-amine
  • One-pot method for preparing pyrrolo[2,1-F][1,2,4]triazin-4-amine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Add 100mL of acetonitrile, 10g (149mmol, 1.0eq) of pyrrole, and 21g (149mmol, 1eq) of chlorosulfonic acid isocyanate into a 500ml three-necked flask, stir and dissolve, and after the dissolution is complete, lower the temperature. When the temperature of the reaction system is 0°C, start slowly Slowly add 10mL N,N-dimethylformamide dropwise, and keep the reaction for 1h. After the heat preservation is over, the temperature rises to 30°C, and 33g of O-[4-nitro-2-(trifluoromethyl)phenyl]hydroxylamine ( 149mmol, 1eq) was added to the reaction solution, then the temperature was raised to 60°C, and the temperature was kept for 2 hours. Maintain at 70 to 80°C and keep warm for 5 hours. After the heat preservation is over, slowly add 100ml of water to the reaction system, then concentrate the reaction solution until no liquid drips out, cool down to 5°C, stir and crystallize for 1h, wash the filter cake with 100ml of water, wash the filter cake with 150ml of acetic acid Ethyl ...

Embodiment 2

[0039] Add 4L of acetonitrile, 100g (1.49mol, 1.0eq) of pyrrole, and 844g (5.96mol, 4eq) of chlorosulfonic acid isocyanate into a 10L three-necked flask, stir and dissolve, and after the dissolution is complete, lower the temperature. When the temperature of the reaction system is 10°C, Start to slowly add 100mL N,N-dimethylformamide dropwise, keep the reaction for 5h, after the keep warm, the temperature rises to 50°C, O-[4-nitro-2-(trifluoromethyl)phenyl]hydroxylamine 992g (4.47mol, 3eq) was added to the reaction solution, then the temperature was raised to 80°C, and the reaction was kept for 8 hours. After the heat preservation was completed, 1240g (11.9mol, 8eq) of formamidine acetate and 2056g (14.9mol, 10eq) of potassium carbonate were added to the system. ), the temperature was maintained at 70 to 80°C, and kept for 10 hours. After the heat preservation was completed, 1L of water was slowly added to the reaction system, and then the reaction solution was concentrated unt...

Embodiment 3

[0044]Add 40L of acetonitrile, 1000g (14.9mol, 1.0eq) of pyrrole, and 4218g (29.8mol, 2eq) of chlorosulfonic acid isocyanate into a 100L reaction kettle, stir and dissolve, and after the dissolution is complete, lower the temperature. When the temperature of the reaction system is 5°C, Start to slowly add 1 LN, N-dimethylformamide dropwise, and keep the reaction for 2.5h. Add 4962g (22.4mol, 1.5eq) of hydroxylamine into the reaction solution, then raise the temperature to 80°C, and keep the temperature for 4 hours. ,5eq), the temperature was maintained at 70 to 80°C, and kept for 5 hours. After the end of the heat preservation, slowly added 10L of water to the reaction system, then concentrated the reaction solution until no liquid dripped out, cooled to 10°C, stirred and crystallized for 5h, washed and filtered with 10L of water Cake, recrystallize the filter cake with 15L ethyl acetate, filter and dry the filter cake, and vacuum-dry at 45°C to obtain 1358.6 g of light yellow...

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Abstract

The invention discloses a one-pot method for preparing pyrrolo[2,1-F][1,2,4]triazin-4-amine, and belongs to the field of organic chemical synthesis. According to the method, a one-pot method is adopted, pyrrole is used as a raw material, chlorosulfonyl isocyanate is used as a cyanation reagent, O-[4-nitro-2-(trifluoromethyl)phenyl] hydroxylamine is used as an amination reagent, formamidine acetateis used as a cyclization reagent, and the pyrrolo[2,1-F][1,2,4]triazin-4-amine with a high yield and high purity is prepared. The method disclosed by the invention is simple to operate, high in product yield, high in purity, mild in reaction condition, less in energy consumption, less in pollution and very suitable for industrial production.

Description

technical field [0001] The invention relates to a method for preparing pyrrolo[2,1-F][1,2,4]triazine-4-amine by a one-pot method, belonging to the field of organic chemical synthesis. Background technique [0002] Remdesivir is a nucleoside analog and an RNA-dependent RNA polymerase (RdRp) inhibitor, and its antiviral mechanism of action is by inhibiting viral nucleic acid synthesis. On January 31, the New England Journal of Medicine (NEJM) published online the use of the drug in the treatment of the first confirmed case of novel coronavirus in the United States. It has aroused great attention at home and abroad, and quickly started clinical trials in our country with the approval of our country, which also brought great hope to the treatment of new coronaviruses in our country. [0003] At present, the published synthesis routes of remdesivir are divided into the first-line route and the second-generation route. These two routes were published in J.Med.Chem., a well-known ...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 陆茜崔赛德匡逸
Owner SHANGHAI LINKCHEM TECH CO LTD
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