CN106928226A - A kind of preparation method of doxofylline - Google Patents
A kind of preparation method of doxofylline Download PDFInfo
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- CN106928226A CN106928226A CN201710147435.2A CN201710147435A CN106928226A CN 106928226 A CN106928226 A CN 106928226A CN 201710147435 A CN201710147435 A CN 201710147435A CN 106928226 A CN106928226 A CN 106928226A
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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
Abstract
The present invention provides a kind of preparation method of doxofylline, the synthetic method of bromoacetaldehyde condensed ethandiol and doxofylline specifically related to shown in formula 2, including by acetaldehyde, ethylene glycol, the side chain bromoacetaldehyde condensed ethandiol of bromine one pot reaction formula 2, and the compound of formula 2 carries out N hydrocarbyl reactions and can obtain described doxofylline with theophylline again.Synthetic method raw material of the invention is easy to get, low cost, yield high, concise in technology, economic and environment-friendly, is conducive to the industry extension production of the medicine.
Description
It is on December 23rd, 2015, Application No. 201510977332.X, entitled " one kind the applying date that the application is
The divisional application of the application for a patent for invention of the preparation method of doxofylline ".
Technical field
The present invention relates to a kind of preparation method of doxofylline, belong 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, is listed in Italy in 1988.Its security, apparently higher than theophylline and aminophylline, is to substitute theophylline class
The methyl purine derivative of new generation of medicine.Doxofylline be used clinically for bronchial astehma, COPD and
The treatment of the diseases such as the expiratory dyspnea that other bronchial spasms cause, its mechanism of action is by suppressing inflammation medium, thin
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 as to 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 is 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, doxofylline is prepared 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 in polar solvent, acid absorbent, single step reaction generation is done with alkali using theophylline and Haloacetaldehydes condensed ethandiol
Doxofylline, the method yield is 75~85%.Patent CN1041728C theophylline is with 1,1- diethoxy -2- bromoethanes in N, N-
In solvent dimethylformamide, make condensing agent with potassium carbonate and prepare intermediate 7- (2,2- dialkoxy ethyl) theophylline, the step yield
It is 85%, intermediate makees condensing agent, to first again with ethylene glycol in DMF solvent with alkali carbonate
It is condensed under the catalysis of base benzene sulfonic acid and doxofylline is obtained, the step yield is 89~91.3%, the method completes reaction in two steps, total to receive
Rate is relatively low.Liu Hongxia etc. obtains bromoacetaldehyde dimethoxym ethane using vinyl acetate through bromination alcoholysis, then is obtained with glycol reaction
Side chain bromoacetaldehyde condensed ethandiol, the method for then preparing doxofylline with theophylline condensation again, method has reached pilot scale level, and
Propose that it is the moisture in solvent dimethylformamide that larger factor is influenceed on product yield in the process, therefore use
External import solvent, the raw materials technology is not easy to obtain, relatively costly.
To solve the problems, such as above-mentioned art methods, the present invention provides a kind of improvement preparation side of doxofylline
Method, the method meets the Atom economy synthesis theory of Green Chemistry, and raw material is easy to get, and low cost, yield is high, concise in technology, warp
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 following steps：
In the presence of alkali and phase transfer catalyst, make the theophylline shown in formula 3 and the bromoacetaldehyde condensed ethandiol shown in formula 2
React that 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 NaOH, potassium hydroxide, sodium carbonate, potassium carbonate
The mixture planted；
The phase transfer catalyst (PTC) can be (poly- selected from TBAB, 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；
When the phase transfer catalyst is TBAB or 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 delivers material.
Above-mentioned reaction is condensation reaction, and it 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
One or more in ester of mixture.For example, when the phase transfer catalyst is TBAB or benzyl triethyl ammonium chlorine
When changing ammonium, can be carried out in the non-protonic solvent or under condition of no solvent；When phase transfer catalyst is PEG-400
When, theophylline also can be first made theophylline salt, then condensation reaction is carried out under condition of no solvent with bromoacetaldehyde condensed ethandiol.It is described
The preparation of theophylline salt can be carried out using methods known in the art, for example：In water or organic solvent such as absolute ethyl alcohol, N, N- diformazans
In the presence of base formamide or DMA, by theophylline (or theophylline anhydrous) and suitable alkali, such as NaOH,
One or more in potassium hydroxide, sodium carbonate, potassium carbonate, sodium acid carbonate or saleratus etc. of mixture reaction, is made tea
Alkali 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.
The compound of the formula 2 can add reaction system after other reaction substrates are mixed by way of being added dropwise.
After reaction terminates, can be post-processed as follows：Frozen water is washed, and filtering, filter residue recrystallizes to obtain 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%.
Preparation method of the invention furthermore provides the preparation method of the bromoacetaldehyde condensed ethandiol shown in formula 2, described
Method includes making ethylene glycol, acetaldehyde and bromine through condensation and bromination reaction so that 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 preferably less than 10 DEG C below room temperature, such as 0~10 DEG C, reaction
Time can be such as 1~5h, preferably 2~4h.
Methods described can be one kettle way (one-pot reaction).The one kettle way refers to, by reaction raw materials same
Reacted in reactor, separated without intermediate, directly obtain the synthetic method of target compound；
Preferably, first to ethylene glycol is added in reactor, acetaldehyde is then added slowly with stirring, and stir at room temperature
0.5~4h, is added dropwise process temperature less than below room temperature, preferably less than 10 DEG C, example then to bromine and controlling is added dropwise in reaction solution
Such as 0~10 DEG C, after completion of dropping, such as 1~5h, preferably 2~4h are reacted under the reaction temperature.
Preferably, after the completion of reaction, following post-processing step is carried out：Vacuum fractionation is obtaining target compound.
Used as example, the present invention provides the preparation method of doxofylline, comprises the following 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 2 of the present invention, including by acetaldehyde, ethylene glycol,
The side chain bromoacetaldehyde condensed ethandiol of bromine one pot reaction formula 2, and the compound of formula 2 to carry out N- hydrocarbylations with theophylline again anti-
Should be that can obtain described doxofylline.Synthetic method raw material of the invention is easy to get, low cost, yield high, 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 indicated, 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
To 12.414Kg ethylene glycol (200mol) is added in retort, 4.41Kg is slowly added under agitation and newly steams second
Aldehyde (100mol) is simultaneously stirred at room temperature 30min, be added dropwise bromine 15.98Kg (100mol), control be added dropwise process temperature for 10 DEG C with
Under, after completion of dropping, 0~10 DEG C of reaction 3h, vacuum fractionation collects 80~82 DEG C of cut (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
To 10.326Kg ethylene glycol (166.37mol) is added in retort, 3.66Kg is slowly added under agitation new
Steam acetaldehyde (83.185mol) and 30min is stirred at room temperature, bromine 14.622Kg (91.504mol) is added dropwise, control dropwise addition process temperature
It is less than 10 DEG C to spend, and after completion of dropping, 0~3 DEG C of reaction 3.5h, vacuum fractionation collects 80~82 DEG C of cuts (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 NaOH (144.32mol),
0.7Kg TBABs (2.16mol), 14.47Kg bromoacetaldehydes condensed ethandiol (86.64mmol) are added dropwise after stirring 10min,
6.3h is stirred at reflux, (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, filtering, filter residue absolute ethyl 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 are added in retort
Benzyltriethylammoinium chloride (2.10mol), 14.02Kg bromoacetaldehydes condensed ethandiol (83.93mol), water are added dropwise after stirring 10min
60~70 DEG C of temperature control of bath, stirring reaction 6h, with thin-layer chromatography monitoring reaction end, (solvent is as acetone：Dichloromethane=3：1).
After reaction terminates, vacuum distillation solvent evaporated, with saturated common salt water washing 3 times, filtering, filter residue is recrystallized to give with absolute ethyl 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 absolute ethyl alcohols, 3.35Kg NaOH are added in retort
(83.71mol), is stirred at reflux 4h, vacuum distillation recovered solvent, gained theophylline salt and 722.68mlPEG-400,12.9Kg bromo
Ethylidene ether (77.27mol) is well mixed, 60~70 DEG C of water-bath temperature control, stirring reaction 6h, is monitored with thin-layer chromatography and reacted
(solvent is acetone to terminal：Dichloromethane=3：1).After reaction terminates, washed with 1000ml frozen water three times, filtered, filter 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 NaOH (90.19mol),
0.671Kg TBABs (2.08mol), 13.9Kg bromoacetaldehydes condensed ethandiol (83.26mol) are well mixed, water-bath control
60~70 DEG C of temperature, stirring reaction 6.3h, with thin-layer chromatography monitoring reaction end, (solvent is as acetone：Dichloromethane=3：1).Instead
After should terminating, washed with 1200ml frozen water three times, filtered, filter 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 the present invention synthesis 1Kg doxofyllines of table 1
The cost of present invention synthesis 1Kg doxofyllines is 139.672~150.869 yuan.
Claims (10)
1. a kind of preparation method of doxofylline, comprises the following steps：
In the presence of alkali and phase transfer catalyst, the theophylline shown in formula 3 is set to be reacted with the bromoacetaldehyde condensed ethandiol shown in formula 2
So that the doxofylline shown in formula 1 is obtained：
2. the preparation method described in claim 1, wherein：
The alkali can be selected from the mixture of one or more in NaOH, potassium hydroxide, sodium carbonate, potassium carbonate；
The phase transfer catalyst (PTC) can be selected from TBAB, benzyltriethylammoinium chloride, PEG-400 (poly- second two
Alcohol 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；
When the phase transfer catalyst is TBAB or benzyltriethylammoinium chloride, described theophylline and phase transfer catalysis (PTC)
The molar ratio of agent 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) PEG-400
Ratio deliver material.
3. the preparation method described in claim 1 or 2, wherein：
The reaction is condensation reaction, and it can be carried out in non-protonic solvent or under condition of no solvent；
The non-protonic solvent can be in such as acetone, N,N-dimethylformamide, acetonitrile, dichloromethane, ethyl acetate
One or more of mixture；
The reaction can be carried out in backflow or non-reflow state；
The reaction temperature is specifically as follows 50~150 DEG C；
Reaction time can be 1~12h, such as 4~8h, such as 6~7h.
4. the preparation method described in any one of claim 1-3, wherein：
The compound of formula 2 can add reaction system after other reaction substrates are mixed by way of being added dropwise；
Preferably, after reaction terminates, can be post-processed as follows：Frozen water is washed, and filtering, filter residue recrystallizes to obtain target chemical combination
Thing；
Recrystallization preferably uses anhydrous or aqueous alcohols solvent, preferred alcohol；In the aqueous alcohols solvent, water and alcohols solvent
Volume ratio can be (10~1):1, such as (5~2):1, such as 3:1.
5. the preparation method of the bromoacetaldehyde condensed ethandiol shown in formula 2, methods described includes making ethylene glycol, acetaldehyde and bromine through condensation
With bromination reaction with the bromoacetaldehyde condensed ethandiol shown in prepared formula 2：
6. the preparation method described in claim 5, wherein：
The molar ratio of the ethylene glycol, acetaldehyde and bromine is 1~5:1:1~2, such as 2~4:1:1~1.5；
The reaction temperature of methods described can be for below room temperature, preferably less than 10 DEG C, such as 0~10 DEG C, and the reaction time can be
Such as 1~5h, preferably 2~4h.
7. the preparation method described in claim 5 or 6, wherein：
Methods described can be one kettle way；
Preferably, first to ethylene glycol is added in reactor, acetaldehyde is then added slowly with stirring, and stir 0.5 at room temperature
~4h, is added dropwise process temperature less than below room temperature, preferably less than 10 DEG C, such as 0 then to bromine and controlling is added dropwise in reaction solution
~10 DEG C, after completion of dropping, such as 1~5h, preferably 2~4h are reacted under the reaction temperature.
8. the method described in any one of claim 5-7, wherein：
After the completion of reaction, following post-processing step is carried out：Vacuum fractionation, to obtain target compound.
9. the method described in any one of claim 1-8, comprises the following steps：
10. application of the method described in any one of claim 5-8 in doxofylline is prepared.
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| CN201710147435.2A CN106928226B (en) | 2015-12-23 | 2015-12-23 | A kind of preparation method of bromoacetaldehyde condensed ethandiol |
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| 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 |
| CN111995625A (en) * | 2020-08-28 | 2020-11-27 | 开封康诺药业有限公司 | Preparation method of doxofylline |
Families Citing this family (2)
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| CN108774208A (en) * | 2018-07-10 | 2018-11-09 | 盐城市胜达化工有限公司 | A kind of method of silver bicarbonate activation 2- bromomethyl -1,3- dioxolanes |
| CN111233864B (en) * | 2020-03-07 | 2020-12-22 | 安徽恒星制药有限公司 | Method for industrially producing doxofylline |
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| US4255182A (en) * | 1980-03-10 | 1981-03-10 | Velsicol Chemical Corporation | Aminosulfonylthiadiazolylureas |
| 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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| CN1133842A (en) * | 1995-04-18 | 1996-10-23 | 绍兴市医药工业研究所 | Process for preparing doxofylline |
| CN102276586B (en) * | 2010-06-09 | 2014-04-09 | 扬子江药业集团四川海蓉药业有限公司 | Preparation methods of losartan potassium and preparation thereof |
| CN102807564A (en) * | 2012-08-30 | 2012-12-05 | 珠海润都制药股份有限公司 | Preparation method of irbesartan |
| 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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2015
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4255182A (en) * | 1980-03-10 | 1981-03-10 | Velsicol Chemical Corporation | Aminosulfonylthiadiazolylureas |
| 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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| HAROLDH IBBERT ET AL.: "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", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
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| CN106928226B (en) | 2019-01-08 |
| CN106916156B (en) | 2019-03-26 |
| CN105418612B (en) | 2017-03-22 |
| CN105418612A (en) | 2016-03-23 |
| CN106916156A (en) | 2017-07-04 |
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