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A preparation method of candesartan cilexetil and intermediates thereof

A compound and reaction technology, applied in the field of preparation of candesartan cilexetil, can solve the problems of inconvenient transportation and storage, poor stability, and difficulty in large-scale industrial production of candesartan cilexetil, and achieve the effect of simple operation

Inactive Publication Date: 2012-12-26
TOPHARMAN SHANGHAI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The stability of cyclohexyl iodide (chloro) ethyl carbonate as an esterification reagent is not good, and it is inconvenient to transport and store, which brings difficulties to the large-scale industrial production of candesartan cilexetil

Method used

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  • A preparation method of candesartan cilexetil and intermediates thereof
  • A preparation method of candesartan cilexetil and intermediates thereof
  • A preparation method of candesartan cilexetil and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Embodiment 1: the preparation of cyclohexyl carbonate monoester

[0046] Ethyl chloroformate (7.5g, 0.069mol) was dissolved in dichloromethane (20ml), cyclohexanol (3.8g, 0.038mol) was added successively, and pyridine (1ml) was stirred at room temperature for about 20min. TLC detected no raw material, washed with water (10ml×2), dried over anhydrous sodium sulfate, and concentrated to obtain cyclohexylethyl carbonate (4.734g, 72.6%), a pale yellow oily liquid. MS (ESI) m / z: 173.8 (M+1), 172.8 (base peak), 80.1, 91.0, 128.1.

[0047]Dissolve cyclohexyl ethyl carbonate (4.248g, 0.025mol) in a mixed solution of ethanol and water (15ml, V (ethanol:water)=95:5), add sodium hydroxide (1.189g, 0.030mol) and stir at room temperature About 30min. TLC detects that there is no raw material, concentrate, add water (20ml), add dropwise hydrochloric acid to adjust the pH value of the solution to about 3, then extract with dichloromethane (10ml×2), dry over anhydrous sodium sulfate,...

Embodiment 2

[0048] Example 2: 1-chloroethyl-2-ethoxy-3-((2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methanol Base)-3H-benzimidazole-4-ester (compound shown in formula II, R 1 =Cl) preparation

[0049] Mix trityl candesartan (212mg, 0.310mmol), 1,1-chlorobromoethane (437mg, 3.10mmol), potassium carbonate (100mg, 0.620mmol) and dry DMF (4ml), 20°C- The reaction is complete under the condition of 60° C. (specifically, 50° C. is selected to react for 24 hours). After cooling, pour into ice water (15ml), stir for half an hour, extract with ethyl acetate (10ml×3), wash the organic phase with water (10ml×2), wash with saturated brine (10ml), and dry over anhydrous sodium sulfate. Concentrate and recrystallize from acetone to give 1-chloroethyl-2-ethoxy-3-((2′-(1-trityl-1H-tetrazol-5-yl)biphenyl as a white solid Base-4-yl)methyl)-3H-benzimidazole-4-ester (compound shown in formula II, R 1 =Cl), yield 50%. MS (ESI) m / z: 745 (M+1).

Embodiment 3

[0050] Example 3: 1-chloroethyl-2-ethoxy-3-((2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methanol Base)-3H-benzimidazole-4-ester (compound shown in formula II, R 1 =Cl) preparation

[0051] The 1,1-chlorobromoethane in Example 2 was replaced by 1,1-dichloroethane (294mg, 3.10mmol) to obtain 1-chloroethyl-2-ethoxy-3-( (2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-3H-benzimidazole-4-ester (compound shown in formula II, R 1 =Cl), yield 35%.

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Abstract

A preparation method of candesartan cilexetil and intermediates thereof. A compound of formula I, wherein R1 is chloride, bromide, iodide, hydroxy, sulfonyl, mesyl, p-tosyloxy, methanesulfonyloxy, acetoxy, benzoyloxy, or dimethylmercapto group. A preparation method of candesartan cilexetil from the compound of formula I. The material used in the method is stable.

Description

technical field [0001] The invention relates to a preparation method of candesartan cilexetil and an intermediate thereof. Background technique [0002] Candesartan cilexetil is a good active ingredient of antihypertensive drugs. [0003] As a prodrug form, candesartan cilexetil is absorbed through the intestinal tract in vivo, and is completely hydrolyzed into the active metabolite of candesartan, which binds to the angiotensin II subtype I receptor (AT1) with high selectivity , produce antihypertensive effect. [0004] Candesartan cilexetil was developed by Takeda Corporation of Japan, and then Astra joined in the joint development. It was first launched in Sweden in December 1997 under the trade name Atacand. [0005] [0006] The preparation method of candesartan cilexetil can be found in EP459136; J.Med.Chem., 1993, 36(15), 2182-2195; J.Med.Chem., 1993, 36(16), 2343-2349; EP881212; CN1800179A CN1361101A; CN1425654A; CN1510031A; CN1666989A etc. [0007] In the met...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/10
CPCC07D403/10
Inventor 李海泓蒋翔锐赵庆杰杨池沈敬山
Owner TOPHARMAN SHANGHAI
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