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Preparation method of losartan

A technology of losartan and cyano group, applied in the field of preparation of losartan, can solve the problems of inability to eliminate the risk of impurity contamination, violent reaction of the quenching system, difficult control of the quenching process, etc., so as to eliminate the genotoxic impurity nitrosamines. The effect of forming, less reagent dosage, suitable for large-scale industrial production

Active Publication Date: 2019-11-19
ZHEJIANG TIANYU PHARMA +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Chinese patent CN 109748905A discloses an improved method for quenching azide, which needs to be quenched with hydrogen peroxide in the water layer containing losartan. The quenching system reacts violently and produces a large number of bubbles. It is not easy to control, and there may be potential safety hazards such as blasting and explosion during enlarged production. In addition, hydrogen peroxide may also oxidize the hydroxyl functional group in the structure of losartan in the quenching system, resulting in oxidized impurities of losartan
[0006] It can be seen that in the existing losartan production process, the process of quenching azide is required in the feed liquid containing the losartan product, and the risk of impurity contamination cannot be completely eliminated under mild production conditions

Method used

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preparation example Construction

[0052] Preparation of Preparation Example Compound 4

[0053]Put 365g of toluene into the reaction flask, add 56g of compound 1, 33.6g of sodium carbonate and 5.6g of tetraethylammonium bromide under slow stirring, speed up the stirring and raise the temperature to 90-95°C. Control the temperature at 90-95°C, add 39.2g of compound 2 in 142g toluene solution dropwise, control the dropping time for 3-4h, keep warm for 4-5h after the dropwise addition is completed, add 140g of water after the reaction is completed, separate layers, and the toluene layer Add 1g of tetraethylammonium bromide, control the temperature at 20-25°C, add dropwise the pre-prepared mixed solution of sodium borohydride and sodium hydroxide (9g sodium borohydride, 5.6g sodium hydroxide, 24.5g water), dropwise Complete the heat preservation reaction at 20-25°C for 4 hours, then raise the temperature to 80-85°C heat preservation reaction, add 105g water after the reaction, control the temperature at 80-85°C he...

Embodiment 1

[0054] The preparation of embodiment 1 losartan

[0055] Put 40g of toluene into the four-necked bottle, add 20g of compound 4, 10.3g of sodium azide and 18g of triethylamine hydrochloride under slow stirring, after feeding is completed, heat up to 90-95°C, keep the temperature for 35-45 hours, and react After completion, add 40g of water, lower the temperature to 60-70°C, let stand for stratification, separate the middle layer material liquid, add 40ml of n-butanol to dissolve, wash twice with 20g of saturated sodium chloride aqueous solution, add 0.4g of triphenylphosphine and 0.8g of activated carbon, stirred and heated to 50-60°C for decolorization for 2 hours. Filtrate hot, rinse the filter cake with 10ml n-butanol, combine the filtrates, control the temperature at 50-80°C, vacuum dehydration above the vacuum degree of 0.08MPa, add 7.7g liquid caustic soda (concentrated hydrogen with a mass concentration of about 50%) Sodium oxide solution) and 160g water, stir to dissol...

Embodiment 2

[0056] The preparation of embodiment 2 losartan

[0057] Put 40g of toluene into the four-necked bottle, add 20g of compound 4, 10.3g of sodium azide and 18g of triethylamine hydrochloride under slow stirring, after feeding is completed, heat up to 90-95°C, keep the temperature for 35-45 hours, and react After completion, add 40g of water, lower the temperature to 60-70°C, let stand for stratification, separate the middle layer material liquid, add 40ml of n-butanol to dissolve, wash twice with 20g of saturated sodium chloride aqueous solution, add 1.0g of triphenylphosphine and 0.8g of activated carbon, stirred and heated to 50-60°C for decolorization for 2 hours. Filtrate hot, rinse the filter cake with 10ml n-butanol, combine the filtrates, control the temperature at 50-80°C, vacuum dehydration above the vacuum degree of 0.08MPa, add 7.7g liquid caustic soda (concentrated hydrogen with a mass concentration of about 50%) Sodium oxide solution) and 160g water, stir to dissol...

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Abstract

The invention provides a preparation method of losartan. The losartan is prepared by reacting a cyano-containing intermediate as shown in a formula (I), which is described in the specification, with an azide reagent in toluene in the presence of a catalyst. After the reaction is finished, azide ions are removed through the following procedures: adding water to divide a reaction system into three layers, separating out a middle layer, adding n-butyl alcohol into the middle layer for dilution, and adding triphenylphosphine into the obtained diluted solution to remove the residual azide ions in the diluted solution. According to the preparation method, sodium nitrite is not needed, so formation of the genotoxic impurity nitrosamine is fundamentally eradicated; the obtained target losartan isgood in purity and high in yield; and the method is simple and convenient in preparation process, mild and easily controllable in operation conditions, good in safety, and suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the field of preparation of pharmaceutical intermediates, in particular to a preparation method of losartan. Background technique [0002] Losartan potassium (Losartan Potassium) is a commonly used angiotensin II receptor 1 antagonist (ARB) antihypertensive drug, and its chemical name is 5-(4'-((2-butyl-4-chloro-5 -(Hydroxymethyl)-1H-imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-yl)tetrazolium potassium salt, CAS: 124750-99-8, the chemical structure is as follows : [0003] [0004] Losartan is an important intermediate for the synthesis of losartan potassium. In the existing synthetic technology, losartan synthetic method such as figure 1 shown. In the synthetic method of losartan disclosed by patents such as IN1524 / MUM / 2011A, dimethylformamide (DMF) is used as a solvent to synthesize cyanobiphenyl intermediate 3, and then the corresponding cyanobiphenyl intermediate Body 3 (containing DMF residues) and sodium azide (NaN 3 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/10
CPCC07D403/10
Inventor 何祖伟刘刚苏德泉吕瑞云肖伟王臻朱国荣屠勇军
Owner ZHEJIANG TIANYU PHARMA
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