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Preparation of losartan

A solvent and formyl technology, applied in the field of medicinal chemistry, can solve the problems of cumbersome operation, low yield, and many steps, and achieve the effects of high product quality, easy product, and simple operation

Active Publication Date: 2008-12-24
CHINA RESOURCES SAIKE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The above method is cumbersome to operate, with many steps, low yield and poor purity

Method used

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  • Preparation of losartan
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: 2-butyl-4-chloro-5-formyl-1-[[(2'-(1-trityl-tetrazol-5-yl)-biphenyl-4-)methyl ] the synthesis of imidazole (structural formula IV)

[0029] In a 1L three-necked flask, add 33.5g (0.179mol) 2-butyl-4-chloro-5-hydroxymethylimidazole, 100g (0.179mol) 5-(4-bromomethylbiphenyl-2-yl)- 1-trityl-1H-tetrazole, 300ml DMF, 47g (0.340mol) of potassium carbonate as a base, the reaction was carried out at room temperature for 24 hours, the reaction was completed, the reaction solution was poured into 600ml of water, and a white solid was obtained by suction filtration. Wash with 100ml of water to obtain 2-butyl-4-chloro-5-formyl-1-[[(2'-(1-trityl-tetrazol-5-yl)-biphenyl-4-)methyl Base] imidazole crude product, the crude product does not need to be treated, and the next step reaction is carried out directly, and the yield is 89%.

[0030] 1 HNMR ((CDCl3): 0.85(t, 3H), 1.23-1.32(sextet, 2H), 1.60-1.68(m, 2H), 2.50(t, 2H), 5.45(s, 2H), 6.83(d, 2H ), 6.91-6.93(m, 6H), 7.10...

Embodiment 2

[0031] Example 2: 2-butyl-4-chloro-5-formyl-1-[[(2'-(1-H-tetrazol-5-yl)-biphenyl-4-)methyl]imidazole ( Synthesis of structural formula III)

[0032] 82g (0.123mol) 2-butyl-4-chloro-5-formyl-1-[2'-(1-trityl-tetrazolyl-5-)biphenyl-4-]methyl Imidazole, methanol 420ml, stirred, then added 3.4N HCl40ml (0.136mol) in 10min, stirred overnight at room temperature, added 10N NaOH, adjusted to pH = 13, evaporated ethanol (420mL), added 206mL deionized water. The aqueous layer was washed twice with 2×100ml of toluene, and the separated aqueous layer was slowly dripped with 3.4N hydrochloric acid to pH=3.0, added with 200ml of dichloromethane and stirred for 1 hour, left to stand for liquid separation, and the organic layer was dried with magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the crude product, which was separated by column chromatography, using ethyl acetate:petroleum ether (volume ratio) 3:1 as eluent, to obtain 2-butyl-4-chloro-5-formyl- Pure ...

Embodiment 3

[0034] Example 3: 2-butyl-4-chloro-5-formyl-1-[[(2'-(1-H-tetrazol-5-yl)-biphenyl-4-)methyl]imidazole ( Synthesis of structural formula III)

[0035] Other conditions remain unchanged, the solvent is changed from methanol to tetrahydrofuran, and the yield is 35%

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Abstract

The invention relates to a method for preparing losartan. The method comprises the following steps of: removing a protective group of triphenylmethyl from 2-butyl-4-chloro-5-formyl-l-[(2'-(1-triphenylmethyl-tetrazole-5-yl)-biphenyl-4-)methyl] imidazole in the presence of a strong acid to give an intermediate of 2-butyl-4-chloro-5-formyl-1-[(2'-(1-H-tetrazole-5-)-biphenyl-4-)methyl] imidazole; producing 2-butyl-4-chloro-5-(hydroxymethyl)-1[(2'-(1-H-tetrazole-5-yl)-biphenyl-4-) methyl] imidazole in the presence of a reducer.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a new preparation method of losartan, an important intermediate of losartan potassium. Background technique [0002] Losartan potassium (losatan), the chemical name is 2-butyl-4-chloro-5-(hydroxymethyl)-1-[[(2'-(1-H-tetrazol-5-yl)-linked Benzene-4-)methyl]imidazole. Its structure is shown in Structural Formula II. Losartan Potassium is the first sartan antihypertensive drug, which controls blood pressure by selectively inhibiting AT receptors and blocking RAS. It is the first non-peptide vascular drug on the market. As a tensin II receptor antagonist, pharmacological and clinical tests have shown that losartan potassium has the advantages of wide range of effects, significant antihypertensive effect, convenient administration, and little impact on renal function. At present, there are many studies on the preparation process of losartan potassium and its intermediate losartan, bu...

Claims

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Application Information

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IPC IPC(8): C07D403/10A61P9/12
CPCY02P20/55
Inventor 闫启强谢苏豪祁伟
Owner CHINA RESOURCES SAIKE PHARMA
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