CN112047947A - Synthetic method of theophylline - Google Patents
Synthetic method of theophylline Download PDFInfo
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- CN112047947A CN112047947A CN202011089722.0A CN202011089722A CN112047947A CN 112047947 A CN112047947 A CN 112047947A CN 202011089722 A CN202011089722 A CN 202011089722A CN 112047947 A CN112047947 A CN 112047947A
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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
- C07D473/08—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 and 3, e.g. theophylline
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Abstract
The invention discloses a synthesis method of theophylline, 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 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 (3) adding dilute sulfuric acid into dimethyl FAU to adjust the pH value to 3-6, heating to 90-100 ℃, passing feed liquid through an ozone reactor and a decolorizer, crystallizing by a crystallizer, and carrying out cold filtration to obtain theophylline. 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.
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 theophylline.
Background
Theophylline (Theophylline) is also called dioxodimethyl purine; 1, 3-dimethyl-3, 7-dihydro-1H-purine-2, 6-dione; 1, 3-dimethyl xanthine. Theophylline is a methylpurine drug. Has effects in tonifying heart, promoting urination, dilating coronary artery, relaxing smooth muscle of bronchus, and exciting central nervous system. It is mainly used for treating bronchial asthma, emphysema, bronchitis, and cardiac dyspnea.
The existing method for industrially synthesizing theophylline uses cyanoacetic acid and dimethyl urea as raw materials, and comprises the steps of condensation, cyclization, imidization, washing, hydrogenation, acylation, ring closure, filtration and the like, so that an intermediate product theophylline sodium salt is firstly generated, and then the finished product theophylline is produced through the steps of acid adjustment, refining, crystallization, filtration, drying, granulation, crushing and the like.
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; in the refining and impurity removing process, a traditional potassium permanganate oxidation and activated carbon decoloration method is used, so that manganese ion residues exist in a finished product, and are used along with hazardous wastes; meanwhile, the yield is inhibited from being improved by multi-step reaction and filtering purification operation, and the total yield is less than 80%; 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 process defects, various manufacturing enterprises have made a great deal of research on key preparation processes of theophylline. For example, a new hydrogenation reduction system is developed by diverse glory, and a preparation method for preparing N, N-1, 3-dimethyl-4, 5-diaminocarbamide oxazine (dimethyl DAU) is invented, so that the reaction is more stable and controllable, the catalytic activity is improved, and the quality of the dimethyl DAU is stable, and the yield and the quality are 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 crude theophylline 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; 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 invention aims to solve the technical problem of providing a method for synthesizing theophylline, which 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.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows: a method for synthesizing theophylline 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: to produce theophylline
And (3) adding dilute sulfuric acid into dimethyl FAU to adjust the pH value to 3-6, heating to 90-100 ℃, passing feed liquid through an ozone reactor and a decolorizer, crystallizing by a crystallizer, and carrying out cold filtration to obtain theophylline.
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.
Adopt the produced beneficial effect of above-mentioned technical scheme to lie in: the invention develops a new theophylline 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 3 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) compared with the prior art that theophylline is synthesized by dimethyl FAU firstly and then theophylline sodium salt, the method reduces the procedures of one-step synthesis and one-step separation, reduces the labor intensity and reduces the discharge capacity.
(6) 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 are combined, liquid alkali is added to adjust the pH value to 9, then the mixture reacts at 90 ℃ for half an hour, and the temperature is reduced to room temperature for filtration to obtain 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 dilute sulfuric acid to enable the pH to be 5, heating to 90 ℃, enabling feed liquid to pass through an ozone reactor and a high-efficiency decolorizer, crystallizing by a crystallizer, and carrying out cold filtration to obtain theophylline. The total yield is 92.5%. The purity is 99.95%.
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 are combined, liquid alkali is added to adjust the pH value to 8, then the reaction is carried out for half an hour at 80 ℃, the temperature is reduced to room temperature, and the dimethyl 4AU is obtained after filtration.
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 dilute sulfuric acid to make the pH value equal to 6, heating to 95 ℃, enabling feed liquid to pass through an ozone reactor and a high-efficiency decolorizer, crystallizing by a crystallizer, and carrying out cold filtration to obtain theophylline. The total yield is 90.3%. The purity is 99.91%.
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 are combined, added with liquid alkali to adjust the pH value to 10, reacted at 100 ℃ for half an hour, cooled to room temperature and filtered to obtain 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 dilute sulfuric acid to make the pH value equal to 6.5, heating to 100 ℃, enabling feed liquid to pass through an ozone reactor and a high-efficiency decolorizer, crystallizing by a crystallizer, and carrying out cold filtration to obtain theophylline. The total yield was 91.0%. The purity is 99.93%.
Comparative examples
The existing theophylline 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 alkali, keeping the temperature at 90-100 ℃ for 0.5-2 hours, cooling, and carrying out cold filtration to obtain theophylline sodium salt.
Step 6: to produce theophylline
Adding sulfuric acid into theophylline sodium salt to adjust pH to 6.5, adding potassium permanganate and active carbon, preserving heat for 40 minutes, filtering to obtain crude theophylline, adding sulfuric acid into the crude theophylline to adjust pH to 6, adding potassium permanganate and active carbon, preserving heat for 30 minutes, filtering to obtain theophylline, wherein the total yield is 74.1%. The purity is 99.82%.
Claims (9)
1. A synthetic method of theophylline is characterized by comprising the following steps:
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, adding a catalyst, 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: to produce theophylline
And (3) adding dilute sulfuric acid into dimethyl FAU to adjust the pH value to 3-6, heating to 90-100 ℃, passing feed liquid through an ozone reactor and a decolorizer, crystallizing by a crystallizer, and carrying out cold filtration to obtain theophylline.
2. The method for synthesizing theophylline according to claim 1, wherein in step 1, the solvent is one of toluene, benzene, dichloromethane, chloroform and cyclohexane.
3. The method for synthesizing theophylline according to claim 1, wherein in the step 1, the molar ratio of cyanoacetic acid, dimethylurea and acetic anhydride is 1: 1-1.3.
4. The method for synthesizing theophylline according to claim 1, wherein in step 1, cyanoacetic acid and acetic anhydride are mixed and reacted at 30-80 ℃ for 1-5 hours, a solvent and dimethyl urea are added, the reaction is cooled to room temperature after 1-5 hours of reflux reaction, the filtrate is filtered, the solid is combined to obtain dimethyl cyanoacetylurea, liquid alkali is added to adjust the pH value to 8-11, and the reaction is carried out at 80-100 ℃ for half an hour to generate dimethyl 4 AU.
5. The method for synthesizing theophylline according to claim 1, wherein in the step 2, the mass ratio of dimethyl 4AU to formic acid is 1: 4-10.
6. The method for synthesizing theophylline according to claim 1, wherein in the step 2, the temperature of adding the sodium nitrite is-10 to 10 ℃, and the molar ratio of the sodium nitrite to the dimethyl 4AU is 1 to 1.5: 1.
7. The method for synthesizing theophylline 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.
8. the method for synthesizing theophylline of claim 7, wherein in step 2, the palladium content in palladium carbon is 5 wt%, and the platinum content in platinum carbon is 5 wt%.
9. The method for synthesizing theophylline according to claim 1, wherein in step 2, dimethyl 4AU is completely dissolved in formic acid, sodium nitrite is added, after the reaction is carried out for 1-5 hours at room temperature, catalyst and water are added, the temperature is kept at 30-70 ℃ for 3-7 hours, the catalyst is recovered after the reaction is finished, and the mother liquor is concentrated to recover formic acid, so as to obtain dimethyl FAU.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114213342A (en) * | 2021-11-29 | 2022-03-22 | 青岛科技大学 | Production system and method for preparing 6-amino-1,3-dimethyl uracil |
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| CN114213342A (en) * | 2021-11-29 | 2022-03-22 | 青岛科技大学 | Production system and method for preparing 6-amino-1,3-dimethyl uracil |
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Application publication date: 20201208 |