Refining method for enkephalin enzyme inhibitor and angiotensin II receptor antagonist eutectic compound
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An angiotensin and receptor antagonist technology, applied in the field of medicine, can solve the problems of unstable quality of the final product LCZ696, and achieve the effects of high product yield, improved purity, and simple operation
Inactive Publication Date: 2016-06-08
BEIJING VOBAN PHARMA TECH CO LTD
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Problems solved by technology
[0007] After research, it was found that the existence of the above-mentioned hydrolyzed impurities will lead to the instability of the quality of the final product LCZ696
At present, there is no relevant literature report on how to purify and refine the crude LCZ696, thereby reducing the content of hydrolyzed impurities and other impurities, and improving the quality stability of LCZ696
Method used
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Embodiment 1
[0032] (1) Take a certain amount of LCZ696 crude product and add methanol, stir at 55°C until completely dissolved, then add toluene in batches; wherein, the weight ratio of LCZ696 crude product, methanol and toluene is 1:5:200;
[0033] (2) Put the solution obtained in step 1 into a clean crystallizer, cool down to 0°C, and after a small amount of crystals are precipitated, stir and crystallize at 45°C for 12 hours;
[0034] (3) Filtration, drying the solid obtained by filtration under reduced pressure at 35° C. to constant weight to obtain a purified product with a yield of 88.9%.
Embodiment 2
[0036] (1) Take a certain amount of LCZ696 crude product and add ethanol, stir at 40°C until completely dissolved, then add n-heptane in batches; wherein, the weight ratio of LCZ696 crude product, ethanol and n-heptane is 1:5:200;
[0037] (2) Put the solution obtained in step 1 into a clean crystallizer, cool down to -10°C, and after a small amount of crystals are precipitated, stir and crystallize at 33°C for 12 hours;
[0038] (3) The solid obtained by filtration was dried under reduced pressure at 35° C. to constant weight to obtain a purified product with a yield of 90.5%.
Embodiment 3
[0040] (1) Take a certain amount of LCZ696 crude product and add n-propanol, stir at -10°C until completely dissolved, then add isopropyl acetate; among them, the weight ratio of LCZ696 crude product, n-propanol and isopropyl acetate is 1:5:300 ;
[0041] (2) Put the solution obtained in step 1 into a clean crystallizer, add seed crystals, and after a small amount of crystals are precipitated, stir and crystallize at 25°C for 12 hours;
[0042] (3) centrifugation, drying the solid obtained by centrifugation under reduced pressure at 35° C. to constant weight to obtain a purified product with a yield of 93.1%.
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Abstract
The invention provides a refining method for an enkephalin enzyme inhibitor and angiotensin II receptor antagonist eutectic compound. The refining method comprises the following steps that firstly, under the condition of minus 10-80 DEG C, an LCZ696 crude product is put into a good solvent and stirred to complete dissolution, wherein LCZ696 is the enkephalin enzyme inhibitor and angiotensin II receptor antagonist eutectic compound; secondly, the solution obtained in the first step is added with a poor solvent, crystallization and filtering are carried out, and a solid is obtained; thirdly, the solid obtained in the second step is dried to the constant weight, and an LCZ696 product is obtained. The refining method has the advantages that enkephalin enzyme inhibitor hydrolysis impurities and other impurities in the LCZ696 crude product can be effectively removed, the purity of the LCZ696 product can be improved, and thus the quality stability of LCZ696 can be ensured; in addition, the refining method is high in product yield and easy to implement.
Description
technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for refining a cocrystal compound of a neprilysin inhibitor and an angiotensin II receptor antagonist. Background technique [0002] Entresto is a new type of antihypertensive drug developed by the Swiss pharmaceutical giant Novartis. It was launched in the United States in July 2015 and was approved by the European Union in November 2015. The drug combines Novartis' Diovan (generic name) : valsartan) and the experimental drug Sacubitril. Among them, valsartan can improve vasodilation and stimulate the body to excrete sodium and water; while Sacubitril can block the mechanism of action of two peptides that threaten to lower blood pressure. Entresto, a dual-acting angiotensin receptor-neprilysin inhibitor with a unique mode of action that enhances the heart's protective neuroendocrine system while inhibiting harmful systems, is thought to reduce strain on the...
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