Preparation method of R-diphenyl alaninol

A coupling reaction, amino protecting group technology, applied in the field of medicine and chemical industry, can solve the problems of high cost, long route and high operation requirements

Active Publication Date: 2018-01-05
XILING LAB CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] It can be seen that the current method using the second strategy still has the defects of high cost, long route or high operation requirements, and the industrial application is limited.

Method used

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  • Preparation method of R-diphenyl alaninol
  • Preparation method of R-diphenyl alaninol
  • Preparation method of R-diphenyl alaninol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] Embodiment 1 synthetic compound III

[0103] Weigh 20 g of D-Boc tyrosine methyl ester into the reaction flask, add 60 mL of anhydrous tetrahydrofuran as a solvent, add 21.6 mL of triethylamine under ice cooling, then slowly add 12.7 g of benzenesulfonyl chloride dropwise into the reaction flask, and immediately A large amount of white solid formed. After the dropwise addition, the ice bath was removed, and the reaction was carried out at room temperature for 5 hours. The solvent was evaporated to dryness, 80 mL of ethyl acetate was added thereto, and the organic phase was washed successively with saturated aqueous sodium carbonate, saturated aqueous ammonium chloride, and saturated brine. After drying and evaporating to dryness, 29.3 g of yellow oil compound III (4-benzenesulfonyl-D-Boc tyrosine methyl ester) was obtained, with a yield of 99.4%.

Embodiment 2

[0104] Embodiment 2 is synthesized compound Ⅱ by compound Ⅲ

[0105] Weigh 10 g of compound III (4-benzenesulfonyl-D-Boc tyrosine methyl ester) in the reaction flask, add 50 mL of methyl tert-butyl ether to it to dissolve, slowly add 3.49 g of lithium aluminum tetrahydrogen in an ice bath, and add After completion, remove the ice bath and react at room temperature for 1 h. After slow dropwise addition of ethanol to quench, filter. After the filtrate was spin-dried, 50 mL of ethyl acetate was added, and the organic phase was washed successively with saturated aqueous ammonium chloride solution, water, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and column chromatography (PE:EA=5 : 1) 8.5 g of yellow oil compound II (4-benzenesulfonyl-D-Boc phenylalaninol) was obtained, with a yield of 90.8%.

Embodiment 3

[0106] Embodiment 3 is synthesized compound I by compound II

[0107] Add compound II (4-benzenesulfonyl-D-Boc phenylalaninol) 50mg, 0.123mmol) to the reaction flask, phenylboronic acid (60mg, 0.491mmol), potassium carbonate (68mg, 0.491mmol) and [(IMes)Pd (Py)Cl 2 ] (5mol%), add 1 mL of solvent morpholine, and react at 120° C. for 24 h under an argon atmosphere to obtain R biphenylalaninol. Yield: 62.5%, e.e. value>99%, [α]D 25 =+21.9 (c=0.01g / mL, CHCl 3 ).

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Abstract

The invention relates to a preparation method of a sacubitril intermediate, in particular to a preparation method of R-diphenyl alaninol. The preparation method comprises the following steps: performing a reaction on a D-tyrosine derivative serving as a raw material and different substituted sulfonyl chloride (or anhydride) to obtain a compound as shown in a formula III, and preparing the R-diphenyl alaninol by using the compound as shown in the formula III through two routes. The route I is that the compound as shown in the formula III is reduced into a compound as shown in a formula II and the compound as shown in a formula II is coupled to obtain the R-diphenyl alaninol; and the route II is that the compound as shown in the formula III is coupled to obtain a compound as shown in a formula V and reduction is performed to obtain the R-diphenyl alaninol. The compound R-diphenyl alaninol prepared by the method is a key intermediate of one component sacubitril (AHU-377) of a novel pressure-reducing medicine LCZ696 (Entresto). The method is simple to operate, short in route and suitable for industrialized production. (The formulas are as shown in the description.).

Description

technical field [0001] The invention relates to a preparation method of a sacubitril intermediate, in particular to a preparation method of R-biphenylalaninol, which belongs to the field of medicine and chemical industry. Background technique [0002] Sacubitril (AHU-377) has the mechanism of blocking two polypeptides that are responsible for lowering blood pressure, and is one of the important components of the antihypertensive drug LCZ696. LCZ696 is a new type of antihypertensive drug developed by Novartis. The drug has dual action standards of angiotensin II receptor and neprilysin. Strain, the antihypertensive effect is superior to standard drugs, and has obtained the fast-track review qualifications of the US FDA and the EU EMEA. The industry generally believes that LCZ696 will bring about a revolution in the treatment of traumatic heart failure. [0003] R-biphenylalaninol is a key intermediate in the synthesis of Sacubitril. For example, patents US5217996, WO2008031...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/16C07C271/22C07C309/73C07C269/06C07C303/28C07C303/30
CPCY02P20/55
Inventor 王启卫代祯黄晴菲黄金昆
Owner XILING LAB CO LTD
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