Fondaparinux sodium, intermediates thereof and preparation methods

A technology of fondaparinux sodium and dimethyl tert-butyl silicon trifluoromethanesulfonate, which is applied in the preparation of fondaparinux sodium and its intermediates, fondaparinux sodium and disaccharides, tetrasaccharides and The pentasaccharide intermediate can solve the problems of high purity of fondaparinux sodium, high product purity, and high production cost, and achieve the effects of reducing the difficulty of purification and production cost, the difficulty of synthesis, and the production cost

Active Publication Date: 2014-02-26
SHANGHAI ACANA PHARMTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The pentasaccharide compound needs to be obtained through nearly 50 steps of chemical synthesis, the synthetic route is long, the synthesis is difficult, and the product purity is difficult to achieve.
As a result, the purity of subsequent fondaparinux sodium is difficult to make high, and the production cost is high

Method used

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  • Fondaparinux sodium, intermediates thereof and preparation methods
  • Fondaparinux sodium, intermediates thereof and preparation methods
  • Fondaparinux sodium, intermediates thereof and preparation methods

Examples

Experimental program
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Effect test

preparation example Construction

[0057] 2. Preparation route of disaccharide (BA-2) ;

[0058] Step 1, in the presence of a catalyst, monosaccharide B-1 and monosaccharide A-1 are coupled to obtain disaccharide BA-1; step 2, in the presence of an organic solvent and an organic base, disaccharide BA-1 is obtained by using Thiourea is deprotected to obtain the disaccharide BA-2. The synthetic route is as follows:

[0059]

[0060] 3. Preparation route of tetrasaccharide (DCBA-2) ;

[0061] Step 1, in the presence of an organic solvent and a catalyst, the disaccharide BA-2 and the disaccharide DC-3 are coupled to obtain the tetrasaccharide DCBA-1; Step 2, in the presence of an organic solvent and an organic base, the tetrasaccharide DCBA-1 -1 was deprotected with thiourea to give the tetrasaccharide DCBA-2. The synthetic route is as follows:

[0062]

[0063] 4. Preparation route of pentasaccharide (EDCBA-1) ;

[0064] In the presence of organic solvents and catalysts, tetrasaccharide DCBA-2 and...

Embodiment 1

[0069] Embodiment 1, the preparation of disaccharide (BA-2);

[0070] 0.3 kg of compound (A-1) and 0.41 kg of compound (B-1) were dissolved in 4.5 liters of dichloromethane, cooled to 0°C, added with 0.15 kg of silver trifluoromethanesulfonate, and stirred at 0°C for 2-3 hours. After filtration and concentration under reduced pressure, 0.7 kg of disaccharide compound (BA-1) was obtained.

[0071] 0.7 kg of disaccharide compound (BA-1) and 0.07 kg of thiourea were dissolved in 1.2 liters of ethanol and 1.8 liters of pyridine, and the reaction was heated to 70-80°C and stirred for 1 hour. After the reaction was completed, the temperature was lowered to room temperature, followed by post-treatment with water and dichloromethane, and the separated organic phase was successively washed with potassium bisulfate solution, sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After concentration, the crude product was purified by column chromatog...

Embodiment 2

[0076] Embodiment 2, the preparation of disaccharide (BA-2);

[0077] 0.3 kg of compound (A-1) and 0.41 kg of compound (B-1) were dissolved in 4.5 liters of dichloromethane, cooled to -50 ° C, added 0.15 kg of silver trifluoromethanesulfonate, stirred at -50 ° C for 2-3 Hour. After filtration and concentration under reduced pressure, 0.7 kg of disaccharide compound (BA-1) was obtained.

[0078] 0.7 kg of disaccharide compound (BA-1) and 0.07 kg of thiourea were dissolved in 1.2 liters of ethanol and 1.8 liters of pyridine, and the reaction was heated to 60-70°C and stirred for 1 hour. After the reaction was completed, the temperature was lowered to room temperature, followed by post-treatment with water and dichloromethane, and the separated organic phase was successively washed with potassium bisulfate solution, sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After concentration, the crude product was purified by column chromatogr...

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Abstract

The invention relates to fondaparinux sodium, intermediates thereof and preparation methods in the technical field of chemical preparation, particularly relates to the preparation methods of the fondaparinux sodium and the intermediates of the fondaparinux sodium, comprising the fondaparinux sodium, a disaccharide intermediate of the fondaparinux sodium, a tetrasccharide intermediate of the fondaparinux sodium, a pentasaccharide intermediate of the fondaparinux sodium and the corresponding preparation methods. The structure of the fondaparinux sodium is shown as the chemical compound (1). The invention also relates to the disaccharide intermediate, the tetrasccharide intermediate and the pentasaccharide intermediate which are used for preparing the fondaparinux sodium. The invention designs a novel synthetic route to prepare the fondaparinux sodium. The novel synthetic route has mild reactions, good reaction selectivity, strong controllability and low operation difficulty, and is prone to achievement of industrial production.

Description

technical field [0001] The present invention relates to the technical field of chemical preparation, in particular to a fondaparinux sodium and its intermediate, and a preparation method, in particular to a preparation method of fondaparinux sodium and its intermediate, including fondaparinux sodium and disaccharide , tetrasaccharide and pentasaccharide intermediates, and related preparation methods. Background technique [0002] Fondaparinux sodium is a synthetic heparin drug, mainly used to prevent venous thromboembolism. [0003] Vascular thrombosis is a cardiovascular disease characterized by partial or complete blockage of blood vessels by clots containing blood cells and fibrin. In arteries, this is mainly due to activation of platelets and can lead to heart attack, angina or stroke. And the formation of venous thrombosis can cause inflammation and pulmonary embolism. Coagulation of blood is the result of a cascade of events using various enzymes, collectively known...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/18C07H15/04C07H1/00
Inventor 樊林峰黄嘉慧郑栋郭志云仇爱云朱杨伟
Owner SHANGHAI ACANA PHARMTECH
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