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New crystal of sacubitril potassium salt, and preparing method and use thereof

A technology of sacubitril and potassium salt, which can be used in the preparation of organic compounds, the preparation of carboxylic acid amides, chemical instruments and methods, etc., and can solve problems such as undisclosed crystal physical and chemical data

Inactive Publication Date: 2016-11-23
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Patent CN1615134A discloses triethanolamine salt of triethanolamine salt and tri(hydroxymethyl)aminomethane salt of sacubitrix and its preparation method, but does not disclose specific physical and chemical data such as its crystal form

Method used

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  • New crystal of sacubitril potassium salt, and preparing method and use thereof
  • New crystal of sacubitril potassium salt, and preparing method and use thereof
  • New crystal of sacubitril potassium salt, and preparing method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1: Preparation of Shakubiqu Potassium Salt Form B

[0084] Dissolve 2.7 g (24.3 mmol) of potassium tert-butoxide in 20 ml of absolute ethanol, and dissolve 10.0 g (24.3 mmol) of sacubi in 100 ml of absolute ethanol. Under stirring, the above-mentioned ethanol solution of potassium tert-butoxide was added dropwise to the ethanol solution of sacubitril. Concentrate under reduced pressure at 40-45°C to a foamy solid. Dissolve the concentrate in 20 ml of isobutanol at 55-60°C, and cool to about 10°C. Filtrate, wash the filter cake with isobutanol, and dry under reduced pressure at 55-60°C to obtain crystalline form B of sacubitril potassium salt.

[0085] 1 H NMR (400MHz, CD 3 OD)δ:1.143-1.161(d,3H),1.206-1.241(t,3H),1.453-1.525(m,1H),1.885-1.966(m,1H),2.414(s,4H),2.564-2.608 (m,1H),2.740-2.817(m,2H),4.059-4.156(m,3H),7.286-7.336(m,3H),7.404-442(t,3H),7.534-7.564(d,2H) ,7.590-7.618(d,2H).

[0086] The measured powder X-ray diffraction pattern is shown in fig...

Embodiment 2

[0090] Example 2: Preparation of Shakubiqu Potassium Salt Form B

[0091] Dissolve 0.12 g (2.19 mmol) of potassium hydroxide in 2 ml of absolute ethanol, and dissolve 1.00 g (2.43 mmol) of sacubi in 10 ml of absolute ethanol. Under stirring, the above-mentioned ethanol solution of potassium hydroxide was added dropwise to the ethanol solution of Shakubiqu. Concentrate under reduced pressure at 40-45°C. Dissolve the concentrate in 5ml of isopropanol at 50-55°C, then add n-heptane dropwise, stop the dropwise addition when a precipitate precipitates and dissolves rapidly again (about 15ml of heptane is consumed), and cool to about -10 ℃. Filtrate, wash the filter cake with n-heptane, and dry under reduced pressure at 40-45°C to obtain the crystal form B of sacubitril potassium salt.

Embodiment 3

[0092] Example 3: Preparation of Shakubiqu Potassium Salt Form B

[0093] Dissolve 0.16 g (1.94 mmol) of potassium ethoxide in 2 ml of absolute ethanol, and 1.00 g (2.43 mmol) of sacubiqu in 10 ml of absolute ethanol. Under stirring, the above-mentioned ethanol solution of potassium ethoxide was added dropwise to the ethanol solution of Sacubitra. Concentrate under reduced pressure at 40-45°C. At 55-60°C, dissolve the concentrate in a mixed solvent composed of 4ml of isobutanol and 10ml of methyl tert-butyl ether, and cool to about 20°C. After filtering, the filter cake was washed with methyl tert-butyl ether to obtain the crystal form B of the potassium salt of Shakubiqu.

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PUM

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Abstract

The invention relates to a sacubitril potassium salt crystal form B. The crystal form has the advantages of small hygroscopicity, simple preparation method, easy control of the crystal form, and good stability, and is suitable for preparing various preparations; the invention also relates to the preparing method of the sacubitril potassium salt crystal form B, a pharmaceutical composition containing the sacubitril potassium salt crystal form B, and a use of the sacubitril potassium salt crystal form B in preparing drugs for prevention or treatment of chronic heart failure or hypertension.

Description

technical field [0001] The present invention relates to the fields of organic chemistry and pharmacy, in particular to a new crystal form B of sacubitril potassium salt and a preparation method thereof, a pharmaceutical composition comprising sacubitril potassium salt crystal form B, and sacubitril potassium salt Use of the potassium salt crystal form B in the preparation of drugs for preventing or treating chronic heart failure or hypertension. 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-ethoxyl-4-methyl-5-oxopent-2-yl]amino}-4-oxobutanoic acid is a kind of enkephalinase inhibitor, the structure is as shown in formula I: [0003] [0004] When sacubitril or its salt is administered in combination with angiotensin II AT1 receptor antagonists, such as valsartan, it can simultaneously inhibit neprilysin and angiotensin receptors, that is, it can simultaneously act ...

Claims

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Application Information

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IPC IPC(8): C07C233/47C07C231/12A61K31/216A61P9/04A61P9/12
Inventor 陈大峰赵永龙何永耀惠帅李方群曾琴罗杰向志祥
Owner SICHUAN HAISCO PHARMA CO LTD
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