Unlock instant, AI-driven research and patent intelligence for your innovation.

Preparation method of doxofylline

A technology of doxofylline and theophylline, which is applied in the field of drug synthesis and can solve the problems of unavailable raw materials and high cost

Active Publication Date: 2016-03-23
北京颐方生物科技有限公司
View PDF7 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Liu Hongxia and others used vinyl acetate to obtain bromoacetaldehyde formal through bromination alcoholysis, and then reacted with ethylene glycol to prepare side chain bromoacetaldehyde ethylene acetal, and then condensed with theophylline to prepare doxofylline 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 moisture content in the solvent dimethylformamide. Therefore, the imported solvent is used, and the raw materials for this process are not easy to obtain. higher cost

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of doxofylline
  • Preparation method of doxofylline
  • Preparation method of doxofylline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] a. Preparation of bromoacetaldehyde ethylene acetal

[0038] Add 12.414Kg ethylene glycol (200mol) to the reaction tank, slowly add 4.41Kg freshly distilled acetaldehyde (100mol) under stirring conditions and stir at room temperature for 30min, add bromine 15.98Kg (100mol) dropwise, and control the dropping process The temperature is below 10°C. After the dropwise addition, react at 0-10°C for 3 hours, fractionate under reduced pressure, and collect 13.126Kg (78.6mol) of 80-82°C fraction (3.6KPa), which is bromoacetaldehyde ethylene acetal. The yield is 78.6%, and the content is more than 95%.

[0039] b. Preparation of bromoacetaldehyde ethylene acetal

[0040] Add 10.326Kg ethylene glycol (166.37mol) in the reaction tank, slowly add 3.66Kg newly distilled acetaldehyde (83.185mol) under stirring condition and stir at room temperature for 30min, dropwise add bromine 14.622Kg (91.504mol), control The temperature of the dropping process is below 10°C. After the dropwise...

Embodiment 2

[0044] Add theophylline 12.6Kg (69.94mol), 7.85Kg potassium hydroxide (139.88mol), 0.478Kg benzyltriethylammonium chloride (2.10mol) in the reaction tank, add dropwise 14.02Kg bromoacetaldehyde after stirring for 10min Ethylene glycol (83.93mol), temperature controlled in a water bath at 60-70°C, stirred for 6 hours, and monitored by thin-layer chromatography (developing solvent: acetone: dichloromethane = 3:1). After the reaction was finished, the solvent was evaporated to dryness by distillation under reduced pressure, washed 3 times with saturated brine, filtered, and the filter residue was recrystallized with absolute ethanol to obtain 16.69Kg doxofylline (62.74mol), with a yield of 89.7% and a melting point of 143.5- 145°C, the content is above 98.5%.

Embodiment 3

[0046] Add 11.6Kg (64.39mol) of theophylline, 7.3L of absolute ethanol, 3.35Kg of sodium hydroxide (83.71mol) into the reaction tank, stir and reflux for 4 hours, and recover the solvent by distillation under reduced pressure. The obtained theophylline salt is mixed with 722.68ml of PEG-400 , 12.9Kg bromoacetaldehyde ethylene acetal (77.27mol) mixed evenly, water bath temperature control 60 ~ 70 ℃, stirring reaction for 6h, using thin layer chromatography to monitor the end of the reaction (developing agent is acetone: dichloromethane = 3:1 ). After the reaction, wash three times with 1000ml of ice water, filter, and recrystallize the filter residue with water: ethanol=3:1 (v / v) to obtain 15.24Kg doxofylline (57.31mol), with a yield of 89%, and a melting point of 143.5- 145°C, the content is above 98.5%.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
Melting pointaaaaaaaaaa
Melting pointaaaaaaaaaa
Login to View More

Abstract

The invention provides a preparation method of doxofylline and particularly relates to a synthetic method of bromoacetaldehyde ethylene acetal represented as the formula II and the doxofylline. The method includes the steps of preparing the side-chain bromoacetaldehyde ethylene acetal represented as the formula II through a one-pot reaction of acetaldehyde, ethylene glycol and bromine, and then carrying out a N-alkylation reaction to the compound represented as the formula II with theophylline to prepare the doxofylline. The synthetic method is carried out with easy-to-obtain raw materials, is low in cost, is high in yield, is simple in processes, is economical and environment-friendly, and is beneficial to industrial scale-up production of the drug.

Description

technical field [0001] The invention relates to a preparation method of doxofylline, which belongs to the field of drug synthesis. Background technique [0002] Doxofylline (Doxofylline) chemical name is 1,3-dimethyl-7-(1,3-dioxol-2-yl)methyl-3,7-dihydro-1H-purine-2 ,6-diketone. Doxofylline has a strong antiasthmatic effect and is a new drug for dilating the bronchi. The trade name is Anismar, which was launched in Italy in 1988. Its safety is obviously higher than that of theophylline and aminophylline, and it is a new generation of methylpurine derivatives replacing 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; inhibit intracellular phosphodiesterase activation...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D473/08C07D317/16
CPCC07D317/16C07D473/08
Inventor 王姣石清东
Owner 北京颐方生物科技有限公司