SKLB1039 compound, and preparation method and application thereof

Abstract

The invention belongs to the technical field of preparation of novel compounds, and particularly relates to an SKLB1039 compound, and a preparation method and application thereof. 2-methyl-3-nitrobenzoic acid taken as an initial raw material undergoes bromination, esterification, reduction, two times of reductive amination and hydrolysis to synthesize 5-bromo-2-methyl-3-(N-ethyl, N-(tetrahydropyran-4-yl))aminobenzoic acid; cylohexanone taken as a raw material undergoes carbonyl alpha acetylation andacetyl cyclohexanone and cyanopyridone catalytic hydrogenation reduction to synthesize 4-aminomethyl-1-methyl-5, 6, 7, 8-tetrahydroisoquinoline-3(2H)-one; and the 5-bromo-2-methyl-3-(N-ethyl, N-(tetrahydropyran-4-yl))aminobenzoic acid and the 4-aminomethyl-1-methyl-5, 6, 7, 8-tetrahydroisoquinoline-3(2H)-one are coupled into amide, and then the amide is catalytically coupled with aryl pinacol borate to obtain the SKLB1039 compound. The invention provides the large-scale preparation process of the SKLB1039, the operation is easy, the post-treatment purification process is simple, the total yield of the route is improved, the raw materials are easy to purchase and low in price, and the production cost is greatly reduced.

Description

technical field [0001] The invention belongs to the technical field of preparation of new compounds, specifically a SKLB1039 compound and its preparation method and application. Background technique [0002] Cancer is a major public health problem worldwide, and targeting epigenetic regulators provides us with a new cancer treatment strategy; enhancers of Zeste Homolog 2 (EZH2), a family of histone lysine methyltransferases A member of polycomb repressive complex 2 (PRC2), PRC2 catalyzes the methylation of histone 3 lysine 27 (H3K27), resulting in trimethylation of H3K27 (H3K27me3), which is a transcriptional repressor Germ genetic markers and can silence target genes. [0003] Overexpression of EZH2 has been observed in many blood and solid tumors, such as Hodgkin's disease, non-Hodgkin's lymphoma, prostate cancer, breast cancer, kidney cancer, melanoma, and tongue cancer, and EZH2 is widely involved in cancer progression , metastasis, and poor prognosis; somatic mutation...

AI Technical Summary

Problems solved by technology

[0004] In recent years, multiple groups including GlaxoSmithKline, Epizyme, Novartis, UNC Eshelman, and Constellation have reported various structures of small molecule inhibitors of EZH2; it is reported that EPZ6438, the most potent compound so far, inhibits the IC of EZH2. 50 2.5nM, and exhibited significant tumor growth inhibition in several human DLBCL and malignant striated muscle xenograft models, a Phase I / II study of EPZ6438 was initiated in 2013 for the treatment of advanced solid tumors and B cell lymphoma, however, the WSU-DLCL2 xenograft model has poor physicochemical properties, such as solubility, so a highly effective EZH2 inhibitor with improved physicochemical properties is urgently needed

[0005] The document "Design, synthesis and biological evaluation of novel1-methyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinolins as potential EZH2 inhibitors" is disclosed in the prior art, and the SKLB1049 compound and its Preparation method, in further research, it was found that the prepared compound SKLB1039 compound has more excellent anti-tumor activity than SKLB1049 compound; and the disclosed synthesis method of SKLB1049 compound has high cost, large amount of raw material reagents, and difficult purification of intermediate products , The disadvantage of low total yield of the route

Images