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Method for preparing chiral biaryl substituted 4-amino-butyric acid and derivative thereof

An aryl and chiral ligand technology, which is applied in the field of preparing biaryl-substituted 4-amino-butyric acid or its derivatives, can solve the problem of insufficient stereoselectivity, unsuitable for industrial and commercial scale production, and expensive price. And other issues

Pending Publication Date: 2021-08-31
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the chiral ligands and catalysts are expensive, not active enough, and the dosage ratio is high (such as close to 10%), which leads to high production costs, is not suitable for industrial and commercial scale production, or the stereoselectivity is not enough, resulting in the catalyzed The purity of the target chiral compound is low

Method used

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  • Method for preparing chiral biaryl substituted 4-amino-butyric acid and derivative thereof
  • Method for preparing chiral biaryl substituted 4-amino-butyric acid and derivative thereof
  • Method for preparing chiral biaryl substituted 4-amino-butyric acid and derivative thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045]

[0046] Dissolve 2g of [Ru] catalyst (diiodo(p-cymene) ruthenium(II) dimer) and 1.3g of (R,R)-Me-Duphos in 20mL of toluene, react at 65-70℃ for one hour , prepared as a chiral catalyst. Add the above-mentioned chiral catalyst toluene solution into a clean hydrogenation kettle, and add SM1 (763g), triethylamine 202g, and 16L methanol solvent in sequence, and then replace the hydrogen gas (0.4-0.5MPa) three times with nitrogen in the closed hydrogenation kettle React under pressure at 55°C for 12 hours, take the reaction solution for liquid phase detection, the reaction SM1 conversion rate reaches 99.99%, product A:B=98.88:1.09, the reaction solution is filtered and concentrated, n-hexane and ethyl acetate (1 : 1) Pure product A can be obtained by beating; the yield is 96.1%, and the product is off-white solid.

[0047]1 HNMR (CD 3 OD, 400MHz): 1.15-1.17(d, J=8Hz, 3H), 1.22-1.36(d, 9H), 1.38-1.50(m, 1H), 1.85-1.93(m, 1H), 2.55-2.76(m , 3H), 3.82-3.85 (m, 1H), 7.25-...

Embodiment 2

[0050]

[0051] Dissolve 2g of [Ru] catalyst (diiodo(p-cymene) ruthenium(II) dimer) and 1.3g of (S,S)-Me-Duphos in 20mL of toluene, react at 65-70°C for one hour, prepared as a chiral catalyst. Add the above-mentioned chiral catalyst toluene solution into a clean hydrogenation kettle, and add SM1 (763g), triethylamine 202g, and 16L methanol solvent in sequence, and then replace the hydrogen gas (0.4-0.5MPa) three times with nitrogen in the closed hydrogenation kettle React under pressure at 55°C for 12 hours, take the reaction solution for liquid phase detection, the reaction SM1 conversion rate reaches 99.97%, product A:B=1.52:98.45, the reaction solution is filtered and concentrated, n-hexane and ethyl acetate (1 :1) Pure product B can be obtained by beating; the yield is 95.7%, and the product is off-white solid.

[0052] 1 HNMR (CH 3 OD, 400MHz): 1.13-1.15(d, J=8Hz, 3H), 1.23-1.35(d, 9H), 1.52-1.58(m, 1H), 1.78-1.88(m, 1H), 2.48-2.50(m , 1H), 2.74-2.78 (m, 2H), 3.82...

Embodiment 3

[0055]

[0056] Dissolve 1.3g of [Ru] catalyst (dichloro(p-cymene) ruthenium(II) dimer) and 1.3g of (R,R)-Me-Duphos in 20mL of toluene, react at 65-70℃ for one hour , prepared as a chiral catalyst. Add the above-mentioned chiral catalyst toluene solution into a clean hydrogenation kettle, and add SM1 (763g), triethylamine 202g, and 16L methanol solvent in sequence, and then replace the hydrogen gas (0.4-0.5MPa) three times with nitrogen in the closed hydrogenation kettle React under pressure at 55°C for 12 hours, take the reaction solution for liquid phase detection, the reaction SM1 conversion rate reaches 95.8%, product A:B=93.9:1.8, the reaction solution is filtered and concentrated, n-hexane and ethyl acetate (1 : 1) Pure product A can be obtained by beating; the yield is 90.5%, and the product is off-white solid.

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Abstract

The invention discloses a method for preparing chiral biaryl substituted 4-amino-butyric acid and a derivative thereof. The method belongs to chiral catalytic hydrogenation reaction, and has the advantages of high conversion rate, good selectivity, simplicity in operation, low catalyst dosage, low production cost, suitability for industrial large-scale production and the like.

Description

technical field [0001] The method for preparing biaryl-substituted 4-amino-butyric acid or its derivatives can be used to prepare sacubitril-valsartan sodium drug intermediates, diastereoisomers and other intermediate derivatives things. Background technique [0002] Biaryl-substituted 4-amino-butyric acid or derivatives thereof (such as compound IA) are important intermediates of anti-heart failure drug sacubitril-valsartan sodium, especially important for the control of the chiral center in compound IA . The direct hydrogenation reduction will obtain the diastereoisomers of the two configurations of compound IA and compound IB each accounting for about 50%, so the efficiency of the preparation of the target product will be greatly reduced. [0003] [0004] In order to selectively prepare target chiral compounds, chiral catalysts and chiral ligands are essential. Most of the chiral ligands and catalysts are expensive, not active enough, and the dosage ratio is high (...

Claims

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Application Information

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IPC IPC(8): C07C271/22C07C269/06
CPCC07C271/22Y02P20/55
Inventor 董勃良张生烈郭军辉王超潘钧铸王晶翼
Owner SICHUAN KELUN PHARMA RES INST CO LTD
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