CN1044810C - Synthetic process of new drug dosotheophylline - Google Patents
Synthetic process of new drug dosotheophylline Download PDFInfo
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- CN1044810C CN1044810C CN94113971A CN94113971A CN1044810C CN 1044810 C CN1044810 C CN 1044810C CN 94113971 A CN94113971 A CN 94113971A CN 94113971 A CN94113971 A CN 94113971A CN 1044810 C CN1044810 C CN 1044810C
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- synthetic method
- theophylline
- reaction
- doxofylline
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Abstract
The present invention relates to a synthesizing method of doxofylline. In the method, theophylline is used to react with 2-halomethyl-1, 3-dimethoxacyclo pantane in polar solvent by using alkali as an acid absorbent to generate doxofylline in one step. Yield can reach 75 to 85%. The synthesizing method has the advantages of easy acquirement of reaction raw materials, easy control of reaction conditions and convenient separation and purification, and is suitable for industrial production. The novel one-step synthesizing method exploits a new method for the reorganization of purine medicines.
Description
The present invention relates to the synthetic method of Xanthine compounds, specifically a kind of synthetic method of doxofylline.
Doxofylline (Doxofylline) is a benzene bases novel drugs, is xanthic derivative.Formal name used at school is 2-(7 ' theophylline methyl)-1, the 3-dioxolane [2-(7 '-theophyllinemethyl)-1,3-dioxolane] or 7-(1,3-dioxane penta methyl)-benzene alkali [7-(1,3-dioxolan 2yl methyl) theophylline].It is antibechic Zhichuan, the new drug of expansion bronchus, and commodity are called Anismar.Its drug effect is 10-15 a times of similar medicine aminophylline, and no habituation is paid effect to central nervous system and cardiovascular nothing.United States Patent (USP) (US4187308,1980) has been reported the synthetic method of doxofylline, is to use Theophylline Anhydrous acetaldehyde and ethylene glycol under Catalyzed by p-Toluenesulfonic Acid, in benzene, reflux and generate, productive rate is on average about 70%, only reports fusing point 144-145.5 ℃, not mentioned spectroscopic data.The raw materials used Theophylline Anhydrous acetaldehyde of this method is difficult for making, and synthesis step is many, and productive rate is low, also need add tosic acid in reaction, the separation and purification trouble, and in addition, the toxicity of solvent benzol is big, belongs to carcinogenic substance, is unwell to industrial production.Therefore, seek a simple synthesis, be still the important topic that to study for doxofylline.
Above-mentioned united states patent law is that doxofylline is considered as theophylline acetaldehyde Glycol Acetal, and the present invention regards doxofylline as theophylline 7-position hydrogen by methylcyclopentyl group
Substituent, design and explored synthetic method of the present invention on this new design basis.
The object of the invention provides the new synthetic method of a kind of doxofylline, is to make raw material with theophylline, and with 2-monochloromethyl-1,3-dioxolane single step reaction is synthetic, easy control of reaction conditions, and the product separation and purification is easy, is suitable for industrial production.
The synthetic method of doxofylline of the present invention is theophylline and 2-monochloromethyl-1, and the 3-dioxolane is made acid absorber with alkali in polar solvent, and single step reaction can generate.
The present invention's reaction is represented with following reaction formula:
X is a halogen in the formula, is chlorine, bromine or iodine.Used alkali is alkaline carbonate such as yellow soda ash, salt of wormwood and Quilonum Retard etc. in the reaction; Alkaline earth metal carbonate such as magnesiumcarbonate, lime carbonate and barium carbonate etc.; Volatile salt or organic bases such as triethylamine, tripropyl amine and pyridine etc.Used polar solvent is alcohols such as ethanol, Virahol and hexalin etc. in the reaction; Ethers such as tetrahydrofuran (THF), dioxane and glycol dimethyl ether etc.; Dried meat class such as acetonitrile, butyronitrile and benzene nitrile etc.; Amides such as N, dinethylformamide, N,N-dimethylacetamide and N-N-methyl 2-pyrrolidone N-etc. or any two kinds mixed solvent in them.The reactant mole ratio is a theophylline: 2-monochloromethyl-1, the 3-dioxolane: alkali=1: 1-5: 1-3, theophylline and polar solvent weight ratio are 1: 6-12.Temperature of reaction 60-125 ℃, reaction times 8-18 hour, follow the tracks of detection with gas-chromatography in the reaction process, treat that raw material almost completely transforms, i.e. stopped reaction.Reaction solvent can reclaim, and product is through recrystallization purifying.The solvent that recrystallization uses is ethyl acetate, ethanol, dioxane, methyl alcohol, chloroform, Virahol, glycol monomethyl methyl esters etc. or any two kinds mixed solvent in them.Productive rate can reach 75-85%.Product structure is used
1HNMR,
13CNMR, IR, UV, MS and ultimate analysis confirm.
The advantage of doxofylline synthetic method of the present invention is that reaction preference is strong, and product is single, good reproducibility, and the productive rate height is for synthetic doxofylline provides shortcut.This reaction raw materials is easy to get, easily-controlled reaction conditions, and separation and purification is easy, the recyclable usefulness again of solvent, cost is low, and income is fast, is suitable for industrial production, by pharmaceutical industry is welcome.In addition, this new reaction replaces theophylline 7-position hydrogen with ring penta oxa alkyl first, and the reaction of theophylline is expanded to the oxa-cycloalkylation, for the purine chemistry increases fresh content, is purine medicines structure transformation developing novel method.Therefore, the present invention has shown theoretical and industrial double meaning,
The present invention further sets forth by following examples, but does not place restrictions on scope of the present invention.
Embodiment 1
Benzene alkali (1,3 dimethyl xanthine-hydrate) 24g (0.12mole), 200ml glycol dimethyl ether and 80ml N-methyl are given a tongue-lashing and are coughed up ketone, Na
2CO
313g (0.12mole) places three mouthfuls of reaction flasks, be heated with stirring to 50 ℃, 2-chloromethyl-1,3-dioxolane 15.5g (0.13mole) is dropwise added by separating funnel, after dropwising, is heated to 120-125 ℃, maintain under this temperature and react, follow the tracks of with gas chromatogram, when raw material almost completely transforms, stopped reaction.Reclaim behind the solvent crude product, through ethyl acetate: ethanol (1: 3 volume ratio) recrystallization, white, needle-shaped crystals doxofylline 27g, productive rate 85%.The physical constant of product is as follows:
Fusing point 145-145.5 ℃
Ultimate analysis calculated value (%) C 49,62; H 5.27; N 21.05; O 24.06
Measured value (%) C 49.51; H 5.30; N 21.16; O 24.03
1HNMR[CDCl
3,δ(ppm)]3.42(s,3H,N-CH
3)；3.62(s,3H,NCH
3)3.96(s,4H,OCH
2×2)；4.62(d,2H,CH
2)；5.23(t,1H,CH)；7.63(s,lH,CH=N)
13CNMR[CDCl
3,δ(ppm)]27.786(CH
3)；29.605(CH
3)；47.857(CH
2)；65.294(OCH
2)；100.757(CH)；107.056(C=C)；148.215(C=C)；142.143(CH=N)；151.053(C=O)；155.146(C=O)
IR(KBr,cm
-1)1012-1032(C-O-C)；1654(C=C)；1696(C=O)；2950(C-H)
UV(CHCl
3,nm)276(ε=8900)；232(ε=2100)Ms?267(M
++1)5.5％；266(M
+)12.5％；73
100％；193
3.8％；87
9.5％
Embodiment 2
24g theophylline (0.12mole), 250ml Virahol and 10gMgCO
3(0.12mole) place three mouthfuls of reaction flasks under the room temperature.Be heated with stirring to 50 ℃, 19.2g2-chloromethyl-1,3-dioxolane (0.16mole) is splashed in the reaction flask by separating funnel, after dropwising, be heated to 80 ℃, react about 18 hours after, reclaim solvent, crude product dioxane recrystallization gets white, needle-shaped crystals doxofylline 23.5g, productive rate 75%.
Embodiment 3
24g theophylline (0.12mole), 200ml acetonitrile and 51.4g tripropyl amine (0.36mole) at room temperature place three mouthfuls of reaction flasks, be heated to 50 ℃, 20g 2-brooethyl-1,3-dioxolane (0.12mole) splashes in the reaction flask, is heated to 60-70 ℃ of reaction and finishes in about 10 hours, reclaim solvent, crude product is through methyl alcohol: chloroform (5: 1 volume ratios) recrystallization, white, needle-shaped crystals doxofylline 25.2g, productive rate 80%.
Embodiment 4
Theophylline 19.8g (0.1mole), 240ml glycol dimethyl ether and 20g lime carbonate (0.2mole) place three mouthfuls of reaction flasks, be heated with stirring to 50 ℃, 21,4g 2-iodomethyl-1,3-dioxolane (0.1mole) is dropwise added by separating funnel, drip off post-heating to 80-85 ℃, follow the tracks of with gas chromatogram, stopped reaction when raw material almost completely transforms gets crude product behind the recovery solvent, get white, needle-shaped crystals doxofylline 20.7g, productive rate 78% through the Virahol crystallization.
Embodiment 5
Theophylline 19.8g (0.1mole), 150ml N, N N,N-DIMETHYLACETAMIDE and 24g pyridine (0.3mole) place there-necked flask, are heated to 50 ℃, 42.7g 2-chloromethyl-1,3-dioxolane (0.35mole) splashes in the reaction flask, be heated to 80-90 ℃, react about 8 hours after, decompression and solvent recovery, crude product gets white, needle-shaped crystals doxofylline 22.5g through the crystallization of di-alcohol monomethyl ether, productive rate about 85%.
Embodiment 6
Theophylline 19.8g (0.1mole), 100ml ethanol, 50ml acetonitrile and 124g volatile salt (0.25mole) place three mouthfuls of reaction flasks, are heated to 50 ℃, 61g chloromethyl-1,3-dioxolane (0.50mole) splashes in the reaction flask.Keep temperature of reaction 55-60 ℃ 18 hours, stopped reaction reclaim behind the solvent crude product, use ethyl acetate: methyl alcohol (1: volume ratio) recrystallization, must white, needle-shaped crystals doxofylline 21g, productive rate 80%.
Claims (6)
1. the synthetic method of a doxofylline, it is characterized in that by theophylline and 2-monochloromethyl-1, the 3-dioxolane is in polar solvent, make acid absorber with alkali, single step reaction generates doxofylline, and the reactant mole ratio is a theophylline: 2-monochloromethyl-1,3-dioxolane: alkali=1: 1-5: 1-3, temperature of reaction 60-125 ℃, reaction times 8-18 hour.
2. synthetic method as claimed in claim 1 is characterized in that 2-monochloromethyl-1, and the halogen rope in the 3-dioxolane is chlorine, bromine or iodine.
3. synthetic method as claimed in claim 1 is characterized in that described alkali is metal carbonate, alkaline earth metal carbonate, volatile salt or organic bases.
4. synthetic method as claimed in claim 1 is characterized in that described polar solvent is alcohols, ethers, nitrile, amides or any two kinds mixed solvent in them.
5. synthetic method as claimed in claim 1 is characterized in that reactant theophylline and weight of solvent ratio are 1: 6-12.
6. synthetic method as claimed in claim 1 is characterized in that solvent that the crude product recrystallization uses is ethyl acetate, ethanol, methyl alcohol, chlorine wound, dioxane, Virahol, glycol monomethyl methyl esters or any two kinds mixed solvent in them.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94113971A CN1044810C (en) | 1994-11-03 | 1994-11-03 | Synthetic process of new drug dosotheophylline |
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| CN94113971A CN1044810C (en) | 1994-11-03 | 1994-11-03 | Synthetic process of new drug dosotheophylline |
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| CN1106404A CN1106404A (en) | 1995-08-09 |
| CN1044810C true CN1044810C (en) | 1999-08-25 |
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| CN94113971A Expired - Fee Related CN1044810C (en) | 1994-11-03 | 1994-11-03 | Synthetic process of new drug dosotheophylline |
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Families Citing this family (11)
| 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 |
| CN1041728C (en) * | 1997-03-03 | 1999-01-20 | 黑龙江华星制药股份有限公司 | Synthsis of doxofylline |
| CN102367254B (en) * | 2011-08-26 | 2012-11-28 | 贺金凤 | More stable doxofylline compound and pharmaceutical composite thereof |
| CN102775405B (en) * | 2012-08-23 | 2014-03-12 | 天津梅花医药有限公司 | High-solubility doxofylline compound |
| CN102936248A (en) * | 2012-10-30 | 2013-02-20 | 开封明仁药业有限公司 | Method for preparing doxofylline |
| CN103145713A (en) * | 2013-03-26 | 2013-06-12 | 山西普德药业股份有限公司 | Doxofylline crystalline compound and lyophilized powder 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 |
| CN105418612B (en) * | 2015-12-23 | 2017-03-22 | 北京颐方生物科技有限公司 | Preparation method of doxofylline |
| CN108840872A (en) * | 2018-08-22 | 2018-11-20 | 湖北泓肽生物科技有限公司 | The synthetic method of doxofylline |
| CN113030285B (en) * | 2019-12-25 | 2023-04-14 | 北京新领先医药科技发展有限公司 | Method for detecting residual 2-bromomethyl-1, 3-dioxolane in doxofylline |
| CN114380830A (en) * | 2021-12-28 | 2022-04-22 | 赤峰万泽药业股份有限公司 | Synthesis process of doxofylline |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1106404A (en) * | 1994-11-03 | 1995-08-09 | 中国科学院上海有机化学研究所 | Synthetic process of new drug dosotheophylline |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1106404A (en) * | 1994-11-03 | 1995-08-09 | 中国科学院上海有机化学研究所 | Synthetic process of new drug dosotheophylline |
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