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Method for preparing eribulin and intermediate thereof

A technology for compounds and analogs, applied in the field of preparation of eribulin, can solve problems such as difficulty in total synthesis, complex structure, etc., and achieve the effects of avoiding complex and tedious processes and improving yield

Active Publication Date: 2018-07-31
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Eribulin is the first macrocyclic ketone analog obtained by optimizing the structure of halichondrin B. At present, Eribulin mesylate injection has been marketed in many countries for the treatment of metastatic breast cancer, but its structure is complex And it contains multiple chiral neutrals, and the total synthesis is difficult

Method used

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  • Method for preparing eribulin and intermediate thereof
  • Method for preparing eribulin and intermediate thereof
  • Method for preparing eribulin and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111]

[0112] Weigh benzylbromoethanol (5.00g) in an eggplant-shaped bottle, dissolve it with acetonitrile (50mL), add triphenylphosphine (9.21g), react at about 80°C for 24h, cool the reaction to room temperature naturally, and evaporate under reduced pressure solvent, added ethyl acetate (50 mL) and stirred for 30 minutes, filtered and washed with ethyl acetate to obtain 9.54 g of white solid with a yield of 86% and a purity of 96%.

Embodiment 2

[0114]

[0115] Weigh quaternary phosphorus salt 9aa (4.76g) in an eggplant-shaped bottle, add anhydrous tetrahydrofuran (300mL), put the reaction solution into dry ice-ethanol to cool, add 2.5M n-BuLi (4mL) dropwise to the reaction, After the dropwise addition, keep the temperature for reaction for 30min, then add 1mL of THF solution of 2d compound (1.32g) dropwise, stir for 10min, then naturally warm up to room temperature, continue the reaction for 1h, add water (50mL) to quench the reaction, and depressurize The solvent was evaporated, ethyl acetate (200 mL) was added, washed with water and saturated sodium chloride successively, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. After separation and purification by column chromatography, 1.80 g of oily compound 4aa was obtained with a yield of 85%.

[0116] Add methanol 10mL, palladium carbon (0.33g) in reaction bottle, add compound C (1.80g), replace hydrogen three ti...

Embodiment 3

[0119]

[0120] Weigh compound E (10.37g) and formylmethylenetriphenylphosphine (12.21g) in an eggplant-shaped bottle, add THF (15ml) to dissolve, react at room temperature for 3h, add tetrabutylammonium fluoride triphenyl Hydrate (36.89g). After reacting at about 50°C for 6 hours, the reaction solution was naturally cooled, concentrated, and separated and purified by silica gel column chromatography to obtain 4.66 g of oily compound G with a yield of 61% and a purity of 95%.

[0121] Add ethanol 100mL, Raney nickel (1.66g) in reaction bottle, add compound G (3.32g), replace hydrogen three times, in H 2 (40Psi) and reacted for 24h, filtered through diatomaceous earth, evaporated the solvent under reduced pressure, separated and purified through silica gel column to obtain 2.94g oily compound D, yield: 87%, purity: 97% d.e.>99.5%.

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PUM

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Abstract

The present invention relates to a method for preparing eribulin and an intermediate thereof. In particular, the invention relates to a method for preparing a compound of formula 5, R3 is selected from aldehyde or OR1, n=0 or 1, R1 is a hydroxy protecting group, and preferably the hydroxy protecting group is selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, p-methoxybenzyl or benzyl.The invention also provides a method for preparing halichondrin and derivatives thereof such as the eribulin from the compound of formula 5.

Description

technical field [0001] The present invention relates to a method for preparing eribulin and a preparation method of its intermediate compound of formula 5. Background technique [0002] Halichondrin B (Halichondrin B) is a natural product with anti-tumor activity, which was originally isolated from the marine sponge black soft sponge. Eribulin is the first macrocyclic ketone analog obtained by optimizing the structure of halichondrin B. At present, Eribulin mesylate injection has been marketed in many countries for the treatment of metastatic breast cancer, but its structure is complex And it contains multiple chiral neutrals, and the total synthesis is difficult. [0003] [0004] Therefore, development of a synthetic method for preparing eribulin for use as an antitumor agent is required. [0005] US6214865 and US5436238 reported the synthesis of halichondrin and its derivatives using compound 2,5-disubstituted (2S,5S)-3-methylene-tetrahydrofuran (compound of formula ...

Claims

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Application Information

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IPC IPC(8): C07D493/04C07D493/22C07D307/12C07F7/18
CPCC07B2200/07C07D307/12C07D493/04C07D493/22C07F7/188Y02P20/55
Inventor 黄建祝令建管忠俊
Owner JIANGSU HENGRUI MEDICINE CO LTD
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