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Chiral preparation method for N-t-butyloxycarboryl-(4S)-(p-phenyl phenyl methyl)-4-amino-(2R)-methylbutyric acid

A technology of phenylphenylmethyl and tert-butoxycarbonyl is applied in the field of chiral preparation of N-tert-butoxycarbonyl---4-amino-methylbutyric acid, which can solve the problem of unsuitable industrial production and price Expensive, increased reaction costs, etc., to achieve the effect of easy to obtain reagents, simple reaction conditions, and guaranteed purity

Active Publication Date: 2015-12-16
ZHEJIANG YONGNING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Patent CN101516831 discloses a synthetic method about N-tert-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid, which specifically includes (i-a ) reacts with a chiral catalyst to obtain (ii-a) and (ii-b); using two kinds of chiral catalysts in this method can increase the ratio of diastereoisomers to more than 88:12, but the two The price of chiral catalysts is very expensive, which greatly increases the reaction cost and is not suitable for industrial production. The reaction route is as follows:

Method used

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  • Chiral preparation method for N-t-butyloxycarboryl-(4S)-(p-phenyl phenyl methyl)-4-amino-(2R)-methylbutyric acid
  • Chiral preparation method for N-t-butyloxycarboryl-(4S)-(p-phenyl phenyl methyl)-4-amino-(2R)-methylbutyric acid
  • Chiral preparation method for N-t-butyloxycarboryl-(4S)-(p-phenyl phenyl methyl)-4-amino-(2R)-methylbutyric acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029]

[0030] Get compound (1) (20.0g, 1.0 equivalent) and dissolve in ethanol (50ml), add (S)-phenethylamine (5.9g, 1.0 equivalent), 10%Pd / C (2.0g), in 4.0bar Under hydrogen pressure, the reaction solution was placed in an oil bath at 40°C, heated and stirred for 2.5 hours, then cooled to room temperature, the system was a gray suspension, filtered directly to obtain an off-white solid, which was placed in a reaction flask, and water (20ml) was added , dichloromethane (80ml), hydrochloric acid (6mol / L, 10ml), stirred at room temperature for 1 hour, filtered to remove Pd / C, then separated the system, collected the dichloromethane layer, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure The solvent was removed to obtain 20.1 g of a white solid. HPLC detection showed that the diastereomer ratio was (2-a):(2-b)=97.62:2.38.

[0031] Purified by recrystallization with 100ml of ethyl acetate / heptane (1:4) to obtain 18.5g of white solid. HPLC...

Embodiment 2

[0035]

[0036] Get compound (1) (500g, 1.0 equivalent) and dissolve in ethanol (1300ml), add (S)-phenethylamine (148g, 1.0 equivalent), 10%Pd / C (50g), under the hydrogen pressure of 4.0bar The reaction solution was heated and stirred in a 40°C oil bath for 2.5 hours, then cooled to room temperature, the system was a gray suspension, filtered directly to obtain an off-white solid, which was placed in a reaction bottle, and water (500ml), dichloro Methane (2000ml), hydrochloric acid (6mol / L, 250ml), stirred at room temperature for 1 hour, filtered to remove Pd / C, then separated the system, collected the dichloromethane layer, dried over anhydrous sodium sulfate, filtered, evaporated the solvent under reduced pressure, 484.8 g of white solid were obtained. HPLC detection showed that the diastereomer ratio was (2-a):(2-b)=97.69:2.31.

[0037]Purified by recrystallization with 2500ml of ethyl acetate / heptane (1:4) to obtain 452.2g of white solid. HPLC detection showed that th...

Embodiment 3

[0039]

[0040] Dissolve compound (1) (20.0 g) in ethanol (50 ml), add 10% Pd / C (2.0 g), and place the reaction solution in a 40° C. oil bath with stirring for 2 hours under a hydrogen pressure of 3.5 bar, and then After cooling to room temperature, Pd / C was removed by filtration, and the solvent was evaporated under reduced pressure to obtain compound (2) (21.0 g) as a white solid. HPLC detection, compound (2-a):(2-b)=73.34:26.66.

[0041] The above compound (2) (21.0 g, 1.0 equivalent) was dissolved in 210 ml of ethanol, and (S)-phenethylamine (6.3 g, 1.0 equivalent) was slowly added under stirring at room temperature, and a white solid gradually precipitated out of the system. After stirring for 2 hours, , filtered, and the filter cake was washed with 105ml ethanol. Place the washed filter cake in a reaction flask, add water (20ml), methylene chloride (80ml), hydrochloric acid (6mol / L, 10ml), stir at room temperature for 1 hour, separate the system, and collect the meth...

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Abstract

The invention relates to a chiral preparation method for N-t-butyloxycarboryl-(4S)-(p-phenyl phenyl methyl)-4-amino-(2R)-methylbutyric acid. The chiral preparation method comprises the following step: enabling a compound (1) and hydrogen to react in the presence of Pd / C and (S-phenylethylamine), thereby preparing a compound (2-a) as shown in the specification. The chiral preparation method is simple in reaction condition, easy to operate, easy in obtaining reagents, and applicable to industrial production, the cost can be lowered as an expensive chiral catalyst is not used, and both the reaction efficiency is improved and the product purity is ensured.

Description

technical field [0001] The invention relates to a chiral preparation method of N-tert-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid. Background technique [0002] LCZ696 is a compound composed of sacubitril (ie AHU-377) and valsartan. It is the first and only drug whose curative effect significantly surpasses that of the standard treatment drug enalapril in clinical trials, and shows higher safety; at the same time, it is also a first-in-class dual-effect angiotensin receptor-neprilysin inhibitor (ARNI), which has a unique mode of action and can enhance the protective neuroendocrine system of the heart (NP system, natriuretic Peptide system), and inhibit harmful systems (RAAS system, renin-angiotensin-aldosterone system), which are thought to reduce the strain of the failing heart. The drug was developed by Novartis and was approved by the FDA on July 7, 2015. It is used for heart failure patients with reduced ejection fraction to reduce the ri...

Claims

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Application Information

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IPC IPC(8): C07C271/22C07C269/06C07C269/08
Inventor 叶天健陆修伟郁光亮刘婷
Owner ZHEJIANG YONGNING PHARMA
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