Preparation method of candesartan cilexetil

A technology of candesartan cilexetil and candesartan acid, applied in the field of medicine, can solve the problems of poor product quality, cumbersome synthesis process, and low yield

Active Publication Date: 2013-11-20
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The problem to be solved in the present invention is that the synthesis process of candesartan cilexetil is cumbersome, the yield is not high, and the problem of poor product quality is that candesartan acid is a raw material.

Method used

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  • Preparation method of candesartan cilexetil
  • Preparation method of candesartan cilexetil

Examples

Experimental program
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Effect test

example 1

[0030] The first step, add 130 kilograms of N in the 500L reactor, N dimethylacetamide, drop into 22 kilograms of candesartan acid and 17.3 kilograms of anhydrous potassium carbonate, 16.7 kilograms of trityl chloride, tetrabutyl bromide under stirring 0.2 kg of ammonium chloride, stirred for 10 minutes, started to heat up to 63±3°C, stirred and reacted, and the remaining amount of candesartan acid in the reaction solution was detected by HPLC <2.0%. The reaction solution was directly reserved for feeding in the next step.

[0031] In the second step, the temperature of the reaction solution in the first step is lowered to 55°C, 12.4 kg of 1-chloroethylcyclohexyl carbonate is added, and the temperature is controlled at 55-60°C for reaction. The raw materials of the reaction solution are completely reacted by HPLC, and the temperature of the reaction solution is cooled to 20°C. Under stirring, inject the reaction solution into 400 kg of ice water at a slow speed, precipitate so...

example 2

[0035] In the first step, add 260 kilograms of N,N-dimethylformamide into a 500L reactor, and add 44 kilograms of candesartan acid and 25.3 kilograms of triethylamine, 33.5 kilograms of trityl chloride, and triethyl chloride under stirring. 0.5 kg of benzyl ammonium, after stirring evenly, start to heat up to 80° C., stirring and reacting, HPLC detects that the remaining amount of candesartan acid in the reaction solution is <2.0%. The reaction solution was directly reserved for feeding in the next step.

[0036] In the second step, the temperature of the reaction solution in the first step was lowered to 55°C, 24.8 kg of 1-chloroethylcyclohexyl carbonate was added, and the temperature was controlled at 50-55°C to react. The raw materials of the reaction liquid were completely reacted by HPLC, and the temperature of the reaction liquid was lowered to 20°C. Under stirring, inject the reaction liquid into 800 kg of ice water at a slow speed, precipitate solids, filter, wash the ...

example 3

[0040]In the first step, add 232 kilograms of dimethyl sulfoxide to a 500L reactor, add 33 kilograms of candesartan acid and 30.0 kilograms of potassium bicarbonate, 25.1 kilograms of trityl chloride, and 0.3 kilograms of potassium iodide under stirring, and start The temperature was raised to 88±2°C, and the reaction was stirred, and the remaining amount of candesartan acid in the reaction liquid was detected by HPLC to be <2.0%. The reaction solution is fed directly to the next step.

[0041] In the second step, the temperature of the reaction liquid in the first step is lowered to 55°C, 18.6 kg of 1-chloroethylcyclohexyl carbonate is added, and the temperature is controlled at 55-60°C for 6 hours. The raw materials of the reaction liquid are completely reacted by HPLC, and the temperature of the reaction liquid is lowered to 20°C. ℃, under stirring, slowly inject the reaction solution into 600 kg of ice water, precipitate solids, filter, wash the filter cake with water, the...

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Abstract

The invention relates to a preparation method of candesartan cilexetil. The method takes candesartan acid as a starting material to acquire trityl candesartan cilexetil by a one-pot process, and then the trityl is removed from the trityl candesartan cilexetil in lower alcohol, thus obtaining the candesartan cilexetil. The candesartan cilexetil product prepared by the method has purity up to more than 99.80%. The method reduces the operation steps of reaction and solvent consumption, shortens the reaction period, and greatly improves the yield of trityl candesartan cilexetil, thus being more suitable for industrial production.

Description

Technical field: [0001] The invention relates to a preparation method of candesartan cilexetil, which belongs to the technical field of medicine. Background technique: [0002] Candesartan cilexetil is the prodrug of candesartan, which can be completely hydrolyzed in the gastrointestinal tract and converted into candesartan with antihypertensive activity. Candesartan cilexetil is clinically used to treat all kinds of mild to moderate hypertension. While lowering arterial blood pressure, the drug is usually not accompanied by adverse reactions such as tachycardia, and there is no blood pressure rebound after stopping the drug. It is more acceptable to hypertensive patients, especially elderly patients. [0003] Industrialized large-scale production generally uses candesartan acid as a raw material to prepare candesartan cilexetil, and the methods for synthesizing candesartan cilexetil reported in the literature have the following several types: [0004] In the first step of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/10
Inventor 于年余李宗文武云飞吴荣贵
Owner 迪嘉药业集团股份有限公司
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