Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Preparation of key intermediates of lcz696

A process, amino technology, applied in the preparation of organic compounds, the preparation of cyanide reactions, the production of bulk chemicals, etc., can solve the problems of industrial production restrictions, expensive commercialization, difficult to purchase in large quantities, etc., and achieve the realization of large-scale commercial production. Effect

Active Publication Date: 2017-09-29
WISDOM PHARM CO LTD
View PDF2 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route not only has many synthesis steps, but also uses metal catalysts that are very expensive and difficult to commercialize in large quantities [RuI 2 (p-cymene)] 2 and chiral ligand mandyphos SL-M004-1, so industrial production is limited

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation of key intermediates of lcz696
  • Preparation of key intermediates of lcz696
  • Preparation of key intermediates of lcz696

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1: ( S Preparation of )-1-([1,1'-biphenyl]-4-yl)-3-chloro-propan-2-ol (formula IV, X=Cl)

[0027] In a 500ml three-necked flask, add 5 grams of 4-bromobiphenyl and anhydrous THF (80ml), stir the system evenly and cool to -78°C, then slowly add n-BuLi n-hexane solution (1.6 M in n-hexane, 15ml). After the dropwise addition, the system was kept at -78°C and stirred for 30 minutes, then slowly raised to -10°C and stirred for 2 hours. A THF solution (3 g, 40 ml THF) of (S)-epichlorohydrin (formula III, X=Cl) was slowly added to the reaction system. After the dropwise addition, the reaction system was naturally warmed up to room temperature and reacted for 5 hours, and then 100 ml of saturated ammonium chloride aqueous solution was slowly added to the reaction system to quench the reaction. Add CH to the system 2 Cl 2 Extract (3×50ml), combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, remove the solvent under reduced pr...

Embodiment 2

[0028] Embodiment 2: ( S Preparation of )-1-([1,1'-biphenyl]-4-yl)-3-chloro-propan-2-ol (formula IV, X=Cl)

[0029]In a 10L glass four-necked flask, add 200 grams of 4-bromobiphenyl and anhydrous THF (3.2L), stir the system evenly and cool to -78°C (dry ice acetone bath), and then pour the reaction liquid through the dropping funnel under nitrogen protection. A solution of n-BuLi in n-hexane (1.6M in n-hexane, 600 mL) was slowly added into the mixture. After the dropwise addition, the system was kept at -78°C and stirred for 1 hour, then slowly raised to -10°C and stirred for 4 hours. A THF solution (120 g, 2L THF) of (S)-epichlorohydrin (Formula III, X=Cl) was slowly added to the reaction system. After the dropwise addition, the reaction system was naturally warmed to room temperature and reacted for 7 hours, and then 2L of saturated ammonium chloride aqueous solution was slowly added to the reaction system to quench the reaction. Add CH to the system 2 Cl 2 Extract (3×2...

Embodiment 3

[0030] Embodiment 3: ( S )-1-([1,1'-biphenyl]-4-yl)-3-chloro-prop-2-tert-butyldimethylsilyloxy-propane (Formula V, R 1 = TBS) preparation

[0031] In a 250mL three-neck round bottom flask, equipped with a thermometer and a magnetic stirrer, add ( S )-1-([1,1'-biphenyl]-4-yl)-3-chloro-propan-2-ol (formula IV, X = Cl) 8.2 g, then add anhydrous CH 2 Cl 2 (80mL) and DMF (2mL). After the reaction solution was stirred evenly, DMAP (50mg) was added, and the system was cooled to about 0°C in an ice-water bath. Then slowly add the CH of TBSCl to the reaction system through the dropping funnel 2 Cl 2 solution (6 g, 20 mL CH 2 Cl 2 ), the dropwise addition process kept the temperature of the reaction system lower than 5°C. After the dropwise addition, the system was naturally warmed up to room temperature and stirred for 6 hours. After the reaction was followed by TLC point plate tracking, the solvent was removed under reduced pressure, and the residue was purified by column c...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The preparation of LCZ696 key intermediate, the present invention relates to LCZ696 key intermediate (4S,2R)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylvalerate Method for the preparation of acid salts. The two chiral centers of (4S,2R)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylvalerate hydrochloride prepared by this method all come from Based on the chiral segment, it does not involve the use of metal catalysts and chiral ligands that are expensive and difficult to purchase in large quantities for commercialization, and it is easy to achieve commercial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to LCZ696 key intermediate (4 S ,2 R A preparation method of )-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylvalerate hydrochloride. Background technique [0002] LCZ696 is a dual inhibitor of angiotensin receptor and neprilysin, and its English name is Entresto. In 2015, the FDA approved the drug as an angiotensin II receptor blocker based on its excellent clinical trial results to reduce the risk Cardiovascular Death and Hospitalization in Heart Failure Patients with Chronic Heart Failure (NYHA Class II-IV) and Reduced Ejection Fraction LCZ696. LCZ696 is a combination drug of the antihypertensive drug valsartan that has lost patent protection and a new type of antihypertensive drug Sacubitril (a neprilysin inhibitor), and its structural formula is as follows: [0003] [0004] The preparation process of LCZ696 involves key intermediates (2 R ,4 S )-5-([1,1'-biphenyl]-4-yl)-4-ami...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07C227/04C07C229/34
CPCY02P20/55
Inventor 邱小龙胡林邹平王东辉刘呈昭邓贤明游正伟江中兴
Owner WISDOM PHARM CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com