Alpha isomer impurity of regadenoson and preparation method and use thereof

A technology of Reganosine and α isomers, which is applied to the α isomer impurities of Reganosine, and the application field of Reganosine pharmaceutical quality control, which can solve the problem that α isomer impurities cannot be effectively identified and Quality control and other issues

Active Publication Date: 2016-09-28
NANJING HERON PHARMA SCI & TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved by the present invention is to overcome the technical problem that the α-isomer impurity produced in the synthesis of reganosan cannot be effectively identified and quality controlled, and to provide a reganosan α-isomer impurity and its preparation Methods and medicinal uses

Method used

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  • Alpha isomer impurity of regadenoson and preparation method and use thereof
  • Alpha isomer impurity of regadenoson and preparation method and use thereof
  • Alpha isomer impurity of regadenoson and preparation method and use thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0074] The preparation of embodiment 1 formula 2 compound

[0075] Under nitrogen protection, dissolve 2,6-dichloroadenine (500g, 2.64mol) and β-D-tetraacetylribose (923g, 2.90mol) in 10L of anhydrous methyltetrahydrofuran, and cool to -5 ℃, add about 250g of acid resin catalyst "Amberlyst15" and about 28.5g of 3A molecular sieve, after stirring evenly, slowly add 800mL of anhydrous methyl tetrahydrofuran solution of about 450g of tin tetrachloride dropwise, and control the reaction temperature at -5 to 0℃ , after dropping, add 5L of isopropyl acetate, slowly rise to 30-35°C and continue to react for 3-4h, TLC monitors that the reaction is complete, filter, and slowly add 10L of saturated sodium bicarbonate solution and dichloromethane to the filtrate under strong stirring Extract (4L*3), combine the organic phases, concentrate to dryness, add about 5L of methyl tert-butyl ether for beating for 1 hour, filter the obtained solid with suction, and dry it to obtain about 1063g of...

Embodiment 2

[0076] The preparation of embodiment 2 formula 3 compound

[0077] The compound of formula 2 (1063 g, 2.37 mol) was dissolved in 25 L of isopropanol, and dry ammonia gas was continuously introduced, stirred and reacted at 30 ° C for 12 h, and concentrated to dryness to obtain about 595 g of compound of formula 3 with a yield of 83%.

Embodiment 3

[0078] The preparation of embodiment 3 formula 4 compound

[0079] Dissolve the compound of formula 3 (595g, 1.97mol) in 4.5L of dioxane, add L-tartaric acid (310g, 2.05mol), stir and react at 60°C for 4h, slowly add 9L of ethyl acetate, drop it, and cool down to 0°C, stirring and crystallizing for 2 hours, suction filtering the resulting solid, and drying to obtain about 740 g of the compound of formula 4, with a yield of 83% and an HPLC purity of 99.7%.

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Abstract

The invention discloses an alpha isomer impurity of regadenoson and a preparation method and a medicinal use thereof. The impurity is obtained through oriented synthesis; 2,6-dichloropurine and beta-D-1,2,3,5-tetra-o-acetyl-d-ribose are taken as starting raw materials; a salt of alpha 2-chloroadenosine is obtained by concentration, ammonolysis, salifying and purification; the regadenoson alpha isomer impurity is obtained directly through hydrazinolysis, concentration and ammonolysis without dissociation. An isomer is taken as a regadenoson impurity reference substance, so that the content of the impurity produced in synthesis can be effectively identifies, thereby raising the medicine quality standard of regadenoson.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to an α-isomer impurity of Reganosan, its preparation method and its application in the quality control of Reganosan. Background technique [0002] Regadenoson, chemical name 1-(6-amino-9-((2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran ring-yl)- 9H-purin-2-yl)-N-methyl-1H-pyrazole-4-carboxamide monohydrate, the structural formula is as follows, [0003] . [0004] Regadenoson is a highly selective adenosine A2A receptor agonist, which can promote coronary vasodilation and increase coronary blood flow by activating A2A adenosine receptors, as shown in myocardial perfusion angiography studies Its stress effect is effective. This drug is used for radionuclide myocardial perfusion imaging in patients who cannot undergo exercise stress testing. Clinicians also use it for CT imaging beyond the applicable disease. This product was developed by CV Therapeutics,...

Claims

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Application Information

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IPC IPC(8): C07H19/19C07H1/00G01N30/02
CPCC07H1/00C07H19/19G01N30/02G01N2030/027
Inventor 郭彦飞闵涛黄鹏袁尚胡永康
Owner NANJING HERON PHARMA SCI & TECH CO LTD
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