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Sacubitril sodium salt, eutectic mixture of sacubitril free acid and acetic acid, crystal form of eutectic mixture, and preparation method and use of crystal form

A technology of sacubitril and co-crystal, applied in the field of pharmaceutical polymorphs, can solve problems such as unfavorable purification, storage, difficult purification, easy moisture absorption, etc., and achieves control of species and content, good thermal stability, and difficult moisture absorption. Effect

Active Publication Date: 2018-09-14
ZHEJIANG TIANYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Due to the influence of the long-chain alkyl group in its own molecular structure, the crude product of Shakubi Qu is a colorless viscous liquid in the large-scale production process, which makes it difficult to purify and control the quality of Shakubi Qu. Not conducive to purification, storage and subsequent LCZ696 formulation development
Moreover, after in-depth research by the inventor, it was found that the sodium salt formed by Shakubiqu and sodium hydroxide has high hygroscopicity and cannot form a stable crystal form, which is not conducive to quality control and storage.
In addition, although patents US5217996, WO2006086456, WO2007056546 and WO2007056546 all disclose that Shakubiqu can also be prepared into various salt-type compounds, such as alkali metal salts, alkaline earth metal salts, alkylamine salts, hydroxyalkylamine salts, etc., however, The preparation of LCZ696 from the obtained salt-type compound needs to be further dissociated, which will cause the residue of other cations or amines, and it is not suitable to control the content of other counter cations and residual organic amines of LCZ696
[0008] Therefore, it is necessary to develop a more stable aggregation state of the sodium salt of shakobiko, to overcome the difficult purification, hygroscopicity, difficulty in forming stable crystal forms, difficulty in quality control, and unfavorable storage of the sodium salt of kokobiko in the prior art. And defects that do not meet the development needs of LCZ696

Method used

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  • Sacubitril sodium salt, eutectic mixture of sacubitril free acid and acetic acid, crystal form of eutectic mixture, and preparation method and use of crystal form
  • Sacubitril sodium salt, eutectic mixture of sacubitril free acid and acetic acid, crystal form of eutectic mixture, and preparation method and use of crystal form
  • Sacubitril sodium salt, eutectic mixture of sacubitril free acid and acetic acid, crystal form of eutectic mixture, and preparation method and use of crystal form

Examples

Experimental program
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Effect test

example 1

[0058] Example 1: Preparation of cocrystal IV of sacubitril sodium salt, sacubitril free acid and acetic acid

[0059] Add 150mL of dichloromethane and 41.1g of sacubitril free acid oil into the reaction flask, stir to dissolve, then add 9.0g of anhydrous sodium acetate, heat up to 30-35°C and keep the reaction for 1 hour. After the heat preservation is completed, filter. Add 1500mL n-heptane to another reaction flask and cool down to 0-5°C. At this temperature, slowly add the dichloromethane solution obtained from the previous step into the n-heptane dropwise. °C for 1 hour. Filtration, vacuum extraction to obtain 38 g of eutectic IV, yield 83%, chromatographic purity 99.3%.

[0060] Three copies of the eutectic obtained in Example 1 were taken in parallel, and the moisture content of these eutectics was measured by a Karl Fischer moisture meter to be 0.15wt.% to 0.30wt.%, which was far from satisfying that at least one water content was contained in the eutectic. The mass ...

example 2

[0073] Example 2: Preparation of LCZ696 from Cocrystal IV

[0074] The eutectic IV (64g, 142mmol) prepared by the method described in Example 1 was dissolved in a mixed solvent of isopropyl acetate 60mL and acetone 1220mL, heated to 50-55°C and stirred to dissolve, then added valsartan (63g , 145mmol), then dropwise added 142g of aqueous sodium hydroxide solution (10%, 355mmol) at this temperature, then kept at 40~45°C for 2 hours, then cooled to room temperature (25~30°C) for 2 hours. After the heat preservation is completed, the temperature is raised to 40±3°C, 600mL of isopropyl acetate is added dropwise, and the temperature is kept at 40±3°C for 0.5 hours. At the end of the heat preservation, 760mL of solvent was removed under reduced pressure at a temperature of 35±5°C. After the removal is completed, the temperature is raised to 40±3°C, 920 mL of isopropyl acetate is added dropwise, and the temperature is controlled at 40±3°C for 0.5 hours. At the end of the heat prese...

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Abstract

The invention relates to sacubitril sodium salt shown in a formula (IV), a eutectic mixture of sacubitril free acid and acetic acid, a crystal form of the eutectic mixture, a preparation method of thecrystal form, and a method for preparing LCZ696 by using the eutectic mixture with the crystal form. The eutectic mixture provided by the invention can form the stable crystal form, and does not easily absorb moisture; the eutectic mixture is better in thermal stability, convenient for purification of sacubitril, convenient to store and beneficial to synthesis of LCZ696. Furthermore, the eutecticmixture provided by the invention can be directly used for preparing the LCZ696 without needing additional ion exchange, and helps to control the type and content of the counter cations.

Description

technical field [0001] The invention relates to the field of drug polymorphs, in particular to sacubitril sodium salt, a cocrystal of sacubitril free acid and acetic acid, its crystal form, a preparation method and application of the crystal form. Background technique [0002] LCZ696 is a new antihypertensive drug developed by Novartis, which contains Novartis' Diovan (generic name: valsartan) and experimental drug Sacubitril (AHU-377), etc. Two components, among which Sacubitril can block the mechanism of action of two polypeptides that threaten to lower blood pressure. The drug was approved by the US FDA on July 7, 2015 for heart failure with reduced ejection fraction. ) patients, reduce the risk of cardiovascular death and heart failure hospitalization. LCZ696 is usually obtained by co-crystallization of Diovan and Sacubitril in an equimolar ratio in a mixed solvent of excess sodium hydroxide aqueous solution and an organic solvent. The chemical composition of LCZ696 is ...

Claims

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Application Information

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IPC IPC(8): C07D257/04C07C231/24C07C233/47C07C53/08C07C51/43A61K31/216A61K31/41A61P9/12
CPCA61K31/216A61K31/41A61P9/12C07B2200/07C07B2200/13C07C53/08C07C233/47C07D257/04A61K2300/00
Inventor 屠勇军朱国荣谢文龙段正华王臻
Owner ZHEJIANG TIANYU PHARMA
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