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Refining method for improving optical purity of eribulin intermediate compound

A technology of optical purity and purification method, applied in the fields of organic chemistry methods, chemical instruments and methods, compounds of elements of Group 4/14 of the periodic table, etc. The product has high optical purity, fast speed, and avoids the effect of column chromatography

Inactive Publication Date: 2020-04-10
ZENJI RES LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, the means of repeated column chromatography is used to purify and refine. Although the method is simple, the reproducibility is not high, and it is difficult to scale up. A large amount of organic solvents are used in the column chromatography process, resulting in high cost and many waste liquids.

Method used

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  • Refining method for improving optical purity of eribulin intermediate compound
  • Refining method for improving optical purity of eribulin intermediate compound
  • Refining method for improving optical purity of eribulin intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] (1) Preparation of compound formula (ⅡA)

[0029]

[0030] (a) Add 100 grams of compound formula (IA), 500 grams of methanol, 200 grams of water, and 100 grams of sodium bisulfite into a 2L reaction flask, start stirring, and react at 25-30°C;

[0031] (b) After the reaction was complete, filter with suction, wash the filter cake with 20 g of methanol, filter with suction, collect the filter cake, and dry in vacuum at 30° C. to obtain 114.1 g of compound (ⅡA) as a white solid, with a yield of 92.0%.

[0032] (2) Preparation of compound formula (IA)

[0033]

[0034] (c) Add 100 grams of compound formula (ⅡA) and 400 grams of ethyl acetate to the reaction flask respectively, heat up and reflux until the solid dissolves, slowly add 120 grams of n-heptane, continue stirring for 30 minutes after adding, turn off the heating and slowly cool down to Recrystallize at 25°C to precipitate a solid, filter with suction, and collect the filter cake.

[0035] (d) filter cake...

Embodiment 2

[0037] (1) Preparation of compound formula (ⅡA)

[0038]

[0039] (a) Add 100 grams of compound formula (IA), 500 grams of toluene, 200 grams of water, and 100 grams of sodium bisulfite into a 2L reaction bottle, start stirring, and react at 20°C;

[0040] (b) After the reaction is complete, filter with suction, rinse the filter cake with 20 g of tetrahydrofuran, filter with suction, collect the filter cake, and dry in vacuum at 30° C. to obtain 114.1 g of compound (ⅡA) as a white solid, with a yield of 91.0%.

[0041] (2) Preparation of compound formula (IA)

[0042]

[0043] (c) Add 100 grams of compound formula (ⅡA) and 400 grams of water to the reaction flask, raise the temperature and reflux until the solid dissolves, slowly add 120 grams of n-hexane, continue stirring for 30 minutes after adding, turn off the heating and slowly cool down to 20°C A solid crystallized out and was suction filtered to collect the filter cake.

[0044] (d) filter cake, 500 grams of et...

Embodiment 3

[0046] (1) Preparation of compound formula (ⅡA)

[0047]

[0048] (a) Add 100 grams of compound formula (IA), 500 grams of N,N,-dimethylformamide, 200 grams of water, and 100 grams of sodium bisulfite into a 2L reaction bottle, start stirring, and react at 80°C;

[0049] (b) Complete reaction, suction filtration, rinse the filter cake with 20 g of isopropanol, suction filtration, collect the filter cake, and vacuum-dry at 30° C. to obtain 114.1 g of white solid compound (ⅡA), with a yield of 91.8%.

[0050] (2) Preparation of compound formula (IA)

[0051]

[0052] (c) Add 100 grams of compound formula (ⅡA) and 400 grams of xylene to the reaction flask respectively, heat up and reflux until the solid dissolves, slowly add 120 grams of n-pentane, continue stirring for 30 minutes after adding, turn off the heating and slowly cool down to 80 °C recrystallized to precipitate a solid, filtered with suction, and collected the filter cake.

[0053] (d) filter cake, 500 grams ...

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Abstract

The invention discloses a refining method for improving optical purity of an eribulin intermediate compound. The refining method specifically comprises the following steps: (1) reacting a free compound (I) with sodium hydrogen sulfite to obtain a solid compound (II); and (2) recrystallizing the compound (II) and then dissociating into a compound (I). The reaction is a process of recrystallizationafter dissolution, column chromatography is avoided, and the method is safe, environmentally friendly, high in speed, clean in reaction process, free of redundant products, high in optical purity of products and suitable for large-scale production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a refining method for improving the optical purity of an eribulin intermediate compound. Background technique [0002] Eribulin mesylate (Eribulin mesylate) blocks the G2 / M cell circuit through the anti-mitotic pathway of tubulin, affects the mitotic spindle, and finally the mitotic process is blocked and the cells die. It is suitable for treatment that has received at least Patients with metastatic breast cancer treated with 2 chemotherapy regimens. Developed by Japan's Eisa, the trade name is HALAVENTM. Eribulin mesylate contains 19 chiral centers, has many isomers, and is difficult to synthesize, and most intermediates are oily liquids, making industrial production and purification extremely difficult. Therefore, it is particularly important to improve the optical purity of eribulin mesylate by controlling the chiral purity of the eribulin mesylate intermediate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18
CPCC07F7/1892C07B2200/07Y02P20/55
Inventor 葛敏王怀秋
Owner ZENJI RES LAB
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