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Beta-hydroxy-alpha-amino acid derivative, and synthesis method and application thereof

A technology of derivatives and hydroxy esters, applied in the field of new β-hydroxy-α-amino acid derivatives and their chemical synthesis, can solve the limitation of the scope of reaction substrates, reduce the variety of α-amino-β-hydroxy ester derivatives The problems such as low chemical selectivity and low chemical selectivity can be solved, and the effect of low cost, high diastereoselectivity and simple synthesis route can be achieved.

Active Publication Date: 2015-07-29
广东和博制药有限公司
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  • Abstract
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Problems solved by technology

However, this method has several limitations, such as: 1) overall, the chemoselectivity of the reaction is low; 2) only moderate diastereoselectivity; 3) the range of reaction substrates is relatively limited, only electron-deficient aromatic aldehydes Only applicable to this method, greatly reducing the diversity of product α-amino-β-hydroxy acid ester derivatives

Method used

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  • Beta-hydroxy-alpha-amino acid derivative, and synthesis method and application thereof
  • Beta-hydroxy-alpha-amino acid derivative, and synthesis method and application thereof
  • Beta-hydroxy-alpha-amino acid derivative, and synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 Preparation of compound 4a of the present invention

[0029] First take by weighing p-nitrobenzaldehyde 3a (0.1mmol), o-methoxyaniline 2a (0.12mmol), benzyldiazoethyl ester 1a (0.2mmol), (1,5-cyclooctadiene) rhodium chloride ( I) dimer (5.0 mg, 0.01 mmol), p-nitrobenzaldehyde 3a, (1,5-cyclooctadiene) rhodium(I) chloride dimer and 1 ml dichloromethane were added to a small test tube reactor , let p-nitrobenzaldehyde 3a and (1,5-cyclooctadiene) rhodium chloride (I) dimer dissolve, then, benzyl diazoethyl ester 1a and o-methoxyaniline 2a with 1ml dichloro Methane was dissolved to obtain 1 ml of a mixed solution of benzyldiazoethyl ester 1a and o-methoxyaniline 2a, and then the mixture of benzyldiazoethyl ester 1a and o-methoxyaniline 2a was mixed by a peristaltic pump for 0.5 hours at room temperature The solution was slowly added dropwise to the reaction flask, and after the reaction was completed, the solvent was removed by rotary evaporation at 30°C-40°C to o...

Embodiment 2-13

[0034] Example 2-13 Preparation of Compound β-Hydroxy-α-Amino Acid Derivatives (4b~4m)

[0035]In Examples 2-13, see Table 1 for the changes of substituents, compound numbers, d.r.

[0036] Table 1

[0037]

[0038] The characterization of the product β-hydroxy-α-amino acid derivatives 4b to 4m is as follows:

[0039] Characterization of 4b:

[0040] 1 H NMR (400MHz, CDCl3, 25°C, TMS) δ7.36(d, J=12.0Hz, 2H), 7.14(d, J=12.0Hz, 2H), 7.08(m, 3H), 6.94(m, 2H ), 6.84-6.81(m, 2H), 6.79-6.71(m, 2H), 5.32-5.26(m, 2H), 4.04-3.97(m, 2H), 3.85(d, J=8.0Hz, 1H), 3.72-3.68(m, 4H), 3.53-3.49(d, J=8.0Hz, 1H), 1.05(t, J=8.0Hz, 3H).

[0041] 13 C NMR (400MHz, CDCl3, 25°C, TMS) δ172.54, 147.86, 138.86, 135.66, 134.73, 130.77, 130.19, 128.78, 127.89, 126.68, 121.75, 120.90, 117.75, 113.40, 1140.437, 6 55.78, 37.76.13.75.

[0042] Characterization of 4c:

[0043] 1 H NMR (400MHz, CDCl3, 25°C, TMS) δ7.47-7.40(m, 2H), 7.29(s, 1H), 7.16(d, J=7.4Hz, 4H), 7.00(s, 2H), 6.86 -6.82(m, 2H), 6...

Embodiment 14

[0075] Example 14 Inhibition of protein tyrosine phosphatase activity by β-hydroxy-α-amino acid derivatives 4a, 4b, 4f, 4g, 4k, 4l, 4m of the present invention

[0076] PTP1B is the first identified protein tyrosine phosphatase (protein tyrosine phosphatase). Experiments with PTP1B knockout mice have shown that PTP1B regulates insulin sensitivity and fat metabolism through dephosphorylation of insulin receptors. play a very important role in the process. Therefore, selective and highly active PTP1B inhibitors are of great value in the treatment of diabetes and obesity.

[0077] Screening method:

[0078] Protocol id: 25

[0079] Protocol name: PTP1B activity assay, absorbance

[0080] Instrument: VERSAmax (Molecular Devices, USA).

[0081] Material: PTP1B, our laboratory uses E. coli expression system to obtain GST fusion protein.

[0082] Substrate, pNPP.

[0083] Procedure: Enzyme activity is detected in 96-well or 384-well flat-bottomed clear microplates using light a...

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Abstract

The invention relates to a beta-hydroxy-alpha-amino acid derivative represented by formula (I), and a chemical synthesis method thereof. The method comprises the following steps: carrying out a one-step reaction on raw materials comprising alpha-aryldiazoester, arylamine and arylaldehyde at room temperature with monovalent metal rhodium as a catalyst and an organic solvent as a solvent, and carrying out column chromatography purification to obtain a product. The preparation method has the advantages of high step economy, strong atom economy, high diastereoselectivity, high yield, mild reaction conditions, and simple and safe operation. The beta-hydroxy-alpha-amino acid novel derivative is an important compound for preparing various bioactive natural products and medicines. The invention also discloses an application of the beta-hydroxy-alpha-amino acid derivative in the inhibition of activity of protein tyrosine phosphatase. The derivative has a wide application prospect in the field of pharmaceutical and chemical engineering.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and relates to a novel beta-hydroxyl-alpha-amino acid derivative and its chemical synthesis method and application. Background technique [0002] β-Hydroxy-α-amino acid derivatives are an important class of compounds to construct a variety of biologically active natural products and drugs, and β-hydroxy- α-amino acid backbone. [0003] [0004] The inventor's research group has disclosed the three-component reaction (Chem.Commun., 2004, 2486-2487) of α-aryl diazo ester, aromatic amine and aromatic aldehyde in 2003-2004, under the catalysis of rhodium acetate , the ammonium ylide generated by α-aryldiazoester and arylamine was successfully captured by aryl aldehyde, and the important skeleton of β-hydroxy-α-amino acid derivative was constructed in one step. However, this method has several limitations, such as: 1) overall, the chemoselectivity of the reaction is low; 2) only modera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/36C07C227/18C07C255/59C07C253/30A61K31/223A61K31/277A61P3/10A61P3/04
Inventor 胡文浩姚文峰江俊刘顺英杨杨马晓初
Owner 广东和博制药有限公司
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