Preparation method of LZ969

A biphenyl and methyl technology, applied in the field of preparation of LZ969, can solve the problems of cumbersome process route and low yield, and achieve the effects of optimized process route, simple operation and high yield

Inactive Publication Date: 2015-10-28
ZHEJIANG TIANSHUN BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, there are various problems in the process route of the two components of LZ696, the process route is cumbersome, and the yield is not high

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Synthesis of L-valine methyl ester.

[0026] Add thionyl chloride, anhydrous methanol and L-valine into the reaction vessel for esterification reaction, the molar ratio of thionyl chloride to L-valine is 1-1.5:1, the volume of anhydrous methanol is equal to L - The mass ratio of valine is 10-15L / kg, the esterification reaction temperature is 15-20°C, and the reaction time is 30h. After the reaction, ethyl acetate is added for recrystallization to obtain L-valine methyl ester hydrochloride.

Embodiment 2

[0028] Add 2'-cyano-4-bromomethyl-biphenyl to L-valine methyl ester hydrochloride, L-valine methyl ester hydrochloride and 2'-cyano-4-bromomethyl - The molar ratio of biphenyl is 1-1.5:1, adding acid-binding agent sodium carbonate, the molar ratio of sodium carbonate to 2'-cyano-4-bromomethyl-biphenyl is 2-2.5:1, using tetrahydrofuran as solvent, the reaction temperature is 70°C, and the reaction time is 2 hours. After the reaction, add toluene for extraction and separation to obtain N-[2'-cyano-(biphenyl-4-yl)-methyl]-L-valine Methyl ester hydrochloride.

Embodiment 3

[0030] Add valeryl chloride to N-[2'-cyano-(biphenyl-4-yl)-methyl]-L-valine methyl ester hydrochloride, use sodium carbonate as an acid-binding agent, N-[2 The molar ratio of '-cyano-(biphenyl-4-yl)-methyl]-L-valine methyl ester hydrochloride to valeryl chloride is 1:1.6-2, N-[2'-cyano- The molar ratio of (biphenyl-4-yl)-methyl]-L-valine methyl ester hydrochloride to sodium carbonate is 1:2.5-3, acetone is used as solvent, the reaction temperature is 50°C, and the reaction time is 8h , The reaction gives N-[2'-cyano-(biphenyl-4-yl)-methyl]-N-pentanoyl.

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PUM

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Abstract

The invention provides a preparation method of LZ969. According to the preparation method, LZ969 is used for representing a compound of valsartan and 4-(((2S, 4R)-1-(1, 1'-biphenyl-4-yl)-5-ethoxy-4-methyl-5-oxo pentane-2-yl) amino)-4-oxo butyric acid at a molar ratio of 1:1. A preparation method of valsartan comprises following steps: L-valine methyl ester hydrochloride is synthesized; nucleophilic substitution is carried out so as to obtain N-[2'-cyano-(biphenyl-4-yl)-methyl]-L-valine methyl ester hydrochloride; valeryl chloride is added, sodium carbonate is taken as an acid-binding agent, acetone is taken as a solvent, and N-[2'-cyano-(biphenyl-4-yl)-methyl]-N-valeryl is obtained via reaction; and N-[2'-cyano-(biphenyl-4-yl)-methyl]-N-valeryl, sodium azide, and chloro-substituted tributyltin are subjected to heating reaction by taking pyridine as a solvent so as to obtain valsartan. Technical route reaction of the preparation method is mild; operation is simple; and yield is high.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a preparation method of LZ969. Background technique [0002] Heart failure is a progressive debilitating disease. The patient's heart cannot pump enough blood to supply the whole body. Symptoms such as dyspnea, fatigue, and fluid retention may appear slowly and gradually worsen, significantly affecting the quality of life. Heart failure is also an important and growing public health problem. The global annual expenditure on heart failure is US$108 billion15, of which hospitalization costs account for 60%-70% of treatment costs. [0003] LCZ696 is an angiotensin receptor neprilysin inhibitor (ARNI), which is a complex of valsartan and sacubitril (AHU377), containing half molecule of valsartan and half molecule of AHU377 (1:1 ratio) LCZ696 is a complex of valsartan and sacubitril (AHU377), containing half a molecule of valsartan and half a molecule of AHU377 (1:1 ratio). [0004] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/04C07C233/47C07C231/00
CPCC07D257/04C07C231/00
Inventor 张胜
Owner ZHEJIANG TIANSHUN BIOTECH
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