Synthesis method of eltrombopag

Abstract

The invention discloses a synthesis method of eltrombopag. The synthesis method comprises the following steps: subjecting cheap hydrazine hydrate to reacting with ethyl acetoacetate, and then subjecting a reaction product to reacting with 3,4-dimethyl iodobenzene to prepare an important starting material 1-(3,4-dimethylphenyl)-3-methyl-1H-pyrazol-5 (4H)-one (8). Thus, the problem that the starting material 3,4-dimethylphenylhydrazine is difficult to obtain is overcome. N,N-carbonyl-diimidazole (CDI) can be adopted to react with ortho-aminophenol, amino groups and hydroxyl groups are protected at the same time, then bromination is carried out, coupling with m-carboxyphenylboronic acid is carried out, and deprotection is conducted, so 2-hydroxy-3-nitrobiphenyl-4'-formic acid is prepared, and a process is simpler and more convenient. An eltrombopag ethanolamine preparation taking eltrombopag as a raw material is mainly used for patients who are ineffective to treatment with glucocorticoid drugs and immune globulins or for patients with chronic primary immune thrombocytopenia (ITP) after splenectomy.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, in particular to the synthesis of Eltrombopag Background technique [0002] The U.S. FDA approved GlaxoSmithKline’s eltrombopag (Promacta) for the treatment of glucocorticoids, immune globulin therapy or splenectomy Thrombocytopenia in patients with postoperative chronic idiopathic thrombocytopenic purpura (ITP), whose chemical structure is as follows: [0003] [0004] The main synthetic route of Eltrombopag reported in the literature is as follows: [0005] U.S. Patent US2004019190 uses 2-bromophenol (1) as a raw material, and nitrates to obtain 2-bromo-6-nitrophenol (2), uses methyl iodide to protect the phenolic hydroxyl group, and couples with 4-bromophenylboronic acid. After the joint reaction, use hydrobromic acid to demethylate to obtain 2-hydroxy-3-nitrobiphenyl-4'-carboxylic acid (6), and to obtain 3-amino-2-...

AI Technical Summary

Problems solved by technology

[0011] In addition to the unfavorable factors of long process route and expensive raw materials in the above synthetic route, methyl iodide is also used to protect the methyl group. In addition to high toxicity, it will also bring other unfavorable factors. The main reason is that although it is easy to protect the hydroxyl group, it is also difficult. Deprotection, use very acidic hydrobromic acid, intermediate 2-methoxy-3-nitrobiphenyl-4-formic acid (5) to prepare intermediate 2-hydroxyl-3-nitrate under the action of hydrobromic acid base biphenyl-4-carboxylic acid (6), it is easy to decompose, resulting in low yield

[0012] 1-(3,4-Xylyl)-3-methyl-1H-pyrazol-5(4H)-one (8) is prepared by cyclization of 3,4-dimethylphenylhydrazine and ethyl acetoacetate , 3,4-Dimethylphenylhydrazine requires custom synthesis due to the small market demand, which is expensive and difficult to obtain

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