CN105418612B - Preparation method of doxofylline - Google Patents
Preparation method of doxofylline Download PDFInfo
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- CN105418612B CN105418612B CN201510977332.XA CN201510977332A CN105418612B CN 105418612 B CN105418612 B CN 105418612B CN 201510977332 A CN201510977332 A CN 201510977332A CN 105418612 B CN105418612 B CN 105418612B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/16—Radicals substituted by halogen atoms or nitro radicals
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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
The present invention relates to a kind of preparation method of doxofylline, belongs to pharmaceutical synthesis field.
Background technology
Doxofylline (Doxofylline) chemical name is 1,3- dimethyl -7- (1,3- dioxy cyclopenta -2- bases) first
Base -3,7- dihydro -1H- purine -2,6- diketone.Doxofylline has stronger antiasthmatic effect, is the new drug of expansion bronchus, business
The name of an article is Anismar, in 1988 in Italy's listing.Its safety, apparently higher than theophylline and aminophylline, is to substitute theophylline class
The methyl purine derivant of new generation of medicine.Doxofylline be used clinically for bronchial asthma, chronic obstructive pulmonary disease and
The treatment of the diseases such as the dyspnea that other bronchospasms cause, its mechanism of action are by suppression inflammation medium, carefully
The release of intracellular cytokine, controls the development of respiratory tract chronic inflammation；Suppress di-phosphate ester enzyme activition egg in asm cell
White enzyme A and G, so that reduce intracellular Ca2+Concentration and respiratory tract tension force.Additionally, the lax bronchial smooth muscle of doxofylline is made
It is with being 10～15 times of aminophylline and rapid-action, it is only necessary to which that 30min, duration of efficacy are up to 12h.
At present, the document report both at home and abroad in terms of doxofylline synthetic method has：United States Patent (USP) US4187308 is with tea
Alkali acetaldehyde is raw material, with ethylene glycol under the catalytic action of p-methyl benzenesulfonic acid, prepares doxofylline by solvent refluxing of benzene, the method
Yield 59.5%, but the toxicity of its solvent benzol is larger.Patent CN1133842A theophylline in the presence of water or organic solvent, with alkali
Reaction is obtained theophylline salt, then prepares doxofylline with Haloacetaldehydes condensed ethandiol condensation, and yield is 75～85%.Patent
CN1044810C does acid absorbent with alkali using theophylline and Haloacetaldehydes condensed ethandiol in polar solvent, and single step reaction is generated
Doxofylline, the method yield are 75～85%.Patent CN1041728C theophylline is with 1,1- diethoxy -2- bromoethanes in N, N-
In solvent dimethylformamide, condensing agent is made with potassium carbonate and prepare intermediate 7- (2,2- dialkoxy ethyl) theophylline, the step yield
For 85%, intermediate makees condensing agent with alkali carbonate, to first again with ethylene glycol in DMF solvent
It is condensed under the catalysis of base benzenesulfonic acid and doxofylline is obtained, the step yield is 89～91.3%, the method completes reaction in two steps, total to receive
Rate is low.Liu Hongxia etc. obtains bromoacetaldehyde dimethoxym ethane using vinyl acetate Jing bromination alcoholysis, then is obtained with glycol reaction
Side chain bromoacetaldehyde condensed ethandiol, the method for then preparing doxofylline with theophylline condensation again, the method have reached pilot scale level, and
Propose to affect product yield larger factor to be the moisture in solvent dimethylformamide in the process, therefore adopt
External import solvent, the raw materials technology are not easy to obtain, relatively costly.
For solving the problems, such as above-mentioned art methods, the present invention provides a kind of improvement preparation side of doxofylline
Method, the method meet the Atom economy synthesis theory of Green Chemistry, and raw material is easy to get, and low cost, yield are high, concise in technology, Jing
Ji environmental protection, is conducive to the industrialized production of the medicine.
The content of the invention
The present invention provides a kind of preparation method of doxofylline, comprises the steps：
In the presence of alkali and phase transfer catalyst, the theophylline and the bromoacetaldehyde condensed ethandiol shown in formula 2 shown in formula 3 is made
React the doxofylline shown in formula 1 is obtained：
According to the present invention, the alkali can be selected from the one kind or many in sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate
The mixture planted；
Phase transfer catalyst (PTC) can be (poly- selected from tetrabutyl ammonium bromide, benzyltriethylammoinium chloride, PEG-400
Ethylene glycol 400) in one or more of mixture.
The theophylline is 1 with the molar ratio of bromoacetaldehyde condensed ethandiol:1.0～1.8, such as 1:1.1～1.6,1:
1.2～1.5 or 1:1.2～1.4；
The theophylline is 1 with the molar ratio of alkali:1～3, such as 1:1.2、1:1.3、1:1.5、1:2 or 1:2.5；
The phase transfer catalyst is tetrabutyl ammonium bromide or during benzyltriethylammoinium chloride, described theophylline and phase transfer
The molar ratio of catalyst is 1:0.01～0.1, such as 1:0.03～0.05；
When described phase transfer catalyst is PEG-400, can be by every mole of 10～30ml of theophylline (such as 12～16ml)
The ratio of PEG-400 throws in material.
Above-mentioned reaction is condensation reaction, and which can be carried out in non-protonic solvent or under condition of no solvent.
The non-protonic solvent can be such as acetone, N,N-dimethylformamide, acetonitrile, dichloromethane, acetic acid second
The mixture of one or more in ester.For example, when the phase transfer catalyst is tetrabutyl ammonium bromide or benzyl triethyl ammonium chlorine
When changing ammonium, can carry out in the non-protonic solvent or under condition of no solvent；When phase transfer catalyst is PEG-400
When, theophylline also can first be made theophylline salt, then condensation reaction be carried out under condition of no solvent with bromoacetaldehyde condensed ethandiol.The tea
The preparation of alkali salt can be carried out using methods known in the art, for example：In water or organic solvent such as dehydrated alcohol, N, N- dimethyl methyls
In the presence of amide or N,N-dimethylacetamide, by theophylline (or theophylline anhydrous) and suitable alkali, such as sodium hydroxide, hydrogen-oxygen
Change the mixture reaction of one or more in potassium, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate etc., make theophylline salt.
The reaction can be carried out in backflow or non-reflow state.The reaction temperature is specifically as follows 50～150 DEG C.Instead
Can be 1～12h, such as 4～8h, such as 6～7h between seasonable.
2 compound of the formula can add reaction system by way of Deca after by other reaction substrate mixing.
After reaction terminates, following post processing can be carried out：Frozen water is washed, and is filtered, and filtering residue recrystallization is obtaining target compound.
Wherein, recrystallization preferably uses anhydrous or aqueous alcohols solvent, preferred alcohol.In the aqueous alcohols solvent, water is molten with alcohols
The volume ratio of agent can be (10～1):1, such as (5～2):1, such as 3:1.
Preferably, the doxofylline purity of the formula 1 that preparation method of the present invention is obtained is more than 98.5%.
The preparation method of the present invention furthermore provides the preparation method of the bromoacetaldehyde condensed ethandiol shown in formula 2, described
Method includes making ethylene glycol, acetaldehyde and bromine Jing condensation and bromination reaction the bromoacetaldehyde condensed ethandiol shown in formula 2 is obtained：
The preparation method of the bromoacetaldehyde condensed ethandiol shown in formula of the invention 2：
Preferably, the molar ratio of the ethylene glycol, acetaldehyde and bromine is 1～5:1:1～2, such as 2～4:1:1～1.5.
Preferably, the reaction temperature of methods described can be below room temperature, preferably less than 10 DEG C, such as 0～10 DEG C, react
Time can be such as 1～5h, preferably 2～4h.
Methods described can be one kettle way (one-pot reaction).The one kettle way is referred to, by reaction raw materials same
React in reactor, separate without intermediate, directly obtain the synthetic method of target compound；
Preferably, ethylene glycol is added in reactor first, be then added slowly with stirring acetaldehyde, and stir at room temperature
0.5～4h, then to Deca bromine in reactant liquor and controls Deca process temperature less than below room temperature, preferably less than 10 DEG C, example
Such as 0～10 DEG C, after completion of dropping, such as 1～5h, preferably 2～4h is reacted under the reaction temperature.
Preferably, after the completion of reaction, carry out following post-processing step：Vacuum fractionation is obtaining target compound.
Used as example, the present invention provides the preparation method of doxofylline, comprises the steps：
Preferably, the bromoacetaldehyde condensed ethandiol purity of the formula 2 that the present invention is prepared is more than 95%.
The present invention also provides the preparation method of the bromoacetaldehyde condensed ethandiol shown in above-mentioned formula 2 in doxofylline is prepared
Using.
Beneficial effects of the present invention
The synthetic method of compound and doxofylline shown in offer formula of the present invention 2, including by acetaldehyde, ethylene glycol,
The side chain bromoacetaldehyde condensed ethandiol of bromine one pot reaction formula 2, and 2 compound of formula to carry out N- hydrocarbylations with theophylline again anti-
Described doxofylline should be obtained.The synthetic method raw material of the present invention is easy to get, low cost, yield height, concise in technology, economy
Environmental protection, is conducive to the industry extension production of the medicine.
Specific embodiment
The present invention is further described by following case study on implementation, however the scope of the present invention be not necessarily limited to it is following
Case study on implementation.
Unless otherwise stated, following reaction raw materials and reagent are commercially available prod.Those skilled in the art are also dependent on
Perception method prepares them.
Embodiment 1
A. the preparation of bromoacetaldehyde condensed ethandiol
12.414Kg ethylene glycol (200mol) is added in retort, is slowly added into 4.41Kg under agitation and is newly steamed second
Aldehyde (100mol) is simultaneously stirred at room temperature 30min, Deca bromine 15.98Kg (100mol), control Deca process temperature for 10 DEG C with
Under, after completion of dropping, 0～10 DEG C of reaction 3h, vacuum fractionation collect 80～82 DEG C of fraction (3.6KPa) 13.126Kg
(78.6mol), as bromoacetaldehyde condensed ethandiol, yield is 78.6%, and content is more than 95%.
B. the preparation of bromoacetaldehyde condensed ethandiol
10.326Kg ethylene glycol (166.37mol) is added in retort, is slowly added into 3.66Kg under agitation new
Steam acetaldehyde (83.185mol) and 30min is stirred at room temperature, Deca bromine 14.622Kg (91.504mol) controls Deca process temperature
Spend for less than 10 DEG C, after completion of dropping, 0～3 DEG C of reaction 3.5h, vacuum fractionation collect 80～82 DEG C of fractions (3.6KPa)
11.002Kg (65.883mol), as bromoacetaldehyde condensed ethandiol, yield is 79.2%, and content is more than 95%.
C. the preparation of doxofylline
Addition theophylline 13Kg (72.16mol) in retort, 8L acetone, 5.77Kg sodium hydroxide (144.32mol),
0.7Kg tetrabutyl ammonium bromide (2.16mol), Deca 14.47Kg bromoacetaldehyde condensed ethandiol (86.64mmol) after stirring 10min,
6.3h is stirred at reflux, (developing solvent is as acetone with thin layer chromatography monitoring reaction end：Dichloromethane=3：1).After reaction terminates, subtract
Pressure distillation solvent evaporated, with saturated common salt water washing 3 times, filters, and filtering residue dehydrated alcohol is recrystallized to give many rope tea of 17.28Kg
Alkali (64.98mol), yield is 90%, and fusing point is 143.5～145 DEG C, and content is more than 98.5%.
Embodiment 2
Theophylline 12.6Kg (69.94mol), 7.85Kg potassium hydroxide (139.88mol), 0.478Kg is added in retort
Benzyltriethylammoinium chloride (2.10mol), Deca 14.02Kg bromoacetaldehyde condensed ethandiol (83.93mol) after stirring 10min, water
60～70 DEG C of temperature control of bath, stirring reaction 6h, with thin layer chromatography monitoring reaction end, (developing solvent is as acetone：Dichloromethane=3：1).
After reaction terminates, vacuum distillation solvent evaporated, with saturated common salt water washing 3 times, is filtered, and filtering residue is recrystallized to give with dehydrated alcohol
16.69Kg doxofyllines (62.74mol), yield is 89.7%, and fusing point is 143.5～145 DEG C, and content is more than 98.5%.
Embodiment 3
Theophylline 11.6Kg (64.39mol), 7.3L dehydrated alcohol, 3.35Kg sodium hydroxide is added in retort
(83.71mol) 4h, vacuum distillation recovered solvent, gained theophylline salt and 722.68mlPEG-400,12.9Kg bromo, are stirred at reflux
Ethylidene ether (77.27mol) mix homogeneously, 60～70 DEG C of water-bath temperature control, stirring reaction 6h are reacted with thin layer chromatography monitoring
(developing solvent is acetone to terminal：Dichloromethane=3：1).After reaction terminates, washed with 1000ml frozen water three times, filtered, filtering residue is used
Water：Ethanol=3:1 (v/v) is recrystallized to give 15.24Kg doxofyllines (57.31mol), and yield is 89%, fusing point be 143.5～
145 DEG C, content is more than 98.5%.
Embodiment 4
Addition theophylline 12.5Kg (69.38mol) in retort, 3.61Kg sodium hydroxide (90.19mol),
0.671Kg tetrabutyl ammonium bromide (2.08mol), 13.9Kg bromoacetaldehyde condensed ethandiol (83.26mol) mix homogeneously, water-bath control
60～70 DEG C of temperature, stirring reaction 6.3h, with thin layer chromatography monitoring reaction end, (developing solvent is as acetone：Dichloromethane=3：1).Instead
After should terminating, washed with 1200ml frozen water three times, filtered, filtering residue water：Ethanol=3:It is many that 1 (v/v) is recrystallized to give 16.24Kg
Rope theophylline (61.05mol), yield is 88%, and fusing point is 143.5～145 DEG C, and content is more than 98.5%.
The cost (being calculated with embodiment 4) of 1 present invention synthesis 1Kg doxofyllines of table
The cost of present invention synthesis 1Kg doxofyllines is 139.672～150.869 yuan.
Claims (20)
1. a kind of preparation method of doxofylline, comprises the steps：
1) make ethylene glycol, acetaldehyde and bromine Jing condensation and bromination one pot reaction the bromoacetaldehyde condensed ethandiol shown in formula 2 is obtained：
With
2) in the presence of alkali and phase transfer catalyst, the theophylline shown in formula 3 is made to exist with the bromoacetaldehyde condensed ethandiol shown in formula 2
Reacted the doxofylline shown in formula 1 is obtained in non-protonic solvent or under condition of no solvent：
The one kind of the non-protonic solvent in acetone, N,N-dimethylformamide, acetonitrile, dichloromethane, ethyl acetate
Or various mixture；
The theophylline is 1 with the molar ratio of bromoacetaldehyde condensed ethandiol:1.0～1.8；
The theophylline is 1 with the molar ratio of alkali:1～3；
The mixture that one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate of the alkali；
The phase transfer catalyst is selected from one or more in tetrabutyl ammonium bromide, benzyltriethylammoinium chloride, PEG-400
Mixture.
2. the preparation method described in claim 1, wherein step 2) in：
The theophylline is 1 with the molar ratio of bromoacetaldehyde condensed ethandiol:1.1～1.6；
The theophylline is 1 with the molar ratio of alkali:1.2、1:1.3、1:1.5、1:2 or 1:2.5；
The phase transfer catalyst is tetrabutyl ammonium bromide or during benzyltriethylammoinium chloride, described theophylline and phase transfer catalysis
The molar ratio of agent is 1:0.01～0.1；
When described phase transfer catalyst is PEG-400, can be in the ratio missile of every mole of theophylline 10～30ml PEG-400
Material.
3. the preparation method described in claim 2, wherein step 2) in：
The theophylline is 1 with the molar ratio of bromoacetaldehyde condensed ethandiol:1.2～1.5；
The phase transfer catalyst is tetrabutyl ammonium bromide or during benzyltriethylammoinium chloride, described theophylline and phase transfer catalysis
The molar ratio of agent is 1:0.03～0.05；
When described phase transfer catalyst is PEG-400, can be in the ratio missile of every mole of theophylline 12～16ml PEG-400
Material.
4. the preparation method described in claim 3, wherein step 2) described in theophylline rub with feeding intake for bromoacetaldehyde condensed ethandiol
You are than being 1:1.2～1.4.
5. the preparation method described in any one of claim 1-4, wherein step 2) in：
The reaction is condensation reaction；
The reaction is carried out in backflow or non-reflow state；
The reaction temperature is 50～150 DEG C；
Response time is 1～12h.
6. the preparation method described in claim 5, wherein step 2) in the response time be 4～8h.
7. preparation method as claimed in claim 6, wherein step 2) in the response time be 6～7h.
8. the preparation method described in any one of claim 1-4,6-7, wherein step 2) in：
2 compound of formula adds reaction system by way of Deca after by other reaction substrate mixing；
After reaction terminates, following post processing is carried out：Frozen water is washed, and is filtered, and filtering residue recrystallization is obtaining target compound.
9. the preparation method described in claim 5, wherein step 2) in：
2 compound of formula adds reaction system by way of Deca after by other reaction substrate mixing；
After reaction terminates, following post processing is carried out：Frozen water is washed, and is filtered, and filtering residue recrystallization is obtaining target compound.
10. the preparation method described in claim 8, wherein step 2) in recrystallization use anhydrous or aqueous alcohols solvent.
Preparation method described in 11. claim 9, wherein step 2) in recrystallization use anhydrous or aqueous alcohols solvent.
Preparation method described in 12. claim 10 or 11, wherein step 2) described in aqueous alcohols solvent, water is molten with alcohols
The volume ratio of agent is (10～1):1.
Preparation method described in 13. claim 12, wherein step 2) described in aqueous alcohols solvent, water and alcohols solvent
Volume ratio is (5～2):1.
Preparation method described in 14. claim 13, wherein step 2) described in aqueous alcohols solvent, water and alcohols solvent
Volume ratio is 3:1.
Preparation method described in 15. claim 12, wherein step 2) described in aqueous alcohols solvent be ethanol.
Preparation method described in 16. claim 1, wherein step 1) in：
The molar ratio of the ethylene glycol, acetaldehyde and bromine is 1～5:1:1～2；
The reaction temperature of methods described is below room temperature, and the response time is 1～5h.
Preparation method described in 17. claim 16, wherein step 1) in：
The molar ratio of the ethylene glycol, acetaldehyde and bromine is 2～4:1:1～1.5；
The reaction temperature of methods described is 0～10 DEG C, and the response time is 2～4h.
Preparation method described in 18. claim 16, wherein step 1) in：
Ethylene glycol is added in reactor first, is then added slowly with stirring acetaldehyde, and is stirred 0.5～4h at room temperature, with
Deca bromine Deca process temperature is controlled less than below room temperature in backward reactant liquor, after completion of dropping, in the reaction temperature
1～5h of lower reaction.
Preparation method described in 19. claim 17, wherein step 1) in：
Ethylene glycol is added in reactor first, is then added slowly with stirring acetaldehyde, and is stirred 0.5～4h at room temperature, with
Deca bromine 0～10 DEG C of Deca process temperature is controlled in backward reactant liquor, after completion of dropping, react under the reaction temperature
2～4h.
Preparation method described in 20. any one of claim 16-19, wherein step 1) in：
After the completion of reaction, carry out following post-processing step：Vacuum fractionation, to obtain bromoacetaldehyde condensed ethandiol.
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| CN201710147435.2A CN106928226B (en) | 2015-12-23 | 2015-12-23 | A kind of preparation method of bromoacetaldehyde condensed ethandiol |
| CN201510977332.XA CN105418612B (en) | 2015-12-23 | 2015-12-23 | Preparation method of doxofylline |
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| CN111233864B (en) * | 2020-03-07 | 2020-12-22 | 安徽恒星制药有限公司 | Method for industrially producing doxofylline |
| CN111995625B (en) * | 2020-08-28 | 2024-03-26 | 开封康诺药业有限公司 | Preparation method of doxofylline |
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| CN1133842A (en) * | 1995-04-18 | 1996-10-23 | 绍兴市医药工业研究所 | Process for preparing doxofylline |
| CN103554110A (en) * | 2013-10-29 | 2014-02-05 | 安徽省郎溪县联科实业有限公司 | Preparation method for synthesizing doxofylline |
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| Studies on Cellulose Chemistry. III. Parabromoacetaldehyde and Monobromo-Acetaldehyde. their Preparation, Properties and Utilization for the Synthesis of Bromo- and Hydroxy-Cyclic Acetals Related to Polysaccharides;HAROLDH IBBERT et al.;《 Journal of the American Chemical Society》;19230331;第45卷;734-51 * |
| 多索茶碱的合成工艺研究;刘红霞等;《齐齐哈尔大学学报》;20021231;第18卷(第4期);23-24 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106928226B (en) | 2019-01-08 |
| CN106916156A (en) | 2017-07-04 |
| CN106928226A (en) | 2017-07-07 |
| CN105418612A (en) | 2016-03-23 |
| CN106916156B (en) | 2019-03-26 |
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