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Preparation method of eribulin and intermediate thereof

A reaction system and compound technology, applied in the field of medicine, can solve the problems of high cost, difficult application, heavy metal pollution of the environment, etc., and achieve the effects of improving reaction yield, reducing chromium pollution, and being easy to purify

Pending Publication Date: 2021-06-25
NANTONG NUOTAI BIOLOGICAL PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In this preparation method, the hydroxyl group of the raw material D-gulonolactone is protected by cyclohexanone, and the total yield to the synthetic compound B is 19.2%, and the amount of chromium reagent used in the NHK reaction of the synthetic compound B is usually 400mol%~ Between 1600mol%, the cost is high, heavy metals pollute the environment, and it is difficult to apply in scale-up production

Method used

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  • Preparation method of eribulin and intermediate thereof
  • Preparation method of eribulin and intermediate thereof
  • Preparation method of eribulin and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] The preparation of embodiment 1 compound C01:

[0052]

[0053]0.11mol of D-gulonolactone, 0.35mol of p-methylcyclohexanone, 100ml of toluene and 0.03mol of anhydrous zinc chloride were stirred and refluxed. After the reaction, the reaction mixture was cooled, and 60ml of bicarbonate Sodium aqueous solution and 60ml saturated sodium chloride aqueous solution were washed. Concentrate the organic phase to remove part of the toluene, add 200ml of n-heptane, heat to reflux for 2-4 hours, cool to 40-50°C and stir for 2 hours. Filtration and drying yielded 34.14 g of compound C01.

Embodiment 2

[0054] The preparation of embodiment 2 compound C02

[0055]

[0056] Dissolve 0.1mol of compound C01 in 250ml of toluene, cool to -10°C, slowly add 80ml of DIBALH (1.5M toluene solution), control the temperature not to exceed -10°C, stir for 30 minutes, add the reaction solution into potassium sodium tartrate solution, and the mixture to room temperature and stirred for 4 hours. The layers were separated by filtration, extracted twice with 60ml of ethyl acetate, the organic layers were combined, dried, filtered and concentrated to obtain 31g of compound C02.

Embodiment 3

[0057] The preparation of embodiment 3 compound C03

[0058]

[0059] 0.1 mol of compound C02 was dissolved in 80 ml of tetrahydrofuran, and 65 g of (methoxymethyl)triphenylphosphine chloride was added. At room temperature, 80 ml of tetrahydrofuran solution in which 36.5 g of NaHMDS was dissolved was slowly added dropwise. After the dropwise addition, the stirring was continued at room temperature. After the reaction was completed, 100 ml of brine, 100 ml of water, and 160 ml of ethyl acetate were added. Stir and separate layers, and slowly add 100 g of 20% sodium hydroxide solution to the organic phase under stirring. The organic layer was separated and concentrated to obtain the crude product of the compound represented by formula (C03). The crude product was stirred with 160ml of n-heptane and 20g of diatomaceous earth for 1 hour. Filter and wash the filter cake with 180 g of n-heptane. The filtrate was concentrated to 25% methanol solution and extracted three times w...

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Abstract

The invention provides an eribulin intermediate and a preparation method thereof, particularly an intermediate which takes cyclopentanone as a hydroxyl protecting group of a plurality of eribulin intermediates, and further discloses a brand-new structure intermediate and a preparation method thereof. Compared with the prior art, the preparation method of the eribulin intermediate, provided by the invention, has the advantages that the yield is high, the use of a chromium reagent is reduced through multiple steps, the production cost is greatly reduced, and the environmental pollution is reduced. The invention also provides a method for preparing eribulin from the intermediates. The method provided by the invention can obviously improve the total yield of eribulin.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of eribulin and its intermediate. Background technique [0002] Eribulin mesylate, as a tubulin polymerization inhibitor with a new mechanism of action, is the first single-agent chemotherapy drug for improving overall survival in patients with metastatic breast cancer. It was developed by Japan's Eisai Pharmaceutical Co., Ltd. The injection was approved by the US FDA in November 2010 under the trade name HALAVEN. Eribulin mesylate provides a new treatment method for patients with locally advanced breast cancer or metastatic breast cancer to improve the survival rate and quality of life, and is a drug with great application value. Its structure is as follows: [0003] [0004] Kishi etc. have reported a kind of preparation method of eribulin key intermediate C (the following formula C), specifically as follows: [0005] [0006] In this ...

Claims

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Application Information

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IPC IPC(8): C07D493/10C07F7/08C07D493/22C07C309/04C07C303/32
CPCC07D493/10C07F7/0812C07D493/22C07C309/04C07C303/32Y02P20/55
Inventor 徐安佗周宁张晓光
Owner NANTONG NUOTAI BIOLOGICAL PHARMA CO LTD
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