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Asymmetric hydrogenation method of alpha-oxo-alpha, beta-unsaturated carboxylic acid

An asymmetric and unsaturated technology, applied in the field of asymmetric hydrogenation of α-oxo-α, β-unsaturated carboxylic acids, can solve the problem of narrow application range of catalyst substrates

Inactive Publication Date: 2016-04-13
WUHAN CATALYS TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The catalytic system that can achieve the best results in this catalytic reaction is Zhou Qilin 9 The reported iridium-phosphine-oxazoline complex catalyst with a chiral spiro ring skeleton, but an external base is required to promote the reaction in the reaction
Although there have been a large number of research reports, the substrate scope of most catalysts is narrow, and there are few examples of high catalytic efficiency and high enantioselectivity.

Method used

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  • Asymmetric hydrogenation method of alpha-oxo-alpha, beta-unsaturated carboxylic acid
  • Asymmetric hydrogenation method of alpha-oxo-alpha, beta-unsaturated carboxylic acid
  • Asymmetric hydrogenation method of alpha-oxo-alpha, beta-unsaturated carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Example 1, Effect of Metal Precursors

[0017] Initially selected (Z)-2-methoxyl-3-phenylacrylic acid (1a) as the template substrate to investigate the reaction, to our delight: with methanol as solvent, under 20atm hydrogen pressure, [Rh(COD ) 2 ] BF 4 (1.0mol%; NBD=2,5-norbornadiene) and ChenPhos (1.1 equivalent with respect to Rh) in situ generated ChenPhos-Rh complex can successfully catalyze the hydrogenation conversion of all substrate 1a, and obtain an ee value of 87% (Table 1 , entry1). Encouraged by this result, we next investigated metal precursors and found that different types of rhodium sources gave similar results, where [Rh(NBD)Cl] 2 gave the best results, and the ee value was only increased by 2%; in terms of iridium source, [Ir(COD)Cl] 2 gives similar ee values ​​to rhodium, but is significantly less catalytically active.

[0018]

[0019] [a] Reaction conditions: 0.2mmol, substrate concentration 0.1mol / L, solvent 2mL, catalyst 1.0mol%.[b] 1 Th...

Embodiment 3

[0023] The suitability of embodiment 3 substrates

[0024] Determined by CF 3 CH 2 OH is used as a solvent, hydrogen gas at 20 atmospheres, 0.1 mol% ChenPhos-rhodium complex is used, and the reaction at room temperature for 20 hours is the optimal hydrogenation condition, and then the substrate applicability of the reaction is investigated.

[0025]

[0026][a-b] Reaction conditions: 0.2mmol, substrate concentration 0.1mol / L, solvent 2mL, catalyst 0.1mol%. All examples of substrates reacted completely. [b] Chiral HPLC confirmed, and the configuration was confirmed by literature comparison.

[0027]

[0028] Under optimal hydrogenation conditions, different types of α-aryloxy and α-alkyl α,β-unsaturated acid substrates can be completely converted and give very desirable enantioselectivities. The position and steric hindrance effect of the substituent on the aromatic ring of the substrate have little effect on the hydrogenation strategy, and both α-aryloxy and α-alkyl α,...

Embodiment 4

[0029] Embodiment 4 control experiment

[0030]

[0031] In order to gain a deeper understanding of the asymmetric hydrogenation conversion process of α-oxyl functionalized α,β unsaturated carboxylic acid substrates, we conducted two sets of control experiments to verify the ligands of dimethylamino and carboxylic acid Whether ionic interactions between units contribute to the high enantioselectivity of the reaction. On the one hand, with the corresponding unsaturated ester as the substrate under optimal hydrogenation conditions, the reaction does not take place, and all the raw materials are recovered (formula 1); on the other hand, when the reaction adds 50mol% Upon complete conversion, the enantioselectivity drops sharply to 46% (Eq. 2), which may be due to the interaction of the external base with the ligand and substrate, which interferes with the steric control of the reaction. These results verified our initial hypothesis that the ionic interactions in this catalyti...

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Abstract

The invention relates to an asymmetric hydrogenation method of alpha-oxo-alpha, beta-unsaturated carboxylic acid. A metal complex containing ChenPhos chiral ligand is a catalyst high in conversion efficiency, and particularly, the catalyst can be used for synthesizing a core framework in enkephalinase inhibitor Sacubitril through asymmetric hydrogenation. The inhibitor is one of components of medicine LCZ 696 approved by American Food and Drug Administration. The asymmetric hydrogenation method of the alpha-oxo-alpha, beta-unsaturated carboxylic acid is efficient, and the application range of substrate is wide.

Description

technical field [0001] The invention relates to an asymmetric hydrogenation method of α-oxo-α, β-unsaturated carboxylic acid, wherein the metal complex containing ChenPhos chiral ligand is a kind of catalyst with high conversion efficiency, especially the catalyst can pass through Symmetrical hydrogenation synthesis of the core skeleton of Sacubitril, a neprilysin inhibitor, is one of the components of the drug LCZ696 approved by the US Food and Drug Administration. Background technique [0002] Optically pure α-oxocarboxylic acid compounds are an important class of organic synthesis intermediates, and are widely used as crop protection agents in the field of agricultural chemistry 1 . Moreover, they display important pharmacological properties for nootropic, cholesterol-lowering and hyperlipidemic 2 . Many α-aryloxy and α-alkoxycinnamic acid derivatives have attracted much attention as potential agonists for peroxisome proliferator-activated receptors (PPARs) in the trea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B35/02C07C51/36C07C59/64C07C59/68C07C59/66C07D307/54C07D333/24C07D265/38C07D333/74C07C231/12C07C235/40C07C303/30C07C309/66C07D413/12C07D263/58C07C233/47C07C271/22B01J31/24
CPCC07B35/02B01J31/2409B01J31/2414B01J2231/645B01J2531/0225B01J2531/0238B01J2531/822C07B2200/07C07C51/36C07C231/12C07C233/47C07C271/22C07C303/30C07D263/58C07D265/38C07D307/54C07D333/24C07D333/74C07D413/12C07C59/64C07C59/68C07C59/66C07C235/40C07C309/66
Inventor 张绪穆
Owner WUHAN CATALYS TECH CO LTD
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