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Sacubitril sodium crystal forms, preparation method and application thereof

A technology of sacubitril sodium and sacubitril, which is applied in the preparation of organic compounds, the preparation of carboxylic acid amides, chemical instruments and methods, etc., can solve problems such as unfavorable medication adjustment, fixed composition ratio and the like

Inactive Publication Date: 2016-08-10
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the physical properties of the LCZ-696 co-crystal have been improved, the combination of sacubitril sodium with different ratios of valsartan or other AT1 receptor antagonists is limited due to the fixed composition ratio, which is not conducive to clinical application. Medication adjustments according to different situations

Method used

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  • Sacubitril sodium crystal forms, preparation method and application thereof
  • Sacubitril sodium crystal forms, preparation method and application thereof
  • Sacubitril sodium crystal forms, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0214] Example 1: Preparation of Sacubitrone Sodium Form A

[0215] Dissolve 0.09g (2.19mmol) of sodium hydroxide in 2ml of absolute ethanol at 40-45°C; dissolve 1.00g (2.43mmol) of sacubiqu in 10ml of absolute ethanol at room temperature. Under stirring, the ethanol solution of the above-mentioned sodium hydroxide was added dropwise to the absolute ethanol solution of Sacubitril to obtain a clear solution. At 55-60°C, add methyl tert-butyl ether dropwise until solid precipitates, then cool. Filtrate, wash the filter cake with methyl tert-butyl ether, and dry under reduced pressure at 105-110°C to obtain crystalline form A of sacubitronic sodium.

[0216] Moisture content: 0.64%.

[0217] 1 H NMR (400MHz, CD 3 OD)δ:1.143-1.161(d,3H),1.208-1.242(t,3H),1.453-1.525(m,1H),1.886-1.966(m,1H),2.394-2.441(m,4H),2.554 -2.608(m,1H),2.758-2.801(m,2H),4.042-4.156(m,3H),7.286-7.335(m,3H),7.403-7.441(m,2H),7.538-7.818(m, 4H).

[0218] The measured powder X-ray diffraction pattern is ...

Embodiment 2

[0221] Example 2: Preparation of Sacubitrone Sodium Form A

[0222] Dissolve 0.09g (2.19mmol) of sodium hydroxide in 2ml of absolute ethanol at 40-45°C; dissolve 1.00g (2.43mmol) of sacubiqu in 10ml of absolute ethanol at room temperature. Under stirring, the ethanol solution of the above-mentioned sodium hydroxide was added dropwise to the absolute ethanol solution of Sacubitril to obtain a clear solution. At 55-60°C, add methyl tert-butyl ether dropwise until solid precipitates, then cool. After filtering, the filter cake was washed with methyl tert-butyl ether, and dried under reduced pressure at 20-30°C to obtain crystalline form A of sacubitronic sodium.

[0223] Moisture content: 3.2%.

Embodiment 3

[0224] Example 3: Preparation of Sacubitrone Sodium Form B

[0225] Dissolve 0.09g (2.19mmol) of sodium hydroxide in 2ml of absolute ethanol at 40-45°C; dissolve 1.00g (2.43mmol) of sacubiqu in 10ml of absolute ethanol at room temperature. Under stirring, the ethanol solution of the above-mentioned sodium hydroxide was added dropwise to the absolute ethanol solution of Sacubitril to obtain a clear solution. Concentrate under reduced pressure at 40-45°C to an oil. Dissolve the concentrated oil in 10ml of ethyl acetate at 55-60°C, then add 5ml of petroleum ether (60-90°C) dropwise, and cool. After filtering, the filter cake was washed with petroleum ether (60-90°C), and dried under reduced pressure at 105-110°C to obtain crystalline form B of sacubitronic sodium.

[0226] The moisture content is 0.39%.

[0227] 1 H NMR (400MHz, CD 3 OD)δ:1.144-1.181(d,3H),1.206-1.241(t,3H),1.464-1.526(m,1H),1.886-1.966(m,1H),2.395-2.442(m,4H),2.554 -2.615(m,1H),2.758-2.801(m,2H),4.059-4.15...

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PUM

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Abstract

The invention relates to sacubitril sodium being lower than 15% in water content, and a crystal form A, a crystal form B, a crystal form C, a crystal form D and amorphous form [alpha] of the sacubitril sodium. These crystal forms are easy to prepare, have good stability and solubility and are suitable for various preparations. The invention also relates to a preparation of the sacubitril sodium crystal forms, a medicine composition comprising the same and a preparation method thereof, and applications of the sacubitril sodium crystal forms in preparation of medicines for preventing and / or treating cardiac failure and hypertension.

Description

technical field [0001] The present invention relates to the fields of organic chemistry and pharmacy, in particular to crystalline forms of sacubitrone sodium and a preparation method thereof, pharmaceutical compositions containing these crystalline forms, and the preparation of these crystalline forms for preventing or treating heart failure or hypertension Uses in medicine. Background technique [0002] Sacubitril, English common name: sacubitril, also known as: AHU-377, chemical name: 4-{[(2S,4R)-1-([1,1'-biphenyl]-4-yl)- 5-ethoxy-4-methyl-5-oxopent-2-yl]amino}-4-oxobutanoic acid, the structure of which is shown in formula I, is a kind of neprilysin inhibitor. [0003] [0004] When sacubitril and its salts are administered in combination with angiotensin II AT1 receptor antagonists, such as valsartan, etc., they can simultaneously inhibit neprilysin and angiotensin receptors, that is, they can simultaneously act on The renin-angiotensin system and promotes the circu...

Claims

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Application Information

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IPC IPC(8): C07C233/47C07C231/24C07C231/12A61K31/216A61P9/04A61P9/12
Inventor 陈大峰惠帅赵永龙何永耀曾琴李方群罗杰向志祥
Owner SICHUAN HAISCO PHARMA CO LTD
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