Intermediate for preparing halichondrin compounds and preparation method thereof

A compound, halogen technology, applied in the field of organic synthesis, can solve the problems of cost control, environment and labor protection, high toxicity, lengthy synthetic route, etc.

Active Publication Date: 2021-03-05
BEIJING TIENYI LUFU PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, in the prior art, there are many defects in the preparation method of the above-mentioned compound of formula 4 or formula 6, for example, the synthetic route is too lengthy, the optical purity of the starting material is difficult to control, and it involves highly toxic and expensive n-Bu 3 SnH reagent, poor stereoselectivity, etc.
These defects will bring about a series of production problems such as cost control, environmental and labor protection, and product quality.

Method used

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  • Intermediate for preparing halichondrin compounds and preparation method thereof
  • Intermediate for preparing halichondrin compounds and preparation method thereof
  • Intermediate for preparing halichondrin compounds and preparation method thereof

Examples

Experimental program
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Embodiment 1

[0132] Embodiment 1: Preparation method one of compound 8 (see attached figure 1 )

[0133] 1.1 Preparation of Compound 1

[0134] method one:

[0135]Add (s)-4-phenyl-2-oxazolidinone (15.6g) into a 500ml three-necked flask, add dry THF (200ml) to dissolve, change the argon and protect it with argon, then cool the reaction solution to - 78°C, add n-BuLi solution in THF (2.5M, 38ml) dropwise (keep the internal temperature ≤ -60°C), after dropping, keep the reaction at -78°C for 15min, then add crotonyl chloride (10g) dropwise, dropwise , kept at -78°C for 30min, then rose to 0°C for 1.5h. After the completion of the reaction as detected by TLC, slowly add saturated ammonium chloride solution to quench, and stir well until the solid disappears, and the layers can be clearly separated. The liquids were separated, the aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined and washed once with saturated sodium chloride solution. The organic...

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Abstract

The invention relates to an intermediate for preparing halichondrin compounds and a preparation method thereof. In particular, it relates to intermediates, preparation methods and uses for preparing halichondrin, eribulin or analogues thereof. The intermediate, its preparation method and application are used to construct the C20-C26 structural fragment of halichondrin compounds. The starting materials of the synthetic route of the present invention are cheap and easy to obtain, stable in source and reliable in quality; the structural characteristics of the reactant itself are fully utilized in the selection of the chiral center construction method, which effectively improves the synthetic efficiency and reduces the difficulty of product quality control and risks; and avoid the use of highly toxic and expensive organotin catalysts, significantly improving cost and environmental friendliness.

Description

technical field [0001] The present invention relates to intermediate compounds that can be used to prepare halichondrin or its analogs, especially eribulin, and the preparation methods of these intermediate compounds, belonging to the technical field of organic synthesis. Background technique [0002] Halichondrin (HB for short) is a kind of natural product that exists in the cavernous body and has a polyether macrolide structure. This kind of substance has a strong anti-tumor effect and broad medicinal prospects. Based on their structural differences, these natural products are divided into the following categories: norhalichondrin, halichondrin, homohalichondrin, etc., and each category has a series of representative subgroups. type, the subtype and specific structure are known in the art, and are disclosed in detail in WO2016003975A1, which is incorporated in this prior art document in its entirety; Eribulin (Eribulin, hereinafter referred to as EB) is a kind of halichond...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F7/18
CPCC07F7/1892C07F7/1804C07F7/0812C07D263/26C07D277/16C07D493/22
Inventor 徐为平
Owner BEIJING TIENYI LUFU PHARMATECH CO LTD
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