A kind of method of synthesizing trametinib

Abstract

The invention discloses a method for synthesizing trametinib. The method comprises the steps of dehydrating N-(2-fluoro-4-iodophenyl)-N'-methylurea to form carbodiimide, then enabling the product to be subjected to a cyclization reaction with 2-methyl-3-oxo-diethyl glutarate to obtain 2-(2-fluoro-4-iodophenylamino)-4-hydroxyl-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-nonanoic acid-ethyl ester; after that, carrying out cyclization on the obtained product with N-(3-nitrophenyl)-N'-cyclopropyl urea to obtain 3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-methyl-1-(3-nitrophenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione; finally, reducing a nitro group first, then performing acetylation to obtain the trametinib. The invention provides a new synthesis route of the trametinib by means of retrosynthetic analysis, and can greatly shorten the technological process; furthermore, expensive reagents are not used in a preparation process; the method has the advantages of being simple and convenient to operate and lower in cost; a reference is provided for the preparation of the trametinib.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a synthesis method 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 chlorination to obtain chlorina...

AI Technical Summary

Problems solved by technology

However, there are still many steps in this method, and the one-step yield of compound 5 obtained by condensation is relatively low.

[0005] Even if the advantages and disadvantages of the two methods are complemented, only the raw materials of the condensation step and the replacement step with lower yields can be changed, which may have a certain effect on improving the overall yield, but the idea of ​​​​reaction route design has not been changed, and the operation remains the same. More cumbersome and difficult to solve problems with many steps

[0006] Of course, Med Chem Lett, 2011, 2(6), 320-324 reported a sequence of introducing substituted anilines that is different from the above two methods, that is, the 3-acetamidoaniline structure is firstly constructed into a ring, and finally 2 -Fluoro-4-iodoaniline, the advantage of this method is that it avoids the amide exchange process under alkaline conditions in the first two methods, but the whole route is relatively cumbersome, the control of intermediates is difficult, and the process stability will face greater difficulties

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