Preparation method of eltrombopag intermediate and preparation method of eltrombopag diethanolamine salt

Abstract

The invention provides a preparation method of an eltrombopag intermediate and a preparation method of eltrombopag diethanolamine salt, and relates to the technical field of medicinal chemistry. According to the preparation method of the eltrombopag intermediate, p-bromophenol is taken as a raw material, and the problem of poor selectivity of nitration reaction is solved. After iodination, the coupling reaction yield of the intermediate compound as shown in a formula (I) and phenylboronic acid is high. Subsequently reduction reaction is carried out, the debromination reaction is complete, the yield is 90% or more, the refining is simpler, and the synthesis yield of the compound of the formula (I) is higher and the operation is simple. Through the improvement, the yield of the key compound shown as the formula (I) is relatively high, the subsequent treatment operation is simple, the process is easy for amplified production, the yield of the whole synthesis process of the eltrombopag diethanolamine salt is 48.1%, the operation is simple, less three wastes are generated, and the synthesis process is suitable for amplified production.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of an Eltrombopag intermediate and a preparation method of Eltrombopag diethanolamine salt. Background technique [0002] Chronic idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease caused by an autoimmune reaction that causes thrombocytopenia. Eltrombopag Diolamine is the first FDA-approved oral non-peptide thrombopoietin receptor agonist for the treatment of chronic idiopathic thrombocytopenia after glucocorticoids, immunoglobulin therapy, or splenectomy in adults with chronic ITP Thrombocytopenia in patients with ITP. The chemical name is 3`-[2-[(2Z)-1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazole-4 -Ylidene]hydrazino]-2'-hydroxyl-[1,1'-biphenyl]-3-carboxylic acid, diethanolamine salt (compound of formula VIII). Eltrombopag Diolamine is a new oral drug for the treatment of chronic ITP. Its mechanism of action is ...

AI Technical Summary

Problems solved by technology

[0006] Or route 2, the specific steps are as follows, mainly using 4-chloro-2-nitrophenol as the starting material, but the reported coupling reaction yield is only 50-60%, and reductive dechlorination is difficult, resulting in greater difficulty in refining

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