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LCZ696 novel crystal form and preparation method thereof

A crystal form and map technology, applied in organic chemistry, carboxylic acid amide separation/purification, etc., can solve the problems of reducing industrial production value and high cost of deuterated hydrate, and achieve the effect of reducing product quality fluctuation and good thermal stability

Inactive Publication Date: 2019-06-21
陈文辉
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The shortcoming of this technology (1) there is the problem of document 1; (2) the cost of preparing deuterated hydrate is relatively high, reduces the value in industrialized production

Method used

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  • LCZ696 novel crystal form and preparation method thereof
  • LCZ696 novel crystal form and preparation method thereof
  • LCZ696 novel crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Add AHU-377 (5.0g) and valsartan (5.29g) into a three-necked flask, add acetone (100g), isopropanol (10.0g) and stir to dissolve, then add 40% sodium hydroxide dropwise at 20-30°C Aqueous solution (1.46g of sodium hydroxide dissolved in 2.19g of purified water), after the dropwise addition, the temperature was raised to 45-50°C, stirred for 30-60 minutes, cooled to 0-10°C, and stirred for 2-3 hours. After filtering, the filter cake was rinsed twice with acetone (6.0 g). The filter cake was dried (45-50° C.) for 12 hours to obtain 8.5 g of LCZ-696 bisesquihydrate, with a yield of 75.1%.

[0055] Test data:

[0056]

Embodiment 2

[0058] Add AHU-377 (20.0g) and valsartan (21.16g) into a three-necked flask, add acetone (240g) and isopropanol (30g), stir to dissolve, add 45% sodium hydroxide dropwise at 20-30°C Aqueous solution (5.84g sodium hydroxide dissolved in 7.14g purified water), after dropwise addition, warm up to 40-45°C, stir for 30-60 minutes, gradually cool down to 35-40°C, stir and crystallize for 3-8 hours, cool down to 0 ~10°C, stirring for 2-5 hours. After filtering, the filter cake was rinsed twice with acetone (24.0 g). The filter cake was vacuum-dried (45-50° C.) for 15 hours to obtain 37.0 g of LCZ-696 monohydrate, with a yield of 81.8%.

[0059] Test data:

[0060]

Embodiment 3

[0062] Add AHU-377 (50g) and valsartan (52.9g) into a three-necked flask, add acetone (1250g), stir and dissolve isopropanol (100g), and add dropwise a 50% aqueous solution of sodium hydroxide ( 14.6g of sodium hydroxide dissolved in 14.6g of purified water), the dropwise addition is completed, the temperature is raised to 45-50°C, stirred for 30-60 minutes, the temperature is gradually lowered to 35-40°C, stirred and crystallized for 3-8 hours, and the temperature is lowered to 0~ 10°C, stirring for 2-4 hours. After filtering, the filter cake was rinsed twice with acetone (60g). The filter cake was vacuum-dried (45-50° C.) for 20 hours to obtain 90.0 g of LCZ-696 monohydrate with a yield of 79.6%.

[0063] Test data:

[0064]

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Abstract

The invention relates to an LCZ696 novel crystal form and a preparation method thereof. The preparation method of the novel crystal form comprises the following steps: dissolving Valsartan and AHU-377in acetone and isopropanol, adding into an alkaline compound aqueous solution at a temperature of 20-40 DEG C, raising the temperature to 30-50 DEG C, stirring to crystallize for 1-10 hours and reducing the temperature to 20-30 DEG C; performing suction filtration and vacuum-drying to obtain a monohydrate.

Description

[0001] Technical field: [0002] The invention relates to a new crystal form of medicine, in particular to a new crystal form of cardiovascular drug LCZ696 and a preparation method thereof. Background technique [0003] Sacubitril / Valsartan Sodium Tablets (trade name: Entresto, commodity code: LCZ696)), is a drug for adults with chronic heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure medicine. LCZ696, consisting of sacubitril-valsartan sodium at a 1:1 molar ratio, is an orally bioavailable, dual-acting ARNi for the treatment of hypertension and heart failure. Chinese patent CN 200680001733.0 discloses LCZ696, which is trisodium 2.5 hydrate composed of valsartan and NEP inhibitor prodrug AHU-377 (sacubitril) according to the molar ratio (1:1), and its structural formula is as follows: [0004] [0005] The disadvantage of this structure is that in the subsequent preparation and storage process, d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/04C07C233/47C07C231/24
Inventor 陈文辉
Owner 陈文辉