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Preparation method of fondaparin sodium intermediate

A technology for fondaparinux sodium and preparation steps, which is applied in the field of medicine, and can solve the problems of complicated purification process, low purity of intermediates, cumbersome process, etc.

Active Publication Date: 2018-10-23
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] If the above method is applied to the preparation process of the compound of formula 3 and the compound of formula D5, the process is cumbersome and the obtained intermediate has low purity and poor yield. At the same time, because the compound of formula 3 is highly polar and oily, the purification process is also relatively complicated.

Method used

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  • Preparation method of fondaparin sodium intermediate
  • Preparation method of fondaparin sodium intermediate
  • Preparation method of fondaparin sodium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082]

[0083] Put 250L of anhydrous methanol into the reaction kettle, lower the temperature to 15-20°C, add 19.4kg of concentrated sulfuric acid dropwise, fully stir for 15min after the dropwise completion, then add 25kg of acetylglucosamine (a), heat and reflux for reaction, and TLC detects that the reaction is complete ( Rf=0.3, dichloromethane:methanol=3:1), lower the temperature and add 31.24kg of potassium carbonate to adjust the pH to alkaline, filter, and wash the filter cake with 50L of anhydrous methanol to obtain a methanol solution of compound b.

Embodiment 2

[0085]

[0086] Add the methanol solution of compound b to the reaction kettle, then add 180g of anhydrous copper sulfate and 18.7kg of potassium carbonate, cool to about 0°C, and add 28.4kg of ImSO 2 N 3 After adding hydrochloride, heat up to 25-30°C to react, TLC detects that the reaction is complete (Rf=0.6, dichloromethane:methanol=3:1), filter, and wash the filter cake with 50L methanol, and concentrate the filtrate under reduced pressure Methanol was removed to obtain the crude product of compound c.

Embodiment 3

[0088]

[0089] Add 300L of glacial acetic acid to the crude compound c to dissolve, then add 51.9kg of acetic anhydride, rise to 30-40°C to react, and TLC monitors that the reaction is complete (petroleum ether: ethyl acetate = 3:1, Rf = 0.4). Add 20L of anhydrous methanol to quench the reaction, then add 500L of ethyl acetate to dilute, successively wash with 500L×2 purified water, 500L×2 saturated sodium bicarbonate solution and 500L saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain Compound d crude. Add 30L of anhydrous methanol to the crude product, heat to reflux to dissolve, then cool down to crystallize, and filter to obtain 27.9kg of compound d with a purity of 98.5% and a yield of 71.7%.

[0090] Add 279L of methanol, 0.9kg of sodium methoxide and compound d into the reactor, react at 25-30°C for 1-2 hours, TLC detects that the reaction is complete (petroleum ether: ethyl acetate = 3:1, the product is at the origin, the raw mate...

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PUM

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Abstract

The invention relates to a preparation method of a fondaparin sodium intermediate. In particular, the invention relates to a preparation method of a compound of formula 3, R1 is an alkyl protecting group or a hydroxy protecting group; and a process for preparation of fondaparin sodium from the compound of formula 3.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a method for preparing an intermediate of fondaparinux sodium. Background technique [0002] Fondaparinux sodium (Fondaparinux sodium) was developed by Choay, S.A. This compound is a synthetic pentose sugar Xa inhibitor, which can be used to prevent the formation of venous thrombosis in patients undergoing plastic surgery, and can also be used to treat venous thrombosis and Pulmonary embolism, its chemical name is: oxy-[2-deoxy-6-oxo-sulfonic acid-2-(sulfonyl)-α-D-glucopyranosyl]-(1--4)-oxygen-( β-D-glucopyranose)-(1--4)-oxo-[2-deoxy-3,6-di-oxo-sulfonic acid-2-(sulfonylamino)-α-D-pyran Glucose]-(1--4)-oxy-(2-oxo-sulfonic acid-α-L-pyraniduronic acid)-(1--4)-oxy-[2-deoxy-1- Oxy-methyl-6-oxo-sulfonic acid group-2-(sulfonylamino)-α-D-glucopyranoside] decasodium salt, the structural formula is as follows: [0003] [0004] A variety of synthetic processes have been disclosed in t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H1/00C07H15/04C07H13/04A61K31/7028A61K31/702
CPCA61K31/702A61K31/7028C07H1/00C07H13/04C07H15/04Y02P20/55
Inventor 窦月磊王磊朱宽张顺吉田伟伟
Owner JIANGSU HENGRUI MEDICINE CO LTD
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