Synthesis Of 3,4-Difluoro-2-Methylbenzoic Acid

Baloxavir marboxil is a new anti-influenza drug with a new mechanism of action pioneered in the past 20 years.It was first developed by Shionoyi Pharmaceutical Co.,Ltd.and was launched in the United States and Japan in 2019.Savir dipivoxil acts on the endonuclease of polymerase acidic protein,which is necessary for the transcription of influenza virus genome,and has strong inhibitory activity on both influenza A and B viruses.3,4-Difluoro-2-methylbenzoic acid is a key and important intermediate in the synthesis of baloxavir dipivoxil.This paper first reviews and analyzes the synthetic process route of baloxavir dipivoxil,and then analyzes and reviews the synthetic route of3,4-difluoro-2-methylbenzoic acid and similar compounds and the specific synthetic methods of each step.Two better synthetic routes were selected and designed.The advantages and disadvantages of these two routes are systematically analyzed and discussed.Through the analysis of the reaction mechanism,the study of possible side reactions,the screening of reaction conditions and the study of post-processing,we finally studied a low cost,high quality,practical application value,high safety factor and suitable for industrial production.The synthetic process route of difluoro-2-methylbenzoic acid.Using 2,3,4-trifluoronitrobenzene as the starting material,the product produced by the reaction of potassium carbonate with dimethyl malonate under alkaline conditions is hydrolyzed under hydrochloric acid and acetic acid conditions to obtain 2,3-difluoro-6-Nitrophenylacetic acid;decarboxylated under the action of the catalyst copper oxide to obtain 1,2-difluoro-3-methyl-4-nitrobenzene;under the catalysis of Raney nickel,it reacts with hydrazine hydrate to be reduced to 3,4-Difluoro-2-methylaniline;then use sulfuric acid and sodium nitrite to prepare diazonium salt,and react under the conditions of catalyst cuprous bromide and hydrobromic acid to obtain 1-bromo-3,4-difluoro-2-methylbenzene;finally,the bromide is reacted with magnesium chips in tetrahydrofuran to prepare a Grignard reagent,and carbon dioxide is passed into the Grignard reagent to prepare the target 3,4-difluoro-2-methylbenzoic acid.The whole route consists of 6 steps of reaction.Under this technological condition,the total yield of the reaction reaches32.5% and the purity is 99.9%.