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Chiral beta-amino acid derivative and preparation method thereof

A technology of derivatives and amino acids, which is applied in the field of chiral β-amino acid derivatives and their preparation, can solve problems such as the inability to truly meet the requirements of high-efficiency synthesis of β-amino acids, low selectivity, cumbersome process, etc., and reduce the cost of synthesis , high optical selectivity and high catalytic efficiency

Active Publication Date: 2017-11-24
INST OF CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In these studies, the amine groups are often aromatic amine structures, which require further protection / deprotection processes, making the process too cumbersome and less applicable
In the majority of studies, there are only a few reports on the direct synthesis of β-amino acid esters, and the selectivity is not high, which cannot really meet the actual production of optically pure and efficient synthesis of β-amino acids to meet the needs of actual production.

Method used

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  • Chiral beta-amino acid derivative and preparation method thereof
  • Chiral beta-amino acid derivative and preparation method thereof
  • Chiral beta-amino acid derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Embodiment 1, N, the preparation of O-acetal

[0077] The present invention prepares N, O-acetal, is to use CbzNH 2 As the starting material, the N, O-acetal compound can be obtained through the condensation of amine and aldehyde and the protection of the hydroxyl group through Ac, which includes the following steps:

[0078] CbzNH 2 (Benzyl carbamate), paraformaldehyde are mixed at a molar ratio of 1:1.1, acetic acid and acetic anhydride are mixed at a volume ratio of 1:3 as a reaction solvent, stirred at 60°C for 1 day, and unreacted acetic anhydride is removed and acetic acid to obtain the corresponding very stable Cbz-protected amino N, O-acetal compound, the specific reaction equation is as figure 2 shown;

[0079]

[0080] The structure is confirmed as follows: 1 H NMR (400MHz, CDCl 3 )δ7.44–7.27(m,5H),5.97(s,1H),5.21(t,J=7.9Hz,2H),5.14(s,2H),2.06(s,3H). 13 C NMR (101MHz, CDCl 3 )δ171.29, 155.81, 135.74, 128.26, 128.01, 127.98, 66.92, 66.47, 20.58.

Embodiment 2

[0081] The preparation of embodiment 2, β-amino acid ester

[0082] Prepare according to the reaction equation shown below:

[0083]

[0084] Add ethyl 2-methylacetoacetate (50mmol) and N,O-acetal (75mmol) into the reactor, then dissolve compound 8 (2.5mmol) in 1ml of dichloromethane, drop trifluoro Methanesulfonic acid (2.5mmol), after dichloromethane was distilled off, the catalyst was added to the reactor, and finally m-nitrobenzoic acid (12.5mmol) was added, heated to 60°C, and the reaction was completed after stirring for 3 days, and the target was obtained by column chromatography. Product β-amino acid ester 83%, 99% ee.

[0085] The NMR data for the confirmation of the structure of β-amino acid ester are as follows: 1 H NMR (400MHz, CDCl 3 )δ7.42–7.26(m,5H),5.30(s,1H),5.07(s,2H),4.17(dt,J=6.9,4.1Hz,2H),3.68–3.48(m,2H),2.18 (s,3H),1.40(s,3H),1.24(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl 3 )δ205.68, 171.72, 156.63, 136.57, 128.64, 128.26, 128.20, 66.96, 61.92, 60.60...

Embodiment 3

[0087] Prepare as follows according to the following reaction equation:

[0088]

[0089] Add ethyl cyclohexanone (50mmol) and N,O-acetal (75mmol) into the reactor, then add the chiral primary tertiary diamine organic small molecule catalyst (2.5mmol) shown in formula 5-1 with 1ml Dichloromethane was dissolved, and trifluoromethanesulfonic acid (2.5mmol) was added dropwise under a low-temperature ice bath. After dichloromethane was evaporated, the catalyst was added to the reactor, and m-nitrobenzoic acid (12.5mmol) was added at last, and heated to 60 ℃, the reaction was completed after stirring for 2 days, and the target product β-amino acid ester was obtained by column chromatography with 86% and >99% ee. The NMR data of its structural confirmation are as follows: 1 H NMR (400MHz, CDCl 3 )δ7.40–7.26(m,5H),5.44(d,J=19.0Hz,1H),5.13–4.99(m,2H),4.15(q,J=7.1Hz,2H),3.61(dd,J =13.8,7.8Hz,1H),3.43(dd,J=13.8,5.5Hz,1H),2.63–2.49(m,1H),2.49–2.35(m,2H),2.01(dt,J=9.6,6.1 Hz,1H),1....

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Abstract

The invention discloses a chiral beta-amino acid derivative and a preparation method thereof. The structural formula of the chiral beta-amino acid derivative is represented by a formula I (shown in the description). The preparation method comprises the steps of mixing a mixture of a carbonyl compound and N,O-acetal with chiral primary-tertiary diamine organic small-molecule catalyst, strong acid and weak acid to react, so as to obtain the chiral beta-amino acid derivative, wherein the carbonyl compound includes aldehyde and / or ketone. The chiral beta-amino acid derivative is catalyzed by virtue of the chiral primary-tertiary diamine organic small-molecule catalyst with a simple structure, is synthesized through a one-step method, and is solvent-free, simple and efficient.

Description

technical field [0001] The invention relates to a chiral β-amino acid derivative and a preparation method thereof, belonging to the technical field of organic synthesis. Background technique [0002] At the beginning of the 20th century, Mannich et al. reported the first Mannich reaction, which realized the functionalization process of the α-position of N. Subsequently, the report and application of the Mannich reaction were widely developed, and the report on the application of asymmetric methods was not until 1997. Achieved by Kobayashi through a chiral Zr catalyst. The application of Mannich reaction to realize the construction of chiral skeleton has been further developed, and the construction of amino acids at α-position and β-position directly through Mannich reaction is also a new synthetic method. [0003] The chiral amino acid structure has a very wide range of applications, and can be applied to the synthesis of ligands in organic synthesis and the design of new l...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/06C07C271/16C07C271/22C07C271/18C07C227/20C07C229/22C07C229/46C07C229/30C07C231/12C07C237/04C07C237/08C07C237/06C07C229/28C07C237/24C07C253/30C07C255/46C07C237/10
CPCY02P20/55C07C269/06C07B2200/07C07C227/20C07C229/22C07C229/28C07C229/30C07C229/46C07C231/12C07C237/04C07C237/06C07C237/08C07C237/10C07C237/24C07C253/30C07C255/46C07C271/16C07C271/18C07C271/22
Inventor 罗三中尤扬恩张龙
Owner INST OF CHEM CHINESE ACAD OF SCI
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