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Preparation method of doxofylline

A technology of doxofylline and theophylline, which is applied in the field of drug synthesis, can solve the problems of high risk of registration declaration, lack of control points, unsatisfactory and other problems, and achieve the effects of no high-risk reactions, improved reaction conversion rate, and simple operation

Pending Publication Date: 2020-11-27
开封康诺药业有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] This route adopts theophylline to generate theophylline salt under alkaline conditions, and then docks with halogenated acetaldehyde ethylene glycol to obtain doxofylline, with a total yield of 75-85%; this route has only one step, and is simple to operate, but halogen The acetaldehyde ethylene acetal has a warning structure and is a genotoxic impurity, which cannot be controlled after only one refinement; as a pharmaceutical process, this route is short and lacks control points. The risk of registration and declaration is relatively high, and it does not meet the requirements of current drug declaration regulations.

Method used

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  • Preparation method of doxofylline
  • Preparation method of doxofylline
  • Preparation method of doxofylline

Examples

Experimental program
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Effect test

Embodiment 1

[0041] Preparation of doxofylline:

[0042] S1. Add 1000mL of N,N-dimethylformamide into a three-necked flask, add 100g of theophylline, 104.1g of bromoacetaldehyde dimethyl acetal and 84.4g of potassium carbonate successively under stirring, and stir at 120°C for 12h. After completion, filter, concentrate the filtrate under reduced pressure, then add 500mL of methanol, heat up to dissolve, cool down to stir and crystallize, filter, and blow dry at 50°C to obtain an intermediate. The yield of the intermediate is 92.0%;

[0043] S2. Add 400mL of toluene to the three-necked flask, add 100g of intermediates, 34.7g of ethylene glycol, and 3.6g of p-toluenesulfonic acid in turn under stirring, reflux at 110°C for 4 hours, then add 8g of sodium carbonate and mix evenly, filter, and The filtrate was concentrated under reduced pressure, then 400ml of absolute ethanol was added, the temperature was lowered to 25° C., stirred and crystallized for 1 h, filtered, and air-dried at 60° C. t...

Embodiment 2

[0045] Preparation of doxofylline:

[0046] S1. Add 1000mL of N,N-dimethylformamide into a three-necked flask, add 200g of theophylline, 220.5g of bromoacetaldehyde diethyl acetal and 168.8g of potassium carbonate successively under stirring, and stir and react at 125°C for 12h. After completion, filter, concentrate the filtrate under reduced pressure, then add 500mL of methanol, heat up to dissolve, cool down to stir and crystallize, filter, and blow dry at 50°C to obtain an intermediate. The yield of the intermediate is 92.0%;

[0047] S2. Add 400mL of toluene to the three-necked flask, add 100g of intermediates, 34.7g of ethylene glycol, and 3.6g of p-toluenesulfonic acid in turn under stirring, reflux at 110°C for 4 hours, then add 8g of sodium carbonate and mix evenly, filter, and The filtrate was concentrated under reduced pressure, then 400ml of absolute ethanol was added, the temperature was lowered to 25° C., stirred and crystallized for 1 h, filtered, and air-dried a...

Embodiment 3

[0049] Preparation of doxofylline:

[0050] S1. Add 1000mL N,N-dimethylformamide into the three-necked flask, add 95g of theophylline, 95g of bromoacetaldehyde dimethyl acetal and 76g of potassium carbonate successively under stirring, and stir and react at 115°C for 14h. After the reaction is completed, Filtrate, concentrate the filtrate under reduced pressure, then add 500mL of methanol, heat up to dissolve, cool down to stir and crystallize, filter, and blow dry at 50°C to obtain an intermediate, the yield of which is 92.2%;

[0051] S2. Add 400mL of toluene to the three-necked flask, add 95g of intermediates, 28.5g of ethylene glycol, and 2.85g of p-toluenesulfonic acid in turn under stirring, and reflux at 105°C for 5 hours, then add 4g of sodium carbonate and mix evenly, filter, and The filtrate was concentrated under reduced pressure, then 400ml of absolute ethanol was added, the temperature was lowered to 20° C., stirred and crystallized for 1 h, filtered, and air-drie...

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Abstract

The invention discloses a preparation method of doxofylline. The method comprises: S1, in a first solvent, in the presence of an alkali, heating theophylline and halogenated acetal to carry out an alkylation reaction to obtain an intermediate; and S2, in a second solvent, in the presence of a catalyst, heating the intermediate and ethylene glycol to carry out an acetal exchange reaction so as to obtain the doxofylline. According to the route designed by the invention, quality control points can be increased in the doxofylline preparation process, the impurity content is favorably controlled, the risk of drug registration declaration is reduced, the total yield reaches 85 percent or above, the operation is simple, and high-risk reaction is avoided.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of doxofylline. Background technique [0002] Doxofylline (Doxofylline) chemical name is 7-[(1,3-dioxol-2-yl)methyl]-1,3-dimethyl-3,7-dihydro-lH-purine -2,6-dione, listed in Italy in 1988, trade name: Ansimar. Doxofylline has a strong anti-asthma effect and is a new drug for dilating the bronchi. It is suitable for chronic obstructive pulmonary disease (COPD), bronchial asthma, chronic asthmatic bronchitis and other dyspnea caused by bronchospasm. [0003] At present, the methods for synthesizing doxofylline mainly include: [0004] Route 1 (patent US4187308A): [0005] [0006] In this route, diprophylline is used as raw material, and doxofylline is obtained through two steps of reaction, with a total yield of 59.5%. This route is longer, and yield is on the low side, and wherein has one-step oxidation reaction, is difficult to control. [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/08
CPCC07D473/08
Inventor 王康林周多玲张文腾孙跃军杨甲旺林子荣
Owner 开封康诺药业有限公司
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