Preparation method of retegravir intermediate

A technology of remdesivir and intermediates, which is applied in the field of preparation of remdesivir intermediates, can solve the problem of poor selectivity of route 1, and achieve the effects of saving costs and improving chiral purity

Active Publication Date: 2020-05-29
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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  • Preparation method of retegravir intermediate
  • Preparation method of retegravir intermediate
  • Preparation method of retegravir intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0031] A (2R,3R,4R,5R)-2-(4-aminopyrrole[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy )-5-((benzyloxy) methyl) tetrahydrofuran-2-carbonitrile preparation method, concrete steps are:

[0032] 1. Synthesis of (2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-hydroxytetrahydrofuran-2-carbonitrile

[0033] Dissolve 2,3,5-tribenzyloxy-D-ribonic acid-1,4-lactone (41.9g, 0.1mol) in anhydrous dichloromethane (300mL), control the temperature at 0-10°C, drop Add titanium tetrachloride (5.5 mL, 0.05 mol), and then add trimethylsilyl cyanide (19.8 g, 0.2 mol) after the dropwise addition. After the dropwise addition, react for 1 hour, add 200 mL of saturated aqueous sodium bicarbonate solution to the reaction solution, stir and separate the liquids, dry the organic phase over anhydrous magnesium sulfate for 6 hours, remove the solvent under reduced pressure, and add ethyl acetate (50 mL) to the residue , petroleum ether (150mL), heated to 40°C and stirred to dissolve, then gradual...

Embodiment 2

[0037] A (2R,3R,4R,5R)-2-(4-aminopyrrole[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy )-5-((benzyloxy) methyl) tetrahydrofuran-2-carbonitrile preparation method, concrete steps are:

[0038] 1. Synthesis of (2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-hydroxytetrahydrofuran-2-carbonitrile

[0039] Dissolve 2,3,5-tribenzyloxy-D-ribonic acid-1,4-lactone (41.9g, 0.1mol) in 1,2-dichloroethane (300mL) and control the temperature for 20-30 °C, add anhydrous aluminum trichloride (20 g, 0.15 mol), and then add tert-butylcyanodimethylsilane (56 g, 0.4 mol) after the dropwise addition. After the dropwise addition, react for 1 hour, add 200 mL of saturated aqueous sodium bicarbonate solution to the reaction solution, stir and separate the liquids, dry the organic phase over anhydrous magnesium sulfate for 6 hours, remove the solvent under reduced pressure, and add 4-methyl 2- Pentanone (50mL) and n-heptane (100mL) were heated to 45°C and stirred to dissolve, then gradually ...

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Abstract

The invention relates to the technical field of medical intermediates, in particular to a preparation method of a retegravir intermediate. The chemical name of the compound is (2R, 3R, 4R, 5R)-2-(4-aminopyrrole [2, 1-f] [1, 2, 4] triazine-7-yl)-3, 4, 5, 6-tetracarboxylic acid. The preparation method comprises the following steps: (1) in a solvent, carrying out asymmetric addition on 2, 3, 5-tribenzyloxy-D-ribose-1, 4-lactone to form (2R, 3R, 4R, 5R)-3, 4-bis (benzyloxy)-5-(((benzyloxy) methyl) tetrahydrofuran-2-nitrile; and 2) in a solvent, enabling (2R, 3R, 4R, 5R)-3, 4-bis (benzyloxy)-5-((benzyloxy) methyl)-2-hydroxytetrahydrofuran-2-nitrile to react with a hydroxyl activator and then react with 7-iodopyrrole[2, 1-f][1, 2, 4]triazine-4-amine to form (2R, 3R, 4R, 5R)-2-(4-aminopyrrole [2,1-f][1, 2, 4]triazine-7-yl)-3, 4-bis (benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-nitrile.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, specifically a method for preparing 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-generat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07B2200/07C07D487/04
Inventor 陈本顺张亮刘洋翟必林周祥祥
Owner JIANGSU ALPHA PHARM CO LTD
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