CN1160715A - Synthsis of doxofylline - Google Patents
Synthsis of doxofylline Download PDFInfo
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- CN1160715A CN1160715A CN 97100911 CN97100911A CN1160715A CN 1160715 A CN1160715 A CN 1160715A CN 97100911 CN97100911 CN 97100911 CN 97100911 A CN97100911 A CN 97100911A CN 1160715 A CN1160715 A CN 1160715A
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- theophylline
- doxofylline
- ethyl
- reaction
- synthetic method
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Abstract
The synthesis of doxofylline includes the reaction of 7-(2,2-dialkoxylethyl) theocin and glycol in N,N-dimethyl formamide solution and the catalyst condensation of toluene-p-sulfonic acid with basic carbonate as condensing agent. The said method has easy-to-obtain material, mild and controllable reaction condition, simple operation, short period, high yield and no toxic matter produced, and its easy use in industrial production provides a new way for producing xanthines as asthma relieving medicine.
Description
The present invention relates to a kind of synthetic method of doxofylline.
Doxofylline is the xanthine anti-asthmatic, and its formal name used at school is 7-(1.3-dioxolane-ethyl-methyl)-3.7-dihydro-1.3-dimethyl-1H-purine-2.6-diketone.This medicine is by the development of Italian Roberts company, and in listing in 1988, its commercial tablets was called Ansimar.This product compares with similar anti-asthmatic, the curative effect height, and toxicity is low, the oral LD of mouse
50Be 1.5 times of aminophylline, no habituation.And it is non-adenosine blocker, therefore can not produce the outer side effect of broncho-pulmonary, the influence of no aminophylline sample maincenter and cardiovascular systems.United States Patent (USP) (US4187308) has been reported the synthetic method of doxofylline, be by theophylline acetaldehyde and ethylene glycol under Catalyzed by p-Toluenesulfonic Acid, be that solvent reaction generates doxofylline with benzene.The theophylline acetaldehyde of this method can be by the reaction of diprophylline and peroxide acid iodide or 7-(2.2-dialkoxy ethyl) theophylline decomposition and inversion in aqueous ammonium chloride solution be theophylline acetaldehyde.Before method operation more numerous, and with peroxide acid iodide cost height, back method yield is low.And the solvent benzol toxicity of using when theophylline acetaldehyde and glycol reaction is big, health is brought harm, and productive rate is low, and is average about 70%, is unwell to suitability for industrialized production.
The object of the present invention is to provide that a kind of raw material is easy to get, reaction conditions relaxes, easy and simple to handle, the yield height, doxofylline novel synthesis with short production cycle is realized suitability for industrialized production easily.
The objective of the invention is to be achieved by the following scheme.Present method by 7-(2.2-dialkoxy ethyl) theophylline and ethylene glycol at N, in the dinethylformamide solvent, make condensing agent with carbonic acid alkali, condensation forms under Catalyzed by p-Toluenesulfonic Acid, the reactant mole ratio is 7-(2.2-dialkoxy ethyl) theophylline: ethylene glycol=1: 1～3,60～110 ℃ of temperature of reaction, 1～8 hour reaction times.
Method of the present invention is represented with following reaction formula:
R is methyl or ethyl in the formula, and used alkaline condensing agent is Anhydrous potassium carbonate or anhydrous sodium carbonate.Present method raw material midbody 7-(2.2-dialkoxy ethyl) but the manufacture method reference literature Die Makromolekulare Chemie 169:327-331 of theophylline, 1973.
Method raw material of the present invention is easy to get, reaction conditions relaxes reaction easy to control, easy and simple to handle, with short production cycle, the yield height can reach more than 90%, nontoxicity material in the reaction process, realize suitability for industrialized production easily, provide a new route of synthesis for producing the xanthine anti-asthmatic and synthesizing 7-substituted xanthine compounds.
Further specify technical scheme of the present invention in conjunction with the embodiments.
Embodiment 1:
1, the preparation of raw material midbody 7-(2.2-diethoxy ethyl) theophylline
Take by weighing 14.9 gram (75.1mmol) theophylline-hydrates, 14.9 gram (75.6mmol) 1.1-diethoxy-2-monobromethanes, 10.5 gram anhydrous K
2CO
3, be added to 225mlN respectively, in the dinethylformamide solvent, under 100 ℃ of temperature, stirred 15 hours, leach precipitation, concentrated filtrate is put and cold crystallization is separated out fully, and suction filtration press dry, use recrystallizing methanol, get needle crystal 19 grams, 125～126 ℃ of fusing points, yield 85%.
2, the preparation of doxofylline
Add 50ml N in the three-necked bottle, dinethylformamide, 3.4 gram (54.8mmol) ethylene glycol, 0.13 gram tosic acid, under agitation add 15 gram (50.6mmol) 7-(2.2-diethoxy ethyl) theophylline then, stirred 20 minutes in 60 ℃, be warming up to 100 ℃ gradually, continue to stir 5 hours, remove N under reduced pressure, dinethylformamide, residue dehydrated alcohol recrystallization with adding Anhydrous potassium carbonate 0.1 gram after the ethanol evaporation that generates in the reaction, decolour to such an extent that white, needle-shaped crystals doxofylline 12 restrains yield 89% simultaneously.
Embodiment 2:
Add 85ml N in the there-necked flask successively, dinethylformamide, 14.5 gram (233.6mmol) ethylene glycol, 0.22 gram tosic acid, under agitation add 23.1 gram (86.1mmol) 7-(2.2-dimethoxy ethyl) theophylline then, stirred 20～30 minutes down at 60 ℃, be warming up to 90 ℃ gradually, constant temperature stirred 3 hours, after the methyl alcohol evaporation that generates in the reaction is reclaimed, added anhydrous sodium carbonate 0.2 gram, remove N under reduced pressure, dinethylformamide is to doing residue dehydrated alcohol recrystallization, decolouring simultaneously, get white, needle-shaped crystals doxofylline 20.9 grams, yield 91.3%.
144.5～145 ℃ of the product fusing points that present method obtains.
Product structure usefulness ultimate analysis and UV, IR,
1H-NMR,
13C-NMR, MS analyze confirmation.
Ultimate analysis analysis project theoretical value (%) measured value (%) measured value mean value (%) C 49.62 49.79 49.96 49.84 49.86 H 5.30 5.31 5.42 5.32 5.35 N 21.04 21.10 21.20 21.16 21.16
UV(95％C
2H
5OH，nm)λmax273(ε9230)；λmin244(ε2190)
IR(KBr，cm
-1)1134(C-O)；1233(C-N)；1547(C＝N)；1656(C＝C)；1700(C＝O)；2993(C-H)
1H-NMR[CDCl
3，δ(ppm)]3.399(s，3H，N-CH
3)；3.586(S，3H，N-CH
3)；3.815-3.885(m，4H，OCH
2×2)；4.581(d，2H，CH
2)；5.211(t，1H，CH)；7.652(S，1H，CH＝N)
13C-NMR[CDCL
3，δ(ppm)]27.88(CH
3)；29.69(CH
3)；47.87(CH
2)；65.37(OCH
2)；100.76(CH)；107.26(C＝C)；142.16(CH＝N)；148.22(C＝C)；151.59(C＝O)；155.25(C＝O)。
Ms 266(M
+)；
Claims (3)
1, a kind of synthetic method of doxofylline, it is characterized in that: by 7-(2.2-dialkoxy ethyl) theophylline and ethylene glycol at N, in the dinethylformamide solvent, make condensing agent with carbonic acid alkali, condensation forms under Catalyzed by p-Toluenesulfonic Acid, the reactant mole ratio is 7-(2.2-dialkoxy ethyl) theophylline: ethylene glycol=1: 1～3,60～110 ℃ of temperature of reaction, 1～8 hour reaction times.
2, synthetic method according to claim 1 is characterized in that: the alkyl in 7-(the 2.2-dialkoxy ethyl) theophylline is methyl or ethyl.
3, synthetic method according to claim 1 is characterized in that: said carbonic acid alkali is Anhydrous potassium carbonate or anhydrous sodium carbonate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97100911A CN1041728C (en) | 1997-03-03 | 1997-03-03 | Synthsis of doxofylline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97100911A CN1041728C (en) | 1997-03-03 | 1997-03-03 | Synthsis of doxofylline |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1160715A true CN1160715A (en) | 1997-10-01 |
| CN1041728C CN1041728C (en) | 1999-01-20 |
Family
ID=5165393
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97100911A Expired - Fee Related CN1041728C (en) | 1997-03-03 | 1997-03-03 | Synthsis of doxofylline |
Country Status (1)
| Country | Link |
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| CN (1) | CN1041728C (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159769A (en) * | 2013-04-01 | 2013-06-19 | 湖北美林药业有限公司 | Doxofylline compound and medicine composition thereof |
| CN105237538A (en) * | 2015-10-10 | 2016-01-13 | 斯卫东 | Preparation methods of doxofylline |
| CN111995625A (en) * | 2020-08-28 | 2020-11-27 | 开封康诺药业有限公司 | Preparation method of doxofylline |
| CN113045572A (en) * | 2019-12-27 | 2021-06-29 | 北京弘德信医药科技有限公司 | Preparation method of doxofylline impurity A |
| CN113234076A (en) * | 2021-05-26 | 2021-08-10 | 湖北午时药业股份有限公司 | Preparation method of doxofylline |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1044810C (en) * | 1994-11-03 | 1999-08-25 | 中国科学院上海有机化学研究所 | Synthetic process of new drug dosotheophylline |
-
1997
- 1997-03-03 CN CN97100911A patent/CN1041728C/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159769A (en) * | 2013-04-01 | 2013-06-19 | 湖北美林药业有限公司 | Doxofylline compound and medicine composition thereof |
| CN103159769B (en) * | 2013-04-01 | 2015-03-11 | 湖北美林药业有限公司 | Doxofylline compound and medicine composition thereof |
| CN105237538A (en) * | 2015-10-10 | 2016-01-13 | 斯卫东 | Preparation methods of doxofylline |
| CN105237538B (en) * | 2015-10-10 | 2017-08-08 | 斯卫东 | A kind of preparation method of doxofylline |
| CN113045572A (en) * | 2019-12-27 | 2021-06-29 | 北京弘德信医药科技有限公司 | Preparation method of doxofylline impurity A |
| CN111995625A (en) * | 2020-08-28 | 2020-11-27 | 开封康诺药业有限公司 | Preparation method of doxofylline |
| CN111995625B (en) * | 2020-08-28 | 2024-03-26 | 开封康诺药业有限公司 | Preparation method of doxofylline |
| CN113234076A (en) * | 2021-05-26 | 2021-08-10 | 湖北午时药业股份有限公司 | Preparation method of doxofylline |
| CN113234076B (en) * | 2021-05-26 | 2023-08-18 | 湖北午时药业股份有限公司 | Preparation method of doxofylline |
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| Publication number | Publication date |
|---|---|
| CN1041728C (en) | 1999-01-20 |
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