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Method for preparing 1,6-Anhydro-2-azido-2-deoxy-beta-D-glucopyranose

A technology of glucopyranose and sulfonyl azide hydrochloride, which is applied in the field of pharmaceutical synthesis technology, can solve problems such as unfavorable process amplification, unfavorable safety operation, high explosion risk, etc., and is conducive to process amplification to achieve large-scale production , simplification of post-processing operations, the effect of safety explosion risk

Active Publication Date: 2012-11-14
EAST CHINA NORMAL UNIV +2
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

Tetrahedron: Asymmetry.16 (2005) 411-424 etc. reported the synthetic route of 1,6-anhydro-2-azido-2-deoxy-β-D-glucopyranose (1), which described the introduction of azide Key step: the conversion from compound (7) to compound (1) using sodium azide (NaN 3 ), and requires enhanced heat (120°C), which has a high risk of explosion and is not conducive to process scale-up
In addition, the synthesis of compound (7) uses equivalent organotin reagents and more expensive elemental iodine, which is not conducive to safe operation, cost reduction and environmental friendliness.

Method used

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  • Method for preparing 1,6-Anhydro-2-azido-2-deoxy-beta-D-glucopyranose
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  • Method for preparing 1,6-Anhydro-2-azido-2-deoxy-beta-D-glucopyranose

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1 Preparation of 1,6-anhydro-2-azido-2-deoxy-β-D-glucopyranose

[0030]

[0031] Step 1: At room temperature, add 12.77g of 2-amino-2-deoxy-D-glucopyranose hydrochloride (4), 148mg of copper sulfate pentahydrate, and 22.1g of potassium carbonate to 300mL of methanol in turn, stir well; replacement. Cool to 0°C, add 14.9g imidazole-1-sulfonyl azide hydrochloride in batches, and stir evenly. Stirring was continued for 12 h at room temperature, and the reaction was complete. The solid was removed by suction filtration, evaporated to dryness, and carried twice with 200 mL of toluene to obtain a residue. The residue was dissolved in 400 mL of dichloromethane, stirred evenly, cooled to 0°C, 70 g of Dowex 1X8 resin was added, and 30 mL of acetic anhydride was slowly added dropwise while stirring. After dripping, rise to room temperature and continue to stir for ~12h, the reaction is complete. The resin was removed by filtration, and the solvent was evaporated to...

Embodiment 2

[0034] Example 2 Preparation of 1,6-anhydro-2-azido-2-deoxy-β-D-glucopyranose

[0035]

[0036] The first step, second step: same as embodiment 1

[0037] The third step: 10.3g 1-O-silyl-6-O-p-toluenesulfonyl-2-azido-2-deoxy-β-D-glucopyranose (6) was dissolved in 150mL tetrahydrofuran, nitrogen protection, cold to 0°C. Add 1.6mL of acetic acid and 12mL of 2M hydrogen fluoride pyridine complex successively. Stirring was continued at 0 °C for ~8 h, and the reaction was complete. The tetrahydrofuran was evaporated, and the residue was dissolved in 150 mL of ethanol. At room temperature, 30 g of Dowex1X8 resin was added, and stirring was continued at room temperature for ~24 hours after the addition. After the reaction was complete, the resin was removed by filtration, and the solvent was evaporated. Purified by column chromatography to obtain 3.3 g of 1,6-anhydro-2-azido-2-deoxy-β-D-glucopyranose (1), with a yield of 81%. 1 H NMR(500MHz,DMSO-6d):5.40(d,J=4.5Hz,1H),5.37(s,1...

Embodiment 3

[0038] Example 3 Preparation of 1,6-anhydro-2-azido-2-deoxy-β-D-glucopyranose

[0039]

[0040] Step 1: At room temperature, add 12.77g of 2-amino-2-deoxy-D-glucopyranose hydrochloride (4), 300mg of copper sulfate pentahydrate, and 21g of potassium carbonate to 400mL of methanol in turn, stir well; replace with nitrogen . Cool to 0°C, add 15.3g imidazole-1-sulfonyl azide hydrochloride in batches, and stir evenly. Stirring was continued for 18 h at room temperature, and the reaction was complete. The solid was removed by suction filtration, evaporated to dryness, and carried twice with 200 mL of toluene to obtain a residue. The residue was dissolved in 400 mL of dichloromethane, stirred evenly, cooled to 0°C, 80 g of Dowex 1X8 resin was added, and 50 mL of acetic anhydride was slowly added dropwise while stirring. After dripping, rise to room temperature and continue to stir for 18h, the reaction is complete. The resin was removed by filtration, and the solvent was evapo...

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Abstract

The invention provides a method for preparing the 1,6-Anhydro-2-azido-2-deoxy-beta-D-glucopyranose. At a room temperature, 2-Amido-2-deoxy-D-glucopyranose hydrochloride serves as a raw material, imidazole-1-sulfonyl azide hydrochloride serves as a nitrine reagent, a dowex1X8 resin serves as a acid-binding agent for acylation, silylation and sulfonylation, 1,8-Diazabicyclo-(5,4,0) undec-7-ene or the dowex1X8 resin serves as an alkali reagent for ring closing reaction, and the 1,6-Anhydro-2-azido-2-deoxy-beta-D-glucopyranose is synthesized through nitrine introduction, acylation reaction, silylation reaction, sulfonylation reaction and ring closing reaction in sequence; and the reaction process is represented as formula (I). The 1,-Anhydro-2-azido-2-deoxy-beta-D-glucopyranose can serve as an intermediate for synthesizing anticoagulant drug fondaparinux sodium. The method for preparing the 1,6-Anhydro-2-azido-2-deoxy-beta-D-glucopyranose has the advantages of being mild in reaction, simple in synthetic route, low in cost, safe and reliable, and suitable for large scale production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis technology, and specifically relates to a preparation method of 1,6-anhydro-2-azido-2-deoxy-β-D-glucopyranose. Background technique [0002] 1,6-anhydro-2-azido-2-deoxy-β-D-glucopyranose (1) compound is an intermediate in the synthesis of anticoagulant drug fondaparinux sodium (2). Fondaparinux sodium (2) English name: Fondaparinux sodium, trade name: Android (ARIXTRA). It is the first purely chemically synthesized antithrombotic drug discovered and developed by Sanofi-Sandraberg and Organon. It is a small molecule substance with 5 sugar chain units. It was launched in the United States for the first time in February 2002, and the domestic preparation obtained the import registration certificate in March 2008. It is used for the prevention of deep vein thrombosis in adult patients undergoing hip fracture surgery and hip and knee replacement. It will have a good application pros...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H5/04C07H1/00
Inventor 胡文浩周俊史敏张俊杰
Owner EAST CHINA NORMAL UNIV
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