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Preparation method of sacubitril valsartan sodium

A sodium hydroxide and compound technology, applied in the field of medicine and chemical industry, can solve the problems of inconvenient solvent recovery, low yield and the like

Pending Publication Date: 2021-03-30
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Patent documents such as CN101098689A and CN102702119A, CN106397248A adopt mixed solvents such as isopropyl acetate and acetone or IPA and acetone in the synthetic process of LCZ696, adopt composite solvent, bring inconvenience to solvent recovery; CN104557600A, CN105168205A prepare LCZ696 or its intermediate The yields obtained by the method of the body compound are all low

Method used

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  • Preparation method of sacubitril valsartan sodium
  • Preparation method of sacubitril valsartan sodium
  • Preparation method of sacubitril valsartan sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] The preparation of embodiment 1 compound SAC04

[0083]

[0084] At room temperature, 100mL of ethanol, ruthenium reagent and iron reagent were stirred in a one-mouth bottle for 30min, and stirred evenly. S309A03 (50 g), ruthenium reagent (40 mg) and iron reagent (65 mg) solutions and 400 mL of ethanol were sequentially added into the reaction kettle. After replacing three times with nitrogen gas, replace it with hydrogen gas three times, then charge hydrogen pressure to 3.0MPa, and raise the temperature to 65-80°C for reaction. After 24 hours of reaction, the heating was turned off to lower the temperature, and the reaction solution of BPA08 obtained was directly used in subsequent reactions.

[0085] The room temperature was 27°C, and the above BPA08 solution was added to a 1L four-neck flask at room temperature, and 18.64g SOCl2 was added dropwise. After the drop was complete, it was stirred at 45°C, and the transition state product was detected by HPLC <0.5%, an...

Embodiment 2

[0087] The preparation of embodiment 2 compound SAC04

[0088] At room temperature, 100 mL of ethanol, ruthenium reagent (20 mg) and iron reagent (32.5 mg) were stirred in a one-mouth bottle for 30 min, and stirred evenly. Add S309A03 (50g), ruthenium reagent and iron reagent solution and 400mL ethanol to the reaction kettle successively. After replacing three times with nitrogen gas, replace it with hydrogen gas three times, then charge hydrogen pressure to 3.0MPa, and raise the temperature to 65-80°C for reaction. After 24 hours of reaction, the heating was turned off to cool down, and the reaction solution of BPA08 was obtained, which was directly used in subsequent reactions.

[0089] At room temperature 27°C, add the above BPA08 solution to a 1L four-neck flask at room temperature, add 23.3g SOCl2 dropwise, after the drop is complete, place it at 65°C and stir at 65°C to detect transition state products < 0.5%, then stop the reaction, and the reaction solution is at 50-6...

Embodiment 3

[0091] The preparation of embodiment 3 compound SAC04

[0092] At room temperature, 100 mL of ethanol, ruthenium reagent (20 mg) and iron reagent (32.5 mg) were stirred in a one-mouth bottle for 30 min, and stirred evenly. Add S309A03 (50g), ruthenium reagent and iron reagent solution and 400mL ethanol to the reaction kettle sequentially. After replacing three times with nitrogen gas, replace it with hydrogen gas three times, then charge hydrogen pressure to 3.0MPa, and raise the temperature to 65-80°C for reaction. After 24 hours of reaction, the heating was turned off to cool down, and the reaction solution of BPA08 was obtained, which was directly used in subsequent reactions.

[0093] At room temperature of 27°C, add the above-mentioned BPA08 solution to a 1L four-neck flask at room temperature, add 23.3g of SOCl2 dropwise, after the drop is complete, place it at 65°C and stir for 1 hour, then take a sample and send it to HPLC to detect that the transition state product i...

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Abstract

The invention provides a preparation method of sacubitril valsartan sodium, and belongs to the field of medical chemistry. The preparation method comprises the following steps: by using a compound S309A03 as a raw material, carrying out hydrogenation reaction to generate a compound BPA08, reacting the compound BPA08 in ethanol to generate a compound SAC01, reacting the compound SAC01 with succinicanhydride to generate a compound SAC02, optionally reacting the compound SAC02 with sodium hydroxide, and reacting the compound SAC03 with calcium chloride to generate a compound SAC04; and subjecting the compound SAC04 to acid treatment to obtain a compound YJX01, and enabling the compound YJX01 to react with VST in a single solvent in the presence of sodium hydroxide to prepare the compound YJX02. The preparation method disclosed by the invention is simple to operate, the time required by the process is reduced, the total yield of the process route is greatly improved, an unexpected technical effect is obtained, impurities in the process are removed, and a product with higher purity is obtained. The method has mild process conditions and easily available raw materials, and is suitable for industrial amplification.

Description

technical field [0001] The present invention relates to the field of medicine and chemical industry, and more specifically relates to a Shakubiqu intermediate and a preparation method thereof. Background technique [0002] Sacubitril valsartan sodium, also known as LCZ696 (trade name: Entresto), is a dual-effect angiotensin receptor neprilysin inhibitor developed by Novartis. It has a unique mode of action and is considered Able to reduce the strain on a failing heart. The drug was approved by the FDA in July 2015. Its chemical name is six (4-{[(1S,3R)-1-([1,1'-biphenyl]-4-methyl)-4-ethoxy-3-methyl-4-oxo Butyl]amino}-4-oxobutyric acid)hexa(N-pentanoyl-N-{[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]- 4-yl] methyl}-L-valine) - octadecadeca sodium salt pentahydrate. [0003] The structural formula of LCZ696 is as follows: [0004] [0005] U.S. Patent US 5217996 discloses the preparation method of LCZ696 intermediate compound, but this method uses expensive (D)-4-hydroxyphenyl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/04C07C233/47C07C231/12C07C231/02C07C227/20C07C229/34C07C269/06C07C271/22
CPCC07D257/04C07C233/47C07C231/12C07C231/02C07C227/20C07C269/06C07B2200/07C07C271/22C07C229/34
Inventor 王仲清王海龙杨四王健罗忠华
Owner SUNSHINE LAKE PHARM CO LTD
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