CN112125903A - Synthetic method of caffeine - Google Patents
Synthetic method of caffeine Download PDFInfo
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- CN112125903A CN112125903A CN202011089709.5A CN202011089709A CN112125903A CN 112125903 A CN112125903 A CN 112125903A CN 202011089709 A CN202011089709 A CN 202011089709A CN 112125903 A CN112125903 A CN 112125903A
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- 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
- C07D473/12—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 1, 3, and 7, e.g. caffeine
Abstract
The invention discloses a synthesis method of caffeine, and relates to the technical field of preparation of heterocyclic compounds containing purine ring systems. The method comprises the following steps: mixing cyanoacetic acid and acetic anhydride, reacting at 30-80 ℃, adding a solvent and dimethyl urea, cooling to room temperature after the reflux reaction is finished, filtering, concentrating the filtrate, mixing the solids to obtain dimethyl cyanoacetylurea, adding liquid alkali to adjust the pH value to 8-11, and reacting at 80-100 ℃ to generate dimethyl 4 AU; completely dissolving dimethyl 4AU in formic acid, adding sodium nitrite, reacting at room temperature, adding a catalyst, keeping the temperature at 30-70 ℃, recovering the catalyst after the reaction is finished, and concentrating the mother liquor to recover formic acid to obtain dimethyl FAU; adding water and liquid alkali into dimethyl FAU, and carrying out ring closure reaction to obtain theophylline sodium salt; and (3) carrying out methylation reaction and refining on the theophylline sodium salt to obtain the caffeine. The method has the advantages of easily obtained raw materials, mild and easily controlled reaction conditions, few steps, simple and convenient operation, high yield, greatly improved product quality and easy realization of industrial production.
Description
Technical Field
The invention relates to the technical field of preparation of heterocyclic compounds containing purine ring systems, in particular to a synthetic method of caffeine.
Background
Caffeine (Caffeine) is also known as 1,3, 7-trimethylxanthine or 3, 7-dihydro-1, 3, 7-trimethyl-1H-purine-2, 6-dione. Caffeine is a xanthine compound, has a nerve excitation effect, is applied to the fields of food, medicines and the like, is widely applied to cola, biscuits and functional foods, and is popular with people.
The currently known industrial process for the synthesis of caffeine is mainly the dimethylurea process. The method comprises the steps of taking cyanoacetic acid and dimethyl urea as raw materials, carrying out condensation, cyclization, sulfination, washing, hydrogenation, acylation and ring closure, filtering and the like to generate an intermediate product theophylline sodium salt, carrying out methylation and filtering to generate crude caffeine, and carrying out refining, crystallization, filtering, drying, granulation, crushing and the like to produce the finished product caffeine.
The process has low requirement on equipment, simple and easy reaction and easy realization of industrialization, and is adopted by various manufacturers for many years. However, the process has various defects, such as complicated process steps, long route, more side reactions and long production period; in order to ensure the quality of subsequent finished products in actual production, filtration and separation operations are added in a plurality of intermediate steps, so that part of impurities leave a reaction system along with mother liquor, a large amount of sewage is discharged, COD and salinity are high, and the environmental protection treatment is challenged; the influence of impurities causes that the crude caffeine needs to be refined twice to obtain a finished product with qualified quality; meanwhile, the yield is inhibited from being improved by multi-step reaction, and the total yield is less than 60%; in addition, the process has large equipment amount and intermittent reaction, so that more manpower and energy are used, and a large amount of cost is increased; meanwhile, due to intermittent reaction, accidental factors exist between batches, and hidden danger is brought to quality stability.
In view of the above-mentioned process defects, various manufacturing enterprises and expert scholars have conducted a great deal of research for many years. The invention discloses a preparation method for preparing N, N-1, 3-dimethyl-4, 5-diaminocarbamidazine (dimethyl DAU) by virtue of diverse wormwood herbs and the like, develops a new hydrogenation reduction system, can enable the reaction to be more stable and controllable, and improves the catalytic activity to enable the quality of the dimethyl DAU to be stable and the yield and the quality to be improved; guojimin and the like, the step of removing reductive impurities by adding an oxidant after the ring-closure reaction and removing oxidative impurities by adding a reductant in the refining process of the caffeine crude product improves the product yield and purity, omits the separation of 1, 3-dimethyl-4-amino-5-formamide carbamidazine (dimethyl FAU), and shortens the production period; the invention discloses a closed-loop reaction method of diverse wormwood herb and the like, wherein a low-alkalinity catalytic system containing ethylamine is used for closed-loop reaction, so that the defects that the appearance of theophylline sodium salt (called tea sodium for short) is poor and the salinity in waste liquid is high due to the fact that side reaction is easy to occur under the high-alkalinity closed-loop reaction in the prior art are avoided, the yield of the tea sodium is improved, and the environmental protection pressure is reduced; the method has the advantages that the methylate is carried out by using dimethyl carbonate, a catalyst, a surfactant and the like to replace toxic dimethyl sulfate in the Yangfeng department and the like, so that the environmental protection pressure is reduced, and the methylation yield is increased to 97.8%; the invention provides a new refining process, and a new decolorizing material carbon fiber filter is used for replacing powdered carbon for decolorization, so that the carbon usage is reduced, the energy is saved, and the consumption is reduced; the research on caffeine crystallization process and equipment by Zhu Mei et al invents a sectional tubular continuous crystallization method, replaces the original kettle type intermittent crystallization, reduces equipment investment, reduces energy consumption, and reduces cooling water consumption by about 60%.
However, the above researches are based on the existing process, and development and improvement of a reaction system, equipment, raw materials and the like are carried out in a single step, so that reaction steps are reduced, reaction yield is improved, product quality is improved or beneficial effects for environmental protection are produced, but the original process is not substantially changed or the reaction steps are greatly reduced.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a synthesis method of caffeine, which has the advantages of easily available raw materials, mild and easily controlled reaction conditions, few steps, simple and convenient operation, high yield which can reach more than 70%, greatly improved product quality, easy realization of industrial production and provision of a new synthesis way for producing caffeine and theophylline sodium salt.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows: a method for synthesizing caffeine comprises the following steps:
step 1: formation of dimethyl 4AU (1, 3-dimethyl-4-iminourea oxazine)
Mixing cyanoacetic acid and acetic anhydride, reacting at 30-80 ℃, adding a solvent and dimethyl urea, cooling the reaction to room temperature after the reflux reaction is finished, filtering, concentrating the filtrate, combining the solid to obtain dimethyl cyanoacetylurea, adding liquid alkali to adjust the pH value to be 8-11, and reacting at 80-100 ℃ to generate dimethyl 4 AU;
step 2: formation of dimethyl FAU (1, 3-dimethyl-4-amino-5-carboxamido-urea-oxazine)
Completely dissolving dimethyl 4AU in formic acid, adding sodium nitrite, reacting at room temperature, then adding a catalyst and water, keeping the temperature at 30-70 ℃, recovering the catalyst after the reaction is finished, and concentrating mother liquor to recover formic acid to obtain dimethyl FAU;
and step 3: formation of theophylline sodium salt
Adding water and liquid alkali into dimethyl FAU, and carrying out ring closure reaction to obtain theophylline sodium salt;
and 4, step 4: production of caffeine
And (3) carrying out methylation reaction and refining on the theophylline sodium salt to obtain the caffeine.
Preferably, in step 1, the solvent is one of toluene, benzene, dichloromethane, chloroform and cyclohexane.
Preferably, in the step 1, the molar ratio of cyanoacetic acid to dimethylurea to acetic anhydride is 1: 1-1.3.
Preferably, in the step 1, cyanoacetic acid and acetic anhydride are mixed and then react at 30-80 ℃ for 1-5 hours, a solvent and dimethyl urea are added, the reaction is cooled to room temperature after reflux reaction for 1-5 hours, the filtrate is concentrated and the solids are combined to obtain dimethyl cyanoacetylurea, liquid alkali is added to adjust the pH value to 8-11, and then the reaction is carried out at 80-100 ℃ for half an hour to generate dimethyl 4 AU.
Preferably, in the step 2, the mass ratio of the dimethyl 4AU to the formic acid is 1: 4-10.
Preferably, in the step 2, the temperature of the added sodium nitrite is-10 ℃, and the molar ratio of the sodium nitrite to the dimethyl 4AU is 1-1.5: 1.
Preferably, in the step 2, the catalyst is one of raney nickel, palladium carbon and platinum carbon, and the mass ratio of the catalyst to the dimethyl 4AU is 0.005-0.05: 1.
further preferably, in step 2, the palladium content in palladium carbon is 5 wt%, and the platinum content in platinum carbon is 5 wt%.
Preferably, in the step 2, the dimethyl 4AU is completely dissolved in the formic acid, the sodium nitrite is added, the reaction is carried out for 1 to 5 hours at room temperature, the catalyst is added, the temperature is kept at 30 to 70 ℃ for 3 to 7 hours, the catalyst is recovered after the reaction is finished, and the mother liquor is concentrated to recover the formic acid, so that the dimethyl FAU is obtained.
Preferably, in the step 3, the dimethyl FAU is added with water, stirred, heated to 70 ℃, added with liquid alkali, kept at the temperature of 90-100 ℃ for 0.5-2 hours, cooled and filtered to obtain theophylline sodium salt.
Preferably, in the step 3, the alkalinity is adjusted to 1.5-3.0.
Adopt the produced beneficial effect of above-mentioned technical scheme to lie in: the invention develops a novel caffeine synthesis method, which has the following advantages compared with the prior art:
(1) the reaction steps are greatly reduced, 6 steps are needed in the prior art, and the method only needs 4 steps to complete, so that the multiple washing and separating steps are reduced, the stability of the product quality is improved, the product yield is improved, the discharge capacity is reduced, and the environmental protection treatment difficulty is reduced;
(2) according to the invention, the solvent is added in the condensation reaction for generating the dimethylcyanoacetylurea, so that the anhydrous condition of the reaction is ensured, the reaction is carried out more thoroughly, and the occurrence of side reactions is reduced;
(3) the method combines three steps of imidization, hydrogenation reduction and acylation in the prior art into one step, thereby greatly reducing reaction steps and reaction time;
(4) the invention uses formic acid as solvent to carry out reduction reaction, thus thoroughly eliminating the use of hydrogen in the prior art and reducing the safety risk;
(5) the method has the advantages of few reaction steps, mild reaction conditions, simple and convenient operation, high yield, stable product quality, small discharge capacity, reduction of environmental protection treatment difficulty and easy industrialization.
Detailed Description
The present invention will be described in further detail with reference to the following embodiments, but the present invention is not limited to these embodiments.
Example 1
Mixing 1mol of cyanoacetic acid and 1.2mol of acetic anhydride, reacting at 40 ℃ for 1 hour, adding 2mol of toluene and 1.2mol of dimethyl urea as solvents, carrying out reflux reaction for 3 hours, cooling the reaction to room temperature, filtering, and concentrating the filtrate. The solids were combined, adjusted to pH 9 with liquid base and reacted at 90 ℃ for half an hour and filtered at room temperature to give dimethyl 4 AU.
Taking 20g of dimethyl 4AU, completely dissolving in 150g of formic acid, cooling to 0 ℃, adding 1 molar equivalent of sodium nitrite of the dimethyl 4AU, and reacting for 4 hours at room temperature. Then, 0.6g of a catalyst (5% platinum carbon) was added thereto, and the reaction was continued at 30 ℃ for 5 hours. And filtering and recovering the catalyst, and concentrating the mother liquor to recover formic acid to obtain dimethyl FAU.
Adding the dimethyl FAU obtained in the previous step into a four-mouth bottle, adding 100ml of water, heating to 70 ℃, adding liquid alkali, adjusting the alkalinity to 2.0, heating to 90 ℃, and keeping the temperature for 0.5 hour. Cooling to 18 deg.c and cold filtering to obtain theophylline sodium salt in 92.1% yield.
The caffeine is obtained by the processes of methylation, refining and the like of theophylline sodium salt. The total yield was 81.0%. The purity is 99.98%.
Example 2
Mixing 1mol of cyanoacetic acid and 1.02mol of acetic anhydride, reacting at 30 ℃ for 5 hours, adding 2mol of benzene and 1.02mol of dimethyl urea as solvents, carrying out reflux reaction for 3 hours, cooling the reaction to room temperature, filtering, and concentrating the filtrate. The solids were combined, adjusted to pH 8 with liquid base, reacted at 80 ℃ for half an hour, and filtered at room temperature to give dimethyl 4 AU.
Taking 20g of dimethyl 4AU, completely dissolving in 80g of formic acid, cooling to-10 ℃, adding 1.2 molar equivalents of sodium nitrite of the dimethyl 4AU, and reacting at room temperature for 2.5 hours. Then 0.2g of catalyst (5% palladium carbon) was added, and the reaction was continued at about 50 ℃ for 3 hours. And filtering and recovering the catalyst, and concentrating the mother liquor to recover formic acid to obtain dimethyl FAU.
Adding the dimethyl FAU obtained in the previous step into a four-mouth bottle, adding 100ml of water, heating to 70 ℃, adding liquid alkali, adjusting the alkalinity to 1.5, heating to 95 ℃, and keeping the temperature for 1 hour. Cooling and cold filtering to obtain theophylline sodium salt with yield of 85.5%.
The caffeine is obtained by the processes of methylation, refining and the like of theophylline sodium salt. The total yield was 74.8%. The purity is 99.98%.
Example 3
Mixing 1mol of cyanoacetic acid and 1.3mol of acetic anhydride, reacting at 75 ℃ for 3 hours, adding solvents of chloroform 2mol and dimethyl urea 1.3mol, refluxing and reacting for 5 hours, cooling the reaction to room temperature, filtering, and concentrating the filtrate. The solids were combined, adjusted to pH 10 with liquid base and reacted at 100 ℃ for half an hour, and filtered at room temperature to give dimethyl 4 AU.
Dissolving 20g of dimethyl 4AU in 200g of formic acid completely, cooling to 10 ℃, adding 1.5 molar equivalent of sodium nitrite of the dimethyl 4AU, and reacting for 5 hours at room temperature. Then, 1g of catalyst (Raney nickel) was added thereto, and the reaction was continued at about 70 ℃ for 7 hours. And filtering and recovering the catalyst, and concentrating the mother liquor to recover formic acid to obtain dimethyl FAU.
Adding the dimethyl FAU obtained in the previous step into a four-mouth bottle, adding 100ml of water, heating to 70 ℃, adding liquid alkali, adjusting the alkalinity to 3.0, heating to 98 ℃, and keeping the temperature for 2 hours. Cooling and cold filtering to obtain theophylline sodium salt with yield of 80.6%.
The caffeine is obtained by the processes of methylation, refining and the like of theophylline sodium salt. The total yield is 70.8%. The purity is 99.96%.
Comparative examples
The existing caffeine production process comprises the following steps:
step 1: formation of dimethyl-4 AU (1, 3-dimethyl-4-iminourea oxazine)
Mixing 1mol of cyanoacetic acid and 1-1.2 mol of dimethyl urea, adding 1.1-1.5 mol of acetic anhydride at the temperature of below 80 ℃ to perform condensation reaction, wherein the highest temperature of the condensation reaction is not more than 120 ℃. After the condensation reaction is finished, dimethylcyanoacetylurea is generated. Adding the dimethyl cyanoacetylurea into ionic membrane liquid alkali at 40-45 ℃, adjusting the pH value to 9-10, and preserving the temperature at 80-90 ℃ for 30-40 minutes to generate dimethyl 4 AU.
Step 2: the methylene blue uric acid (1, 3-dimethyl-4-imino-5-isonitro urea oxazine)
Adding sodium nitrite solution with the mass ratio of 20-30% into dimethyl 4AU feed liquid, adding the sodium nitrite solution into dilute sulphuric acid with the concentration of 15-20% at 4-15 ℃ in a same flow manner, controlling the material beating time within 20-30 minutes, adjusting the pH value to 2.0-3.0 at the final temperature of 40-45 ℃ and generating the dimethylvioluric acid.
Repeatedly washing the imidized dimethylvioluric acid with water to neutrality for hydrogenation reduction.
And step 3: hydrogenation reduction to produce dimethyl DAU (N, N-1, 3-dimethyl-4, 5-diamino urea oxazine)
The method comprises the steps of reducing dimethylvioluric acid with hydrogen by using raney nickel as a catalyst, wherein the dosage of the catalyst is 3-10% of the mass of the dimethylvioluric acid, the material concentration of the dimethylvioluric acid is 10-20%, the hydrogen pressure is adjusted to be 0.34-0.39 MPa, reacting is carried out, and the temperature is reduced by using low-temperature water to control the end point temperature to be below 90 ℃ so as to generate the dimethyldau.
And 4, step 4: acylation to dimethyl FAU (1, 3-dimethyl-4-amino-5-carboxamido-urea-zine)
Formic acid is added into the dimethyl DAU feed liquid in a flowing mode, the pH value is adjusted to be 3.2-3.5, and the temperature is kept at 90-100 ℃ for 30-60 minutes to generate dimethyl FAU.
And 5: closed-loop generation of theophylline sodium salt
Adding a proper amount of water, stirring, heating to 70 ℃, adding liquid caustic soda, keeping the temperature at 90-100 ℃ for 0.5-2 hours, cooling, and carrying out cold filtration to obtain theophylline sodium salt with the yield of 83.1%.
Step 6: production of caffeine
The caffeine is obtained by the reactions of methylation, primary refining, secondary refining and the like of theophylline sodium salt and dimethyl sulfate, and the total yield is 58.1%. The purity is 99.85%.
Claims (10)
1. A method for synthesizing caffeine, comprising the steps of:
step 1: formation of dimethyl 4AU
Mixing cyanoacetic acid and acetic anhydride, reacting at 30-80 ℃, adding a solvent and dimethyl urea, cooling the reaction to room temperature after the reflux reaction is finished, filtering, concentrating the filtrate, combining the solid to obtain dimethyl cyanoacetylurea, adding liquid alkali to adjust the pH value to be 8-11, and reacting at 80-100 ℃ to generate dimethyl 4 AU;
step 2: formation of dimethyl FAU
Completely dissolving dimethyl 4AU in formic acid, adding sodium nitrite, reacting at room temperature, then adding a catalyst and water, keeping the temperature at 30-70 ℃, recovering the catalyst after the reaction is finished, and concentrating mother liquor to recover formic acid to obtain dimethyl FAU;
and step 3: formation of theophylline sodium salt
Adding water and liquid alkali into dimethyl FAU, and carrying out ring closure reaction to obtain theophylline sodium salt;
and 4, step 4: production of caffeine
And (3) carrying out methylation reaction and refining on the theophylline sodium salt to obtain the caffeine.
2. The method for synthesizing caffeine according to claim 1, wherein in step 1, the solvent is one of toluene, benzene, dichloromethane, chloroform and cyclohexane.
3. The method for synthesizing caffeine according to claim 1, wherein in step 1, the molar ratio of cyanoacetic acid to dimethylurea to acetic anhydride is 1:1 to 1.3.
4. The method for synthesizing caffeine according to claim 1, wherein in step 1, cyanoacetic acid and acetic anhydride are mixed and reacted at 30 to 80 ℃ for 1 to 5 hours, a solvent and dimethyl urea are added, the reaction is cooled to room temperature after 1 to 5 hours of reflux reaction, the filtrate is filtered, the filtrate is concentrated and the solids are combined to obtain dimethyl cyanoacetylurea, and the dimethyl cyanoacetylurea is added to adjust the pH to 8 to 11 and then reacted at 80 to 100 ℃ for half an hour to produce dimethyl 4 AU.
5. The method for synthesizing caffeine according to claim 1, wherein in step 2, the mass ratio of dimethyl 4AU to formic acid is 1:4 to 10.
6. The method for synthesizing caffeine according to claim 1, wherein in step 2, the temperature of the added sodium nitrite is-10 to 10 ℃, and the molar ratio of sodium nitrite to dimethyl 4AU is 1 to 1.5: 1.
7. The method for synthesizing caffeine according to claim 1, wherein in step 2, the catalyst is one of raney nickel, palladium carbon and platinum carbon, and the mass ratio of the catalyst to dimethyl 4AU is 0.005-0.05: 1; the mass ratio of water to dimethyl 4AU is 1-5: 1.
8. The method for synthesizing caffeine according to claim 1, wherein in step 2, dimethyl 4AU is completely dissolved in formic acid, sodium nitrite is added, after reaction for 1 to 5 hours at room temperature, the catalyst is added, heat preservation is performed at 30 to 70 ℃ for 3 to 7 hours, the catalyst is recovered after the reaction is completed, and the mother liquor is concentrated to recover formic acid, so as to obtain dimethyl FAU.
9. The method for synthesizing caffeine according to claim 1, wherein in step 3, dimethyl FAU is added with water, stirred, heated to 70 ℃, added with liquid alkali, kept at 90-100 ℃ for 0.5-2 hours, cooled and filtered to obtain theophylline sodium salt.
10. The method for synthesizing caffeine according to claim 1, wherein the alkalinity is adjusted to 1.5 to 3.0 in step 3.
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| CN102344451A (en) * | 2011-10-19 | 2012-02-08 | 吉林省舒兰合成药业股份有限公司 | Method for preparing caffeine |
| CN106083853A (en) * | 2016-06-25 | 2016-11-09 | 安徽柒柒塑业有限公司 | A kind of production procedure of caffeine |
| CN111592548A (en) * | 2020-06-15 | 2020-08-28 | 石家庄四药有限公司 | Preparation method of theophylline sodium salt |
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2020
- 2020-10-13 CN CN202011089709.5A patent/CN112125903A/en active Pending
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| US2523496A (en) * | 1948-10-21 | 1950-09-26 | Kenneth N Campbell | Method of preparing xanthine and methylated xanthines |
| WO2003024965A2 (en) * | 2001-09-19 | 2003-03-27 | Novo Nordisk A/S | Heterocyclic compounds that are inhibitors of the enzyme dpp-iv |
| CN102344451A (en) * | 2011-10-19 | 2012-02-08 | 吉林省舒兰合成药业股份有限公司 | Method for preparing caffeine |
| CN106083853A (en) * | 2016-06-25 | 2016-11-09 | 安徽柒柒塑业有限公司 | A kind of production procedure of caffeine |
| CN111592548A (en) * | 2020-06-15 | 2020-08-28 | 石家庄四药有限公司 | Preparation method of theophylline sodium salt |
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