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Preparation method for regadenoson

A technology of regadeson and compound, which is applied in the field of preparation of regadeson, can solve the problems of unfavorable intermediate quality control and production scale-up, long reaction route, difficult reaction control, etc. The effect of processing operations and speeding up the reaction process

Inactive Publication Date: 2015-07-01
SHANGHAI ZIYUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the reaction route of acylation after hydrolysis is too long, the acylation operation needs to use complex catalysts, the reaction control is difficult, and the impurities increase
[0011] In the literature report of "NUCLEOSIDES,NUCLEOTIDES&NUCLEIC ACIDS", 1-{9[4S,2R,3R,5R]-3,4-dihydroxy-5-(hydroxymethyl)oxolane-2-yl] -The trimethylsilane derivative of ethyl 6-aminopurin-2-yl}pyrazole-4-carboxylate needs to be separated by silica gel chromatography before it can be put into the next step of hydrolysis reaction, which is not conducive to the quality control and production of intermediates enlarge

Method used

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  • Preparation method for regadenoson
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  • Preparation method for regadenoson

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preparation example Construction

[0072] A preparation method for a compound shown in formula III, comprising:

[0073] Step a, in an organic solvent, under the action of a catalyst, using tert-butyldimethylsilyl chloride as a protective agent to protect the hydroxyl group of 2-chloroadenosine to obtain compound 2 shown in formula II;

[0074] Step b, compound 2 shown in formula II undergoes a substitution reaction with hydrazine hydrate in an alcoholic solvent to generate compound 3 shown in formula III;

[0075]

[0076] The preparation method of the compound shown in the formula III of the present invention firstly uses tert-butyldimethylsilyl chloride as a protective agent to protect the hydroxyl group of 2-chloroadenosine to obtain the compound 2 (2', 3' shown in the formula II ,5'-tri-tert-butyldimethylsilyl-2-chloroadenosine); then in an alcoholic solvent, compound 2 shown in formula II and hydrazine hydrate undergo a substitution reaction to generate compound 3 shown in formula III (2',3 ',5'-tri-t...

Embodiment 1

[0096] Example 1: Compound 2, the preparation of 2',3',5'-tri-tert-butyldimethylsilyloxy-2-chloroadenosine

[0097]

[0098] To 500 g of pyridine was added 50 g of compound 1. Continue to add 210g of tert-butyldimethylsilyl chloride and 90g of imidazole under stirring, stir and dissolve completely at 25°C, and react for 24 hours. TLC analysis and tracking, the raw materials are consumed, concentrated at 50 ° C, 100 Pa under reduced pressure to remove pyridine, added 650 g of dichloromethane to the solid to gradually dissolve, added 300 g of saturated sodium bicarbonate solution to the system, stirred for 30 minutes, there were a lot of bubbles After the bubbles disappeared, stand still for 30 minutes, separate the layers, and wash the dichloromethane phase once with 300 g of saturated sodium bicarbonate solution. The dichloromethane phase was washed three times with saturated sodium chloride solution, 400 g each time. The dichloromethane phase was dried with 100 g of anhy...

Embodiment 2

[0099] Example 2: Compound 3, the preparation of 2',3',5'-tri-tert-butyldimethylsilyloxy-2-hydrazinoadenosine

[0100]

[0101] 50 g of compound 2 was dissolved in 200 g of absolute ethanol, stirred and dissolved at 50°C. Under nitrogen protection, 80g of 80% hydrazine monohydrate was added, and the temperature rose to 70°C. After reacting for 20 hours, TLC followed the reaction process. After the raw materials were consumed, the reaction solution was slowly poured into 2 kg of ice water, stirred for 1 hour, and filtered. The filter cake was washed three times with purified water, each 100 g. Drain. Air-dried at 40°C for 12 hours to obtain compound 3. Yield 94%, purity 92%. Mass Spectrometry [M+Na] + =662.

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Abstract

The invention discloses a preparation method for regadenoson, belonging to the field of pharmaceutical chemistry. The preparation method for regadenoson comprises the following steps: with a compound as shown in a formula III as a reaction raw material, subjecting the compound and 2-formyl-3-oxoethyl propanoate to a cyclization reaction in isopropanol so as to produce a compound as shown in a formula IV; then with the compound as shown in the formula IV as a substrate, subjecting the substrate and a methanol solution of methylamine to an acylation reaction so as to produce a compound as shown in a formula V; and reacting the compound as shown in the formula V with tetrabutyl ammonium fluoride in a methanol solution to remove hydroxyl protection so as to prepare regadenoson. According to the preparation method in the invention, the methanol solution of methylamine is used as a reaction medium and reagent, a methanamide compound is produced through one-step reaction under normal pressure, and the acylation reaction is carried out without hydrolysis for formation of a carboxylic acid derivative; thus, reaction steps are reduced, high pressure reaction equipment is not used, cost for production input is lowered, the safety factor of production is increased, and the method is more applicable to large scale production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for preparing regadeson, that is, a method for preparing (1-{9[4S,2R,3R,5R]-3,4-dihydroxy-5-(hydroxymethyl base) oxolane-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-methylformamide method. Background technique [0002] Regadeson, a highly selective adenosine A 2A Agonists, stress agents for radionuclide cardiac perfusion imaging, and cardiac vasodilators for cardiac imaging are already in clinical use in the United States. [0003] Regardson, chemical name (1-{9[4S,2R,3R,5R]-3,4-dihydroxy-5-(hydroxymethyl)oxol-2-yl]-6-amino Purin-2-yl}pyrazol-4-yl)-N-methylformamide, the structural formula is as follows: [0004] [0005] US Patent No. 6403567 discloses the compound and methods for preparing the compound. 1-{9[4S,2R,3R,5R]-3,4-dihydroxy -5-(Hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxylic acid ethyl ester. Then, using the nucleoside d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/167C07H1/00
CPCC07H19/16C07H1/00
Inventor 刘伟张志刚任真
Owner SHANGHAI ZIYUAN PHARMA
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