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Novel method for synthesizing dolutegravir key intermediate 2,4-difluorobenzylamine

A technology of difluorobenzylamine and dolutegravir, applied in the field of synthesis of 2,4-difluorobenzylamine, the key intermediate of dolutegravir, can solve the problems of harsh operating conditions, low yield and high cost, and achieve The effect of simple raw materials, easy access to raw materials, and simple routes

Active Publication Date: 2018-11-06
SHAXING CHEM TAIZHOU CITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] This method has relatively mild reaction conditions and high yield, but there are serious environmental protection problems. After chloromethylation and final hydrolysis, a large amount of waste acid and high-ammonia nitrogen and high-salt wastewater will remain.
[0010] In addition, the most reported route is the method of reducing 2,4-difluorobenzonitrile, wherein there is a method of pressurized hydrogenation reduction under an ammonia atmosphere (US5068371, Chemistry-AEuropean Journal, 2013,19(14 ), 4437-4440), there is also a method for reducing 2,4-dibenzonitrile with borane-THF complex (J.Med.Chem., 2006,49,6197-6208) and with liAlH 4 It is a reducing agent method (WO2012076673), but these methods all have problems such as large safety hazards, harsh operating conditions, low yield, and high cost.
[0011] From the above, it can be seen that the current preparation method of 2,4-difluorobenzylamine still has obvious deficiencies in terms of environmental protection, cost and atom economy, and it is necessary to develop a green and environmentally friendly 2,4-difluorobenzylamine with industrial production value. The production process of benzylamine is of great significance

Method used

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  • Novel method for synthesizing dolutegravir key intermediate 2,4-difluorobenzylamine
  • Novel method for synthesizing dolutegravir key intermediate 2,4-difluorobenzylamine
  • Novel method for synthesizing dolutegravir key intermediate 2,4-difluorobenzylamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Take m-difluorobenzene 114g (1.0mol), AlCl 3 133g (1.0mol) was added to 300ml containing 4.6g Na(Co(CO) 4 ) (0.024mol) in methanol solution (self-made), vacuumize, replace with nitrogen 3 times, fill with CO under stirring until the system pressure reaches 3.5MPa, heat to 60°C, the heat release is severe at the initial stage of the reaction, and condensed water is introduced to control the temperature Not more than 80°C. After 3 hours the reaction was complete. After the reaction, the residual gas was discharged, and 80ml of 10% hydrochloric acid was slowly dropped into the system, filtered, and most of the solvent was evaporated from the filtrate under reduced pressure, and the obtained pale yellow transparent liquid was directly subjected to the next step of reaction.

[0030] Add the light yellow transparent liquid in the previous step to 400ml of methanol, add 5.7g of Raney nickel while stirring, vacuumize the system for nitrogen replacement 3 times, slowly inject...

Embodiment 2

[0032] Take m-difluorobenzene 114g (1mol) and chloroform 125g (1.05mol) into 300ml tetrahydrofuran, stir to dissolve, keep the temperature between 30-40°C, slowly add potassium tert-butoxide 118g (1.05mol) in batches under stirring, The whole feeding process is about 1.5 hours. After the addition, continue to stir and react for 1 hour, filter, and evaporate most of the tetrahydrofuran. Slowly add 100 g (2.1 mol) of formic acid to the system, raise the temperature to 65 ° C and stir for 3 hours. After the reaction, evaporate under reduced pressure. To remove most of the excess formic acid, add 150ml of dichloromethane to the system, wash with 200ml of sodium bicarbonate once, wash once with 200ml of saturated saline, separate the organic layer, distill off the dichloromethane, and the obtained pale yellow liquid is directly used in the next step reaction.

[0033] Add the light yellow liquid oil in the previous step to 400ml of methanol, add 10.5g of 5% Pd / C while stirring, vac...

Embodiment 3

[0035] Take m-difluorobenzene 114g (1mol) and chloroform 125g (1.05mol) into 300ml tetrahydrofuran, stir to dissolve, keep the temperature between 30-40°C, slowly add potassium tert-butoxide 118g (1.05mol) in batches under stirring, The whole feeding process is about 1.5 hours. After the addition, continue to stir and react for 1 hour, filter, and evaporate most of the tetrahydrofuran. Slowly add 100 g (2.1 mol) of formic acid to the system, raise the temperature to 65 ° C and stir for 3 hours. After the reaction, evaporate under reduced pressure. To remove most of the excess formic acid, add 150ml of dichloromethane to the system, wash with 200ml of sodium bicarbonate once, wash once with 200ml of saturated saline, separate the organic layer, distill off the dichloromethane, and the obtained pale yellow liquid is directly used in the next step reaction.

[0036] Add 126g of ammonium formate (2mol) to the light yellow liquid oil in the previous step, slowly raise the temperatu...

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Abstract

The invention discloses a novel production method which is concise and green in route, low in cost and easy to industrialize to prepare 2,4-difluorobenzylamine. The method comprises the following twosteps: a) at certain pressure, carrying out a carbonylation reaction on m-difluorobenzene and CO in the presence of a catalyst so as to generate 2,4-difluorobenzaldehyde, or carrying out a formylationreaction on m-difluorobenzene, namely carrying out chlorocarbene substitution on m-difluorobenzene in a chloroform strong base system, and further carrying out hydrolysis so as to prepare a product 2,4-difluorobenzaldehyde (Reimer-Tiemann reactions); b) putting the product 2,4-difluorobenzaldehyde of the step a) into an alcohol solvent, at certain pressure, in the presence of the catalyst, carrying out a reduction ammonolysis reaction on the component with an ammonia gas and hydrogen directly in the presence of a catalyst, or enabling the component to react with ammonium formate, thereby obtaining the 2,4-difluorobenzylamine. The preparation method disclosed by the invention is simple and easy in raw material obtaining, concise in route, green and environmentally friendly, low in cost andeasy in industrial production.

Description

technical field [0001] The invention relates to the field of synthesis of medicines and pesticide chemicals, and specifically relates to a new method for synthesizing 2,4-difluorobenzylamine, a key intermediate of dolutegravir. Background technique [0002] 2,4-Difluorobenzylamine is a very important chemical intermediate, and its most important use is to prepare the anti-AIDS drug dolutegravir. Dolutegravir is a new type of integrase inhibitor developed by GlaxoSmithKline and approved for marketing in the United States in 2013. Due to its advantages of high efficiency and low toxicity, the market sales have risen rapidly in recent years, and the momentum is unanimously optimistic. Among the several known synthetic routes of dolutegravir, 2,4-difluorobenzylamine is a key intermediate that cannot be bypassed. Therefore, it is very meaningful to develop an efficient, green and low-cost preparation process for 2,4-difluorobenzylamine. [0003] At present, the production indu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/26C07C209/28C07C211/29
CPCC07C45/42C07C45/49C07C209/26C07C209/28C07C211/29C07C47/55
Inventor 黄小庭
Owner SHAXING CHEM TAIZHOU CITY
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