(3R)-2-iodo-4-benzyloxy-3-methyl-1-ene compound as well as preparation method and application thereof

Abstract

The invention provides a (3R)-2-iodo-4-benzyloxy-3-methyl-1-ene compound as well as a preparation method and an application thereof, more particularly relates to a novel compound ERP-2 as well as a preparation method and an application thereof, also provides a novel preparation method of ERP ((3R)-2,4-diiodo-3-N-methyl butylamine-1-ene) and relates to use of the novel compound ERP-2. According tothe method, compared with the prior art, the yield and the quality of ERP-1 and ERP are notably increased when ERP-1 and ERP are prepared through the compound ERP-2, hazardous articles such as dimethylzinc or dimethyl aluminum are not required in the reaction process, expensive Hoveyda-Grubbs catalysts, Amano lipase PS-8000 and the like are not required, aftertreatment of a reaction is simple, theproduction cost is greatly saved, the production safety is improved, and the method is more suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a pharmaceutical intermediate (3R)-2-iodo-4-benzyloxy-3-methyl-1-ene compound and its preparation method and application. Background technique [0002] Halichondrin B (Halichondrin B) is a natural product with anticancer activity isolated from the sponge Halichondria okadai in 1986. It is known as an effective anticancer agent (see US6214865, WO2005118565A1, WO2009124237A1, etc.). In the research on the total synthesis of Halichondrin B by Y Kishi's research group at Harvard University, Eribulin (Eribulin, CAS: 253128-41-5), which has a simpler structure and better efficacy than Halichondrin B, was found. Eribulin was developed by Eisai and was approved by the FDA on November 15, 2010. Its product name is Halaven, and it is used for the treatment of metastatic breast cancer who have received at least two chemical drugs. On January 28, 2016, the FDA approved eribulin mesylate f...

AI Technical Summary

Problems solved by technology

[0006] The first approach involves the asymmetric SN2' reaction of cuprates, and requires the use of Hoveyda-Grubbs catalysts. The cost of the catalyst is relatively high, and the reaction requires the use of dangerous chemicals dimethyl zinc, which has a low boiling point. Flammable, expensive, not convenient for industrial production, isolated product ERP yield 96%, 98% enantiomeric excess (e.e.), where its enantiomer exists just above 0.10%, which in its The final product drug registration quality standard control is just higher than the overall upper limit requirements for simple impurities

[0007] The second method requires the use of field lipase PS-800. The stereoselective catalysis of the enzyme is unique, and the screening of the enzyme is also a very complicated task, with a yield of 46%. Moreover, dangerous chemicals are also used in the synthesis of S7. Trimethylaluminum, trimethylaluminum is a highly flammable substance, expensive, not convenient for industrial production, and the production cost is very high

The initial synthetic route can only synthesize microgram-level samples. Eisei Company Research Institute YU and others have optimized the synthetic method so that important intermediates and simplified products can be prepared in g-level quantities. However, due to the unique anti-tumor properties of eribulin mesylate Mechanism, significant anti-tumor effect, its market demand is large, still need to develop new technology to meet market demand, reduce production costs, benefit more patients

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