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Method for synthesizing fondaparinux sodium monosaccharide intermediate

A synthesis method and compound technology, applied in the field of synthesis of fondaparinux sodium monosaccharide intermediates, can solve the problems of unfavorable purification and refinement of intermediates and products, low yield, lower product quality, etc., and achieve low cost and high yield. The effect of high yield, improving product quality and yield

Active Publication Date: 2019-03-08
江苏美迪克化学品有限公司
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  • 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

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  • Method for synthesizing fondaparinux sodium monosaccharide intermediate
  • Method for synthesizing fondaparinux sodium monosaccharide intermediate
  • Method for synthesizing 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...

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Abstract

The invention discloses a method for synthesizing a fondaparinux sodium monosaccharide intermediate. According to the method, a fondaparinux sodium monosaccharide fragment intermediate, namely 1,6-dehydro-3-O-benzyl-beta-L-idopyranose, is prepared by taking 1,2-O-isopropylidene-3-O-benzyl-alpha-D-glucofuranose as a raw material, subjecting the raw material to an esterification reaction with benzoic acid, subjecting the reaction product to the esterification reaction with substituted sulfonic anhydride and / or substituted sulfonyl chloride, then subjecting the reaction product to a hydrolysis reaction, and adding a sulfuric acid aqueous solution for a reaction. The synthesis method has the advantages of simple process, few side reaction impurities and high yield, and is suitable for amplification synthesis process 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

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Application Information

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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
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