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Preparation method of acetylene amide mediated thioacid amide and application of acetylene amide mediated thioacid amide in thiopeptide synthesis

A technology of thioamide and alkyne amide is applied in the preparation of thioamide mediated by alkyne amide and its application in the synthesis of thiopeptides, achieving broad scientific research and industrial application prospects, mild synthesis, and simple synthesis

Active Publication Date: 2018-09-04
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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  • Preparation method of acetylene amide mediated thioacid amide and application of acetylene amide mediated thioacid amide in thiopeptide synthesis
  • Preparation method of acetylene amide mediated thioacid amide and application of acetylene amide mediated thioacid amide in thiopeptide synthesis
  • Preparation method of acetylene amide mediated thioacid amide and application of acetylene amide mediated thioacid amide in thiopeptide synthesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Add N-methylyne-p-toluenesulfonamide (0.24mmol) and thioacetic acid (0.20mmol) to a clean 25mL reaction tube, add an appropriate amount of dichloromethane as a solvent, react at room temperature for 5min, and detect by TLC spotting. Solvent concentration and column chromatography gave pure products as yellow liquid a1 (53% yield) and white solid a2 (46% yield). The following are the structural formula and NMR experimental data of the product:

[0042]

[0043] 1 H NMR (400MHz, CDCl 3 )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); 13 C NMR (100MHz, CDCl 3 )δ217.5, 150.2, 144.3, 133.5, 129.6, 128.0, 100.4, 38.2, 34.0, 21.6ppm.

[0044]

[0045] 1 H NMR (400MHz, CDCl 3 )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); 13 C NMR (100MHz, CDCl 3 )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-methylyne-p-toluenesulfonamide (0.24mmol) and thiobenzoic acid (0.20mmol) into a clean 25mL reaction tube, add an appropriate amount of dichloromethane as a solvent, react at room temperature for 5min, detect by TLC, and the reaction is over Afterwards, the solvent was concentrated and subjected to column chromatography 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] 1 H NMR (400MHz, CDCl 3 )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); 13 C NMR (100MHz, CDCl 3 )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] 1 H NMR (400MHz, CDCl 3 )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....

Embodiment 3

[0053] Add N-methylyne-p-toluenesulfonamide (0.24mmol) and p-chlorothiobenzoic acid (0.20 mmol) into a clean 25mL reaction tube, add an appropriate amount of dichloromethane as a solvent, react at room temperature for 5min, and detect by TLC , 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] 1 H NMR (400MHz, CDCl 3 )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); 13 C NMR (100MHz, CDCl 3 )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] 1 H NMR (400MHz, CDCl 3 )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....

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Abstract

The invention discloses an acetylene amide mediated method for selectively synthesizing carbonyl thioesters and ordinary thioesters. The ordinary thioesters are further used for preparing amides and peptides, and the carbonyl thioesters are used for preparing thioamides and thiopeptides. An addition reaction is carried out between acetylene amide in m-xylene and thiocarboxylic acid to selectivelyobtain the carbonyl thioester and ordinary thioester of which the ratio is 3:1 under the condition of 40 DEG C below zero; the ordinary thioesters can carry out a combination reaction with amines to produce amides and peptides; and the carbonyl can carry out a combination reaction with the amines to produce thioamides and thiopeptides. The method disclosed by the invention is mild in reaction conditions, free of any metal catalyst, high in reaction speed, high in yield, simple in operation and wide in application range. With respect to chiral thiocarboxylic acid in a position alpha of carboxyl, when thioamide bonds or thiopeptide bonds are formed from the carbonyl thioesters or when amido bonds or peptide bonds are formed from the ordinary thioesters, any racemization phenomenon can be avoided.

Description

technical field [0001] The invention relates to a method for selectively synthesizing thiocarbonyl esters and common thioesters, and the application of thiocarbonyl esters in the preparation of thioamides, thiopolypeptides and common thioesters in the preparation of amides and polypeptides. A method for selectively and efficiently preparing thiocarbonyl esters and common thioester compounds under metal-catalyzed conditions, 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, more and more attention has been paid to peptide and protein drugs and diagnostic reagents due to their low toxicity and side effects. Peptides have also become an important source of new drug research and development. However, peptide drugs have relatively large molecular weight, poor fat s...

Claims

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Application Information

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Patent Type & Authority Applications(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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