A kind of preparation method of Eltrombopag intermediate and the 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, which relate to the technical field of medicinal chemistry. The preparation method of the Eltrombopag intermediate uses p-bromophenol as a raw material, and the nitration reaction does not have the problem of poor selectivity. After iodination, the yield of the coupling reaction between the compound of the intermediate formula (I) and phenylboronic acid is relatively high. Subsequent reduction reaction is carried out, the debromination reaction is complete, the yield is over 90%, and the purification is relatively simple. The synthesis yield of the compound of formula (I) is high and the operation is simple. Through the above improvements, the yield of the key compound of formula (I) is high, the follow-up treatment operation is simple, and the process is easy to scale up production. The yield of the whole synthesis process of Eltrombopag diethanolamine salt is 48.1%. The operation is simple, the three wastes are less, and it is suitable for scale-up 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 an 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 in adults with chronic ITP for the treatment of chronic idiopathic platelets after glucocorticoids, immunoglobulin therapy, or after splenectomy Thrombocytopenia in patients with idiopathic purpura (ITP). The chemical name is 3`-[2-[(2Z)-1-(3,4-dimethylphenyl)-1,5dihydro-3-methyl-5-oxo-4H-pyrazole-4 -Subunit]hydrazino]-2'-hydroxy-[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 me...

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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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