A kind of fondaparinette sodium disaccharide intermediate fragment ba and its synthetic method

A technology of fondaparinette sodium and its synthesis method, which is applied in the field of synthesis and preparation of disaccharide fragment BA, can solve the problems of unfavorable drug promotion and popularization, unfavorable large-scale production, high product price, etc., and achieve optimized synthesis route and product purification Convenience and the effect of fewer synthesis steps

Inactive Publication Date: 2016-03-09
麦科罗夫(南通)生物制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] U.S. Patent US4818816 describes a synthetic method for fondaparinoid sodium, which requires about 50 steps, and the yield is only 0.1%. Because the synthetic route is long and the total yield is low, the product price is relatively expensive, which is not conducive to medicine The promotion and popularization; at the same time, the long synthetic route has brought a lot of environmental pollution, which is not conducive to large-scale industrial production

Method used

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  • A kind of fondaparinette sodium disaccharide intermediate fragment ba and its synthetic method
  • A kind of fondaparinette sodium disaccharide intermediate fragment ba and its synthetic method
  • A kind of fondaparinette sodium disaccharide intermediate fragment ba and its synthetic method

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specific Embodiment 1

[0033] A fondaparinette sodium disaccharide intermediate fragment BA, characterized in that: the structural formula of the fondaparinette sodium disaccharide intermediate fragment BA is: ,in, R 1 For:-CH 3 ;-C 2 h 5 . R 2 is: -OH; -OAc; -OBz. R 3 is: -OH; -OAc; -OBn. R 4 for:-N 3 ; -NHAc; -NHCBz. R 5 For: -COOH; -COOCH 3 ;-COOC 2 h 5 .

[0034] A synthetic method of fondaparinette sodium disaccharide intermediate fragment BA, first synthesizing ring A and ring B respectively, wherein ring A is a compound: , ring B is a compound: ; The A ring and the B ring are coupled into a disaccharide derivative under the action of a Lewis acid; the disaccharide derivative is removed from the carboxylic acid group on the B ring under the action of an alkali to obtain the intermediate disaccharide sodium fondaparinette body fragment BA.

[0035] Such as figure 1 As shown, the A ring synthesis process is as follows:

[0036] Step 1: Preparation of 1-O-methyl 2-acetylam...

specific Embodiment ， example 2

[0069] This example differs from Example 1 in that: the starting material N-acetyl-glucosamine dosage is 200 g; 3-O-benzyl-1,2-O-isopropylidene-6-methyl-α - The amount of L-iduronic acid was 318g, and the amount of other substances was amplified according to the mass ratio. With reference to the steps described in Example 1, 208g of fondaparinoid sodium disaccharide intermediate fragment BA was obtained.

specific Embodiment ， example 3

[0071] The difference between this example and Example 1 is that the starting material N-acetyl-glucosamine dosage is 1 kg; 3-O-benzyl-1,2-O-isopropylidene-6-methyl-α -L-iduronic acid charging amount is 1.59kg, and the charging amount of other substances is amplified according to mass ratio correspondingly, with reference to each step operation described in embodiment 1, obtains 1.17kg of fondaparinette sodium disaccharide intermediate fragment BA, .

[0072] The invention uses a new synthesis strategy, optimizes the synthesis route, adopts mild reaction conditions, fewer synthesis steps, higher yield, convenient product purification, can be effectively scaled up for industrialized large-scale production, and has higher economic benefits.

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Abstract

The invention discloses a fondaparinoid sodium disaccharide intermediate fragment BA and a synthesis method thereof. The invention has novel synthesis strategy, simple and easy-to-obtain raw materials, relatively few reaction steps, mild reaction conditions, simple and easy-to-operate post-treatment conditions, low production cost and high yield, and is suitable for large-scale industrial production.

Description

technical field [0001] The present invention relates to the synthesis of disaccharide fragments of a highly selective factor Xa inhibitor, more specifically, the synthesis and preparation method of the disaccharide fragment BA of fondaparinette sodium, the chemical formula of fondaparinette sodium is . Background technique [0002] Blood coagulation is a process in which coagulation factors participate in a series of limited hydrolysis of proteins to form thrombus, including the sequential activation of various coagulation factors and plasma components, among which the generation of FXa is the core step of the blood coagulation process. The X factor activated in the first step of coagulation acts on prothrombin to break the chemical bond between arginine and isoleucine in the prothrombin molecule, forming thrombin with strong protein activity. [0003] Under the action of thrombin, fibrinogen is cleaved, eventually forming stable cross-linked fibrin. At the same time, the...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/18C07H1/00
CPCY02P20/55
Inventor 季春香汤庆刚白东才王娜颜小香王成牛洪森
Owner 麦科罗夫(南通)生物制药有限公司
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