CN112724143B - Method for preparing theobromine by methylating 3-methylxanthine - Google Patents
Method for preparing theobromine by methylating 3-methylxanthine Download PDFInfo
- Publication number
- CN112724143B CN112724143B CN202110174812.8A CN202110174812A CN112724143B CN 112724143 B CN112724143 B CN 112724143B CN 202110174812 A CN202110174812 A CN 202110174812A CN 112724143 B CN112724143 B CN 112724143B
- Authority
- CN
- China
- Prior art keywords
- methylxanthine
- theobromine
- solvent
- choline chloride
- ethylene glycol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/10—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 3 and 7, e.g. theobromine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for preparing theobromine by methylating 3-methylxanthine. The method comprises the following steps: adding 3-methylxanthine, dimethyl carbonate and a solvent into a reaction kettle, and reacting for 2-11 hours at the temperature of 120-210 ℃ under the stirring condition; cooling to room temperature, filtering, washing a filter cake, and drying at 50-70 ℃ under reduced pressure to obtain a solid, namely crude theobromine; the solvent is one or two of water and eutectic solvent. The invention does not need to adjust the pH value, does not use any catalyst, reduces the production cost, and has the highest 3-methylxanthine reaching 89.9 percent and the theobromine selectivity reaching 98.2 percent.
Description
The technical field is as follows:
the invention relates to the field of organic synthesis, in particular to a preparation method of theobromine.
Background art:
theobromine is a xanthine alkaloid compound, is white needle-shaped crystal or crystalline powder in normal state, and has chemical name of 3, 7-dimethyl xanthine and molecular formula of C7H8N4O2And the molecular weight is 180.16.
Theobromine can be used as bitter agent for food additive, and as a central stimulant of xanthine, and has diuretic, myocardial exciting, vasodilating, and smooth muscle relaxing effects. In addition, theobromine is also used as a starting material for the preparation of pentoxifylline. Pentoxifylline is a methylxanthine derivative that improves blood flow and is used to treat intermittent tauopathy and vascular dementia.
Generally, the theobromine is prepared by a process comprising: (1) theobromine is produced by xanthine methylation. Dissolving xanthine in aqueous solution of sodium hydroxide, controlling pH value to 8.2-8.5, and adding dimethyl sulfate (DMS) dropwise for methylation reaction. (2) Theobromine is produced by the methylation of 3-methylxanthine. Dissolving 3-methylxanthine in alkaline aqueous solution such as sodium hydroxide, sodium carbonate, potassium carbonate and the like, and then dropwise adding DMS to carry out methylation reaction.
Typical methylating agents are methyl iodide, methyl bromide, DMS, methyl chloride, etc., and most of these methylating agents are toxic, so that their use is limited in industrial production. However, in the prior industrial technology, the methylation reagent used for preparing theobromine is still DMS, a large amount of wastewater is generated in the reaction process, and complex treatment is required before discharge; and DMS and the carcinogenic byproduct monomethyl sulfate generated after the reaction have high toxicity, which does not accord with the development trend of green chemistry and chemical industry.
The invention content is as follows:
the invention aims to overcome the defects of the prior art and provides a method for preparing theobromine by methylating 3-methylxanthine. The method is based on dimethyl carbonate (DMC) as a methylating agent, does not use any catalyst, and adopts water, a eutectic solvent or a mixture of the two in any proportion as a solvent. In the solvent environment, the 3-methylxanthine and DMC have high reaction activity, and can avoid over methylation reaction and improve the selectivity of producing theobromine. The invention does not need to adjust the pH value, reduces the production cost, and has the highest 3-methylxanthine reaching 89.9 percent and the theobromine selectivity of 98.2 percent.
The technical scheme of the invention is as follows:
a process for the preparation of theobromine from the methylation of 3-methylxanthines comprising the steps of:
adding 3-methylxanthine, dimethyl carbonate and a solvent into a reaction kettle, and reacting for 2-11 hours at the temperature of 120-210 ℃ under the stirring condition; and cooling to room temperature, filtering, washing a filter cake, and drying at 50-70 ℃ under reduced pressure to obtain a solid, namely the crude theobromine.
Wherein, the mol ratio is 3-methylxanthine: 1: 2-50 parts of dimethyl carbonate; 5-60 mL of solvent is added to 0.01 mol of 3-methylxanthine.
The solvent is one or two of water and eutectic solvent.
The eutectic solvent is choline chloride/urea, choline chloride/ethylene glycol, tetrabutylammonium bromide/ethylene glycol or tetrabutylammonium bromide/triethylene glycol.
When the eutectic solvent is choline chloride/urea, the molar ratio is choline chloride: urea 1: 2; in the case of choline chloride/ethylene glycol, the molar ratio is choline chloride: ethylene glycol 1: 2; in the case of tetrabutylammonium bromide/ethylene glycol, the molar ratio is tetrabutylammonium bromide: ethylene glycol 1: and 4, when the molar ratio is tetrabutylammonium bromide/triethylene glycol, the molar ratio is tetrabutylammonium bromide: triethylene glycol 1: 4.
the invention has the substantive characteristics that:
at present, in the related patents for preparing theobromine by methylating 3-methylxanthine, highly toxic DMS is used as a methylating reagent, and an alkaline environment is required, so that the reaction system is complex, a large amount of byproducts are generated, and the separation is difficult. The invention uses green chemical DMC as methylating agent, does not use any catalyst, uses water, eutectic solvent or the mixture of the water and the eutectic solvent as solvent, does not need to adjust pH value, and has simple reaction system. DMC and 3-methylxanthine are subjected to methylation reaction, the conversion rate of the 3-methylxanthine can reach 89.9% to the maximum, and the selectivity of theobromine is 98.2%.
The invention has the beneficial effects that:
1. the invention uses DMC as a green chemical instead of DMS which is extremely toxic as a methylation reagent.
2. The invention uses water, eutectic solvent or the mixture of the water and the eutectic solvent as the solvent, does not use any catalyst, does not need to adjust the pH value, reduces the complexity of a reaction system and reduces the production cost.
The specific implementation mode is as follows:
the present invention will be described in detail with reference to examples, which should not be construed as limiting the scope of the invention.
The reaction equation of the 3-methylxanthine and DMC of the present invention is shown as follows:
example 1
A100 mL autoclave was charged with 0.009mol of 3-methylxanthine, 0.067mol of DMC and 10mL of water, sealed (the same applies to the following examples), and reacted at 160 ℃ for 3 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the filter cake was washed with water and dried under reduced pressure at 60 ℃ to obtain crude theobromine. High Performance Liquid Chromatography (HPLC) was used to determine 3-methylxanthine conversion to 43.4% and theobromine selectivity to 98.4%.
The obtained crude theobromine is dissolved in sodium hydroxide aqueous solution, decolored by active carbon and recrystallized to obtain a pure product. Purity greater than 99.2% by HPLC analysis.
Example 2
A100 mL autoclave was charged with 0.006mol of 3-methylxanthine, 0.067mol of DMC and 10mL of water and reacted at 160 ℃ for 3 hours. After the reaction is finished, cooling to room temperature, filtering, washing a filter cake by water, and drying at 60 ℃ under reduced pressure to obtain crude theobromine. The conversion of 3-methylxanthine was 60.3% and the theobromine selectivity was 98.1% as determined by HPLC.
Example 3
A100 mL autoclave was charged with 0.006mol of 3-methylxanthine, 0.067mol of DMC and 10mL of water and reacted at 160 ℃ for 9 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the filter cake was washed with water and dried under reduced pressure at 60 ℃ to obtain crude theobromine. The conversion of 3-methylxanthine was 89.9% and the theobromine selectivity was 98.2% as determined by HPLC.
Example 4
A100 mL autoclave was charged with 0.006mol of 3-methylxanthine, 0.03mol of DMC and 10mL of water and reacted at 160 ℃ for 9 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the filter cake was washed with water and dried under reduced pressure at 60 ℃ to obtain crude theobromine. The conversion of 3-methylxanthine was 60.3% and the theobromine selectivity was 96.8% as determined by HPLC.
Example 5
To a 100mL autoclave were added 0.006mol of 3-methylxanthine, 0.067mol of DMC and 10mL of a eutectic solvent (choline chloride/urea (molar ratio 1:2), reacted at 160 ℃ for 9 hours, cooled to room temperature after the reaction was completed, filtered, the filter cake was washed with water and dried under reduced pressure at 60 ℃ to give crude theobromine, which was measured by HPLC to have a 3-methylxanthine conversion of 85.6% and a theobromine selectivity of 95.0%.
Examples 6 to 8
The methylation reaction of 3-methylxanthine and DMC was carried out in the same manner as in example 5 except that the types of eutectic solvents used in the experiment were changed to choline chloride/ethylene glycol (molar ratio 1:2), tetrabutylammonium bromide/ethylene glycol (molar ratio 1:4), and tetrabutylammonium bromide/triethylene glycol (molar ratio 1:4), respectively, and the reaction conditions were the same as in example 5, and the reaction results are shown in the following table.
Example 9
A100 mL autoclave was charged with 0.006mol of 3-methylxanthine, 0.067mol of DMC, 5mL of water, and 5mL of choline chloride/urea (molar ratio 1:2) and reacted at 160 ℃ for 9 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the filter cake was washed with water and dried under reduced pressure at 60 ℃ to obtain crude theobromine. The conversion of 3-methylxanthine was 88.6% and the theobromine selectivity was 93.5% as determined by HPLC.
Examples 10 to 12
The methylation of 3-methylxanthine and DMC was carried out under the same conditions as in example 9, except that the reaction time was changed, and the results are shown in the following Table.
Examples 13 to 15
The methylation reaction of 3-methylxanthine and DMC was carried out in the same manner as in example 10(3 hours) with the same procedure as in example 9, except that the reaction solvent was a mixture of water and another eutectic solvent, and the results were shown in the following Table.
The invention is not the best known technology.
Claims (2)
1. A process for the preparation of theobromine from the methylation of 3-methylxanthines, characterized in that it comprises the following steps:
adding 3-methylxanthine, dimethyl carbonate and a solvent into a reaction kettle, and reacting for 2-11 hours at the temperature of 120-210 ℃ under the stirring condition; cooling to room temperature, filtering, washing a filter cake, and drying at 50-70 ℃ under reduced pressure to obtain a solid, namely crude theobromine;
wherein, the mol ratio is 3-methylxanthine: 1: 2-50 parts of dimethyl carbonate; adding 5-60 mL of solvent into 0.01 mol of 3-methylxanthine;
the solvent is water and eutectic solvent;
the eutectic solvent is choline chloride/urea, choline chloride/ethylene glycol, tetrabutylammonium bromide/ethylene glycol or tetrabutylammonium bromide/triethylene glycol.
2. The process for the preparation of theobromine by the methylation of 3-methylxanthine according to claim 1, characterized in that the eutectic solvent is choline chloride/urea in a molar ratio choline chloride: urea 1: 2; in the case of choline chloride/ethylene glycol, the molar ratio is choline chloride: ethylene glycol 1: 2; in the case of tetrabutylammonium bromide/ethylene glycol, the molar ratio is tetrabutylammonium bromide: ethylene glycol 1: and 4, when the molar ratio is tetrabutylammonium bromide/triethylene glycol, the molar ratio is tetrabutylammonium bromide: triethylene glycol 1: 4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110174812.8A CN112724143B (en) | 2021-02-07 | 2021-02-07 | Method for preparing theobromine by methylating 3-methylxanthine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110174812.8A CN112724143B (en) | 2021-02-07 | 2021-02-07 | Method for preparing theobromine by methylating 3-methylxanthine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112724143A CN112724143A (en) | 2021-04-30 |
| CN112724143B true CN112724143B (en) | 2022-04-15 |
Family
ID=75596571
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110174812.8A Active CN112724143B (en) | 2021-02-07 | 2021-02-07 | Method for preparing theobromine by methylating 3-methylxanthine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112724143B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0319854A2 (en) * | 1987-12-10 | 1989-06-14 | Boehringer Ingelheim Kg | Process for the methylation of xanthins |
| CZ281006B6 (en) * | 1990-10-26 | 1996-05-15 | Slovakofarma A.S. | Process for preparing 3,7-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-1h-purine |
| CN101220032A (en) * | 2007-12-14 | 2008-07-16 | 山东新华制药股份有限公司 | Novel method for producing theobromine with 3_methylxanthine disodium salt methylating |
| CN101896484A (en) * | 2007-12-14 | 2010-11-24 | 百利高贸易（上海）有限公司 | Theobromine production process |
| CN104892611A (en) * | 2015-05-19 | 2015-09-09 | 青岛科技大学 | Synthetic method of caffeine |
| CN105294691A (en) * | 2015-11-23 | 2016-02-03 | 青岛科技大学 | Preparation process for environment-friendly semisynthetic caffeine |
| CN109836424A (en) * | 2019-03-12 | 2019-06-04 | 河北工业大学 | A kind of method that the sodium salt methylation of environment-friendly type theophylline prepares caffeine |
-
2021
- 2021-02-07 CN CN202110174812.8A patent/CN112724143B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0319854A2 (en) * | 1987-12-10 | 1989-06-14 | Boehringer Ingelheim Kg | Process for the methylation of xanthins |
| CZ281006B6 (en) * | 1990-10-26 | 1996-05-15 | Slovakofarma A.S. | Process for preparing 3,7-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-1h-purine |
| CN101220032A (en) * | 2007-12-14 | 2008-07-16 | 山东新华制药股份有限公司 | Novel method for producing theobromine with 3_methylxanthine disodium salt methylating |
| CN101896484A (en) * | 2007-12-14 | 2010-11-24 | 百利高贸易（上海）有限公司 | Theobromine production process |
| CN104892611A (en) * | 2015-05-19 | 2015-09-09 | 青岛科技大学 | Synthetic method of caffeine |
| CN105294691A (en) * | 2015-11-23 | 2016-02-03 | 青岛科技大学 | Preparation process for environment-friendly semisynthetic caffeine |
| CN109836424A (en) * | 2019-03-12 | 2019-06-04 | 河北工业大学 | A kind of method that the sodium salt methylation of environment-friendly type theophylline prepares caffeine |
Non-Patent Citations (1)
| Title |
|---|
| 碳酸二甲酯在化工领域中的应用;江琦;《石油化工》;20000229;第29卷(第2期);第144-147页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112724143A (en) | 2021-04-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4374987A (en) | Process for the preparation of high purity methotrexate and derivatives thereof | |
| JP7365349B2 (en) | Method for producing prostaglandin analogs that donate nitric oxide | |
| JP2009503034A (en) | Process for producing 7H-pyrrolo [2,3-d] pyrimidine derivative | |
| EP0773923B1 (en) | Process for the preparation of a halosubstituted aromatic acid | |
| RU2345085C2 (en) | Oxaliplatin with low content of accompanying admixtures and method of obtaining it | |
| JP4841129B2 (en) | Production method of penum crystals | |
| RU2074854C1 (en) | Method of synthesis of derivatives of o-(2-hydroxy-3-piperidino-1-propyl)-nicotinic acid amideoxime and their salts (variants), o-(2-hydroxy-3-piperidino-1-propyl)-nicotinic acid amideoxime pure crystalline base | |
| CN112724143B (en) | Method for preparing theobromine by methylating 3-methylxanthine | |
| CN111116587A (en) | Preparation method of avibactam intermediate compound | |
| WO2011001976A1 (en) | Method for producing threo-3-(3,4-dihydroxyphenyl)-l-serine | |
| KR101807904B1 (en) | Preparation process of (6r)-tetrahydrobiopterin hydrochloride | |
| CN112341406B (en) | Synthesis method of trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantane-1-ol | |
| US7476760B2 (en) | Purification and production methods of 1-aminocyclopropanecarboxylic acid | |
| JP3926943B2 (en) | Method for producing substituted pyridine | |
| EP0621260B1 (en) | Process for producing N,N-disubstituted p-phenylenediamine derivative sulphate | |
| CN112225736B (en) | Preparation method of 6-bromoimidazo [1.2-a ] pyridine-3-formaldehyde | |
| CN114907380B (en) | Synthesis method of isothiazolo [5,4-B ] pyridine-3 (2H) -ketone 1, 1-dioxide | |
| US5648490A (en) | Process for the preparation of 5-formylaminopyrimidines | |
| CN109535025B (en) | Preparation method of Evonib intermediate 3, 3-difluorocyclobutylamine hydrochloride | |
| JPH072742A (en) | New production method of 4-amino-3-methyl-n-ethyl-n-(beta-hydroxyethyl)aniline sulfuric acid salt | |
| US5679859A (en) | Process for producing improved crystals of 3-amino-2-hydroxyacetophenone salt | |
| JPS6123176B2 (en) | ||
| US5169955A (en) | Process for producing 2-hydroxyquinoxaline derivatives | |
| CN116514666A (en) | Preparation method of bromhexine hydrochloride | |
| CN117945935A (en) | Preparation method of deuterated betaine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |