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Sacubitril and preparation method of midbody of sacubitril

A technology for sacubitril and intermediates, which is applied in the field of preparation of sacubitril and its intermediates, can solve the problems of difficult separation of sacubitril intermediates, low yield and purity, poor diastereoselectivity and the like , to achieve the effect of improving production efficiency, simple operation, high yield and diastereoselectivity

Active Publication Date: 2017-05-24
SICHUAN TONGSHENG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the diastereoselectivity of this method is poor, and it is difficult to separate the obtained sacubitril intermediate and its diastereomer, resulting in lower yield and purity.

Method used

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  • Sacubitril and preparation method of midbody of sacubitril
  • Sacubitril and preparation method of midbody of sacubitril
  • Sacubitril and preparation method of midbody of sacubitril

Examples

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Effect test

preparation example Construction

[0028] The above-mentioned preparation method of a sacubitril intermediate also includes: performing an asymmetric methylation reaction on compound II with a methylating reagent and a base to obtain compound III.

[0029] Further, the methylating agent is any one of methyl iodide, dimethyl sulfate and dimethyl carbonate, preferably methyl iodide. The base is a conventional hydrogen extraction reagent such as an organometallic reagent, such as an alkyllithium reagent, lithium amide reagent, potassium amide reagent, etc., preferably lithium diisopropylamide (LDA) or lithium hexamethyldisilazide (LiHMDS ), most preferably lithium diisopropylamide. These reagents are commonly used reagents in chemical reactions, can be directly purchased from the market, and can be used together to obtain methylated products with high yields.

[0030] Further, the asymmetric methylation reaction is carried out at -80 to -50°C, preferably at -78°C. This temperature range is the preferred value ob...

Embodiment 1

[0038] This example provides a preparation method of compound II, which uses Boc as a protecting group, compound I and chiral prosthetic group react to get the compound Its concrete preparation steps are as follows:

[0039]Add 320mL toluene into the three-neck flask, start stirring, add compound I (16g, 1eq), triethylamine (13.1g, 3eq) and compound IV-a (8.37g, 1.1eq), pH=7~8. Slowly added pivaloyl chloride (5.67g, 1.1eq) to the reaction system, heated to 100°C and refluxed for 16h. After the reaction, dilute with ethyl acetate, wash with water and saturated sodium bicarbonate in sequence, collect the organic phase, dry it with anhydrous sodium sulfate, filter, and distill the filtrate to remove the solvent under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain compound II-a (21.0 g, yield 91%).

Embodiment 2

[0041] This example provides a preparation method of compound II, which uses Boc as a protecting group, compound I and chiral prosthetic group react to get the compound Its concrete preparation steps are as follows:

[0042] Add 320mL toluene to the three-neck flask, start stirring, add compound I (16g, 1eq), triethylamine (13.1g, 3eq) and compound IV-b (7.27g, 1.1eq), pH=7~8. Slowly added pivaloyl chloride (5.67g, 1.1eq) to the reaction system, heated to 90°C and refluxed for 16h. After the reaction, dilute with ethyl acetate, wash with water and saturated sodium bicarbonate in sequence, collect the organic phase, dry it with anhydrous sodium sulfate, filter, and distill the filtrate to remove the solvent under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain compound II-b (17.7 g, yield 86%).

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Abstract

The invention discloses sacubitril and a preparation method of midbody of the sacubitril, and relates to the field of pharmaceutical synthesis. According to preparation method of the sacubitril midbody, a compound I of a first chiral center is taken as a starting material, and is subjected to acylation reaction prothetic group adding, asymmetric methylation reaction and hydrolysis prothetic group removal, so that the sacubitril midbody is obtained. Asymmetric methylation in the alpha-position of the carbanyl group is effectively and selectively is realized through the adding of chiral prothetic group and the cooperative control of the chiral prothetic group and the first chiral center, so as to construct a second chiral center. The preparation method of the sacubitril midbody has the advantages that the raw materials are easy to get, the method is simple to operate, separation and purification are convenient, the yield and diastereoselectivity are high, and the dose is convenient to magnify to realize industrial production. The obtained sacubitril midbody is high in chiral purity, a tedious step for separating a diastereoisomer is canceled, and the production efficiency is improved.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of sacubitril and its intermediates. Background technique [0002] LCZ696 is a dual-action angiotensin receptor neprilysin inhibitor developed by Novartis, which was approved by the FDA on July 7, 2015, and developed for the treatment of patients with heart failure with reduced ejection fraction (HErEF). LCZ696 is a complex composed of Sacubitril (AHU-377) and valsartan (Diovan), which has a unique mode of action and is believed to reduce strain in failing hearts. Among them, sacubitril can block the mechanism of action of two peptides responsible for lowering blood pressure, and valsartan can improve vasodilation and stimulate the body to excrete sodium and water. [0003] Sacubitril is a prodrug whose chemical name is: 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 shown in formul...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/22C07D263/26
CPCY02P20/55C07C269/06C07B2200/07C07D263/26C07C271/22
Inventor 李庚黄青春杨龙伍万兵陈纹锐白顺强
Owner SICHUAN TONGSHENG BIOTECH
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