CN112110921A - Synthesis method of diprophylline - Google Patents
Synthesis method of diprophylline Download PDFInfo
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- CN112110921A CN112110921A CN202010633918.5A CN202010633918A CN112110921A CN 112110921 A CN112110921 A CN 112110921A CN 202010633918 A CN202010633918 A CN 202010633918A CN 112110921 A CN112110921 A CN 112110921A
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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 method for synthesizing diprophylline, which comprises the following steps of 1S 01: preparing materials, namely theophylline, 1-chloropropanol, potassium hydroxide, sodium hydroxide, methanol, dimethylformamide, alcohol and sodium bicarbonate, and performing step 2S 02: putting the material prepared in the step S01 into a condensation reaction kettle for condensation reaction, and carrying out a step 3S 03: and (3) putting the mixed solution after the condensation reaction into a distiller for reduced pressure distillation, and carrying out step 4S 04: putting the mixed solution after reduced pressure distillation into a filter, filtering impurities in the mixed solution, and then performing a desalting operation, wherein the step 5S 05: dehydrating the desalted mixed solution to crystallize, and performing step 6S 06: and (4) after the crystals are filtered, washing the crystals, and carrying out step 7S 07: the washed crystal is dried, so that the reaction in the synthesis process is stable, and the initially synthesized diprophylline can be further cleaned through the step 6S06, so that the finally obtained finished product has higher purity, fewer impurities and better quality.
Description
Technical Field
The invention belongs to the field of chemical industrial production, and particularly relates to a synthetic method of diprophylline.
Background
Currently, the theophylline derivatives which can be used clinically mainly comprise a substituent product 7 of theophylline, wherein the substituent has chlorine, bromine, halogenated alkanes and the like, and the representative products include diprophylline, doxofylline, isobutyltheophylline, propentofylline, hexanotheophylline, lomiteine and the like, wherein the general synthesis mode of diprophylline is divided into two steps, one step is divided into two steps, the first insert forms an alkali metal salt under a strong alkaline condition, the alkali metal salt of the second theophylline and 1-chloropropanol undergo an electrophilic substitution reaction to generate diprophylline, the other step is a direct synthesis step, the theophylline and 2, 3-epoxy-1-propanol directly react under an alkaline condition to generate diprophylline, and the mainstream production process at present is that the diprophylline is mainly prepared by the condensation reaction of theophylline and 10-chloropropanol under the alkaline condition, and then the finished products are obtained by working procedures of refining, crystallization, drying and the like, because a proper condensation and delicate strict detection method of procedures such as refining is lacked in the original production process flow of the diprophylline, the quality of the diprophylline is unstable, the diprophylline with stable quality can be obtained only by further processes such as purification after production, and meanwhile, the problems of high cost, low qualification rate and the like are caused by the existing process flow of the diprophylline, so that the synthesis method of the diprophylline is provided for solving the problems.
Disclosure of Invention
The invention provides a synthetic method of diprophylline, aiming at solving the problems that the quality of diprophylline can be stable only by carrying out further purification and other processes after production, and the cost is high and the yield is low due to the existing process flow of diprophylline.
The invention is realized in such a way that a synthetic method of diprophylline comprises the following steps:
step 1S 01: preparing materials, namely theophylline, 1-chloropropanol, potassium hydroxide, sodium hydroxide, methanol, dimethylformamide, alcohol and sodium bicarbonate;
step 2S 02: placing theophylline, 1-chloropropanol, potassium hydroxide, sodium hydroxide, methanol, dimethylformamide, alcohol and sodium bicarbonate into a condensation reaction kettle for condensation reaction;
step 3S 03: putting the mixed solution after the condensation reaction into a distiller for reduced pressure distillation;
step 4S 04: putting the mixed solution after reduced pressure distillation into a filter, filtering impurities in the mixed solution, and then carrying out desalting operation;
step 5S 05: dehydrating the mixed solution after desalting to obtain crystals;
step 6S 06: carrying out suction filtration on the crystals and then washing the crystals;
step 7S 07: the washed crystals were dried.
Further, in the step S01, the theophylline and the 1-chloropropanol are used as main raw materials, the potassium hydroxide, the sodium hydroxide and the sodium bicarbonate are used as catalysts, the methanol and the alcohol are used as solutions, and the methylformamide is used as a solvent, wherein the concentrations of the potassium hydroxide and the sodium hydroxide are 30% and the alcohol concentration is 98%.
Further, in the condensation reaction of step S02, after theophylline and 1-chloropropanol are mixed in methanol, dimethylformamide is added to fuse the theophylline and 1-chloropropanol, and after potassium hydroxide and sodium hydroxide are added to adjust the PH of the reaction solution, the PH of the reaction solution is adjusted to 6.5-7.5.
Further, in the step S03, the vacuum degree is 0.1Mpa, and the duration is 100 minutes.
Further, the alcohol in step S04 is a salt-removing detergent, wherein the alcohol concentration is 98%.
Further, the crystallization temperature in the reaction kettle of the step S06 is 25 ℃, the suction filtration temperature is 18 ℃, and the crystallization particles in the reaction kettle are uniform in size.
Further, a rapid temperature adjusting device is installed in the reaction kettle of the step S07, and the drying temperature is constant at 80 ℃ in the drying process.
Further, the step S03, the step S06 reaction kettle has good high pressure resistance.
Further, the crystallization temperature of the step S05 is uniformly reduced from 100 ℃ to 18 ℃.
Further, the reaction kettle of the step S02 has a rapid temperature rise function, and the temperature is constantly controlled at 80 ℃.
Drawings
FIG. 1 is a process flow diagram of a synthetic method of diprophylline.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In the description of the present invention, it is to be understood that the terms "length", "width", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", and the like, indicate orientations or positional relationships based on the orientations or positional relationships illustrated in the drawings, and are used merely for convenience in describing the present invention and for simplicity in description, and do not indicate or imply that the devices or elements referred to must have a particular orientation, be constructed in a particular orientation, and be operated, and thus, are not to be construed as limiting the present invention. Further, in the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
Example 1:
referring to fig. 1, a method for synthesizing diprophylline comprises the following steps:
step 1S 01: preparing materials, namely theophylline, 1-chloropropanol, potassium hydroxide, sodium hydroxide, methanol, dimethylformamide, alcohol and sodium bicarbonate;
step 2S 02: placing theophylline, 1-chloropropanol, potassium hydroxide, sodium hydroxide, methanol, dimethylformamide, alcohol and sodium bicarbonate into a condensation reaction kettle for condensation reaction;
step 3S 03: putting the mixed solution after the condensation reaction into a distiller for reduced pressure distillation;
step 4S 04: putting the mixed solution after reduced pressure distillation into a filter, filtering impurities in the mixed solution, and then carrying out desalting operation;
step 5S 05: dehydrating the mixed solution after desalting to obtain crystals;
step 6S 06: carrying out suction filtration on the crystals and then washing the crystals;
step 7S 07: the washed crystals were dried.
Example 2:
in the invention, in step S01, theophylline and 1-chloropropanol are used as main raw materials, potassium hydroxide, sodium hydroxide and sodium bicarbonate are used as catalysts, methanol and alcohol are used as solutions, and methylformamide is used as a solvent, wherein the concentrations of potassium hydroxide and sodium hydroxide are 30% and the alcohol concentration is 98%.
In the present invention, the alcohol in step S04 is a desalting detergent.
In the invention, the crystallization temperature in the reaction kettle of the step S06 is 25 ℃, and the suction filtration temperature is 18 ℃.
In the invention, the drying temperature in the reaction kettle of the step S07 is 80 ℃.
In the invention, the step S03 and the step S06 reaction kettle have good high pressure resistance.
In the invention, the crystallization temperature of the step S05 is uniformly reduced from 100 ℃ to 18 ℃.
In the invention, the temperature in the reaction kettle of the step S02 is constantly controlled at 80 ℃.
Example 3:
the pH value of the reaction solution after the condensation reaction in the step S02 is 6.5-7.5. The vacuum degree in the step S03 is 0.1Mpa, the duration is 100 minutes, the crystallization temperature in the reaction kettle in the step S06 is 25 ℃, and the suction filtration temperature is 18 ℃.
Example 4:
step S02 adding potassium hydroxide, sodium hydroxide and sodium bicarbonate to adjust the pH to 6.5-7.5
The present invention is not limited to the above preferred embodiments, and any modifications, equivalent substitutions and improvements made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A synthetic method of diprophylline comprises the following steps:
step 1S 01: preparing materials, namely theophylline, 1-chloropropanol, potassium hydroxide, sodium hydroxide, methanol, dimethylformamide, alcohol and sodium bicarbonate;
step 2S 02: placing theophylline, 1-chloropropanol, potassium hydroxide, sodium hydroxide, methanol, dimethylformamide, alcohol and sodium bicarbonate into a condensation reaction kettle for condensation reaction;
step 3S 03: putting the mixed solution after the condensation reaction into a distiller for reduced pressure distillation;
step 4S 04: putting the mixed solution after reduced pressure distillation into a filter, filtering impurities in the mixed solution, and then carrying out desalting operation;
step 5S 05: dehydrating the mixed solution after desalting to obtain crystals;
step 6S 06: carrying out suction filtration on the crystals and then washing the crystals;
step 7S 07: the washed crystals were dried.
2. The method for synthesizing diprophylline according to claim 1, which comprises the following steps: in the step S01, theophylline and 1-chloropropanol are used as main raw materials, potassium hydroxide, sodium hydroxide and sodium bicarbonate are used as catalysts, methanol and alcohol are used as solutions, and methylformamide is used as a solvent, wherein the concentrations of potassium hydroxide and sodium hydroxide are 30% and the alcohol concentration is 98%.
3. The method for synthesizing diprophylline according to claim 1, which comprises the following steps: the pH value of the reaction solution after the condensation reaction in the step S02 is 6.5-7.5.
4. The method for synthesizing diprophylline according to claim 1, which comprises the following steps: in the step S03, the vacuum degree is 0.1Mpa, and the duration is 100 minutes.
5. The method for synthesizing diprophylline according to claim 1, which comprises the following steps: the alcohol in the step S04 is a desalting detergent.
6. The method for synthesizing diprophylline according to claim 1, which comprises the following steps: the crystallization temperature in the reaction kettle of the step S06 is 25 ℃, and the suction filtration temperature is 18 ℃.
7. The method for synthesizing diprophylline according to claim 1, which comprises the following steps: the drying temperature in the reaction kettle of the step S07 is 80 ℃.
8. The method for synthesizing diprophylline according to claim 1, which comprises the following steps: the step S03 and the step S06 reaction kettle have good high pressure resistance.
9. The method for synthesizing diprophylline according to claim 1, which comprises the following steps: and the crystallization temperature of the step S05 is uniformly reduced from 100 ℃ to 18 ℃.
10. The method for synthesizing diprophylline according to claim 1, which comprises the following steps: the temperature in the reaction kettle of the step S02 is constantly controlled at 80 ℃.
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| CN202010633918.5A CN112110921A (en) | 2020-07-02 | 2020-07-02 | Synthesis method of diprophylline |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101463033A (en) * | 2009-01-13 | 2009-06-24 | 石药集团新诺威制药股份有限公司 | Method for synthesizing diprophylline |
| CN101560210A (en) * | 2009-06-09 | 2009-10-21 | 湖南尔康制药有限公司 | Method for synthesizing diprophylline |
| CN110256434A (en) * | 2019-06-03 | 2019-09-20 | 上海万巷制药有限公司 | A method of preparing high-purity diprophylline |
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- 2020-07-02 CN CN202010633918.5A patent/CN112110921A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101463033A (en) * | 2009-01-13 | 2009-06-24 | 石药集团新诺威制药股份有限公司 | Method for synthesizing diprophylline |
| CN101560210A (en) * | 2009-06-09 | 2009-10-21 | 湖南尔康制药有限公司 | Method for synthesizing diprophylline |
| CN110256434A (en) * | 2019-06-03 | 2019-09-20 | 上海万巷制药有限公司 | A method of preparing high-purity diprophylline |
Non-Patent Citations (1)
| Title |
|---|
| 任新安: "二羟丙茶碱合成工艺研究", 《中国优秀硕士学位论文全文数据库·工程科技Ⅰ辑》 * |
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Application publication date: 20201222 |