A kind of high-purity heparin benzyl ester salt and its preparation method and application

Abstract

The invention relates to a high-purity heparin benzyl ester salt and its preparation method and application. Specifically, the heparin benzyl ester salt of the present invention is a raw material containing heparin benzyl ester quaternary ammonium salt or heparin benzyl ester quaternary ammonium salt, reacted with an aqueous solution of an alkali metal or alkaline earth metal salt, and then added with heparin benzyl ester metal salt or It is an insoluble solvent for alkaline earth metal salts, which is obtained by precipitation and separation, and has the following characteristics: high purity of heparin benzyl ester salt, especially low residual quaternary ammonium salt, simple preparation method, easy industrial production, and can be used to prepare high-purity low Molecular heparin, high yield.

Description

technical field [0001] The invention relates to a high-purity heparin benzyl ester salt, its preparation method and its application in the preparation of low molecular weight heparin. Background technique [0002] Heparin is a mixture of sulfated polysaccharides of animal (pig or bovine) origin. Because of their good antithrombotic properties, they have been widely used, such as the preparation of antithrombotic drugs, drugs for the treatment of cardiovascular diseases, and drugs for the treatment of cerebrovascular diseases. drugs etc. [0003] However, natural heparin has many drawbacks which limit the application of heparin. A major drawback is that excessive use of heparin can cause spontaneous bleeding, so the clotting time should be measured before each injection. In addition, long-term use, heparin can also cause allergic reactions, thrombocytopenia, osteoporosis and spontaneous fractures. [0004] Heparin sodium has a high risk of spontaneous bleeding, and the coa...

AI Technical Summary

Problems solved by technology

[0006] However, the above-mentioned preparation method has the following disadvantages: (1) the purity of heparin benzyl ester sodium salt is low: when sodium acetate methanol solution reacts with heparin benzyl ester quaternary ammonium salt to generate heparin benzyl ester sodium salt, because heparin is a macromolecular long chain, heparin The solubility of benzyl ester sodium salt in methanol is very low. With the addition of sodium acetate methanol solution, the heparin benzyl ester sodium salt containing quaternary ammonium salt that has no time to react is precipitated at the same time, which leads to incomplete reaction

Experiments have shown that even if long-term stirring or repeated reactions with sodium acetate methanol solution are carried out, after all, it is in a suspended state, and a considerable part of the quaternary ammonium salt cannot be completely reacted, thus remaining on the heparin benzyl ester sodium salt chain

(2) The esterification rate of heparin benzyl ester sodium salt is difficult to accurately measure: due to the non-solution state of the reaction, the reactants and products are all precipitated, and the degree of each reaction is not easy to reproduce. Quaternary ammonium salt, benzyl chloride and acetic acid Sodium residues will vary each time, which brings uncertainty to the determination of esterification rate, which will affect the selection of subsequent degradation conditions, thereby affecting the quality of the product, and even the success rate of production

(3) Potential safety hazards of the final product: the quaternary ammonium salt and excess benzyl chloride and sodium acetate generated during the reaction are not easily washed off by methanol and will remain in the product

New impurities will also be produced in the subsequent degradation, which will bring hidden dangers to the safety of the product

(4) Difficult to industrialize: the precipitate obtained during the preparation of heparin benzyl ester sodium salt is viscous, difficult to filter and purify, and requires a large amount of methanol to wash the precipitate, making industrialization difficult and costly

This preparation method needs to distill off the reaction solvent first, and experiments have proved that heparin benzyl ester quaternary ammonium salt is easily soluble in methanol, so adding methanol after distilling off the reaction solvent cannot obtain precipitation, and at the same time greatly increases the difficulty and cost of industrialization