Preparation method of eribulin intermediate

Abstract

The invention relates to a preparation method of an eribulin intermediate. Specifically, the invention relates to a compound shown as a formula IV; R1 represents a hydroxyl protecting group, preferably (C1-10 alkyl or aryl) 3 silicon alkyl, more preferably TBDPS; R2 represents a hydroxyl protecting group, preferably benzyl or (C1-10 alkyl or aryl) 3 silicon alkyl, and more preferably benzyl or TBS. The invention particularly relates to the preparation method of the compound shown as formula IV. The method has the advantages of mild reaction conditions, simple operation, low cost for synthesis and is applicable to mass production.

Description

technical field [0001] The invention relates to a preparation method of an eribulin intermediate. Background technique [0002] Eribulin (as shown in formula I) is a derivative of the macrolide compound halichondrinB extracted from the marine biological sponge Halichondriaokadai, and is a tubulin inhibitor. On November 15, 2010, the FDA approved Eribulin mesylate (Halaven) injection for the treatment of patients with metastatic breast cancer who have received at least two chemotherapy regimens, and its mechanism of action may be through direct binding to tubulin Inhibits mitosis, inhibits the growth of microtubules, and inhibits the growth of cancer cells to exert a therapeutic effect. As a tubulin polymerization inhibitor with a new mechanism of action, eribulin mesylate provides a new treatment for patients with locally advanced breast cancer or metastatic breast cancer to improve the survival rate and quality of life. [0003] [0004] The molecular structure of Erib...

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Problems solved by technology

[0006] The chiral compound shown in formula II is the key intermediate for the synthesis of eribulin. The synthesis of compound II has attracted great interest and attention from chemists. Synthetic method (Org.Lett.2002, 4, 4435; Org.Lett.2009, 11, 4520; J.Am.Chem.Soc.2009, 131, 15636) which is the key technology, however, NHK reaction requires the use of high toxicity The substance chromium dichloride, and the NHK reaction is extremely sensitive to water and oxygen, and needs to be carried out under extremely strict anhydrous and oxygen-free conditions, and the reproducibility of the reaction is poor, which makes it difficult to scale up the production of this method

The research group of Professor Philips of the University of Colorado in the United States reported a synthetic method (Angew.Chem.Intl.Ed.2009,48,2346) with Noyori asymmetric hydrogenation and rearrangement of diazoketone compounds as the key steps. Although the synthesis process Relatively simple, but requires the use of explosive diazomethane and expensive chiral noble metal catalysts, making it difficult to scale up the synthesis

Recently, the Canadian Alphora Research Company disclosed a method for synthesizing the compound of formula II using natural sugar compounds as chiral sources. However, this synthetic route is relatively lengthy and complicated, and it is difficult to be applied in scale-up production.

In summary, the synthesis method of the compound of formula II reported publicly above not only has harsh reaction conditions, high synthesis cost, cumbersome operation, but also has potential safety hazards, and is not suitable for large-scale production

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