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Method for reducing bipolymer impurities in losartan

A technology for losartan dimer and losartan condensate, which is applied in the field of medicine and chemical industry, can solve the problems of lack of competitiveness and large loss, and achieves the effects of low cost, simple operation and high product conversion rate

Active Publication Date: 2018-05-18
ZHEJIANG HUAHAI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is reported in the literature that the dimer impurities are all removed by refining, and the heavy refining requires a lot of manpower and material resources, and the loss is large, so it is not competitive

Method used

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  • Method for reducing bipolymer impurities in losartan
  • Method for reducing bipolymer impurities in losartan
  • Method for reducing bipolymer impurities in losartan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Add 30g of losartan condensate into the three-neck flask, add 100ml of tetrahydrofuran; control the temperature at 10-20°C, use 4mol / L hydrochloric acid to adjust the pH of the system to 2, keep it warm at 28°C, stir for 12 hours, cool down to 10°C, and use Adjust the pH of the NaOH solution to 12-13, control the temperature at 30-50°C, distill THF to dryness under reduced pressure, add 100mL of water, filter, control the temperature of the filtrate at 10-20°C, adjust the acid to pH 4 with 4mol / L hydrochloric acid, Stir and crystallize at room temperature for 3 hours, filter with suction, and dry to obtain losartan with a yield of 96% and dimer impurities of 0.2%.

Embodiment 2

[0023] Add 30g of losartan condensate into the three-necked flask, add 100ml of tetrahydrofuran; control the temperature at 10-20°C, use 4mol / L hydrochloric acid to adjust the pH of the system to 2, keep warm at 25°C, stir for 12 hours, cool down to 10°C, and use Adjust the pH of the NaOH solution to 12-13, control the temperature at 30-50°C, distill THF to dryness under reduced pressure, add 100mL of water, filter, control the temperature of the filtrate at 10-20°C, adjust the acid to pH 4 with 4mol / L hydrochloric acid, Stir and crystallize at room temperature for 3 hours, filter with suction, and dry to obtain losartan with a yield of 96% and dimer impurities of 0.15%.

Embodiment 3

[0025] Add 30g of losartan condensate into the three-neck flask, add 100ml of tetrahydrofuran; control the temperature at 10-20°C, use 4mol / L hydrochloric acid to adjust the pH of the system to 2, keep warm at 20°C, stir for 12 hours, cool down to 10°C, and use Adjust the pH of the NaOH solution to 12-13, control the temperature at 30-50°C, distill THF to dryness under reduced pressure, add 100mL of water, filter, control the temperature of the filtrate at 10-20°C, adjust the acid to pH 4 with 4mol / L hydrochloric acid, Stir and crystallize at room temperature for 3 hours, filter with suction, and dry to obtain losartan with a yield of 95% and a dimer impurity of 0.1%.

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Abstract

The invention discloses a method for reducing bipolymer impurities in losartan. The method comprises the following steps: firstly, adding losartan condensate into an organic solvent, adding acid, adjusting the pH value to be 1 to 5, and carrying out stirring reaction for 8 to 20 DEG C at a temperature controlled to be 10 to 40 DEG C; secondly, cooling down a system, adding alkali to adjust the pHto be alkaline, completely evaporating an organic layer, adding water, filtering, adjusting the acidity of filtrate, and performing crystallization, so as to obtain losartan. The content of the bipolymer impurities in the formed losartan is smaller than 0.2 percent and even smaller than 0.1 percent, the method is low in cost, the yield is high, and the method is extremely simple to operate, environmentally friendly and suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a method for controlling dimer impurities in the synthesis process of losartan. technical background [0002] Losartan Potassium (Losartan Potassium) is an orally effective specific angiotensin II (AT1) receptor antagonist for the treatment of hypertension. Losartan is its free state or the intermediate of the previous step, its chemical name is {2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl -1H-imidazol-5yl}methanol. It reacts with potassium hydroxide and other potassium-containing salts or alkalis to obtain losartan potassium. [0003] Losartan is affected by the reaction conditions during the synthesis process, especially under acidic conditions, it is easy to produce dimer impurities in the reaction process and solution state, and it is difficult to obtain high-purity losartan potassium through one-time refining, and chlorine The main remaining...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/10
CPCC07D403/10
Inventor 郑扬程龙董鹏揭为成
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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