Alkynamide-mediated preparation of thioamides and its application in the synthesis of thiopeptides

A technology of thioamide and thiocarboxylic acid, which is applied in the preparation of carboxylic acid amides, the preparation of organic compounds, chemical instruments and methods, etc., to achieve the effects of simple synthesis, mild synthesis, broad scientific research and industrial application prospects

Active Publication Date: 2021-01-26
广州新肽生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to solve the problem in the prior art that the addition of thiocarboxylic acid and alkyne amide selectively obtains thiocarbonyl esters and common thioesters, and then the thiocarbonyl esters are used to prepare thioamides and thiopolypeptides, and the common Thioesters are used to make amides and peptides

Method used

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  • Alkynamide-mediated preparation of thioamides and its application in the synthesis of thiopeptides
  • Alkynamide-mediated preparation of thioamides and its application in the synthesis of thiopeptides
  • Alkynamide-mediated preparation of thioamides and its application in the synthesis of thiopeptides

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041]In a clean 25mL reaction tube, add N-methylacetylene p-toluenesulfonamide (0.24mmol), thioacetic acid (0.20mmol), add an appropriate amount of dichloromethane as a solvent, and react at room temperature for 5 minutes. TLC dot plate detection. After the reaction is complete Solvent concentration and column chromatography gave pure products, yellow liquid a1 (yield 53%) and white solid a2 (yield 46%). The following are the structural formula and nuclear magnetic resonance experimental data of the product:

[0042]

[0043]1H NMR(400MHz, CDCl3)δ7.65(d,J=8.0Hz,2H), 7.26(d,J=8.0Hz,2H), 4.72 (d,J=2.8Hz,1H), 4.54(d,J=2.8Hz,1H) ,2.99(s,3H), 2.50(s,3H), 2.37(s,3H);13C NMR(100MHz, CDCl3)δ217.5, 150.2, 144.3, 133.5, 129.6, 128.0, 100.4, 38.2, 34.0, 21.6ppm.

[0044]

[0045]1H NMR(400MHz, CDCl3)δ7.58(d,J=8.0Hz,2H), 7.25(d,J=8.0Hz,2H), 5.84(s,1H), 5.55(s,1H), 2.90(s,3H), 2.38( s,3H),2.22(s,3H);13C NMR(100MHz, CDCl3)δ192.9, 144.1, 135.4, 134.3, 130.1, 129.6, 127.9, 36.4, 30.2, 21.6ppm.

Embodiment 2

[0047]Add N-methylacetylene p-toluenesulfonamide (0.24 mmol) and thiobenzoic acid (0.20 mmol) into a clean 25mL reaction tube, add an appropriate amount of dichloromethane as a solvent, and react at room temperature for 5 minutes. TLC dot plate detection, the reaction is complete Then, the solvent was concentrated and column chromatography was used to obtain pure products, yellow liquid b1 (yield 55%) and colorless liquid b2 (yield 43%). The following are the structural formula and NMR experimental data of the product:

[0048]

[0049]1H NMR(400MHz, CDCl3)δ8.10(dd,J=8.5,1.2Hz,2H),7.72(d,J=8.3Hz,2H),7.56(ddt,J=8.7,7.6,1.2Hz,1H),7.36(t,J =7.9Hz,2H),7.25(d,J=7.9Hz,2H), 4.93(d,J=2.9Hz,1H), 4.81(d,J=2.8Hz,1H), 3.12(s,3H), 2.39(s,3H);13C NMR(100MHz, CDCl3)δ208.6, 150.1, 144.2, 137.4, 133.8, 133.4, 129.5, 129.4, 128.2, 128.1, 101.5, 38.1,21.6ppm.

[0050]

[0051]1H NMR(400MHz, CDCl3)δ7.83(dd,J=8.3,1.3Hz,2H), 7.70(d,J=8.3Hz,2H), 7.59(t, J=7.1Hz,1H), 7.44(t,J=7.9Hz, 2H), 7.33–7.25 (m, 2H), 6.00 (d, J ...

Embodiment 3

[0053]Add N-methylacetylene p-toluenesulfonamide (0.24 mmol) and p-chlorothiobenzoic acid (0.20 mmol) into a clean 25mL reaction tube, add appropriate amount of dichloromethane as a solvent, and react at room temperature for 5 minutes. TLC dot plate detection After the reaction, the solvent was concentrated and column chromatography was used to obtain pure products, yellow solid c1 (yield 57%) and yellow solid c2 (yield 41%). The following are the structural formula and NMR experimental data of the product:

[0054]

[0055]1H NMR(400MHz, CDCl3)δ8.06(d,J=8.7Hz,2H), 7.71(d,J=8.3Hz,2H), 7.34 (d,J=8.7Hz,2H), 7.27(d,J=8.2Hz,2H) ,4.92(d,J=2.9Hz,1H), 4.75(d,J=2.8Hz,1H), 3.11(s,3H),2.41(s,3H);13C NMR(100MHz, CDCl3)δ206.9, 150.2, 144.2, 140.1, 135.9, 133.6, 130.7, 129.5, 128.4, 128.1, 101.3, 38.3, 21.6ppm.

[0056]

[0057]1H NMR(400MHz, CDCl3)δ7.77(d,J=8.6Hz,2H), 7.69(d,J=8.2Hz,2H), 7.41(d,J=8.6Hz,2H), 7.29(d,J=8.0Hz,2H) ,5.96(s,1H),5.74(s,1H),3.07(s,3H),2.41(s,3H);13C NMR(100MHz, CDCl3)δ188.1, 144.0,...

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Abstract

The invention discloses a method for selectively synthesizing thiocarbonyl esters and common thioesters mediated by alkyne amides, further using common thioesters to prepare amides and polypeptides, and using thiocarbonyl esters to prepare thioamides and thioamides peptide. Under the condition of ‑40 degrees Celsius, the addition reaction of alkyne amides and thiocarboxylic acids in m-xylene selectively yields thiocarbonyl esters and common thioesters (3:1); common thioesters can react with amines to form amides, Polypeptides; thiocarbonyl esters can react with amines to generate thioamides or thiopeptides. The invention has mild reaction conditions, no metal catalyst, fast reaction speed, high yield, simple operation and wide application range. For thiocarboxylic acids with chirality at the α position of the carboxyl group, no racemization occurs when thiocarbonyl esters form thioamide bonds or thiopeptide bonds, or ordinary thioesters form amide bonds or peptide bonds. .

Description

Technical field[0001]The invention relates to a method for selectively synthesizing thiocarbonyl esters and ordinary thioesters, and the application of thiocarbonyl esters in the preparation of thioamides, thiopolypeptides and ordinary thioesters in the preparation of amides and polypeptides. A method for selectively and efficiently preparing thiocarbonyl esters and common thioester compounds under metal catalysis, and a method for preparing thioamides, thiopolypeptides and common thioesters to prepare amides and polypeptides from thiocarbonyl esters.Background technique[0002]In recent years, as the development of new organic small molecule drugs has gradually slowed down, peptide and protein drugs and diagnostic reagents have received more and more attention due to their low side effects and other characteristics, and peptides have also become an important source of new drug development. However, peptide drugs have relatively large molecular weights, poor fat solubility, and diffic...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C327/30C07C327/22C07C327/26C07C327/42C07C327/48C07D295/13C07D307/68C07D207/09C07C327/44C07C231/02C07C231/08C07C233/65C07K5/062
CPCC07C231/02C07C231/08C07C327/22C07C327/26C07C327/30C07C327/42C07C327/44C07C327/48C07D207/09C07D295/13C07D307/68C07K5/06026C07K5/06034C07C233/65
Inventor 赵军锋王辉杨进华王长流
Owner 广州新肽生物医药科技有限公司
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