Preparation method of losartan

A technology of losartan and nitrile group, applied in the field of preparation of losartan, can solve the problems of inability to completely eliminate the risk of impurity contamination, high loss of losartan, entry of losartan and the like

Pending Publication Date: 2021-04-20
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But in the process of water extraction, some losartan will enter the water layer, and the loss of losartan is more
[0008] It can be seen that in the existing losartan production process, it is necessary to carry out the process of quenching azide in the feed liquid containing the losartan product, but the risk of impurity contamination cannot be completely eliminated under mild production conditions to obtain high yields. losartan

Method used

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  • Preparation method of losartan
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  • Preparation method of losartan

Examples

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example 1

[0034] In the three-necked flask, add 30g of the nitrile intermediate, 9.8g of sodium azide, 12g of triethylamine hydrochloride, and 120ml of toluene, and control the temperature at 100-103°C to react. After the reaction, add 300ml of 20% sodium bicarbonate aqueous solution , control the temperature at 75°C, stir and wash for 1 hour, remove the lower water layer after washing; add 300ml of 20% sodium bicarbonate aqueous solution, stir and wash at 75°C for 1 hour, separate the intermediate material layer after washing, and azide The ion residue is about 80ppm. Add 150ml of drinking water to the separated intermediate material layer, stir at room temperature, slowly add dilute hydrochloric acid dropwise, adjust the pH to 4-5, crystallize, filter with suction, and dry to obtain 29.9g of losartan, yield 89.6%, purity: 98.8 %, azide: not detected (detection limit: 1 ppm); NDMA: not detected (detection limit: 0.03 ppm); NDEA: not detected (detection limit: 0.02 ppm).

example 2

[0036] In the there-necked flask, add 30g of nitrile-based intermediate, 9.8g of sodium azide, 12g of triethylamine hydrochloride, and 120ml of toluene, and control the temperature to react at 100-103°C. After the reaction, add 300ml of 18% sodium carbonate aqueous solution to control The temperature was 75°C, stirred and washed for 1 hour. After the washing, the lower water layer was removed, and 300ml of 18% sodium carbonate aqueous solution was added for washing, and the washing was performed three times. After washing, the intermediate material layer was separated, and the residual azide ion was about 50ppm. Add 150ml of drinking water to the separated intermediate material layer, stir at room temperature, slowly add dilute hydrochloric acid dropwise, adjust the pH to 4-5, crystallize, filter with suction, and dry to obtain 29.6g of losartan, with a yield of 88.7%, and a purity of: 98.8%, azide: not detected (detection limit: 1 ppm); NDMA: not detected (detection limit: 0.0...

example 3

[0038] In the there-necked flask, add 30g of nitrile-based intermediate, 9.8g of sodium azide, 12g of triethylamine hydrochloride, and 120ml of toluene, and control the temperature to react at 100-103°C. After the reaction, add 500ml of 20% potassium carbonate aqueous solution to control The temperature was 75°C, stirred and washed for 1.5 hours. After washing, the lower water layer was removed, and 500ml of 20% potassium carbonate aqueous solution was added to wash for three times. After washing, the intermediate material layer was separated, and the residual azide ion was about 20ppm. Add 120ml of drinking water to the separated intermediate material layer, stir at room temperature, slowly add dilute hydrochloric acid dropwise, adjust the pH to 4-5, crystallize, filter with suction, and dry to obtain 29.5g of losartan, yield 88.4%, purity: 98.8 %, azide (detection limit: 1 ppm): not detected; NDMA: not detected (detection limit: 0.03 ppm); NDEA: not detected (detection limit:...

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Abstract

The invention provides a preparation method of losartan, wherein the preparation method comprises the steps: reacting a nitrile intermediate shown in the specification with an azide reagent in a solvent, adding an inorganic alkali aqueous solution selected from carbonate or bicarbonate, washing, and separating out an intermediate material layer; and further separating the intermediate material layer to obtain losartan. The azide ions after the reaction can be basically and completely removed by using the conventional inorganic alkali solution, the removal effect is good, the preparation process is simple and convenient, the operation conditions are mild and easy to control, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of losartan, which belongs to the field of medicine and chemical industry. Background technique [0002] Losartan is a drug for the treatment of hypertension developed by DuPont-Merck in the United States. It is a non-peptide angiotensin II (AT II ) type 1 receptor antagonist, its chemical name is 2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4 -yl] methyl] -1H-imidazole-5-methanol, the structure is as follows: [0003] [0004] In the prior art, losartan is prepared by reacting a nitrile-containing intermediate with an azide reagent in a toluene system. After the reaction, there are still some azide reagents remaining in the system, which needs to be quenched to prevent the production of azide. Conventional quenching The killing reagent is sodium nitrite, but the introduction of sodium nitrite will produce nitrosamine impurities. Described nitrile-containing intermediate structural formul...

Claims

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Application Information

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IPC IPC(8): C07D403/10
Inventor 柳靖郑扬杨贤周盼盼梁尊俊
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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