Method for preparing eribulin and intermediate thereof

A technology of compound and leaving group, which is applied in the field of preparation of -2,4-dihalo-3-methylbut-1-ene, can solve the problem of triphenylphosphine oxide by-products with long steps, difficult to remove, and difficult to remove. Suitable for industrial mass production and other issues

Active Publication Date: 2018-07-31
JIANGSU HENGRUI MEDICINE CO LTD +1
View PDF5 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] CN104053645A discloses that the compound 4-hydroxyl protecting group-3-methylbut-1-yne is used as a raw material to prepare 2,4-dihalogen through addition, deprotection, substitution or addition, deprotection, esterification and substitution -3-Methylbut-1-ene, but this method will produce triphenylphosphine oxide by-products that are difficult to remove and take longer steps, and also need to use expensive B-I-9-BBN reagent in the process, which is not suitable in industrial production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 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

[0044] Example 1: Preparation of (2S)-2-methylbut-3-yne-1-p-toluenesulfonate

[0045]

[0046] Dissolve (2S)-2-methylbut-3-ynol (27.7 g) in 180 mL of dry CH 2 Cl 2 In the system, DMAP (2.0g) and triethylamine (50.1g) were added to the system. After cooling to -10 to -5°C, a solution of TsCl (69.2 g) in dichloromethane was slowly added dropwise. After the dropwise addition, the mixture was naturally raised to room temperature and stirred for 2 hours. After the reaction was complete, water (100 mL) was added to the reaction solution. The organic layer was separated, and the aqueous layer was washed with CH 2 Cl 2 Extract and combine the organic layers. The organic phase was washed successively with water, 1N aqueous hydrochloric acid solution and saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, 72.2 g of the product was obtained by separation and purification on a silica gel c...

Embodiment 2

[0047] Example 2: Preparation of (3R)-2,4-diiodo-3-methylbut-1-ene

[0048] Weigh LiI (88.8g) in the reaction bottle, add acetonitrile (500mL), then dropwise add TMSCl (42.6g), the reaction solution becomes cloudy, after stirring for 5 minutes, then add (2S)-2-methylbutan-3 -Alkyne-1-p-toluenesulfonate (38.1 g). After reacting at room temperature for 10 hours, water (200 mL) was added, the organic layer was separated, the aqueous layer was extracted with MTBE, and the organic layers were combined. The organic phase was washed successively with 10% aqueous sodium thiosulfate solution, saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, the product was separated and purified by silica gel column to obtain 44.8 g of oily liquid product, yield: 87%.

Embodiment 3

[0049] Example 3: Preparation of (3S)-4-iodo-3-methylbut-1-yne

[0050] Weigh (2S)-2-methylbut-3-yne-1-p-toluenesulfonate (12.2g) in a reaction flask, add acetonitrile (150mL), LiI (11.5g), and react at room temperature for 20h , filtered, the filter cake was washed with 50 mL of acetonitrile, and the obtained filtrate was concentrated to obtain 8.7 g of an oily liquid product, yield: 88%.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

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 formula 1 compound, (3R)-2,4-dihalo-3-methylbut-1-ene. The invention also provides a method for preparing halichondrin and derivatives thereof such as the eribulin from the formula 1 compound.

Description

technical field [0001] The present invention relates to a preparation method of (3R)-2,4-dihalo-3-methylbut-1-ene. 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. [0003] [0004] US6214865 and US5436238 respectively report the method of synthesizing halichondrin and its derivatives by using the compound 2,5-disubstituted (2S,5S)-3-methylene-tetrahydrofuran (compound of formula B-12) as an intermediate, [0005] [0006] Angew.Chem.Int.Ed.2009,48,2346 has reported (3R)-2,4-diiodo-3-methylbut-1-ene (compound of formula 1) as raw material to obtain formula B-12 compound method, [0007] [0008] CN104053645A di...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07C17/04C07C17/093C07C17/16C07C21/17C07C303/28C07C309/73C07D307/28C07D493/22
CPCC07C17/04C07C17/093C07C17/16C07C303/28C07C309/73C07D307/28C07D493/22C07C21/17
Inventor 黄建祝令建管忠俊唐应刚
Owner JIANGSU HENGRUI MEDICINE CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap