A method for synthesizing amino acid n-methylation and its product and application

A methylation and amino acid technology, applied in the preparation of cyanide reaction, chemical instruments and methods, preparation of organic compounds, etc., can solve the problems of poor industrialization prospects, many reaction steps, and highly toxic reagents, and achieve structural pertinence. Strong, low cost, simple operation effect

Active Publication Date: 2018-09-21
SOUTH CHINA AGRI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are still problems in the methylation process such as many reaction steps, highly toxic reagents, large dosage, and high cost, and the industrialization prospect is not optimistic.

Method used

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  • A method for synthesizing amino acid n-methylation and its product and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] A method for synthesizing amino acid N-methylation, the specific reaction scheme refers to figure 1 .

[0035] In particular, N-methyl(trifluoroacetyl)-amino acid benzyl ester has not been reported, and it needs to be prepared by methylation of N-trifluoroacetyl-amino acid benzyl ester according to the present invention.

[0036] In particular, there are no reports on N-trifluoroacetyl-amino acid benzyl esters, but according to the present invention, amino acid benzyl esters are prepared by trifluoroacetylation protection.

[0037] In particular, when amino acid benzyl ester is not a product that has already been purchased, it is produced from amino acid through esterification.

[0038] Specifically, taking valine as an example to prepare N-methyl (trifluoroacetyl)-valine benzyl ester, the operation is as follows:

[0039] (1) Obtain valine benzyl ester from valine through nucleophilic reaction

[0040] Specifically, in this example, valine is used to synthesize vali...

Embodiment 2

[0049] The N-methyl (trifluoroacetyl)-amino acid benzyl ester prepared by the present invention can be obtained by NaBH 4 N-methyl-amino acid benzyl ester can be obtained by reduction; N-methyl (trifluoroacetyl)-amino acid can be obtained by Pd / C hydrogenation reduction; it can be obtained by K 2 CO 3 / MeOH / H 2 Deprotection of O gives N-methyl-amino acid, which can be selected according to the actual use of N-methyl(trifluoroacetyl)-amino acid benzyl ester.

[0050] Specifically, taking the N-methyl(trifluoroacetyl)-valine benzyl ester prepared in Example 1 as an example, it is hydrogenated and reduced by Pd / C to obtain N-methyl(trifluoroacetyl)-valine Valine.

[0051] Specifically, in this example, N-methyl(trifluoroacetyl)-valine was synthesized using N-methyl(trifluoroacetyl)-valine benzyl ester, and the experimental steps were: 100mL single-necked flask 2.00 g (0.0063 mol) of N-methyl(trifluoroacetyl)-valine benzyl ester prepared in Example 1 was added, tetrahydrofuran...

Embodiment 3

[0054] (1) Obtain alanine benzyl ester through nucleophilic reaction from alanine

[0055] Specifically, in this example, alanine was used to synthesize benzyl alanine, and the experimental procedure was as follows: in a 100mL single-necked flask, 2.00g of alanine (22.4mmol), 3.71g of K 2 CO 3 (1.2eq.26.9mmol, add 50mL acetone, stir at 35°C for 30min, add tetrabutylammonium bromide, nitrogen protection, dropwise add 2.68g benzyl chloride (0.95eq.21.2mmol) acetone (10mL) mixture, react for 12h. After the reaction, suction filtration, the filtrate was spin-dried at 35°C, dissolved in dichloromethane, washed with a saturated aqueous sodium chloride solution, the organic layer was dried with anhydrous sodium sulfate, suction filtration, the filtrate was spin-dried at low temperature, and separated by column chromatography [V (petroleum Ether): V (ethyl acetate) = 4: 1] to obtain 3.07 g of a colorless oily liquid with a yield of 76.5%.

[0056] (2) Obtain N-trifluoroacetyl-alanin...

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Abstract

The invention relates to the technical field of amino acid polypeptide synthesis, and discloses an amino acid N-methylation synthesis method, and a product and an application thereof. According to the invention, through benzyl protection upon the carboxyl group of amino acid and through trifluoroacetyl protection upon the amino group, N-methylated amino acid can be obtained after methylation. The N-methyl(trifluoroacetyl)-amino acid benzyl ester prepared by the method provided by the invention can be directly used in polypeptide synthesis, such that an amino acid benzyl ester product with an N-methyl structure can be obtained. Also, the compound has good deprotection selectivity, and selective deprotection can be carried out upon the N-terminal and the C-terminal. Compared to a Ag2O / CH3I / Boc method (high toxicity and high cost) and a NaH / (CH3O)2SO2 method (high toxicity) abroad, the method provided by the invention has high yield. With the use of nontoxic reagents, the method is safe and nontoxic, and has the advantages of simple operation, common and easy-to-obtain raw material reagents, low cost, and high structural selectivity. The obtained product has low racemization possibility. The method has a good industrial prospect.

Description

technical field [0001] The invention belongs to the technical field of amino acid polypeptide synthesis, and in particular relates to a method for synthesizing amino acid N-methylation and its product and application. Background technique [0002] N-methyl-amino acid is an important fragment of most biologically active peptide natural products, which are reflected in cyclic peptides such as Destruxin, Hirsutellide and chain peptides such as tasiamide. These compounds play an important role in the backbone structure and activity of the polypeptide. The introduction of the methyl group to the polypeptide composed of amino acids after N-methylation sterically affects the structural form of the polypeptide skeleton, reducing the possibility of isomer formation; electronically weakens the electron-absorbing effect of the amide bond N on the carbonyl carbon ability, increases the hydrolytic stability of the protein, and at the same time enhances the membrane permeability (lipophi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C231/08C07C233/47C07C231/12C07C227/20C07C229/12C07C227/18
CPCC07C227/18C07C227/20C07C231/02C07C231/08C07C231/12C07C233/47C07C229/08C07C229/12
Inventor 周琢强刘凯杨晓云刘祖朗
Owner SOUTH CHINA AGRI UNIV
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