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Preparation method of LCZ696 key intermediate

A technology of amino and methyl valerate, which is applied in the field of medicinal chemistry, can solve the problems of industrial production restrictions, expensive commercialization, and difficulty in mass procurement, and achieve the effect of large-scale commercial production

Active Publication Date: 2016-05-25
WISDOM PHARM CO LTD
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  • 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 mandyphosSL-M004-1, so industrial production is limited

Method used

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  • Preparation method of LCZ696 key intermediate
  • Preparation method of LCZ696 key intermediate
  • Preparation method of LCZ696 key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1: Preparation of (S)-1-([1,1'-biphenyl]-4-yl)-3-chloro-propan-2-alcohol (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 Minn-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 press...

Embodiment 2

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

[0029] Add 200 g of 4-bromobiphenyl and anhydrous THF (3.2 L) into a 10 L glass four-neck flask, stir the system evenly and cool to -78°C (dry ice acetone bath), then pour the reaction liquid through the dropping funnel under nitrogen protection. Add n-BuLi in n-hexane solution (1.6 Minn-hexane, 600 mL) slowly. 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, 2 L 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 (3×2L), combine the organic phases, dry...

Embodiment 3

[0030] Example 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-necked round-bottomed flask equipped with a thermometer and magnetic stirring, 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 Cl2 (80 mL) and DMF (2 mL). 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 chromatogr...

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Abstract

The invention provides preparation of an LCZ696 key intermediate and relates to a preparation method of the LCZ696 key intermediate (4S,2R)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride. Two chiral centers of the (4S,2R)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride prepared by adopting the preparation method provided by the invention are respectively from chiral fragments, usage of expensive metal catalysts and chiral ligands which are difficult to commercially purchase in bulk is avoided, and commercialized production can be easily realized.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to the key intermediate of LCZ696 (4S,2R)-5-([1,1'-biphenyl]-4-yl)-4-amino-2-methylvalerate hydrochloride method of preparation. 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 risks. 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 of the antihypertensive drug valsartan that has lost its 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 the synthesis of the key intermediate (2R,4S)-5-([1,1'-biphenyl]-4...

Claims

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Application Information

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IPC IPC(8): C07C227/04C07C229/34
CPCY02P20/55C07C1/26C07C29/36C07C67/327C07C227/04C07D207/408C07D209/48C07F7/1804C07F7/188C07F7/1892C07C15/14C07C33/46C07C69/732C07C229/34
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
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