Preparation method of 8-thiaxanthine compound

Abstract

The invention discloses a preparation method of an 8-thiaxanthine compound. The method comprises the following steps of: in the presence of a copper salt catalyst, carrying out a reaction on an xanthine compound having a structure shown in a formula II and sulfur compound having a structure shown in a formula III to generate the 8-thiaxanthine compound having a structure shown in a formula I, wherein R1, R2 and R3 are methyl, ethyl, benzyl, normal-butyl, isobutyl, allyl or 2-pyrimidyl, R1, R2 and R3 are same or different; and R4 is ethyl, n-propyl, phenyl, benzyl, cyclohexyl, p-methylphenyl, 2-naphthyl, p-chlorphenyl, p-bromophenyl or 3-nitrobenzophenone. According to the preparation method, by using low-cost copper salt as a catalyst, a product can be successfully prepared in one step, and the preparation method is simple and efficient, high in yield and has wide application prospect.

Description

technical field

[0001] The invention relates to the field of chemical synthesis, in particular to a preparation method of an 8-thiaxanthine compound. Background technique

[0002] Xanthine is a purine base that widely exists in the organs and body fluids of the human body and other organisms. It is often used as a mild stimulant and bronchodilator, especially suitable for the treatment of asthma symptoms. Common xanthine compounds include caffeine, theophylline and theobromine. Caffeine and theophylline are often used as natural adenosine antagonists, which can relieve pain or inhibit asthma. Because both caffeine and theophylline contain a common mother nucleus structure - xanthine, people began to study a large number of synthetic xanthine compounds as adenosine receptor antagonists, especially the 8-substituted xanthine compounds are favored . Based on the research on 8-substituted xanthine compounds, chemists have developed a series of clinically effective drug molecu...

Examples

Embodiment 1

[0056] Add silver acetate (7mg, 0.05mmol) and copper acetate (100mg, 0.5mmol) to a 25mL round bottom flask, add 2mL DMF (N,N-dimethylformamide) to dissolve, then add caffeine 1a (385mg, 2.5mmol, that is, in formula II, R 1 , R 2 , R 3 Both are methyl) and diphenyl disulfide 2a (325mg, 1.5mmol, that is, in formula III, R 4 for phenyl) to form a reaction system. After 12 hours at 120°C, the reaction system was quenched by adding 5 mL of water, and extracted three times with dichloromethane (10 mL). After the organic phases were combined and washed with saturated brine, the organic layer obtained was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation, and then separated by silica gel (300-400 mesh) column chromatography (eluent: dichloromethane and acetone) Volume ratio = 20:1) to obtain 717.5 mg of 1,3,7-trimethyl-8-phenylthioxanthine (yield: 95%) as a white solid. The melting point of the product is 135-137°C; 1 H NMR (CDCl 3 ,600MHz):...

Embodiment 2

[0059] Except that the copper acetate of 2.5mmol is used to replace the copper acetate of 0.5mmol in Example 1 as the catalyst, the remaining operating steps are the same as in Example 1 to obtain 1,3,7-trimethyl-8-phenylthioxanthine 3aa, producing Yield 85%, product characterization data are with embodiment 1.

Embodiment 3

[0061] Except that the silver acetate of 0.125mmol is used to replace the silver acetate of 0.05mmol in Example 1 as an additive, the remaining operation steps are the same as in Example 1 to obtain 1,3,7-trimethyl-8-phenylthioxanthine 3aa, producing Yield 91%, product characterization data with embodiment 1.

technical field

[0001] The invention relates to the field of chemical synthesis, in particular to a preparation method of an 8-thiaxanthine compound. Background technique

[0002] Xanthine is a purine base that widely exists in the organs and body fluids of the human body and other organisms. It is often used as a mild stimulant and bronchodilator, especially suitable for the treatment of asthma symptoms. Common xanthine compounds include caffeine, theophylline and theobromine. Caffeine and theophylline are often used as natural adenosine antagonists, which can relieve pain or inhibit asthma. Because both caffeine and theophylline contain a common mother nucleus structure - xanthine, people began to study a large number of synthetic xanthine compounds as adenosine receptor antagonists, especially the 8-substituted xanthine compounds are favored . Based on the research on 8-substituted xanthine compounds, chemists have developed a series of clinically effective drug molecu...

Examples

Embodiment 1

[0056] Add silver acetate (7mg, 0.05mmol) and copper acetate (100mg, 0.5mmol) to a 25mL round bottom flask, add 2mL DMF (N,N-dimethylformamide) to dissolve, then add caffeine 1a (385mg, 2.5mmol, that is, in formula II, R 1 , R 2 , R 3 Both are methyl) and diphenyl disulfide 2a (325mg, 1.5mmol, that is, in formula III, R 4 for phenyl) to form a reaction system. After 12 hours at 120°C, the reaction system was quenched by adding 5 mL of water, and extracted three times with dichloromethane (10 mL). After the organic phases were combined and washed with saturated brine, the organic layer obtained was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation, and then separated by silica gel (300-400 mesh) column chromatography (eluent: dichloromethane and acetone) Volume ratio = 20:1) to obtain 717.5 mg of 1,3,7-trimethyl-8-phenylthioxanthine (yield: 95%) as a white solid. The melting point of the product is 135-137°C; 1 H NMR (CDCl 3 ,600MHz):...

Embodiment 2

[0059] Except that the copper acetate of 2.5mmol is used to replace the copper acetate of 0.5mmol in Example 1 as the catalyst, the remaining operating steps are the same as in Example 1 to obtain 1,3,7-trimethyl-8-phenylthioxanthine 3aa, producing Yield 85%, product characterization data are with embodiment 1.

Embodiment 3

[0061] Except that the silver acetate of 0.125mmol is used to replace the silver acetate of 0.05mmol in Example 1 as an additive, the remaining operation steps are the same as in Example 1 to obtain 1,3,7-trimethyl-8-phenylthioxanthine 3aa, producing Yield 91%, product characterization data with embodiment 1.

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