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Method of synthesizing losartan and losartan intermediates

A technology of losartan and intermediates, which is applied in the field of preparation of drugs and intermediates, can solve the problems of difficult industrialization, difficult operation, and high cost, and achieve the effects of simple operation, safety assurance, and cost saving of raw materials

Inactive Publication Date: 2012-09-19
ZHEJIANG TIANYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The purpose of the present invention is to provide a method for preparing losartan in order to solve the disadvantages of high cost, difficult operation and difficulty in realizing industrialization of the method for preparing losartan and its intermediates in the prior art

Method used

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  • Method of synthesizing losartan and losartan intermediates
  • Method of synthesizing losartan and losartan intermediates
  • Method of synthesizing losartan and losartan intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1: preparation formula 1 compound losartan

[0044] Step a: Preparation of compound of formula 7: 2-butyl-4-chloro-5-formyl-1-[[2'-[2-(1-methyl-1-phenylethyl)tetrazole-5- Base] biphenyl-4-yl] methyl] imidazole

[0045] Add 17.4g (0.04mol) of the compound of formula 5 and 7.5g (0.04mol) of the compound of formula 6 into 135g of N,N-dimethylformamide, cool to 0-5°C, add 7.0g (0.05mol) of potassium carbonate, and React at 0-5°C for 8 hours, then raise the temperature to 30°C and react for 9-12 hours. The reaction solution was poured into 300g of ice-water mixture, a pale yellowish white solid was precipitated, filtered, the filter cake was dissolved in 300mL of dichloromethane, washed with 150mL×2 water, the organic layer was dried with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 26.0 g of oil was obtained, which was purified by silica gel column chromatography, eluting with ethyl acetate / n-hexane, and 19.8...

Embodiment 2

[0060] Embodiment 2: One-pot preparation formula 1 compound losartan:

[0061] 17.4g (0.04mol) formula 5 compound and 7.5g (0.04mol) formula 6 compound add 150mL toluene, 6.4g (0.08mol) 50% sodium hydroxide aqueous solution, 1.6g (0.002mol) tetrabutylammonium bromide, heating React at 90°C for 5 hours. The reaction solution was cooled to 0-5°C, 1.8g (0.048mol) of sodium borohydride was added, and the reaction was carried out at 0-5°C for 3 hours. Separate the layers, wash the organic layer with 150mL×2 water, cool to 0-5°C, add 5% hydrochloric acid dropwise to adjust the pH to 3, separate the water layer, add 90g 36% hydrochloric acid to the organic layer, and react at 30-35°C for 12 hours . Cool to 0-5°C, add 200mL of water dropwise, separate the layers, wash the organic layer with 150mL×2 water, cool to 0-5°C, a solid precipitates, stir for 1 hour, and filter to obtain 15.7g of a light yellow glass-like solid, which is washed by After recrystallization, 13.6 g of white ...

Embodiment 3

[0063] Embodiment 3: preparation formula 1 compound losartan:

[0064] Step a: Preparation of compound of formula 9: 2-butyl-4-chloro-5-formyl-1-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole

[0065] 21.6g (0.04mol) of the compound of formula 7 (from step a in Example 1), was added with 200mL of isopropanol and 90g of 36% hydrochloric acid, and reacted at 30-35°C for 12 hours. Cool to 0-5°C, add 200mL of purified water dropwise, then add dropwise 5% sodium hydroxide solution to adjust the pH to 3, add this mixture dropwise to 3000mL of 0.001mol / L hydrochloric acid, precipitate solids, filter to obtain shallow 19.1 g of yellow solid was recrystallized to obtain 15.4 g of white powdery solid with a yield of 91.7%. Mp 153-154°C.

[0066] 1 H-NMR (DMSO-d 6 , 500MHz) δ: 16.307 (brs, 1H, CN 4 H), 9.696(s, 1H, CHO), 7.678(t, J=7.0Hz, 2H, ArH), 7.579(t, J=7.5Hz, 1H, ArH), 7.524(d, J=7.5Hz, 1H , ArH), 7.133-7.046 (m, 4H, ArH), 5.604 (s, 2H, NCH 2 Ar), 2.641(t, J=7.5Hz, 2H, ...

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Abstract

The invention relates to a method for synthesizing losartan and losartan intermediates and belongs to the technical field of medicine and medicine intermediates. 5-(4'-bromomethyl biphenyl-2-radical)-2-(1- methyl-1- phenylethyl) tetrazole and 2-butyl-4-chlorine-5-formyl radical imidazole are subjected to condensation, reduction and decomposition protection processes, and the losartan is obtained. The method has the advantages that the synthesis process is suitable for industrial production, in addition, the economic value can be generated, the synthesis process is safe, the raw material cost is saved, subsequent products are easy to treat, the reaction raw materials are single, and the synthesis method is convenient.

Description

technical field [0001] The invention belongs to the technical field of preparation of medicines and intermediates thereof, and in particular relates to a method for synthesizing losartan and intermediates thereof. Background technique [0002] Losartan (1) is a non-peptide angiotensin II receptor antagonist with good antihypertensive effect. It is the first compound of its kind to be marketed as a potassium salt for pharmaceutical use. Most of the techniques in the past are to synthesize triphenylmethyl-protected losartan through zero-valent palladium catalytic coupling (eg US5130419); this process has no practical production value due to the high price of zero-valent palladium. [0003] [0004] Condensation of bromomethylbiphenyl (A) with 2-butyl-4-chloro-5-formylimidazole via triphenylmethyltetrazolium (eg EP253310). Then, through reduction, the triphenylmethyl protection is removed to obtain losartan (for example, CN1676523A, CN101328167A, CN101362750A). This proce...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/10
Inventor 屠勇军张毅徐贤光章波
Owner ZHEJIANG TIANYU PHARMA
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