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2-[(substituted aminobenzene)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-3h-pyrimidyl-4-ketone derivative and preparation method and application thereof

A technology of carbonylmethylthio and dichlorobenzyl, applied in the field of derivatives and their preparation, can solve the problems of losing clinical potency

Inactive Publication Date: 2010-02-03
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, due to the spread of drug-resistant strains, this type of drug rapidly loses its clinical efficacy

Method used

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  • 2-[(substituted aminobenzene)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-3h-pyrimidyl-4-ketone derivative and preparation method and application thereof
  • 2-[(substituted aminobenzene)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-3h-pyrimidyl-4-ketone derivative and preparation method and application thereof
  • 2-[(substituted aminobenzene)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-3h-pyrimidyl-4-ketone derivative and preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0031] Embodiment 1: the preparation method of intermediate 6-(2,6-dichlorobenzyl)-2-mercapto-3H-pyrimidin-4-one

[0032] Put 0.1 mol of diethyl malonate (diethyl methylmalonate) 1 in 150 mL of anhydrous acetonitrile, and then add 0.12 mol of anhydrous MgCl 2 , 0.152mol Et 3 N, stirred at room temperature for 2 hours. 0.048mol of 2,6-dichlorophenylacetic acid and 0.05mol of N,N-carbonyldiimidazole were placed in 150mL of acetonitrile to react for 15-20min, and then the reaction mixture was added to diethyl malonate (methylmalonate acid diethyl ester), anhydrous MgCl 2 ,Et 3In the mixture of N. Stir at room temperature for 12-24h, heat to reflux for 2h, TLC tracking until the reaction is complete. Add 150mL of 13% hydrochloric acid dropwise in an ice-bath environment, stir for 15min-20min after dropping, separate the organic layer and evaporate to dryness, and add 150ml of ethyl acetate. The mixture of ethyl acetate was first treated with NaHCO 3 The solution was washed ...

Embodiment 2

[0036] Example 2: Preparation of 2-[(4-methoxyanilino)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-3H-pyrimidin-4-one 4a 6-(2 , 6-dichlorobenzyl)-2-mercapto-3H-pyrimidin-4-one 3 (2mmol, 0.574g) and K 2 CO 3 (2mmol, 0.276g) was placed in a reaction flask, anhydrous N,N-dimethylformamide (DMF) 15mL was added, and after stirring at room temperature for 20min, 2-chloro-N-(4-methoxyphenyl ) Acetamide (0.439g, 2.2mmol), stirred at room temperature, followed by TLC until the starting point disappeared, and the reaction was stopped. Add 100 mL of ice water, a white precipitate occurs. Filter and recrystallize with ethanol-N,N-dimethylformamide (EtOH-DMF) mixed solvent to obtain the target compound 4a. White crystals, yield 25.4%, mp: 238-240°C (dec).

[0037] Product spectral analysis data:

[0038] 1 H-NMR (DMSO-d 6 , ppm) δ: 12.80 (s, 1H, NH), 10.08 (s, 1H, NH), 7.45-7.29 (m, 7H), 5.41 (s, 1H, CH=C=O), 4.05 (s, 2H , S-CH 2 ), 3.99 (s, 2H, CH 2 ), 3.69(s, OCH 3 , 3H); IR (KB...

Embodiment 3

[0039] Example 3.2-[(4-chloroanilino)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-3H-pyrimidin-4-one 4b,

[0040] The preparation method is the same as in Example 2, except that the substituted chloroacetanilide is 2-chloro-N-(4-chlorophenyl)acetamide.

[0041] The obtained product 2-[(4-chloroanilino)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-3H-pyrimidin-4-one 4b was a white crystal with a yield of 23.6%, mp: 223-225℃(dec).

[0042] Product spectral analysis data:

[0043] 1 H-NMR (DMSO-d 6 , ppm) δ: 12.77 (s, 1H, NH), 10.37 (s, 1H, NH), 7.57-7.24 (m, 7H), 5.44 (s, 1H, C-5H pyrimidine ring), 4.00 (4H, CH 2 , S-CH 2 ).IR(KBr, cm -1 ): 3317 (υ NH ), 3052 (υ NH ), 1657 (υ C＝O ).ESI-MS: m / z 456.3(M+1), 478.3(M+Na).C 19 h 14 Cl 3 N 2 S 2 O(454.96).

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Abstract

The invention provides a 2-[(substituted aminobenzene)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-3H-pyrimidyl-4-ketone derivative with the general structure shown on the right, wherein, R1 is H or methyl; R2 is 4-chlorine, 4-methoxyl, 4-nitryl, 3,4-dichloro, 4-bromine, 3,4-difluoro, 3-chlorine-4-fluorin, 3,4-dimethoxy or 4- methyl. The invention also relates to a preparation method of the compoundand application of the compound as an HIV inhibitor.

Description

technical field [0001] The invention relates to a derivative and a preparation method thereof, in particular to 2-[(substituted phenylamino)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-3H-pyrimidin-4-one derivatives The compound and its preparation method and application belong to the technical field of organic compound synthesis and medical application. Background technique [0002] AIDS (AIDS) is caused by human immunodeficiency virus (HIV) and is a major infectious disease that seriously endangers human life and health. HIV is a retrovirus, and the important role of reverse transcriptase in the viral life cycle makes it an important target for antiviral therapy. There are two classes of reverse transcriptase inhibitors: nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have attracted much attention due to their high efficiency, low toxicity, and high selectivity. Howev...

Claims

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Application Information

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IPC IPC(8): C07D239/56A61K31/513A61P31/18
Inventor 刘新泳于明艳
Owner SHANDONG UNIV
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