Highly Efficient Synthesis Of 1H-Indazole-3-Carboxylic Acid Derivatives Via Diazotization Reaction

As a heteroaromatics,1H-indazole and its derivatives are very important intermediates for organic synthesis with good stability and aromaticity,and can be widely used in the synthesis of various pharmaceutical molecules.In this article,the synthesis of 1H-indazole-3-carboxylic acid derivatives via diazotization reaction of o-aminophenylacetic acid derivatives was explored,and it was successfully applied to the synthesis of Granisetron and Lonidamine,specifically including the following four parts:In the first part,the synthetic methods of 1H-indazole were reviewed,including phenyl-hydrazine derivatives intramolecular condensation,hydrazone derivatives intramolecular co N-densation,phenylene compounds addition,phenylazides condensation,2H-indazoles rearra N-gement method,and o-aminophenylethyne derivatives intramolecular condensation.In the second part,1H-indazole-3-carboxylic acid derivatives were synthesized in one step at room temperature,using o-aminophenylacetic acid derivatives as raw materials,^tBu ONO/CH₃COOH as diazotization reagent and acetonitrile as solvent.This method is suitable for the synthesis of both 1H-indazole-3-carboxamide derivatives,and 1H-indazole-3-carboxylic esters with high yields.In the third part,through reviewing the synthetic methods of Granisetron reported in the current literatures,we designed a new synthetic route of Granisetron using diazotization reaction as a key step.Finally,we successfully synthesized Granisetron in a total yield of 46%using o-nitrophenylacetic acid as the starting material.In the last part,we summarized the synthetic methods of anti-tumor drug Lonidamine reported in literatures,and studying the synthesis of Lonidamine by diazotization reaction.Finally,Lonidamine was successfully synthesized using o-aminopheny-lacetic acid methyl ester as the starting material in a total yield of 60%.