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Synthesis of Eribulin Mesylate

A technology of methanesulfonic acid and compounds, which is applied in the field of preparation of key intermediates of the complex natural modified drug Eribulin mesilate, can solve the problems of slow research and development progress and limited sample volume, and achieve the effect of increasing yield

Active Publication Date: 2022-04-08
WISDOM PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the limited amount of samples isolated from sponges in nature alone, the research and development progress is slow.

Method used

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  • Synthesis of Eribulin Mesylate
  • Synthesis of Eribulin Mesylate
  • Synthesis of Eribulin Mesylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Embodiment one: the preparation of formula II compound (using piperidine hydrochloride) (yield 85%)

[0017]

[0018] Dissolve the compound of formula I (460.0mg, 0.348mmol) in THF (21.5mL) at 20-25°C, add piperidine hydrochloride (211.6mg, 1.74mmol) and TBAF (1M THF solution, 3.48mL, 3.48mmol ), keep stirring at this temperature for 20h. The reaction solution was concentrated under reduced pressure at 30°C to remove THF, then dissolved in a small amount of DCM, and purified by column chromatography (EA / n-Hept=1 / 1→EA→MeOH / EA=1 / 15) to obtain the target compound of formula II (white solid, 222.3 mg, 85.3%). ESI-MS:C 40 h 60 o 13 Calculated value: 748.4034, measured value: 749.4065 (M+H + ). 1 H NMR (600MHz, CDCl 3 )5.00 (1H, brd, J = 1.8Hz), 4.85 (1H, brd, J = 1.8Hz), 4.88 (1H, brs), 4.80 (1H, brd, J = 1.2Hz), 4.48-4.54 (1H, m),4.38(1H,dd,J 1 =9.0Hz,J 2 =4.2Hz), 4.34(1H,dt,J 1 =10.2Hz,J 2 =3.6Hz),3.97-4.09(5H,m),3.94-3.99(1H,m),3.85-3.94(3H,m),3.78-3.85(1H,...

Embodiment 2

[0019] Embodiment two: the preparation of formula II compound (using pyridine hydrochloride) (yield 89%)

[0020]

[0021] Dissolve the compound of formula I (460.0mg, 0.348mmol) in THF (21.5mL) at 20-25°C, add pyridine hydrochloride (201.1mg, 1.74mmol) and TBAF (1M THF solution, 3.48mL, 3.48mmol) , Keep stirring at this temperature for 20h. The reaction solution was concentrated under reduced pressure at 30°C to remove THF, then dissolved in a small amount of DCM, and purified by column chromatography (EA / n-Hept=1 / 1→EA→MeOH / EA=1 / 15) to obtain the target compound of formula II (white solid, 232.1 mg, 88.9%).

Embodiment 3

[0022] Embodiment three: the preparation of formula II compound (comparative experiment, only uses TBAF) (yield 38%)

[0023]

[0024]Dissolve the compound of formula I (460.0mg, 0.348mmol) in THF (21.5mL) at 20-25°C, add TBAF (1M THF solution, 3.48mL, 3.48mmol), and keep stirring at this temperature for 20h. The reaction solution was concentrated under reduced pressure at 30°C to remove THF, then dissolved in a small amount of DCM, and purified by column chromatography (EA / n-Hept=1 / 1→EA→MeOH / EA=1 / 15) to obtain the target compound of formula II (white solid, 99.7mg, 38.2%).

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Abstract

The present invention relates to the synthesis of eribulin mesylate. Specifically to provide an intermediate compound formula II ((1R, 2S, 3S, 4S, 5S, 6R, 11S, 14S, 17S, 19R, 21R, 23S, 25R, 26R, 27S) for preparing eribulin mesylate ,31R,34S)‑25‑[(2S)‑2,3‑Dihydroxy]‑2,5‑Dihydroxy‑26‑methoxy‑19‑methyl‑13,20‑bismethylene‑24, 35,36,37,38,39‑hexaoxacycline [29.3.1.1 3 , 6 .1 4 , 34 .11 1 , 14 .1 17 , 21 .0 23 , 27 ] Nonacosane-8,29-dione) method is aimed at avoiding the problem of low reaction yield of traditional synthetic route.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and specifically relates to the preparation of a key intermediate of complex natural modified drug eribulin mesylate. 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 Phakellia, Lissodendory and Axinella 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 anti-cancer cell...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/22
CPCC07D493/22C07B2200/07
Inventor 邱小龙徐涛左智伟葛杰陆信伟储玲玲刘文博王标顾庭伟王伟伟胡林邹平陈俊曹雷
Owner WISDOM PHARM CO LTD
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