CN109836424B - Method for preparing caffeine by methylation of environment-friendly theophylline sodium salt - Google Patents
Method for preparing caffeine by methylation of environment-friendly theophylline sodium salt Download PDFInfo
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- CN109836424B CN109836424B CN201910184371.2A CN201910184371A CN109836424B CN 109836424 B CN109836424 B CN 109836424B CN 201910184371 A CN201910184371 A CN 201910184371A CN 109836424 B CN109836424 B CN 109836424B
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- caffeine
- sodium salt
- methylation
- theophylline
- theophylline sodium
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- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 title claims abstract description 103
- 229960001948 caffeine Drugs 0.000 title claims abstract description 51
- QVGLHVDBDYLFON-UHFFFAOYSA-M sodium;1,3-dimethylpurin-7-ide-2,6-dione Chemical class [Na+].O=C1N(C)C(=O)N(C)C2=C1[N-]C=N2 QVGLHVDBDYLFON-UHFFFAOYSA-M 0.000 title claims abstract description 24
- 238000007069 methylation reaction Methods 0.000 title claims abstract description 17
- 230000011987 methylation Effects 0.000 title claims abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 238000001816 cooling Methods 0.000 claims abstract description 9
- 238000000746 purification Methods 0.000 claims abstract description 6
- 239000007787 solid Substances 0.000 claims abstract description 6
- 238000002390 rotary evaporation Methods 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims abstract description 3
- IEJIGPNLZYLLBP-UHFFFAOYSA-N Dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229910000856 hastalloy Inorganic materials 0.000 claims description 5
- 239000012498 ultrapure water Substances 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N Theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 claims 2
- 229960000278 Theophylline Drugs 0.000 claims 1
- 159000000000 sodium salts Chemical class 0.000 claims 1
- 239000004412 Bulk moulding compound Substances 0.000 abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N Dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 7
- 238000000034 method Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- 206010003549 Asthenia Diseases 0.000 description 1
- 210000003710 Cerebral Cortex Anatomy 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N Chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- MLIREBYILWEBDM-UHFFFAOYSA-N Cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 1
- 229940050176 Methyl Chloride Drugs 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N Methyl iodide Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- MGJKQDOBUOMPEZ-UHFFFAOYSA-N N,N'-dimethylurea Chemical compound CNC(=O)NC MGJKQDOBUOMPEZ-UHFFFAOYSA-N 0.000 description 1
- 208000007443 Neurasthenia Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000711 cancerogenic Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004156 green chemistry Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 230000001035 methylating Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 238000007034 nitrosation reaction Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- -1 xanthine alkaloid compound Chemical class 0.000 description 1
Abstract
The invention relates to a method for preparing caffeine by methylation of environment-friendly theophylline sodium salt. The method comprises the following steps: adding theophylline sodium salt, DMC and methanol into a reaction kettle, and reacting for 1-5 hours at the temperature of 100 ℃ and 180 ℃ under stirring; and after cooling, separating by rotary evaporation to obtain solid, namely crude caffeine. The invention greatly improves the reaction efficiency of the methylation reaction of the theophylline sodium salt and the DMC, and the prepared crude caffeine is purified through simple purification steps; the highest caffeine yield can reach 97.3 percent.
Description
The technical field is as follows:
the invention relates to the field of organic synthesis, in particular to a method for synthesizing caffeine.
Background art:
caffeine is a xanthine alkaloid compound, which is 1,3, 7-trimethyl xanthine, white or slightly yellowish green in normal state, mercerized needle-like monohydrate crystal with molecular formula C8H10N4O2·(H2O), molecular weight 212.2059. Sublimating monohydrated caffeine to obtain hexagonal prismatic anhydrous crystal with molecular formula of C8H10N4O2And the molecular weight is 194.19.
Caffeine is a central nerve stimulant, has a selective excitation effect on cerebral cortex, can temporarily drive drowsiness and restore energy, is clinically used for treating neurasthenia and coma resuscitation, and is also an important antipyretic analgesic.
The caffeine production method mainly includes extraction method, biological synthesis method and chemical synthesis method. Caffeine was first extracted from coffee at 1820 cadaver. butyl. Since the fischer chemical synthesis of caffeine in 1899, the preparation of caffeine by chemical synthesis has become the main source of caffeine.
At present, the synthetic routes of caffeine manufacturers are basically consistent, that is, cyanoacetic acid and dimethyl urea are used as initial raw materials and prepared by multiple reactions such as condensation, cyclization, nitrosation, reduction, phthalylation, methylation and the like, wherein the last step of caffeine synthesis, which is the most critical step, is the methylation reaction of theophylline sodium salt. This step also concerns whether the whole synthetic route has the characteristics of clean production or environmental protection production.
Typical methylating agents such as methyl iodide, dimethyl sulfate, methyl chloride, and the like are mostly limited in production and use due to their toxicity. However, in the prior art, the methylation reagent of caffeine is still dimethyl sulfate (DMS), the amount of wastewater generated by the reaction is large, the wastewater is subjected to very complicated post-treatment before being discharged, and the use of dimethyl sulfate and the carcinogenic byproduct of monomethyl sulfate generated after the reaction are not in line with the development trend of green chemistry and chemical engineering.
The invention content is as follows:
the invention aims to provide an environment-friendly method for preparing caffeine by methylation of theophylline sodium salt, aiming at the defects of the prior art. The method uses methanol as a solvent, does not use any catalyst, adopts a solid-liquid two-phase reaction process method, greatly improves the reaction efficiency of the methylation reaction of theophylline sodium salt and DMC, and purifies the prepared crude caffeine through simple purification steps.
The technical scheme of the invention is as follows:
an environment-friendly method for preparing caffeine by methylation of theophylline sodium salt comprises the following steps:
adding theophylline sodium salt, DMC and methanol into a reaction kettle, and reacting for 1-5 hours at the temperature of 100-180 ℃ under stirring; and cooling to room temperature, and performing rotary evaporation at 50-70 ℃ until the solvent is evaporated to dryness to obtain a solid, namely the crude caffeine.
Wherein the mol ratio is theophylline sodium salt: dimethyl carbonate (DMC) is 1: 1-20.
Wherein 5-30 ml of methanol is added into 0.01mol of theophylline sodium salt. The purification step of the crude caffeine comprises the following steps:
dissolving the obtained crude caffeine in ultrapure water, crystallizing at a low temperature of 0-10 ℃ for 1-3 hours, carrying out suction filtration while the caffeine is cold, putting the obtained solid in a vacuum oven, and carrying out vacuum drying at 60 ℃ for 2-4 hours;
wherein, the mass ratio of the coarse caffeine: the water accounts for 1: 1-10.
The invention has the substantive characteristics that:
in the prior related patents for preparing caffeine by methylation of theophylline sodium salt, catalysts are used, and a common solvent is water, so that the method is complex, difficult to separate and has more byproducts. The method does not use any catalyst, can finish the methylation reaction of theophylline sodium salt by only using organic phase methanol as a solvent, has relatively simple reaction system and method, simpler product separation and higher yield which reaches 97.3 percent.
The invention has the beneficial effects that:
1. the invention does not need any catalyst, thereby greatly reducing the production cost.
2. Both literature reports and actual production processes indicate that the product yield of the DMS process is about 90%. The DMC process of the present application has caffeine yield up to 97.3%, and obviously improves the utilization rate of raw material theophylline sodium salt.
3. The technology adopts a water washing cooling crystallization method to purify the caffeine, and avoids using limited products of chloroform and dichloromethane.
4. Compared with DMS technology, the technology adopts DMC methylation reaction system, and the generated byproduct sodium methoxide can be converted into methanol/water solution of sodium hydroxide in the purification process.
5. In conclusion, compared with the DMS process, the DMC methylation reaction process system has obvious energy-saving and emission-reducing effects.
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 methylation reaction equation of theophylline sodium salt and DMC is as follows:
example 1
0.01mol of theophylline sodium salt, 0.1mol of DMC and 20ml of methanol are respectively added into a liner with a cover of a 100ml Hastelloy reaction kettle. The reaction was carried out at 160 ℃ for 3 hours under sealed conditions. Cooling to room temperature, and rotationally evaporating the mixture in the kettle at 60 ℃ until the solvent is evaporated to dryness to obtain crude caffeine. A certain amount of sample is taken to prepare a solution, and HPLC detection is used for obtaining the reaction yield of 90.9%.
Example 2
0.01mol of theophylline sodium salt, 0.1mol of DMC and 20ml of methanol are respectively added into a liner with a cover of a 100ml Hastelloy reaction kettle. The reaction was carried out at 160 ℃ for 4 hours under sealed conditions. Cooling, evaporating the solvent to obtain crude caffeine. A certain amount of sample is taken to prepare a solution, and HPLC detection is used for obtaining the reaction yield of 94.0%.
Example 3
0.01mol of theophylline sodium salt, 0.05mol of DMC and 20ml of methanol are respectively added into a liner with a cover of a 100ml Hastelloy reaction kettle. The reaction was carried out at 160 ℃ for 3 hours under sealed conditions. Cooling, evaporating the solvent to obtain crude caffeine. A certain amount of sample is taken to prepare a solution, and HPLC detection is used for obtaining that the reaction yield is 85.4%.
Example 4
0.01mol of theophylline sodium salt, 0.06mol of DMC and 10ml of methanol are respectively added into a liner with a cover of a 100ml Hastelloy reaction kettle. The reaction was carried out at 160 ℃ for 3 hours under sealed conditions. Cooling, evaporating the solvent to obtain crude caffeine. A certain amount of sample is taken to prepare a solution, and HPLC detection is used for obtaining the reaction yield of 97.3%.
Example 5
2g of the crude caffeine obtained in example 4 was put into a 100ml beaker, 20ml of ultrapure water at normal temperature was added, the beaker was put into a 5 ℃ refrigerator, crystallized at low temperature for 1 hour, filtered while cold, and the solid was put into a vacuum oven and vacuum-dried at 60 ℃ for 3 hours. A certain amount of sample is taken to prepare a solution, and the purity of the caffeine is 99.0% by HPLC detection.
The purification mechanism is that caffeine with higher purity is obtained by a method of adding a certain amount of water for cooling crystallization.
Because the crude caffeine contains a certain amount of sodium methoxide which is a byproduct in the process of reaction with water, methanol and sodium hydroxide can be generated, and the caffeine and the sodium hydroxide have different solubilities in water according to the data, the invention adds a certain amount of water into the crude caffeine to cool and crystallize the caffeine, and filters and purifies the caffeine while the caffeine is cold.
Wherein the mass ratio of the crude caffeine to the water is 1: 1-1: 10.
Solubility of pure caffeine and sodium hydroxide in water at various temperatures
The invention is not the best known technology.
Claims (2)
1. An environment-friendly method for preparing caffeine by methylation of theophylline sodium salt is characterized by comprising the following steps:
adding theophylline sodium salt, DMC and methanol into a Hastelloy reaction kettle, and reacting for 3 hours at 160 ℃ under stirring; cooling to room temperature, and performing rotary evaporation at 50-70 ℃ until the solvent is evaporated to dryness to obtain a solid, namely crude caffeine;
wherein the mol ratio is theophylline sodium salt: dimethyl carbonate (DMC) =1: 6; 10ml of methanol was added per 0.01 mole of theophylline sodium salt.
2. The process for preparing caffeine by methylation of sodium salt of theophylline under environment-friendly condition as claimed in claim 1, wherein the purification step of crude caffeine comprises:
dissolving the obtained crude caffeine in ultrapure water, crystallizing at a low temperature of 0-10 ℃ for 1-3 hours, carrying out suction filtration while the caffeine is cold, putting the obtained solid in a vacuum oven, and carrying out vacuum drying at 60 ℃ for 2-4 hours;
wherein, the mass ratio of the coarse caffeine: water =1: 1-10.
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| CN201910184371.2A CN109836424B (en) | 2019-03-12 | 2019-03-12 | Method for preparing caffeine by methylation of environment-friendly theophylline sodium salt |
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| CN201910184371.2A CN109836424B (en) | 2019-03-12 | 2019-03-12 | Method for preparing caffeine by methylation of environment-friendly theophylline sodium salt |
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| CN104892611B (en) * | 2015-05-19 | 2017-03-22 | 青岛科技大学 | Synthetic method of caffeine |
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Inventor after: Xue Wei Inventor after: Yang Hansen Inventor after: Feng Zhijun Inventor after: Xie Lisha Inventor after: Zhang Min Inventor after: Li Fang Inventor after: Zhang Dongsheng Inventor after: Wang Yanji Inventor before: Xue Wei Inventor before: Yang Hansen Inventor before: Feng Zhijun Inventor before: Xie Lisha Inventor before: Li Fang Inventor before: Zhang Dongsheng Inventor before: Wang Yanji |
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