Preparation method of sacubitril intermediate having low triphenylphosphine oxide content

Abstract

The invention relates to a preparation method of a sacubitril intermediate having low triphenylphosphine oxide content. The preparation method comprises that water, isopropyl acetate, sodium bromide, sodium bicarbonate and tetramethylpiperidine oxide into (R)-tert-butyl(1-([1, 1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate, adding a sodium hypochlorite solution into the mixture drop by drop for a reaction, after the reaction, carrying out layering, taking an organic layer, adding ethoxyformylethylidenetriphenyl phosphorane into the organic layer, after a reaction, concentrating the reaction product, removing isopropyl acetate, adding ethanol, water and lithium hydroxide into the mixture, carrying out heating until reflux, carrying out concentration until drying, adding water and activated carclazyte into the product, carrying out stirring at the room temperature, filtering the mixture, adding ethanol and acetic acid into the filtrate, carrying out heating until reflux, and carrying out cooling and stirring to precipitate solids which are the sacubitril intermediate finished products. The preparation method can reduce triphenylphosphine oxide content of the (R)-tert-butyl(1-([1, 1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate.

Description

technical field [0001] The invention relates to a preparation method of a sacubitril intermediate, in particular to a sacubitril intermediate (R,E)-5-([1,1'-biphenyl ]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid. Background technique [0002] Sacubitril is an anti-heart failure drug with the chemical name 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4 -Methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid, its structural formula is: [0003] . [0004] Sacubitril / valsartan is a dual-acting angiotensin receptor neprilysin inhibitor, which is believed to be able to reduce the strain of failing hearts, and has the advantages of significantly reducing the risk of cardiovascular death or hospitalization for heart failure. [0005] (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentenoic acid is the preparation of Sha library The key intermediate of Biqu. [0006] WO2014032627A1 reported a method for preparing (R,E)-5-([1,1'-bipheny...

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Problems solved by technology

[0006] WO2014032627A1 reported a method for preparing (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-2-pentyl The method of alkenoic acid, which uses (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl) carbamate as raw material, Prepared through a series of reactions of oxidation, wittig, hydrolysis, and acid-base neutralization. There is no special step for removing triphenylphosphine, which is brought into the final product, affecting the final yield and purity of the product.