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New intermediate for preparing heparin pentasaccharide and preparation method thereof

一种肝素五糖、中间体的技术，应用在糖衍生物制备、化学仪器和方法、氨基糖等方向，能够解决中间体稳定性差、终产物纯化困难、反应选择性低等问题，达到简化操作、简化后处理过程、效率高的效果

Inactive Publication Date: 2013-10-23
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The method in the prior art needs to simultaneously convert the hydroxyl and azide (or the amino protected by benzyloxycarbonyl) to exposed hydroxyl and amino by hydrogenation, and the intermediates have poor stability and are difficult to purify; and finally In the one-step reaction, it is necessary to selectively sulfate all three amino groups among the six exposed hydroxyl groups and three exposed amino groups. The reaction selectivity is low, resulting in a low yield of the reaction, and the purification of the final product is very difficult.

Method used

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  • New intermediate for preparing heparin pentasaccharide and preparation method thereof
  • New intermediate for preparing heparin pentasaccharide and preparation method thereof
  • New intermediate for preparing heparin pentasaccharide and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: Methyl O-(2-azido-3,4-di-O-benzyl-2-deoxy-α-D-glucopyranose)-(1→4)-O-(2, 3-Di-O-benzyl-β-D-glucopyranose)-(1→4)-O-(2-azido-2-deoxy-α-D-glucopyranose)-(1 →4)-O-(3-O-benzyl-α-L-pyraniduronic acid)-(1→4)-2-azido-3-O-benzyl-2-deoxy- Preparation of α-D-glucopyranoside (IV-1)

[0064]

[0065] The fully protected pentasaccharide III-1 compound (10g, 5.4mmol) was dissolved in tetrahydrofuran (220mL), and aqueous sodium hydroxide solution (110mL, 1.0M, 20eq, 110mmol) was added dropwise, and after the addition was completed, it was stirred overnight at room temperature until the reaction completely. Neutralize to neutral with 1M hydrochloric acid, add ethyl acetate to extract, combine the organic phases, wash the organic phases with water, 10% citric acid, and saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to remove the solvent to obtain a foamy solid Compound IV-1 8.0 g.

[0066] ESMS: m / z=1486[M+1] + , 1484[M-1] - . ...

Embodiment 2

[0067] Example 2: Methyl O-(2-amino-3,4-di-O-benzyl-2-deoxy-α-D-glucopyranose)-(1→4)-O-(2,3- Di-O-benzyl-β-D-glucopyranose)-(1→4)-O-(2-amino-2-deoxy-α-D-glucopyranose)-(1→4)- O-(3-O-Benzyl-α-L-pyraniduronic acid)-(1→4)-2-amino-3-O-benzyl-2-deoxy-α-D-pyran Preparation of glucoside (I-1)

[0068]

[0069] Under the protection of nitrogen, dissolve pentasaccharide IV-1 compound (8.0g) in tetrahydrofuran (400mL), add aqueous sodium hydroxide solution (32mL, 1.0M), and drop trimethylphosphine in tetrahydrofuran solution (54mL , 1M), then slowly warmed up to room temperature, stirred overnight, until the reaction was complete, was added dropwise with dilute hydrochloric acid to neutralize to a pH of about 7, concentrated under reduced pressure to remove the solvent to obtain 8.8 g of compound I-1 as a foamy solid. The crude product was directly put into the next reaction without further purification.

[0070] HPLC purity: 90%.

[0071] ESMS: m / z 1408[M+1] + , 1406[M-1] - . ...

Embodiment 3

[0072] Example 3: Methyl O-(2-amino-3,4-di-O-benzyl-2-deoxy-α-D-glucopyranose)-(1→4)-O-(2,3- Di-O-benzyl-β-D-glucopyranose)-(1→4)-O-(2-amino-2-deoxy-α-D-glucopyranose)-(1→4)- O-(3-O-Benzyl-α-L-pyraniduronic acid)-(1→4)-2-amino-3-O-benzyl-2-deoxy-α-D-pyran Preparation of glucoside (I-1)

[0073]

[0074] Under nitrogen protection, dissolve pentasaccharide IV-1 compound (4.0g) in tetrahydrofuran (200mL), add aqueous sodium hydroxide solution (16mL, 1.0M), under ice-water bath, add triphenylphosphine (7.1g), and then Slowly raise the temperature to room temperature, stir overnight until the reaction is complete, add dropwise dilute hydrochloric acid to neutralize to a pH of about 7, and concentrate under reduced pressure to remove the solvent to obtain 11.4 g of crude compound I-1 as a foamy solid. The crude product was directly put into the next reaction without further purification.

[0075] ESMS: m / z 1408[M+1] + , 1406[M-1] - .

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Abstract

The present invention relates to a process of a chemically synthetic drug, and in particular, to a new intermediate of a heparin pentasaccharide and a preparation method thereof. The process has high reaction efficiency, and an easy reaction operation. The reaction intermediate is easy to be purified, and is appropriate for an industrialization production.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a preparation method for converting fully protected heparin pentasaccharide precursors into heparin pentasaccharide. Background technique [0002] Heparin was first isolated from animal liver by Jay McLean of Johns Hopkins University in 1916, and identified as an effective anticoagulant ingredient (a: Chem.Ind.1991, 2, 45-50; b : Bull.Johns Hopkins Hosp.1928,42,199), which is the most complex structure in the glycosaminoglycan (GAG) family. Heparin has been used in the clinical treatment of antithrombotic and cardiovascular diseases for nearly 60 years, and its anticoagulant activity is the most thoroughly researched and elucidated among its many physiological activities, and has contributed to low molecular weight heparin (LMWH) becoming a General antithrombotic agents, replacing traditional antithrombotic agents used clinically (Blood, 1992, 79, 1-17). The blood coagulation ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/18C07H15/04C07H1/00
CPCC07H15/18C07H1/00C07H15/04C07H11/00C07H5/06C08B37/006C08B37/0075
Inventor 丁毅力郭阳辉白骅吴迎秋白灵卫杨仕保
Owner ZHEJIANG HISUN PHARMA CO LTD
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