Synthesis method of sacubitril key intermediate

Abstract

The invention relates to a synthesis method of a sacubitril key intermediate, which comprises the following steps: mixing water, sodium bromide, sodium bicarbonate, isopropyl acetate and N-[(1R)-2-[1, 1 '-biphenyl]-4-yl-1-(hydroxymethyl) ethyl] tert-butyl carbamate at room temperature; 2, 2, 6, 6-tetramethylpiperidine oxide and a sodium hypochlorite solution are added at low temperature for heat preservation reaction; adding a sodium thiosulfate solution for quenching reaction, and taking an organic layer; adding 2-(triphenylphosphine subunit) ethyl propionate into the organic layer, and reacting at room temperature; after the reaction is finished, adding zinc chloride, carrying out heat-preservation stirring, filtering, collecting filtrate, carrying out reduced pressure distillation, and carrying out next-step reaction on the obtained solid; dissolving the obtained solid in ethanol, heating, adding a sodium hydroxide solution, and carrying out heat preservation reaction; and after the reaction is finished, filtering, adjusting the pH value of the filtrate to weak acidity by using an acetic acid solution, cooling, crystallizing, filtering, washing and drying to obtain the current product, namely (R, E)-5-([1, 1 '-biphenyl]-4-yl)-4-((t-butyloxycarboryl) amino)-2-methyl-2-pentenoic acid.

Description

technical field [0001] The invention relates to the technical field of compound synthesis, in particular to a method for synthesizing a key intermediate of sacubitril. Background technique [0002] Sacubitril and Valsartan Sodium Tablets, also known as Novartis, were developed by Novartis for the treatment of adult patients with chronic heart failure with reduced ejection fraction, reducing the risk of cardiovascular death and hospitalization for heart failure. Sacubitril and valsartan sodium is composed of sacubitril and valsartan, wherein the structural formula of sacubitril is shown in formula 1, and its chemical name is 4-(((2S,4R)-1- ([1,1'-Diphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxo-2-pentyl)-amino)-4-oxobutanoic acid. [0003] [0004] During the synthesis of sacubitril, (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl- 2-Pentenoic acid is one of the key intermediates, and its structural formula is shown in formula IV. [0005] [0006] Exis...

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Problems solved by technology

[0007] In the above-mentioned technique, the purity of the obtained compound formula IV is relatively low, and it is difficult to suction and filter in the separation process, which is due to the existence of a large amount of by-product triphenylphosphine oxide (i.e. the wittig reaction of compound formula II to compound formula III) in the system. By-products), and compound formula Ⅳ co-precipitate, cause filter cake viscous, be unfavorable for production operation, directly affect the purity of product

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