A kind of synthetic method of fondaparinux sodium monosaccharide intermediate

A synthesis method and compound technology are applied in the field of synthesis of fondaparinux sodium monosaccharide intermediates, which can solve the problems of being unfavorable for the purification and purification of intermediates and products, reducing product quality, and low yield, etc. Product quality and yield, the effect of high yield

Active Publication Date: 2020-09-29
江苏美迪克化学品有限公司
View PDF5 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The OH on the C6 position is protected by the benzoyl chloride reaction. Due to the strong reactivity, more impurities are generated, which is not conducive to the purification and refining of intermediates and products in the next steps, reducing product quality and low yield.

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
  • A kind of synthetic method of fondaparinux sodium monosaccharide intermediate
  • A kind of synthetic method of fondaparinux sodium monosaccharide intermediate
  • A kind of synthetic method of fondaparinux sodium monosaccharide intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] A) Synthesis of 6-O-benzoyl-1,2-O-isopropylidene-3-O-benzyl-α-D-glucofuranose (compound shown in formula (3)):

[0049] 1,2-O-isopropylidene-3-O-benzyl-α-D-glucofuranose (95g, the compound shown in formula (4)) was dissolved in methyl tert-butyl ether (1L), added benzene Add formic acid (37.4g) and N,N-diisopropylethylamine (59.3g), dropwise add a solution of N,N'-carbonyldiimidazole (59.6g) in methyl tert-butyl ether (300mL), keep warm at 60°C After 12 hours of reaction, the reaction was completed, evaporated to dryness under reduced pressure, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was recrystallized from a mixed solvent of ethyl acetate-petroleum ether to obtain 6- O-benzoyl-1,2-O-isopropylidene-3-O-benzyl-α-D-glucofuranose, white solid (111.6 g), yield 88%, purity 97.3%.

[0050] B) Synthesis of 6-O-benzoyl-1,2-O-isopropylidene-3-O-benzyl-5-O-trifluor...

Embodiment 2

[0055] A) Synthesis of 6-O-benzoyl-1,2-O-isopropylidene-3-O-benzyl-α-D-glucofuranose (compound shown in formula (3)):

[0056] 1,2-O-isopropylidene-3-O-benzyl-α-D-glucofuranose (30g, compound shown in formula (4)) was dissolved in toluene (400mL), added benzoic acid (14.2g) and triethylamine (19.6g), add dropwise a solution of N,N'-dicyclohexylcarbodiimide (31.9g) in toluene (100mL) and react at 20°C for 24h. After the reaction is complete, evaporate to dryness under reduced pressure , extracted with dichloromethane, washed with salt water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was recrystallized from a mixed solvent of ethyl acetate-petroleum ether to obtain 6-O-benzoyl-1,2-O- Isopropylidene-3-O-benzyl-α-D-glucofuranose, white solid (36.1 g), yield 90%, purity 98.1%.

[0057] B) Synthesis of 6-O-benzoyl-1,2-O-isopropylidene-3-O-benzyl-5-O-methylsulfonyl-α-D-glucofuranose (shown in formula (2) compound of): ...

Embodiment 3

[0062] A) Synthesis of 6-O-benzoyl-1,2-O-isopropylidene-3-O-benzyl-α-D-glucofuranose (compound shown in formula (3)):

[0063] 1,2-O-isopropylidene-3-O-benzyl-α-D-glucofuranose (100g, the compound represented by formula (4)) was dissolved in dichloromethane (1L), and benzoic acid (59g ) and N,N-xylaniline (97.6g), slowly added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (111.2g), and kept at 40°C for 18h, After the reaction was completed, the reaction was rotary evaporated to dryness under reduced pressure, extracted with dichloromethane, washed with salt water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was recrystallized from a mixed solvent of ethyl acetate-petroleum ether to obtain 6-O-benzene Formyl-1,2-O-isopropylidene-3-O-benzyl-α-D-glucofuranose, white solid (114.9 g), yield 86%, purity 98.4%.

[0064] B) Synthesis of 6-O-benzoyl-1,2-O-isopropylidene-3-O-benzyl-5-O-tosyl-α-D-glucofuran (formul...

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 invention discloses a method for synthesizing a monosaccharide intermediate of fondaparinux sodium, which uses 1,2-O-isopropylidene-3-O-benzyl-α-D-glucofuranose as a raw material, through mixing with benzene Esterification reaction of formic acid, esterification reaction with substituent sulfonic anhydride and / or substituent sulfonyl chloride, followed by hydrolysis reaction and addition of sulfuric acid aqueous solution to obtain fondaparinux sodium monosaccharide fragment intermediate 1,6-dehydration ‑3‑O‑Benzyl‑β‑L‑Idopyranose. The synthesis method has simple process, less side reaction impurities and high yield, and is suitable for process scale-up synthesis to meet the industrial production of fondaparinux sodium.

Description

technical field [0001] The invention belongs to the field of chemical synthesis of saccharides, and in particular relates to a method for synthesizing a fondaparinux sodium monosaccharide intermediate. Background technique [0002] Fondaparinux sodium (Fondaparinux sodium) is a synthetic heparin pentasaccharide drug, which is the first indirect inhibitor of antithrombin-dependent factor Xa developed and produced by Sanofi Winthrop Industrie in France. The chemical structural formula is as follows (D, E, F, G, H are used to represent 5 monosaccharide fragments from left to right). [0003] [0004] The total synthetic route of fondaparinux sodium is relatively long, and the number of reaction steps varies from 50 steps to more than 70 steps. At present, the main construction strategies are (D+EF)+GH and D+(EF+GH). The following structure (Formula 1) is an important intermediate for introducing G monosaccharide fragments. The Chinese name is 1,6-anhydro- 3-O-benzyl-β-L-id...

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 Patents(China)
IPC IPC(8): C07H15/18C07H1/00
CPCC07H1/00C07H15/18
Inventor 杨盟徐肖洁景亚婷
Owner 江苏美迪克化学品有限公司
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