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Synthesis method of remdesivir intermediate

A technology of Remdesivir and a synthetic method, applied in the field of pharmaceutical intermediates, can solve the problems of poor selectivity of route 1 and the like, and achieve the effect of reducing costs

Inactive Publication Date: 2020-05-22
JIANGSU ALPHA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route is an optimization of route 1. During the cyano substitution step, the product isomer ratio obtained by adding trifluoromethanesulfonic acid is 95:5, and trifluoromethanesulfonic acid greatly improves the desired β-anomer The ratio of chiral purity can be further improved by subsequent recrystallization, while the selectivity of route 1 is poor, and only by chiral column purification

Method used

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  • Synthesis method of remdesivir intermediate
  • Synthesis method of remdesivir intermediate
  • Synthesis method of remdesivir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] A (3R,4R,5R)-2-(4-aminopyrrole[2,1-f][1,2,4]triazine-7-yl)-3,4-bis(benzyloxy) -5-((benzyloxy) methyl) the synthetic method of tetrahydrofuran-2-alcohol, concrete steps are:

[0028] (1) Protection of the amino group in pyrrolo[2,1-F][1,2,4]triazin-4-amine

[0029] 134g of pyrrolo[2,1-F][1,2,4]triazin-4-amine (1mol) was placed in a round bottom flask, 210g of sodium bicarbonate (2.5mol), 500ml of water and 300mL of methanol were added, Heat and stir in a water bath at 40°C to dissolve it, add 188g benzyl chloroformate (1.1mol) dropwise for about 30min while stirring, continue stirring for 2.5h after the addition is complete, then add 300ml water, extract with 40ml ethyl acetate, stir the water phase 3N hydrochloric acid was added to PH=1-2, a white solid was precipitated, the product was filtered and dried, and dried to obtain 232 g of a white solid with a molar yield of 86.6%.

[0030] (2) Addition with 2,3,5-tribenzyloxy-D-ribonic acid-1,4-lactone

[0031] Dissolve ...

Embodiment 2

[0035] A (3R,4R,5R)-2-(4-aminopyrrole[2,1-f][1,2,4]triazine-7-yl)-3,4-bis(benzyloxy) -5-((benzyloxy) methyl) the synthetic method of tetrahydrofuran-2-alcohol, concrete steps are:

[0036] (1) Protection of the amino group in pyrrolo[2,1-F][1,2,4]triazin-4-amine

[0037] Put 134g of pyrrolo[2,1-F][1,2,4]triazin-4-amine (1mol) in a round bottom flask, add 1L of acetonitrile and stir to dissolve, then add 273g of Boc anhydride (1.25eq), The reaction was stirred for 18 hours. Concentrate under reduced pressure to remove the solvent, add 500 mL of ethyl acetate and 300 mL of water to the residue, dissolve and stir, separate liquids, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate to dryness under reduced pressure to obtain 210 g of an off-white solid. Rate 90%.

[0038] (2) Addition with 2,3,5-tribenzyloxy-D-ribonic acid-1,4-lactone

[0039] Dissolve 23.4 g (0.1 mol) of the solid obtained in step 1 in anhydrous tetrahydrofuran (2...

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Abstract

The invention relates to the technical field of medical intermediates, in particular to a synthetic method of a remdesivir intermediate. The chemical name of the intermediate is (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-di(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol. The preparation method comprises the following steps: performing amino protection on pyrrolo[2,1-F][1,2,4]triazin-4-amine with a protecting agent; reacting with lithium diisopropylamide; then adding 2,3,5-tribenzyloxy-D-ribonic acid 1,4-lactone, and finally removing the protective group to obtain the remdesivir intermediate that is the (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-di(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, specifically a method for synthesizing a remdesivir intermediate. Background technique [0002] Remdesivir is a drug under research by Gilead Chemical. Remdesivir is a nucleoside analog with antiviral activity, with an EC50 value of 74 nM against ARS-CoV and MERS-CoV in HAE cells and an EC50 value against murine hepatitis virus in delayed brain tumor cells is 30nM. [0003] At present, there are roughly two routes for the synthesis of remdesivir at home and abroad, as follows: [0004] (1) The route adopted by the original manufacturer Gilead’s patent WO2016069826A1 is: (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2- Alcohol is used as the starting material, and remdesivir is obtained through oxidation, addition, substitution, resolution, debenzylation, protection, substitution, and finally resolution. [0005] [0006] (2) "Nature" reported the second-gene...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04Y02P20/55
Inventor 陈本顺张亮刘洋高忠旗赵云
Owner JIANGSU ALPHA PHARM CO LTD
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