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Preparation method for pentosaccharide intermediate of anticoagulant drug fondaparinux sodium

An intermediate and coupling technology, which is applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., can solve the problems of long synthetic routes, high difficulty, and restrictions on wide application, and achieve convenient and feasible operation and a high preparation route Practical and economical synthesis steps

Active Publication Date: 2016-02-10
四川奥邦古得药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The pentasaccharide intermediate needs to be obtained through nearly 50 steps of chemical synthesis, the synthetic route is long, difficult, and the product purity is not high
As a result, the production cost of follow-up fondaparinux sodium is high, which limits its wide application in clinical practice.

Method used

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  • Preparation method for pentosaccharide intermediate of anticoagulant drug fondaparinux sodium
  • Preparation method for pentosaccharide intermediate of anticoagulant drug fondaparinux sodium
  • Preparation method for pentosaccharide intermediate of anticoagulant drug fondaparinux sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1, the preparation of monosaccharide intermediate B

[0054]

[0055] Compound I (2.4g, 5mmol) was dissolved in a mixed solvent of 60mL dichloromethane and 30mL water, and tetramethylpiperidine nitrogen oxide (156.25mg, 1mmol) and iodobenzene acetate (4.0g, 12.5mmol) were added, Stir at room temperature. After the oxidation is complete, quench the reaction with 20 mL of saturated sodium sulfite aqueous solution, adjust the pH to weak acidity with hydrochloric acid, separate the layers, extract the aqueous phase (20 mL x 4) with dichloromethane, combine the organic phases to dry, and spin to dry the solvent. The product is syrupy.

[0056] After the product obtained in the previous step was pumped on the oil pump for 0.5h, potassium carbonate (1.4g, 10mmol) was added, dissolved in 50mL of dry acetone, and dimethyl sulfate (660uL, 7mmol) was added under ice bath and nitrogen protection conditions, and gradually React at room temperature overnight. After the...

Embodiment 2

[0058] Embodiment 2, the preparation of monosaccharide intermediate C

[0059]

[0060] Dissolve compound III (60g, 188mmol) in toluene (1000mL), add dibutyltin oxide (93.7g, 376mmol), add a water separator, heat slowly to reflux and divide water (about 130°C), and react in this state for 5h Withdraw from the oil bath. Cool down to room temperature, slowly add p-methoxybenzyl chloride (63.8mL, 470mmol) and tetrabutylammonium iodide (34.7g, 94mmol), react at about 90°C for 3h. The reaction solution was lowered to room temperature and left to stand overnight, and tetrabutylammonium iodide was precipitated. The organic phase was washed 3 times with 500 mL water, and the combined aqueous phase was washed twice with ethyl acetate. Combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain a viscous oily residue, mix the sample with silica gel, and obtain 73 g of light yellow oily product C with a yield of 70% by column chr...

Embodiment 3

[0061] Embodiment 3, the preparation of monosaccharide intermediate D

[0062]

[0063] After compound IV (200mg, 1.0eq) and levulinic acid (4.8mL, 1.1eq) were dissolved in dichloromethane, 4-dimethylaminopyridine (5mg, 0.1eq) and dicyclohexylcarbodiimide (130mg , 2.0eq), react at room temperature, after TLC monitoring is complete, add sodium carbonate under ice bath to neutral pH, add appropriate amount of dichloromethane, wash with saturated brine twice, combine water phase, dichloromethane extract 3 times, combine organic phase, adding anhydrous Na 2 SO 4 Dry and evaporate the solvent. The crude product was recrystallized with petroleum ether / ethyl acetate system to obtain 232 mg of monosaccharide intermediate D with a yield of 96%.

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Abstract

The invention discloses a preparation method for a pentosaccharide intermediate of anticoagulant drug fondaparinux sodium. Monosaccharide segments A, B, C and D are prepared through a novel synthesizing method, and the synthesizing steps are simplified; meanwhile, appropriate protecting groups are mainly selected to protect hydroxyl groups and carboxylic acid, the stereospecific glycosylation achievement in the later period is facilitated, and then the needed glycosidic bond types are obtained; in addition, the protecting groups can be removed in one pot, and therefore the synthesizing steps are shortened. The preparation route is practical, convenient to operate and feasible.

Description

technical field [0001] The invention relates to a preparation method of a drug intermediate for treating thrombotic diseases, in particular to a preparation method of an anticoagulant fondaparinux sodium pentasaccharide intermediate. Background technique [0002] Thrombotic disease is one of the major diseases with the highest incidence rate in modern society. Among them, venous thrombosis induced by surgery, trauma (such as large-scale or lower extremity trauma), acute medical diseases (such as myocardial infarction, stroke), cancer treatment (such as hormone therapy, chemotherapy, radiotherapy), etc. Cardiopulmonary syndrome and the third major cardiovascular disease after stroke, which seriously threaten human health. At present, the prevention and treatment of venous thrombosis mainly focus on anticoagulation. Traditional anticoagulant drugs represented by unfractionated heparin and warfarin have been gradually replaced by a new generation of anticoagulant drugs due to...

Claims

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Application Information

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IPC IPC(8): C07H15/18C07H1/00C07F7/18
CPCY02P20/55
Inventor 秦勇程春伟宋颢戴翔刘文涛周启龙王树青唐培刘小宇张丹
Owner 四川奥邦古得药业有限公司
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