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Preparation method of fondaparinux sodium monosaccharide intermediate

A technology of sulfonic acid anhydride and sulfonyl halide, which is applied in the field of preparation of fondaparinux sodium monosaccharide intermediates, can solve the problems of unfavorable industrial production, many impurities, and high cost, and achieve less impurities, controllable reaction process, The effect of increasing the yield

Active Publication Date: 2018-12-28
江苏美迪克化学品有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0025] Method 5: The preparation method reported in the document "Heterocycles, 2012, vol.84(2), pp.1335-1343" is as follows, wherein, the reaction of converting the amino group into an azido group in the second step has many impurities and requires Purification and separation with chromatographic columns is costly and unfavorable for industrial production:

Method used

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  • Preparation method of fondaparinux sodium monosaccharide intermediate
  • Preparation method of fondaparinux sodium monosaccharide intermediate
  • Preparation method of fondaparinux sodium monosaccharide intermediate

Examples

Experimental program
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Effect test

example 1-1

[0070] Example 1-1 : Preparation of 1,6:3,4-dianhydro-2-O-trifluoromethanesulfonyl-β-D-glucopyranose (compound shown in formula (II), X is trifluoromethyl):

[0071] Dissolve 1,6:3,4-dianhydro-β-D-glucopyranose (25.0g, compound represented by formula (I)), N,N-diisopropylethylamine (33.6g) in acetone (400mL), lower the temperature to -20°C, slowly add a solution of trifluoromethanesulfonic anhydride (58.7g) in acetone (100mL) dropwise, stir and react at -20°C for 1h, after the reaction is complete, add water dropwise to quench the reaction solution, and rotary evaporate under reduced pressure to dryness, extracted with dichloromethane, washed with salt water, dried over anhydrous sodium sulfate, and rotary evaporated to dryness under reduced pressure. The crude product was recrystallized from isopropanol to obtain 1,6:3,4-dianhydro-2-O-trifluoro Methylsulfonyl-β-D-glucopyranose, white solid (40.7g), yield 85%, purity 98.5%.

example 1-2

[0072] Example 1-2 : Preparation of 1,6-anhydro-2-O-trifluoromethanesulfonyl-β-D-glucopyranose (compound shown in formula (Ⅲ)):

[0073] Dissolve 1,6:3,4-dianhydro-2-O-trifluoromethanesulfonyl-β-D-glucopyranose (40.0g) in xylene (350mL), slowly add concentrated sulfuric acid (0.14g) dropwise , stirred at 40°C for 4 hours, after the reaction was completed, evaporated to dryness under reduced pressure, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure, the crude product was recrystallized from a mixed solvent of ethyl acetate-petroleum ether , to obtain 1,6-anhydro-2-O-trifluoromethanesulfonyl-β-D-glucopyranose as a white solid (38.3 g), with a yield of 90% and a purity of 98.7%.

example 1-3

[0074] Example 1-3 : Preparation of 1,6-anhydro-2-O-trifluoromethanesulfonyl-3,4-bis-O-benzyl-β-D-glucopyranose (compound shown in formula (IV)):

[0075] Dissolve 1,6-anhydro-2-O-trifluoromethanesulfonyl-β-D-glucopyranose (35.0g), sodium hydroxide (19.0g) in N,N-dimethylacetamide (450mL) , add benzyl bromide (61.0g) in N,N-dimethylacetamide solution (50mL) dropwise, keep warm at 50°C for 8h until the reaction is complete, rotary evaporate to dryness under reduced pressure, extract with dichloromethane, wash with salt water, no Dry over sodium sulfate, evaporate to dryness under reduced pressure, and recrystallize the crude product from a mixed solvent of ethyl acetate-petroleum ether to obtain 1,6-anhydro-2-O-trifluoromethanesulfonyl-3,4-bis-O- Benzyl-β-D-glucopyranose, white solid (46.8g), yield 83%, purity 97.5%.

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Abstract

The invention discloses a preparation method of a fondaparinux sodium monosaccharide intermediate. The preparation method comprises the following steps: (1) in the presence of an acid-binding agent, carrying out esterification reaction on a compound as shown in a formula (I) and a substituent sulfonic anhydride and / or a substituent sulfonyl halogen to generate a compound as shown in a formula (II); (2) carrying out a ring opening reaction on the compound as shown in the formula (II) in an acidic condition to generate a compound as shown in a formula (III); (3) carrying out benzylation reactionon the compound as shown in the formula (III) and benzyl monohalide in an alkaline condition to generate a compound as shown in a formula (IV); and (4) carrying out an azido reaction on the compoundas shown in the formula (IV) and alkali metal azide salt to generate a compound as shown in a formula (V) and caring out inner ether ring opening and acetylation reaction on the compound as shown in the formula (V) in a mixed solution of acetic anhydride and trifluoroacetic acid to generate a compound as shown in a formula (VI). The method can be used for obtaining an ideal product yield, and theraw materials are cheap, easily available and relatively few in three wastes. The formulae are as shown in the description.

Description

technical field [0001] The invention belongs to the field of sugar chemical synthesis, and in particular relates to a preparation method of fondaparinux sodium monosaccharide intermediate. Background technique [0002] Fondaparinux sodium (Fondaparinux sodium) is a synthetic heparin pentasaccharide drug, which is the first indirect inhibitor of antithrombin-dependent factor Xa developed and produced by Sanofi Winthrop Industrie in France. The chemical structural formula is as follows (D, E, F, G, H are used to represent 5 monosaccharide fragments from left to right). [0003] [0004] The total synthetic route of fondaparinux sodium is relatively long, and the number of reaction steps varies from 50 steps to more than 70 steps. At present, the main construction strategies are (D+EF)+GH and D+(EF+GH). Among them, the following structure (Formula VI) is an important intermediate for introducing D monosaccharide fragments. The Chinese name of Formula VI is 1 ,6-bis-O-acety...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H9/02C07H13/04C07H1/00
CPCC07H1/00C07H9/02C07H13/04
Inventor 杨盟徐肖洁景亚婷
Owner 江苏美迪克化学品有限公司
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