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Synthetic method of doxofylline

A technology of doxofylline and its synthesis method, which is applied in the direction of organic chemistry, can solve the problems of high cost and difficult availability of raw materials, and achieve the effects of short reaction time, low reaction temperature and high yield

Inactive Publication Date: 2018-11-20
HUBEI HUNTIDE BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] 4. Liu Hongxia and others used vinyl acetate to obtain bromoacetaldehyde formal through bromination and alcoholysis, and then reacted with ethylene glycol to obtain side chain bromoacetaldehyde ethylene acetal, and then condensed with theophylline to prepare doxor The method of theophylline, the method has reached the pilot test level, and it is proposed that the factor that has a greater impact on the product yield in this process is the water content of the solvent DMF, and the solvent imported from abroad needs to be used. The raw materials of this process are not easy to get, and the cost is relatively high. high

Method used

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  • Synthetic method of doxofylline

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Add 10kg (55.6mol) of theophylline, 6L of acetone, 4.45kg of sodium hydroxide (111.2mol) and 0.56kg of tetrabutylammonium chloride (2mol) into the reaction tank, stir for 20 minutes and add 8.18kg of chloroacetaldehyde acetal Ethylene glycol (66.7mol), stirred and refluxed for 6h, TLC (acetone:dichloromethane=3:1) monitored the complete reaction of the raw material theophylline. After the reaction was over, the solvent was evaporated to dryness under reduced pressure, washed 3 times with saturated saline, filtered, and the filter residue was recrystallized with absolute ethanol to obtain 13.3kg (50.04mol) of product doxofylline, with a yield of 90% and a melting point of 143-145°C.

Embodiment 2

[0024] Add 10kg (55.6mol) of theophylline, 8L of dichloromethane, 6.23kg of potassium hydroxide (111.2mol) and 0.7kg of tetrabutylammonium chloride (2.5mol) into the reaction tank, stir for 20 minutes and then add 12.3kg of chlorinated Acetaldehyde ethylene glycol (100mol), stirred and refluxed for 5h, TLC (acetone: dichloromethane = 3:1) monitoring the complete reaction of the raw material theophylline. After the reaction, the solvent was evaporated to dryness under reduced pressure, washed three times with saturated saline, filtered, and the filter residue was recrystallized with absolute ethanol to obtain the product doxofylline 13kg (48.9mol), with a yield of 88% and a melting point of 143 -145°C.

Embodiment 3

[0026] Add theophylline 10kg (55.6mol), 8L DMF, 8.8kg sodium carbonate (83.4mol) and 0.56kg tetrabutylammonium chloride (2mol) into the reaction tank, stir for 20min and add 8.18kg chloroacetaldehyde acetal dropwise Diol (66.7mol), heated to 110°C and kept stirring at this temperature for 6h, TLC (acetone:dichloromethane=3:1) monitored the complete reaction of the raw material theophylline. After the reaction, the solvent was evaporated to dryness under reduced pressure, washed three times with saturated saline, filtered, and the filter residue was recrystallized with absolute ethanol to obtain the product doxofylline 13kg (48.9mol), with a yield of 88% and a melting point of 143 -145°C.

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Abstract

The invention discloses a synthetic method of doxofylline and belongs to the technical field of organic synthesis. The method comprises the following step: theophylline and 2-chloromethyl-1,3-dioxolane are subjected to a reaction at 60-110 DEG C in an aprotic solvent under the action of alkali and a phase transfer catalyst, and doxofylline is synthesized, wherein the mole ratio of theophylline, 2-chloromethyl-1,3-dioxolane and the alkali is 1:1-2:1-3, the phase transfer catalyst accounts for 3%-5% of the molar weight of theophylline, and the phase transfer catalyst is selected from one or moreof tetrabutylammonium chloride, tetrabutylammonium bromide and tetrabutylammonium fluoride. The provided new synthetic method of doxofylline is short in reaction time and only needs 3-6 h, is low inreaction temperature which is lower by 20-30 DG C than that of the conventional method, is high in yield which is 10% or higher than that of the conventional method, and is beneficial to industrial production of the drug.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and specifically discloses a method for synthesizing doxofylline. The yield of the method can reach more than 85%. Background technique [0002] Doxofylline is 1,3-dimethyl-7-(1,3-dioxolan-2-yl)methyl-3,7-dihydro-1H-purine-2,6 - Diketones. Doxofylline is a new drug for dilating the bronchi, which was launched in Italy in 1988 under the name Anismar. The safety of doxofylline is higher than that of theophylline, and it is a new generation of methylpurine derivatives that can replace theophylline drugs. Doxofylline is clinically used in the treatment of bronchial asthma, chronic obstructive pulmonary disease and other diseases such as dyspnea caused by bronchospasm. Its mechanism of action is to control the chronic inflammation of the respiratory tract by inhibiting the release of various inflammatory mediators and cytokines development of. Inhibit phosphodiesterase activation of prot...

Claims

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Application Information

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IPC IPC(8): C07D473/08
CPCC07D473/08
Inventor 吴伟伟雷玉平汪黎明张锐李建雄
Owner HUBEI HUNTIDE BIOTECH
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