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Preparation methods of doxofylline

A technology of doxofylline and theophylline, which is applied in the field of preparation of doxofylline, can solve problems such as easy residue, benzene residue, high genotoxicity, etc., achieve mild and easy-to-control reaction conditions, solve toxic residues, and yield of finished products high effect

Inactive Publication Date: 2016-01-13
浙江北生药业汉生制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although the order of ethylene glycol condensation into rings in these synthetic routes is slightly different, p-toluenesulfonic acid, which is relatively genotoxic and prone to residue, is used as the condensation ring catalyst, and toluene is used as the reaction solvent. Benzene residue
In addition, the synthesis routes reported in current literature, journals and patents have long steps and low yields, which are not conducive to industrial production

Method used

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  • Preparation methods of doxofylline
  • Preparation methods of doxofylline
  • Preparation methods of doxofylline

Examples

Experimental program
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Effect test

Embodiment 1

[0035] A preparation method of doxofylline, comprising:

[0036] (1) Take 20g of theophylline, 15.4g of anhydrous potassium carbonate, 14.5g of chloroacetaldehyde dimethyl acetal, and 2.8g of tetrabutylammonium bromide, add them to 120mL of dimethylformamide, and heat up to 145°C for reaction until theophylline basically reacts, stop the reaction, lower the temperature, filter, evaporate the filtrate to dryness under reduced pressure, and recrystallize the ethanol with a mass fraction of 95%, to obtain the intermediate 7-(2,2-dimethoxyethyl)tea alkali. The mass of the intermediate 7-(2,2-dimethoxyethyl)theophylline is 21g.

[0037] (2) Add 20g of 7-(2,2-dimethoxyethyl)theophylline, 9.3g of ethylene glycol, and 2.3g of potassium bisulfate to 150ml of anisole, and heat the oil bath to 115°C until the basic reaction of the raw materials Complete, stop heating, lower the temperature, pour out the supernatant, and evaporate the supernatant to dryness under reduced pressure to obt...

Embodiment 2

[0040] A preparation method of doxofylline, comprising:

[0041] (1) Take 200g of theophylline, 129.4g of anhydrous sodium carbonate, 152.1g of chloroacetaldehyde dimethyl acetal, and 15.9g of tetrabutylammonium bromide, add them to 800mL of dimethylformamide, and heat up to 140°C for reaction until theophylline basically reacts, stop the reaction, lower the temperature, filter, evaporate the filtrate to dryness under reduced pressure, and recrystallize the ethanol with a mass fraction of 95%, to obtain the intermediate 7-(2,2-dimethoxyethyl)tea alkali. The mass of the intermediate 7-(2,2-dimethoxyethyl)theophylline is 225g.

[0042] (2) Take 210g intermediate 7-(2,2-dimethoxyethyl)theophylline, 74.5g ethylene glycol, 33.5g potassium bisulfate and add it to 1100ml anisole, and the oil bath is heated to 130°C until After the raw materials have basically reacted, stop heating, lower the temperature, pour out the supernatant, and evaporate the supernatant to dryness under reduc...

Embodiment 3

[0044] A preparation method of doxofylline, comprising:

[0045](1) Take 200g of theophylline, 199.1g of anhydrous potassium carbonate, 179.9g of chloroacetaldehyde dimethyl acetal, and 17.9g of tetrabutylammonium bromide, add them to 1000ml of dimethylacetamide, and heat up to 150°C for reaction until theophylline basically reacts, stop the reaction, lower the temperature, filter, evaporate the filtrate to dryness under reduced pressure, and recrystallize the ethanol with a mass fraction of 95%, to obtain the intermediate 7-(2,2-dimethoxyethyl)tea alkali. The mass of the intermediate 7-(2,2-dimethoxyethyl)theophylline is 210g.

[0046] (2) Take 200g intermediate 7-(2,2-dimethoxyethyl)theophylline, 76.4g ethylene glycol, 15.8g sodium bisulfate and add it to 1200ml anisole, and the oil bath is heated to 135°C until After the raw materials have basically reacted, stop heating, lower the temperature, pour out the supernatant, and evaporate the supernatant to dryness under reduc...

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Abstract

The invention discloses preparation methods of doxofylline. The preparation methods include the steps: under the action of an acid-binding agent, carrying out a condensation reaction of theophylline and halogenated acetaldehyde dimethyl acetal in a polar solvent, to obtain an intermediate 7-(2,2-dimethoxy ethyl)theophylline; and then, with soluble hydrosulfate as a catalyst, carrying out a condensation cyclization reaction of the intermediate 7-(2,2-dimethoxy ethyl)theophylline with ethylene glycol in a solvent, to obtain doxofylline; or, firstly, carrying out a condensation cyclization reaction of halogenated acetaldehyde dimethyl acetal and ethylene glycol to obtain halogenated acetaldehyde ethylene acetal, and carrying out a condensation reaction with theophylline, to obtain doxofylline. The soluble hydrosulfate is used as the catalyst and replaces conventional p-toluenesulfonic acid, moreover, and anisole and other solvents are used for replacing methylbenzene used in a conventional reaction route, so that under a condition of ensuring high yield of the product, the toxicity of the solution in the synthesis reaction is reduced, and the difficult problem that residual toxicity easily exists in the finished product is solved.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of doxofylline. Background technique [0002] Doxofylline (Doxofylline) is a new derivative of methylxanthine, its chemical name is 1,3-dimethyl-7-(1,3-dioxol-2-yl)methyl -3,7-dihydro-1H-purine-2,6-dione. Doxofylline is a bronchodilator that can directly act on the bronchi to relax bronchial smooth muscle. It was first developed by the Italian IstitutoBiologico ChemioterapicoABC company and was produced and marketed abroad in 1988. Clinically, doxofylline is used for the treatment of bronchial asthma, asthmatic chronic bronchitis and other diseases such as dyspnea caused by bronchospasm. [0003] Doxofylline is a new type of phosphodiesterase inhibitor class of anti-asthma and antitussive drugs. Phosphodiesterase inhibitor drugs mainly refer to theophylline series drugs, which have a certain market foundation in China, have a good synergistic anti-asthma ...

Claims

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Application Information

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IPC IPC(8): C07D473/08
CPCC07D473/08
Inventor 斯卫东程绍红王强刘晓锋
Owner 浙江北生药业汉生制药有限公司
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