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(2R, 3S)-beta'-hydroxy-beta-amino-acid ester derivative and preparation method thereof

A technology for amino acid esters and derivatives, which is applied in the field of efficient preparation of -β'-hydroxy-β-amino acid ester derivatives, can solve the problem that the de value is only 70% and needs to be further optimized, and achieves low green pollution and easy industrialization , The effect of high atom economy

Active Publication Date: 2021-09-07
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Diego et al. reported a method for enzymatically constructing β′-hydroxy-β-amino acid ester derivatives (Tetrahedron Lett., 2014, 55, 7051-7053.), the ee value of the product can reach 98%, but its de value is only 70% , to be further optimized

Method used

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  • (2R, 3S)-beta'-hydroxy-beta-amino-acid ester derivative and preparation method thereof
  • (2R, 3S)-beta'-hydroxy-beta-amino-acid ester derivative and preparation method thereof
  • (2R, 3S)-beta'-hydroxy-beta-amino-acid ester derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1: Preparation of (2R,3S)-2-(benzamidomethyl)-3-hydroxyl-3-phenylpropionic acid ethyl ester (Ia)

[0030]

[0031] (1) Add [Ir(COD)Cl] to a 10.0mL flask under argon atmosphere 2 (3.36mg, 0.5 mmol%), ligand L1 (7.17mg, 1.05mmol%) and ethyl acetate (1.5mL), stirred at 25°C for 1h to obtain a golden yellow solution, which was directly used in the next catalytic reaction;

[0032] (2) (IIa) (325.0mg, 1.0mmol), the metal Ir catalyst (1.05mmol%) prepared in step (1), sodium carbonate (5.2mg, 0.05 mmol) and ethyl acetate were added successively to a 10mL sample bottle. ester (4mL), and then put the sample bottle into the autoclave, filled with H 2 (3.5MPa), reacted at 40°C for 20h, after the reaction, concentrated under reduced pressure to recover the solvent, and the residue was separated by column chromatography (ethyl acetate:n-hexane=1:3, volume ratio, the same as in the following examples), the preparation Obtain (2R,3S)-2-(benzamidomethyl)-3-hydroxyl-3-pheny...

Embodiment 2

[0034] Example 2: Preparation of (2R,3S)-2-(benzamidomethyl)-3-hydroxyl-3-phenylpropionic acid ethyl ester (Ia)

[0035]

[0036] (1) Add [Ir(COD)Cl] to a 10.0mL flask under argon atmosphere 2 (3.36mg, 0.5 mmol%), ligand L4 (7.47mg, 1.05mmol%) and ethyl acetate (1.5mL), stirred at 25°C for 1h to obtain a golden solution, which was directly used in the next catalytic reaction.

[0037] (2) (IIa) (325.0mg, 1.0mmol), the metal Ir catalyst (1.05mmol%) prepared in step (1), sodium carbonate (5.2mg, 0.05 mmol) and ethyl acetate were added successively to a 10mL sample bottle. ester (4mL), then put the sample bottle into the kettle, fill with H 2 (3.5MPa), reacted at 40°C for 20h, after the reaction, concentrated under reduced pressure to recover the solvent, and the residue was separated by column chromatography (ethyl acetate:n-hexane=1:3) to obtain (2R,3S)-2 -(benzamidomethyl)-3-hydroxy-3-phenylpropanoic acid ethyl ester (Ia), conversion rate: 99%, ee value 92%, dr value 88 / 1...

Embodiment 3

[0038] Example 3: Preparation of (2R,3S)-2-(benzamidomethyl)-3-hydroxyl-3-phenylpropionic acid ethyl ester (Ia)

[0039]

[0040] (1) Add [Ir(COD)Cl] to a 10.0mL flask under argon atmosphere 2 (3.36mg, 0.5 mmol%), ligand L5 (9.30mg, 1.05mmol%) and ethyl acetate (1.5mL), stirred at 25°C for 1h to obtain a golden yellow solution, which was directly used in the next catalytic reaction.

[0041] (2) (IIa) (325.0mg, 1.0mmol), the metal Ir catalyst (1.05mmol%) prepared in step (1), sodium carbonate (5.2mg, 0.05 mmol) and ethyl acetate were added successively to a 10mL sample bottle. ester (4mL), then put the sample bottle into the kettle, fill with H 2 (3.5MPa), reacted at 40°C for 20h, after the reaction, concentrated under reduced pressure to recover the solvent, and the residue was separated by column chromatography (ethyl acetate:n-hexane=1:3) to obtain (2R,3S)-2 -(benzamidomethyl)-3-hydroxy-3-phenylpropanoic acid ethyl ester (Ia), conversion: 73%, ee value 85%, dr value 89...

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Abstract

The invention discloses a (2R, 3S)-beta'-hydroxy-beta-amino-acid ester derivative and a preparation method thereof. The preparation process comprises the steps that a metal Ir complex and a chiral ligand (III) are added into a solvent A in the argon atmosphere at 0-60 DEG C, and stirred to react for 0.5-6 hours, and a solvent A solution of a metal Ir catalyst is prepared; a beta'-carbonyl-beta-amino-acid ester derivative, the prepared metal Ir catalyst, a solvent B and alkali A are sequentially added into a high-pressure kettle under the protection of nitrogen, react for 2-24 hours at the temperature of 10-100 DEG C and the hydrogen pressure of 1.0-10.0 MPa, after the reaction is finished, concentrating is carried out under reduced pressure to remove the solvent, and column chromatography separation is performed on residues to obtain the (2R, 3S)-beta'-hydroxyl-beta-amino-acid ester derivative. According to the beta'-hydroxyl-beta-amino-acid ester derivative obtained by the method disclosed by the invention, the reaction yield is up to 95%, the enantioselectivity is up to 99%, and the diastereoselectivity is up to 99: 1; and compared with the prior art, the derivative and preparation method thereof have the characteristics of high atom economy, low pollution, easiness in industrialization and the like.

Description

technical field [0001] The invention belongs to the technical field of organic and pharmaceutical synthesis, and relates to a (2R,3S)-β'-hydroxy-β-amino acid ester derivative and a preparation method thereof, in particular to a derivative derived from a β'-carbonyl-β-amino acid ester. Asymmetric hydrogenation reaction of compounds, a method for efficiently preparing (2R,3S)-β'-hydroxy-β-amino acid ester derivatives. Background technique [0002] β′-Hydroxy-β-amino acid ester derivatives can be used to prepare unnatural peptides and biologically active compounds, and β′-hydroxy-β-amino acid esters have been proven to be versatile precursors and effective methods for drug synthesis. Because they can stereoselectively synthesize novel β-lactam rings. Carbapenem antibiotics (imipenem, meropenem, ertapenem and other derivatives) are atypical β-lactam antibiotics with the broadest antibacterial spectrum and strongest antibacterial activity, because of their anti-β-lactam Amidase...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07D307/54C07D317/60C07C233/83C07C233/87C07D209/48C07B41/02
CPCC07C231/12C07D307/54C07D317/60C07C233/83C07C233/87C07D209/48C07B41/02C07B2200/07
Inventor 钟为慧王一凡凌飞
Owner ZHEJIANG UNIV OF TECH