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Preparation method of theobromine

A technology of theobromine and liquid caustic soda, which is applied in the direction of organic chemistry, can solve the problems of no obvious increase in yield, high COD and salinity, and high caffeine residue, so as to reduce reaction time, high yield, and reduce environmental protection treatment effect of difficulty

Inactive Publication Date: 2020-12-29
CSPC INNOVATION PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has long steps, complicated process steps, long production cycle, and many side reactions, resulting in a large amount of sewage discharge, high COD and salinity; Synthesis of theobromine by ring-opening, cyanidation, and ring-closing reactions
This method has simple steps, but the yield is low, less than 40%, the conversion rate is not high, the caffeine residue is high, and the amount of alkali used in the process is large, and a large amount of COD-containing wastewater is discharged; the third is the hydrazine hydrate method, that is, caffeine and Hydrazine hydrate is used as raw material, and theobromine is obtained by adding concentrated sulfuric acid and sodium nitrite for deamination treatment
In recent years, the domestic research on theobromine has focused on the research and development of refined decolorization and biological methods, which has not significantly improved the yield

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] At 20°C, 1.2 mol of oxalyl chloride was added dropwise to 1 mol of cyanoacetic acid and 5 mol of dichloromethane for 20 minutes. After the dropwise addition was completed, the reaction was carried out for 2 hours, and then the reaction solution was concentrated to remove dichloromethane and excess oxalyl chloride. Then slowly add 1.2mol monomethylurea and 5mol dichloromethane at 10°C, and add 1.2mol anhydrous sodium carbonate. After reacting for 5 hours, add water and stir, and filter to obtain the product-formylcyanoacetylurea. The product has a purity of 98%.

[0038] Dimethyl cyanoacetylurea was dissolved in water, and liquid alkali was added to adjust the pH to 9, and then reacted at 90°C for half an hour, cooled to room temperature, and filtered to obtain monomethyl 4AU.

[0039] Take 20g of monomethyl 4AU, completely dissolve it in 150g of formic acid, cool down to 0°C, add 1 molar equivalent of monomethyl 4AU sodium nitrite, and react at room temperature for 4 ...

Embodiment 2

[0043] At 0°C, add 1.5 mol of oxalyl chloride dropwise to 1 mol of cyanoacetic acid and 5 mol of acetone for 40 minutes. After the dropwise addition, the reaction was carried out for 5 hours, and then the reaction solution was concentrated to remove acetone and excess oxalyl chloride. Then slowly add 1 mol of methylurea and acetone at 30°C, and add 1 mol of sodium hydroxide. After reacting for 3 hours, add water and stir, and filter to obtain the product-formylcyanoacetylurea. The product has a purity of 98.5%.

[0044] Dimethyl cyanoacetylurea was dissolved in water, and liquid alkali was added to adjust the pH to 8, and then reacted at 95°C for half an hour to generate monomethyl 4AU.

[0045] Take 20g of monoformazine 4AU, completely dissolve it in 80g of formic acid, and cool down to -10°C. Add 1.2 molar equivalents of sodium nitrite in monomethyl 4AU, and react at room temperature for 2.5 hours. Add 0.2 g of catalyst (5% palladium carbon) and control the temperature a...

Embodiment 3

[0049]At -10°C, add 1 mol of oxalyl chloride dropwise to 1 mol of cyanoacetic acid and 5 mol of chloroform for 60 minutes. After the dropwise addition was completed, the reaction was carried out for 1 hour, and then the reaction solution was concentrated to remove chloroform and excess oxalyl chloride. Then slowly add 1.3mol monomethylurea and chloroform at 0°C, and add 1.5mol triethylamine. After reacting for 7 hours, add water and stir, and filter to obtain the product-formylcyanoacetylurea. The product has a purity of 98.3%.

[0050] Dissolve monomethyl cyanoacetylurea in water and add liquid alkali to adjust pH=10, then react at 100°C for half an hour to generate monomethyl 4AU.

[0051] Take 20g of a 4AU, completely dissolve in 200g of formic acid, and cool down to 10°C. Add 1.5 molar equivalents of sodium nitrite in monomethyl 4AU, and react at room temperature for 5 hours. 1 g of catalyst (Raney nickel) was added, and the temperature was controlled at about 70° C. t...

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Abstract

The invention discloses a preparation method of theobromine, and relates to the technical field of preparation of heterocyclic compounds containing purine ring systems. The method comprises the following steps: adding oxalyl chloride into cyanoacetic acid and a solvent at the temperature of -10-20 DEG C, concentrating to remove the solvent and oxalyl chloride after reaction, adding monomethylureaand the solvent at the temperature of 0-30 DEG C, adding alkali as an acid-binding agent, adding water after reaction, stirring, and filtering to obtain monomethyl cyanoacetylurea; adding water to dissolve cyanuric chloride, adding liquid caustic soda to adjust the pH value to 8-11, and reacting at 80-100 DEG C to generate methyl 4AU; dissolving monomethyl 4AU in formic acid, adding sodium nitrite, reacting at room temperature, adding a catalyst, keeping the temperature at 30-70 DEG C, recovering the catalyst after the reaction is finished, and concentrating mother liquor to recover formic acid, thereby obtaining monomethyl FAU; adding water and liquid caustic soda into monomethyl FAU, carrying out ring-closure reaction, and then adding acid to adjust to be neutral, so as to obtain 3-methyl xanthine; and carrying out a methylation reaction on 3-methylxanthine, and refining to obtain theobromine. The method has the advantages of few reaction steps, few side reactions, high yield and stable product quality.

Description

technical field [0001] The invention relates to the technical field of preparation of heterocyclic compounds containing a purine ring system, in particular to a preparation method of theobromine. Background technique [0002] Theobromine (Theobromine) alias: 3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione. Theobromine is a purine compound that has diuretic, cardiac stimulation, vasodilation, and smooth muscle relaxation effects. It can be used as diuretic, bittering agent, used for weight loss, etc. It is the raw material of pentoxifylline. [0003] There are four main methods for preparing theobromine: one is the methylurea method, that is, using methylurea and cyanoacetic acid as starting materials, the crude product is obtained through condensation, nitrosation, reduction, acylation, ring closure, and methylation. Then refined twice from the crude product. This method has long steps, complicated process steps, long production cycle, and many side reactions, resulting in a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/10
CPCC07D473/10
Inventor 韩峰袁斌李凯郭少卿周云雪付晓琪王坤丽
Owner CSPC INNOVATION PHARMA
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