A method for synthesizing trametinib key intermediate

A technology for trametinib and intermediates, which is applied in the field of synthesizing key intermediates of trametinib, can solve the problems of many steps, low yield of one step, low yield of key steps, etc., and achieves the effect of short steps
CN109336884BActive Publication Date: 2021-02-05安庆奇创药业有限公司
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Patents(China)
Current Assignee / Owner
安庆奇创药业有限公司
Publication Date
2021-02-05

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Abstract

The invention discloses a method for synthesizing a key intermediate of trametinib, which uses monoformamide monoethyl malonate and methylmalonic acid to complete the cyclization reaction to obtain a crude pyridinetrione compound; the obtained pyridinetrione The crude compound is directly cyclized with N-(2-fluoro-4-iodophenyl)-N'-cyclopropylurea to obtain the key intermediate of trametinib. The present invention adopts monoethyl malonate and methylmalonic acid to complete the cyclization reaction to obtain a pyridinetrione compound, which is directly cyclized with a urea compound without purification to obtain a key intermediate for synthesizing trametinib. The method steps are short, the total yield is 47.3%, and it has the potential of scale-up in pilot scale, which provides a new scheme for the synthesis of trametinib.
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Description

technical field

[0001] The invention relates to a synthesis method of trametinib, in particular to a method for synthesizing a key intermediate of trametinib. Background technique

[0002] The Chinese chemical name of Trametinib: N-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetra Hydrogen-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]acetamide, developed by GlaxoSmithKline , Trametinib approved by the U.S. FDA on May 29, 2013, was launched in the U.S. under the trade name Mekinist. For the treatment of unresectable or metastatic melanoma with BRAF (murine sarcoma virulence oncogenic homologue B1 gene) V600E or V600K mutation.

[0003] ACS Medicinal Chemistry Letters, 2011,2(4),320-324 reported its synthetic method, as figure 1 Shown: Urea 1 was prepared by using 2-fluoro-4-iodophenylisocyanate and cyclopropylamine, and then cyclized with malonic acid to obtain pyrimidinetrione compound 2, pyrimidinetrione compound 2 and POCl 3 Selective ...

Claims

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