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Thiouracil derivative, preparation method and application thereof

A technology of thiouracil and derivatives is applied in the field of thiouracil derivatives and their preparation, and achieves the effects of simple operation, strong antibacterial activity and widening of selection range

Inactive Publication Date: 2015-09-02
HEBEI UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, experiments have confirmed that the purpose of inhibiting bacterial growth can be achieved by inhibiting the kinetic protein SecA that hydrolyzes ATP, but there are few reports on antibacterial compounds targeting SecA

Method used

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  • Thiouracil derivative, preparation method and application thereof
  • Thiouracil derivative, preparation method and application thereof
  • Thiouracil derivative, preparation method and application thereof

Examples

Experimental program
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Embodiment 1

[0043] (1) Add 10mmol aromatic aldehyde, 10mmol ethyl cyanoacetate, and 10mmol thiourea to a 250mL flask, add 100mL absolute ethanol to dissolve, add 2mL piperidine as a catalyst, and reflux at 92°C for 12 hours; cool to room temperature , produce a lot of solids, filter to get the crude product, dissolve the crude product in 0.5mmol / L NaOH solution, wash three times with ethyl acetate, collect the water phase in a beaker, adjust the pH value to 3 with 1mmol / L HCl solution Left and right, separate out a large amount of solids, filter, dry, obtain intermediate compound II; Its chemical reaction process is:

[0044]

[0045] where R 1 is hydrogen, halogen or aromatic, preferably one of hydrogen, chlorine, bromine, fluorine or phenyl;

[0046](2) Add 12mmol potassium thiocyanate (KSCN) and 25mL water into a 250mL flask, stir to dissolve KSCN, then add 20mL toluene and 1mmol tetrabutylammonium bromide (TBAB), stir electromagnetically at room temperature for 30 minutes, and dis...

Embodiment 2

[0056] When the aromatic aldehyde is benzaldehyde, ie R 1 For hydrogen, the arylamine is 4-chloroaniline, ie R 2 For chlorine, the final product compound Ib is obtained according to the preparation method of Example 1, named after: 4-[(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-ylsulfur Substitute) methyl]-N-(4-chlorophenyl)benzoylthiourea;

[0057] After detection, compound Ib (4-[(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-ylthio)methyl]-N-(4-chlorobenzene Base) Benzoylthiourea): Pale yellow solid, yield 65.4%, m.p.186.2~187.3℃; 1 H NMR (CD 3 OD,600MHz)δ:7.92(d,J=8.4Hz,2H,ArH),7.74(d,J=7.8Hz,2H,ArH),7.66(d,J=7.8Hz,2H,ArH),7.62( d,J=1.8Hz,1H,ArH),7.48(d,J=7.2Hz,1H,ArH),7.42(m,J=4.2Hz,3H,ArH),7.28(t,J=8.4Hz,1H ,ArH),4.36(s,2H,CH 2 ); 13 C NMR (CD 3 OD,150MHz)δ:36.7,93.4,115.6,126.4,126.4,127.5,127.5,127.8,127.8,127.9,129.1,129.1,131.1,131.1,131.6,133.7,136.6,136.8,160.8,1605.9 180.2; IR (KBr) v: 3396 (N-H) cm -1 ,1650(C=O)cm -1 ,1540(N-H,C-N)cm -1 ,1309(C-N,N...

Embodiment 3

[0059] When the aromatic aldehyde is benzaldehyde, ie R 1 is hydrogen, and the arylamine is 2-methylaniline, namely R 2 For methyl, the final product compound Ic is obtained according to the preparation method of Example 1, named as: 4-[(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl Thio)methyl]-N-(2-methylphenyl)benzoylthiourea;

[0060] After detection, compound Ic (4-[(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-ylthio)methyl]-N-(2-methyl Phenyl)benzoylthiourea): pale yellow solid, yield 63.5%, m.p.185.0~188.3℃; 1 H NMR (CD 3 OD,600MHz)δ:7.95(d,J=7.8Hz,2H,ArH),7.79(d,J=8.4Hz,2H,ArH),7.62(d,J=7.2Hz,1H,ArH),7.55( d,J=4.2Hz,4H,ArH),7.42(d,J=6.6Hz,1H,ArH),7.30(d,J=6.6Hz,1H,ArH),7.24(m,J=4.8Hz,2H ,ArH),4.38(s,2H,CH 2 ),2.28(s,3H,CH 3 ); 13 C NMR (CD 3 OD, 150MHz) δ: 17.9, 36.7, 93.4, 115.8, 126.0, 126.4, 126.4, 127.5, 127.5, 127.8, 127.8, 128.6, 128.6, 129.7, 130.8, 131.6, 135.9, 139.4, 160.8, 160.5, 160.5, 4, 180.3; IR (KBr) v: 3444 (N-H) cm -1 ,1650(C=O)cm -1 ...

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Abstract

The invention discloses a thiouracil derivative. The chemical formula is shown in the formula I, wherein R1 is hydrogen, halogen or aromatic group, R2 is hydrogen, halogen or alkyl group from C1 to C6. Simultaneously, the invention also discloses a method for synthesizing the derivative. The method comprises the following steps : adopting aromatic aldehyde or an aromatic amine compound as a starting material, and reacting the aromatic aldehyde, ethyl cyanoacetate and thiourea under the catalysis of piperidine to obtain a compound II; reacting chloromethyl-benzoyl chloride and potassium thiocyanate in a methylbenzene / water / TBAB system to obtain a compound III; reacting the compound III and aromatic amine in an acetonitrile solvent to obtain a compound IV, reacting the compound II and the compound IV with the equal mole in the acetonitrile solvent under the catalytic action of potassium carbonate to obtain a target product, i.e., a compound I. The method adopted is simple, the operation is easy, and the large-scale production is easy; and verified by experiment, the prepared compound I has stronger bacteriostatic activity and can be widely applied in bacteriostatic medicine preparations.

Description

technical field [0001] The invention relates to antibacterial drugs and a preparation method thereof, in particular to a thiouracil derivative, a preparation method and application thereof. Background technique [0002] With the extensive use of various antibacterial drugs and antibiotics, many microorganisms have developed resistance to antibacterial drugs, which has become one of the most difficult problems in the clinical treatment of anti-infection. Therefore, the continuous development of new antimicrobial agents, especially those that have new drug targets and / or can overcome drug resistance, is a topic actively explored in the current industry. [0003] In bacterial cells, one-third of proteins are synthesized and transported outside the cytoplasm to function. Most of these proteins move across the membrane through the Sec pathway (secretion pathway). SecA is an ATPase known as the "power pump" in the Sec pathway. This enzyme is the only known energy-converting enzy...

Claims

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Application Information

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IPC IPC(8): C07D239/56A61K31/513A61P31/04
CPCC07D239/56
Inventor 李小六崔朋雷陈华王炳和
Owner HEBEI UNIVERSITY
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