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Preparation methods of 1, 7-dimethylxanthine and intermediate thereof, and intermediate

A technology of dimethylxanthine and dimethylformamide, which is applied in the field of medicinal chemistry, can solve the problems of harsh conditions, inability to scale up 7-methyladenine benzylium salt derivatives, and low debenzylation yield. Achieving mild reaction conditions, avoiding column chromatography, and good selectivity

Inactive Publication Date: 2019-03-22
NANJING NUTRABUILDING BIO TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] (1) The preparation of 7-methyladenine benzylium salt derivatives cannot be scaled up, and its raw materials have no commercial sources;
[0019] (2) The hydrolysis operation conditions are harsh, and the production is not easy to realize;
[0020] (3) The yield of debenzylation in the last step is low. If sodium / liquid ammonia is used, the production is not easy to realize; if Pd / C is used, the cost is high and heavy metals are introduced
[0026] Its main raw materials have no commercial sources, and either the yield is low, the conditions are harsh, or highly toxic reagents are used, all of which have no industrial value

Method used

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  • Preparation methods of 1, 7-dimethylxanthine and intermediate thereof, and intermediate
  • Preparation methods of 1, 7-dimethylxanthine and intermediate thereof, and intermediate
  • Preparation methods of 1, 7-dimethylxanthine and intermediate thereof, and intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1 Preparation of 6-amino-3-methyl-5-(methylamino)pyrimidinyl-2,4(1H,3H)-dione

[0066]

[0067] 6-Amino-3-methylpyrimidinyl-2,4(1H,3H)-dione (10g, 70.9mmol) was dissolved in acetonitrile, and N-chlorosuccinimide ( 12.9g, 96.8mmol), and react at 20-30°C for 6 hours after the addition, and the reaction is basically complete. After concentration, add water and dichloromethane, separate the liquids, wash with sodium thiosulfate solution, sodium bicarbonate solution, and water successively, concentrate the organic phase and recrystallize, and dry to obtain a light yellow solid 6-amino-5-chloro-3- 10.4 g (57.0 mmol) of methylpyrimidinyl-2,4(1H,3H)-dione, the yield is 80%.

[0068] 6-Amino-5-chloro-3-methylpyrimidinyl-2,4(1H,3H)-dione (10.4g, 57.0mmol) was suspended in ethanol, and 30% methylamine ethanol solution (28.3g , 274mmol), reacted at 20-30°C for 12 hours, and the reaction was almost complete. Concentrate, add dichloromethane, water solution, concentrate...

Embodiment 2

[0069] Example 2 Preparation of 6-amino-3-methyl-5-(methylamino)pyrimidinyl-2,4(1H,3H)-dione

[0070]

[0071] 6-Amino-3-methylpyrimidinyl-2,4(1H,3H)-dione (10g, 70.9mmol) was dissolved in acetonitrile, and dibromohydantoin (13.8g, 48.4mmol ). After the addition is complete, react at 20-30°C for 6 hours, and the reaction is basically complete. After concentration, add water and dichloromethane, separate the liquids, wash with sodium thiosulfate solution, sodium bicarbonate solution, and water successively, concentrate the organic phase and recrystallize, and dry to obtain a light yellow solid 6-amino-5-bromo-3- Methylpyrimidinyl-2,4(1H,3H)-dione 12.9g (58.6mmol), yield 83%.

[0072] 6-Amino-5-bromo-3-methylpyrimidinyl-2,4(1H,3H)-dione (12.9g, 58.6mmol) was suspended in methyl tetrahydrofuran, and a 30% methanol solution of methylamine was added ( 17.1g, 165mmol), reacted at 20-30°C for 12 hours, and the reaction was almost complete. Concentrate, add dichloromethane and ...

Embodiment 3

[0073] Example 3 Preparation of 6-amino-3-methyl-5-(methylamino)pyrimidinyl-2,4(1H,3H)-dione

[0074]

[0075]6-Amino-3-methylpyrimidinyl-2,4(1H,3H)-dione (10g, 70.9mmol) was dissolved in acetonitrile, and dibromohydantoin (30.3g, 106.4mmol ). After the addition is complete, react at 20-30°C for 6 hours, and the reaction is basically complete. After concentration, add water and dichloromethane, separate the liquids, wash with sodium thiosulfate solution, sodium bicarbonate solution, and water successively, concentrate the organic phase and recrystallize, and dry to obtain a light yellow solid 6-amino-5-bromo-3- Methylpyrimidinyl-2,4(1H,3H)-dione 13.7g (62.4mmol), yield 88%.

[0076] 6-Amino-5-bromo-3-methylpyrimidinyl-2,4(1H,3H)-dione (12.9g, 58.6mmol) was suspended in methyl tetrahydrofuran, and a 30% concentration of methylamine solution (1172mmol ), reacted at 20-30° C. for 12 hours, and the reaction was basically complete. Concentrate, add dichloromethane and water ...

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Abstract

The invention provides two preparation methods of 1, 7-dimethylxanthine, an intermediate thereof and a preparation method of the intermediate. The two preparation methods of 1, 7-dimethylxanthine, provided by the invention, have advantages of convenient operation, high safety, high atomic economy, fewer three wastes, cheapness, easy availability, low toxic, safe and stable raw and auxiliary materials, mild reaction conditions, fewer impurities and high yield; the preparation methods provided by the invention purify products by crystallization or beating, avoid column chromatography, and have advantages of simple and feasible operation, stable process, easy control, convenient reaction and post-treatment, and economical and convenient use for industrial production. The invention also provides a novel compound II and a preparation method of the compound II.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method and an intermediate of 1,7-dimethylxanthine and its intermediate Background technique [0002] Methylxanthine alkaloids are natural alkaloids with a xanthine ring structure, in which 1,3,7-trimethylxanthine (caffeine) is extracted from coffee beans, and its structural formula is as follows: [0003] [0004] 1,3-Dimethylxanthine (theophylline) is widely found in the leaves of Camellia plants, and its structural formula is as follows: [0005] [0006] 3,7-Dimethylxanthine (theobromine) exists in cocoa beans and has the following structural formula: [0007] [0008] The above-mentioned methylxanthine compounds are important components in beverages or desserts, and it is reported that paraxanthine (1,7-dimethylxanthine) is one of the main metabolites of caffeine in the body (more than 80 %), the structural formula is as follo...

Claims

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Application Information

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IPC IPC(8): C07D473/04C07D239/54
CPCC07D239/54C07D473/04
Inventor 张健廖琪林
Owner NANJING NUTRABUILDING BIO TECH CO LTD
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