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Sacubitril intermediate and preparation method and application thereof

A technology for sacubitril and intermediate, which is applied in the field of new intermediate compound and preparation of sacubitril, can solve the problems such as failure to consider atom economy well, difficult to industrialize, complicated operation and the like

Active Publication Date: 2019-01-15
SHANGHAI DESANO CHEM PHARMA +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] It can be seen that, on the one hand, the existing preparation methods are limited by raw materials, reaction reagents, costs, etc., and on the other hand, the atom economy has not been well considered, resulting in the high production cost of Shaku Biqu, cumbersome operation, and difficult industrialization

Method used

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  • Sacubitril intermediate and preparation method and application thereof
  • Sacubitril intermediate and preparation method and application thereof
  • Sacubitril intermediate and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071]

[0072] Add 50g (0.2mol) (S)-1-([1,1'-biphenyl]-4-yl)-3-chloropropan-2-ol and 600ml toluene solvent to a 1L reaction flask, stir at room temperature, and the system Dissolve, lower the temperature of the reaction system to 0-5°C, add 63.8g of triphenylphosphine (0.24mol, 1.2eq) and 23.76g (0.24mol, 1.2eq) of succinimide, add diisoazodicarboxylate Propyl ester 48.5g (0.3mol, 1.5eq), after the addition is complete, the system is heated to 20-30°C and reacted for 3-5 hours, then 150ml of water is added, stirred at room temperature for 5-10 minutes, and the liquid is separated, and the organic layer is washed with saturated saline (100ml ×2) washed, dried over anhydrous MgSO4, and concentrated to obtain 54.68 g of off-white solid compound IIa with a yield of 82.3%.

Embodiment 2

[0074]

[0075] Add 50g (0.17mol) (S)-1-([1,1'-biphenyl]-4-yl)-3-bromopropan-2-ol and 600ml dichloromethane solvent into a 1L reaction flask, stir at room temperature , the system was dissolved, lowered the temperature of the reaction system to 0-5°C, added 53.5g triphenylphosphine (0.204mol, 1.2eq) and 20.2g (0.204mol, 1.2eq) succinimide, added azodicarboxylic acid 38.4g (0.22mol, 1.3eq) of diethyl ester, after the addition, the temperature of the system was raised to 20-30°C for 3-5 hours, and 150ml of water was added, stirred at room temperature for 5-10 minutes, separated, and the organic layer was washed with saturated saline ( 100ml×2) washed, dried with anhydrous MgSO4, and concentrated to obtain 56.7g of solid compound IIb with a yield of 93.4%.

Embodiment 3

[0077]

[0078] Add 50g (0.15mol) (S)-1-([1,1'-biphenyl]-4-yl)-3-iodopropan-2-ol and 600ml dichloromethane solvent to 1L reaction flask, room temperature Stir to dissolve the system, lower the temperature of the reaction system to 0-5°C, add 47.2g of triphenylphosphine (0.18mol, 1.2eq) and 17.8g (0.18mol, 1.2eq) of succinimide, add azobis Diethyl formate 33.9g (0.195mol, 1.3eq), the addition is complete, the system is warmed up to 20-30°C and reacted for 3-5 hours, add 150ml of water, stir at room temperature for 5-10 minutes, separate the liquid, and the organic layer is washed with saturated saline (100ml×2) washed, dried over anhydrous MgSO4, and concentrated to obtain 56.1g of solid compound IIc with a yield of 90.5%.

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Abstract

The invention discloses a sacubitril intermediate and a preparation method and application thereof. The sacubitril intermediate has the chemical structure as shown in the formula III and / or formula IV, wherein R is phenyl, benzyl and isopropyl. The application of the intermediate for synthesis of sacubitril has advantages as follows: the preparation process is simple; the reaction condition is mild; and the environment is protected. The invention has great significance and use value for low-cost, large-sale and high-efficiency preparation of high-purity sacubitril.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a new method for preparing sacubitril, a new intermediate compound involved in the new preparation method, and a preparation method for the intermediate compound. Background technique [0002] Entresto is a dual angiotensin receptor type II (AT II) and neprilysin inhibitor consisting of valsartan and the NEP inhibitor drug Sacubitril in a 1:1 ratio. Its chemical name is: [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionic acid-(S)-3' -Methyl-2'-(pentanoyl{2"-(tetrazole-5-ylate)biphenyl-4'-ylmethyl}amino)butanoic acid]trisodium hemipentahydrate. July 7, 2015 , Entresto was approved by the FDA for the treatment of heart failure patients with reduced ejection fraction, reducing the risk of cardiovascular death and hospitalization for heart failure. [0003] Shakubi song is one of its important components, which is a neprilysin inhibitor, and its chem...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/06C07D207/404C07C233/47C07C231/10A61K31/216A61P9/04
CPCC07C231/10C07D207/404C07D413/06C07C233/47Y02P20/55
Inventor 李金亮赵楠娄彦鹏
Owner SHANGHAI DESANO CHEM PHARMA
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