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Eribulin mesylate preparation method

A technology of methanesulfonic acid and p-toluenesulfonate, which is applied in the preparation of sulfonate, bulk chemical production, organic chemistry, etc., can solve problems such as a large number of isomer impurities

Active Publication Date: 2020-01-14
WISDOM PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention is to provide a new method for preparing eribulin mesylate, which aims to avoid the defect that the traditional synthetic route easily leads to a large amount of isomer impurities

Method used

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  • Eribulin mesylate preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Embodiment one: the preparation of N-ERBL-02 intermediate

[0022] Add N-ERBL-01 intermediate (25.00g, 15.37mmol) and CH 2 Cl 2 (500mL), after stirring to dissolve, add Dess-Martin oxidant (10g, 23.58mmol) in batches. After the addition, the system was stirred at room temperature until the reaction of the starting material was completely monitored by TLC. After the reaction was complete, the system was quenched by adding saturated aqueous sodium bicarbonate solution (500 mL). The system was allowed to stand, and the organic phase was separated. The organic phase was removed under low temperature and reduced pressure to remove the organic solvent, and the residue was purified by column chromatography to obtain N-ERBL-02 intermediate (20.23 g, 81.1%).

Embodiment 2

[0023] Embodiment two: the preparation of N-ERBL-03 intermediate

[0024] Sm (13.05g, 86.79mmol) and THF (500mL) were added into the four-neck flask, and diiodomethane (25.0g, 93.3mmol) was added under stirring. After the addition, the system was stirred at room temperature for 5 hours and set aside. Add N-ERBL-02 intermediate (15.05g, 9.34mmol), methanol (200mL) and THF (500mL) into another four-neck flask, stir the system and cool down to -85°C, then dropwise add the previously prepared SmI 2 solution. After the dropwise addition, the system was stirred for 4 hours until TLC confirmed that the reaction of the raw materials was complete. Add saturated K to the reaction at low temperature 2 CO 3 Aqueous solution (200 mL) was quenched. After the system was warmed up to room temperature, TBME (1 L) was added, stirred for 2 hours, allowed to stand, and the organic phase was separated. The organic solvent was removed from the organic phase under reduced pressure, and the resi...

Embodiment 3

[0025] Embodiment three: the preparation of N-ERBL-04 intermediate

[0026] Add acetonitrile (550mL), CrCl 2 (26.0 g, 211.55 mmol) and ligand (CAS: 480444-15-3, 63.2 g, 213.24 mmol). After the addition was complete, triethylamine (21.5 g, 212.5 mmol) was slowly added dropwise while the system was stirred. After the addition is complete, keep stirring at 30-35°C for 2 hours, then add NiCl 2 (2.75 g, 21.1 mmol), stirred. Then a solution of N-ERBL-03 intermediate (22.5 g, 15.33 mmol) in THF (500 mL) was added dropwise to the reaction system at room temperature. After the dropwise addition, the system was stirred at room temperature for 5 hours until the reaction of the raw materials controlled by TLC was completed. The reaction system was quenched by adding water (300mL), the system was filtered, the filtrate was extracted three times with n-heptane, the organic phase was combined, the organic phase was decompressed to remove the organic solvent, and the residue was purified ...

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Abstract

The invention relates to an eribulin mesylate preparation method, of eribulin mesylate, wherein eribulin mesylate is prepared by using 2-[(2S)-2-benzoyloxy]-3-[(2R,3R,3aS,7R,10S,11S,12S,13R,14S,15S,16E,21S,24S,27S,29R,31R,32aS)-12,13,15-tri[[(1,1-dimethylethyl)disilyl]oxygen]3,3a,4,5,6,7,8,9,10,11,12,13,14,15,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,32a-triaconthydro-3-methoxy-29-methyl-23,30-bis(methylene)-5,18-dioxo-7,11:10,14:21,24:27,31-tetraepoxy-2H-cyclohentriacontane[b]furan-2-ylpropyl]-1H-phthalimide (N-ERBL-05) as an intermediate through a three-step reaction.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to the preparation of eribulin mesylate, a complex natural modified medicine of raw materials. Background technique [0002] Halichondrin B is a poly(poly)ether macrolide isolated from the scarce Japanese sponge Halichondriaokadai in the 1980s by Japanese scientists Uemura et al. Although halichondrin B only contains three types of C\H\O elements, but the compound structure is very complex. Further studies have found that halichondrin B has a very strong inhibitory effect on cancer cells in vivo and in vitro in mice. Further research by the chemists also found that common sponges such as the Phakellia, Lissodendory and Axinella families also contain halichondrin B. The National Cancer Institute of the United States has used halichondrin B to conduct systematic activity evaluations in 60 cancer cell lines, and it has been proved that the mechanism of halichondrin B in ...

Claims

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Application Information

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IPC IPC(8): C07D493/22C07C303/32C07C309/04
CPCC07D493/22C07C303/32C07C309/04Y02P20/55
Inventor 邹平左智伟邱小龙胡林陆信伟葛杰吴伟许志伟左昂禾刘文博储玲玲王平顾庭伟王伟伟王标
Owner WISDOM PHARM CO LTD
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