Compound and preparation method and application thereof

A compound and reaction technology, applied in the field of compounds and their preparation, can solve the problems of low reaction yield, influence on eribulin synthesis efficiency, multiple reaction raw materials, etc., and achieve the effect of improving yield

Inactive Publication Date: 2017-07-14
CHONGQING TAIHAO PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0060] The total reaction yield of the currently disclosed synthetic route of Compound 2 to Compound 5 is low, and more reaction raw materials are required, which seriously affects the synthesis efficiency of Eribulin. Therefore, a new synthetic method for Eribulin has been developed to improve Eribulin synthesis efficiency and overall yield are of great significance

Method used

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  • Compound and preparation method and application thereof
  • Compound and preparation method and application thereof
  • Compound and preparation method and application thereof

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preparation example Construction

[0098] The present invention also provides a preparation method of a compound having a structure of formula (II), comprising:

[0099] The compound of formula (III) structure is converted into the compound with formula (II) structure,

[0100]

[0101]

[0102] where the R 1 , R 2 , R 3 , R 4 , R 5 independently selected from C3-C30 alkylsilyl, C7-C30 benzyl or C1-C25 alkyl;

[0103] The Ar is selected from C6-C30 aryl groups.

[0104] According to the present invention, the present invention converts the compound with formula (III) structure into the compound with formula (II) structure, wherein, R in the compound of formula (III) structure 1 , R 2 , R 3 , R 4 , R 5 And Ar is identical with the definition of substituent in intermediate; Among the present invention, the catalyst of described transformation reaction is CrCl 2 / NiCl 2 、Cp 2 Cr / NiCl 2 、CpCrCl / NiCl 2 , Cr(II) / Mg(0) / TMS-X / NiCl 2 , Cr(II) / Zn(0) / TMS-X / NiCl 2 , Cr(III) / Mg(0) / TMS-X / NiCl 2 , Cr(I...

Embodiment 1

[0124]

[0125] Under nitrogen protection, chiral ligand (2.96g, 10mmol) and anhydrous CrCl2 (1.23g, 10mmol) were added to a 50ml three-neck round bottom flask, and 15ml of anhydrous acetonitrile was added thereto with a syringe. The resulting suspension was heated and TEA (1.01 g, 10 mmol) was added dropwise with stirring to give a dark green mixture. At room temperature, the mixed solution was continued to be stirred for 40 min, and NiCl2·DMP (338 mg, 1 mmol) was added thereto, and the color of the reaction solution became dark rapidly. Stirring was continued for 20 min, and the compound of formula (III) (1.588 g, 1 mmol) was dissolved in a mixed solution of 4 ml of anhydrous THF and 2 ml of acetonitrile, and was added dropwise into the reaction solution within 10 min using a syringe. After the dropwise addition, the mixed reaction solution was stirred at room temperature for 1 h, 20 ml of n-heptane was added, and then filtered, and the filter cake was washed with n-hepta...

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Abstract

The invention provides a compound and a preparation method and application thereof. The preparation method comprises the following steps: firstly, transforming a compound with a structure shown as a formula (III) into an intermediate with a structure shown as a formula (II); transforming the intermediate with the structure shown as the formula (II) into a compound with a structure shown as a formula (IV); then, transforming the compound shown as the formula (IV) into eribulin. In a synthetic route, the reaction yield is high, so that the total yield of the synthesized eribulin is increased.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a compound and its preparation method and application. Background technique [0002] Eribulin (Eribulin) is an effective anticancer agent, and its structure is shown in formula (I). It is a fully synthetic macrocyclic analogue of the natural product halichondrin B with the structure of formula (I-halichondrin B). Halichondrin B is a very complex marine natural product. Eribulin mesylate (formula (I-1 MsOH)), developed by Eisai Co., Ltd., was approved by the FDA in 2010 for the treatment of patients who have received at least two chemical drugs. The treatment of metastatic breast cancer, trade name Halaven. It is also known as E7389, ER-086526, US NCI designation NSC-707389. Eribulin mesylate was approved by the FDA in 2016 for the treatment of advanced liposarcoma. [0003] [0004] [0005] Eribulin is one of the most complex synthetic drugs that has been prepared on a c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/22C07F7/18
CPCC07D493/22C07F7/1804C07F7/1892
Inventor 张宪恕纳撒尼尔·芬尼郑保富
Owner CHONGQING TAIHAO PHARM CO LTD
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