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Fondaparinux sodium pentasaccharide intermediate and preparation method thereof

An organic solvent and catalyst technology, applied in the field of chemical preparation, can solve the problems of low yield of pentasaccharide intermediates and difficult separation of isomers, and achieve the effects of reducing the difficulty of synthesis, easy purification, and strong controllability

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

Problems solved by technology

[0011] In the final step of the route for preparing fondaparinux sodium pentasaccharide intermediates in the 4+1 scheme, the coupling of monosaccharide E-3 and tetrasaccharide DCBA-2 to obtain pentasaccharides will generate a large amount of isomers of pentasaccharides. The structure is difficult to separate, so that the preparation of fondaparinux sodium pentasaccharide intermediate by the 4+1 scheme has great defects
[0013] However, the preparation of the new pentasaccharide intermediate (EDCBA-1) still adopts the 4+1 coupling scheme, and a large number of isomers (nearly 20% isomers) will still be produced in the last step of the reaction. Although in the preparation process of this pentasaccharide (EDCBA-1), the separation of isomers is relatively easy, but the existence of a large number of isomers still makes the yield of the pentasaccharide intermediate prepared by the 4+1 coupling scheme low, which is disappointing. Pity

Method used

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  • Fondaparinux sodium pentasaccharide intermediate and preparation method thereof
  • Fondaparinux sodium pentasaccharide intermediate and preparation method thereof
  • Fondaparinux sodium pentasaccharide intermediate and preparation method thereof

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preparation example Construction

[0051] 1. The preparation route of trisaccharide (EDC-1):

[0052] Monosaccharide E-3 and disaccharide DC-2 were dissolved in an organic solvent, and the trisaccharide EDC-1 was obtained by coupling in the presence of a catalyst. The synthetic route is as follows:

[0053]

[0054] 2. Preparation route of trisaccharide (EDC-4):

[0055] Step 1, in the presence of an organic solvent, the trisaccharide is treated with acetic anhydride and Lewis acid to obtain the trisaccharide EDC-2;

[0056] Step 2, in the presence of an organic solvent, the trisaccharide EDC-2 is treated with an organic base to obtain EDC-3;

[0057] Step 3, in the presence of an organic solvent, trisaccharide EDC-3 is treated with trichloroacetonitrile to obtain trisaccharide EDC-4.

[0058] The synthetic route is as follows:

[0059]

[0060] 3. Preparation route of pentasaccharide (EDCBA-1):

[0061] In the presence of organic solvent and catalyst, trisaccharide EDC-4 and disaccharide BA-2 w...

Embodiment 1、 3

[0063] Embodiment 1, the preparation of trisaccharide (EDC-1);

[0064] 200 grams of compound (DC-2) and 205 grams of compound (E-3) were dissolved in 3.5 liters of dichloromethane, cooled to -50 ° C, added 30 grams of silver trifluoromethanesulfonate, reacted for 3 hours; concentrated under reduced pressure, 220 g of trisaccharide (EDC-1) were obtained by recrystallization and purification; the yield of the obtained product was: 65.5%.

[0065] 1H NMR (400MHz, CDCl3): δ2.03 (s, 3H), 2.10 (s, 3H), 3.20 (d, 1H), 3.26 (dd, 1H), 3.51 (t, 1H), 3.55~3.67 (m , 3H), 3.75(s, 3H), 3.77(dd, 2H), 3.88(t, 1H), 3.99(dd, 2H), 4.15(t, 1H), 4.23(d, 2H), 4.55(m, 2H), 4.71(dd, 2H), 4.82(t, 2H), 4.86(d, 2H), 5.02(dd, 2H), 5.21(d, 1H), 5.47(d, 1H), 5.53(d, 1H ), 7.22~7.37 (m, 20H).

[0066] ESI / MS+(m / z): 1031.9 [M+23=1031.4].

[0067] The structural formula of the trisaccharide EDC-1 is:

[0068]

Embodiment 2、 3

[0069] Embodiment 2, preparation of trisaccharide (EDC-1);

[0070] 200 grams of compound (DC-2) and 205 grams of compound (E-3) were dissolved in 3.5 liters of dichloromethane, cooled to 0 ° C, added 30 grams of silver trifluoromethanesulfonate, reacted for 3 hours; concentrated under reduced pressure, and weighed Crystallization and purification yielded 245 grams of trisaccharide (EDC-1); the yield of the obtained product was: 72.6%.

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Abstract

The invention relates to a fondaparinux sodium pentasaccharide intermediate in the technical field of chemical preparation and a preparation method thereof, particularly to a preparation method of the fondaparinux sodium pentasaccharide intermediate, and comprises a trisaccharide intermediate of fondaparinux sodium and preparation method thereof. The invention designs a novel synthetic route to prepare the fondaparinux sodium pentasaccharide intermediate. The route has mild reactions, good reaction selectivity, strong controllability and low operation difficulty, and is beneficial to achievement of industrial production. The route has a low cost so that the method can meet requirements of large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical preparation, in particular to a fondaparinux sodium pentasaccharide intermediate and a preparation method thereof, in particular to a preparation method of fondaparinux sodium pentasaccharide intermediate, including the trisaccharide of fondaparinux sodium Intermediates, and related preparation methods. Background technique [0002] 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 as coagulation factors. Heparin drugs are a kind of strong and effective anticoagulant, which can prevent the action of coa...

Claims

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Application Information

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