Preparation method of sacubitril calcium salt

A technology of sacubitril calcium and calcium chloride, which is applied in the field of preparation of sacubitril calcium salt, can solve the problems of low conversion rate and many impurities, and achieves easy availability of raw materials, high purity and high yield Effect

Pending Publication Date: 2021-07-20
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Aiming at the problems of low conversion rate and many impurities in the current preparation process of sacubitril, the present invention aims to provide a compound with simple operation, mild reaction conditions, high product yield, high purity and less pollution. Technical method suitable for industrial production of sacubitril calcium salt

Method used

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  • Preparation method of sacubitril calcium salt
  • Preparation method of sacubitril calcium salt
  • Preparation method of sacubitril calcium salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] The preparation of embodiment 1 compound III

[0051] Add compound II (100g), sodium bicarbonate (25.2g, 1.5eq), sodium bromide (37.04g, 1.8eq), TEMPO (0.94g, 0.03eq) into the reaction flask, add isoacetic acid to the reaction flask Propyl ester (2L, 20v / m), lower the temperature to 0-10°C, add sodium hypochlorite solution (99.25g, available chlorine 15%, 1eq) dropwise under stirring, continue stirring for 1h, TLC [developer: petroleum ether : Ethyl acetate=2:1] detect the end of the reaction, add 2L of 9% sodium thiosulfate solution to the reaction solution, continue to stir the reaction for 1h, and let stand to separate layers. The organic layer was transferred to a reaction flask, the temperature was adjusted to 20° C., tert-butoxyformyl ethylene triphenylphosphine (85.84 g, 1.1 eq) was added, and the reaction was stirred for 1 h. The reaction solution was evaporated to dryness under reduced pressure, dissolved in isopropyl acetate (300ml, 3v / m), and n-heptane (600m...

Embodiment 2

[0052] The preparation of embodiment 2 compound III

[0053] Compound II (100g), sodium bicarbonate (25.2g, 1.5eq), sodium bromide (37.04g, 1.8eq), TEMPO (0.94g, 0.03eq) were added to the reaction flask, and ethyl acetate was added to the reaction flask Ester (1.5L, 15v / m), lower the temperature to 0-10°C, add sodium hypochlorite solution (99.25g, available chlorine 10%) dropwise under stirring, continue stirring for 1h, TLC [developer: petroleum ether: acetic acid Ethyl ester = 2:1] to detect the end of the reaction, add 1.5 L of 9% sodium thiosulfate solution to the reaction liquid, continue to stir the reaction for 1 h, and let stand to separate layers. The organic layer was transferred to a reaction flask, the temperature was adjusted to 10° C., tert-butoxyformyl ethylene triphenylphosphine (78.04 g, 1 eq) was added, and the reaction was stirred for 1 h. The reaction solution was evaporated to dryness under reduced pressure, dissolved in isopropyl acetate (300ml, 3v / m), a...

Embodiment 3

[0054] The preparation of embodiment 3 compound III

[0055] Compound II (100g), sodium bicarbonate (25.2g, 1.5eq), sodium bromide (37.04g, 1.8eq), TEMPO (0.94g, 0.03eq) were added to the reaction flask, and acetonitrile ( 2.5L, 25v / m), lower the temperature to 0-10°C, add sodium hypochlorite solution (99.25g, available chlorine 15%) dropwise under stirring, continue stirring for 1h, TLC [developer: petroleum ether: ethyl acetate =2:1] To detect the end of the reaction, add 2.5L of 9% sodium thiosulfate solution to the reaction solution, continue to stir the reaction for 1h, and let stand to separate layers. The organic layer was transferred to a reaction flask, the temperature was adjusted to 30° C., tert-butoxyformyl ethylene triphenylphosphine (93.65 g, 1.2 eq) was added, and the reaction was stirred for 1 h. The reaction solution was evaporated to dryness under reduced pressure, dissolved in isopropyl acetate (300ml, 3v / m), and n-heptane (600ml, 6v / m) was added dropwise w...

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Abstract

The invention provides a preparation method of sacubitril calcium salt. In the preparation method, the compound III can be subjected to hydrogenation reduction reaction without alkaline hydrolysis, so that the reaction steps can be reduced; meanwhile, the selection of the protecting group can effectively avoid the formation of self-condensation impurities during esterification reaction; and the deprotection of the protecting group can be completed in the amidation reaction, so that the reaction steps are reduced, and the reaction yield is increased.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of sacubitril calcium salt. Background technique [0002] LCZ696 is a new antihypertensive drug developed by Novartis. The drug contains two components: valsartan and AHU-377 (sacubitril). Among them, valsartan can improve vasodilation and stimulate the body to excrete sodium and water. , Sacubitril can block the action of two polypeptides that threaten to lower blood pressure, so LCZ696 is called a dual inhibitor of angiotensin Ⅱ receptor and neprilysin. The structural formula is as follows: [0003] [0004] LCZ696 is superior to standard drugs in reducing blood pressure and reducing heart failure, making the drug eligible for fast-track review by the US FDA and the EU EMEA. The industry generally believes that LCZ696 will bring about innovations in traditional heart failure treatment options. [0005] Sacubitril is a prodrug wh...

Claims

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Application Information

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Patent Type & AuthorityApplications(China)
IPC IPC(8): C07C231/12C07C233/47
CPCC07C231/12C07C269/06C07C2603/18C07B2200/07C07C233/47C07C271/22Y02P20/55
Inventor郑艺白文钦刘忠
OwnerLUNAN PHARMA GROUP CORPORATION