CN105418612A - Preparation method of doxofylline - Google Patents
Preparation method of doxofylline Download PDFInfo
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- CN105418612A CN105418612A CN201510977332.XA CN201510977332A CN105418612A CN 105418612 A CN105418612 A CN 105418612A CN 201510977332 A CN201510977332 A CN 201510977332A CN 105418612 A CN105418612 A CN 105418612A
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- 0 CN(c1c(C(N2*)=*)[n]cn1)C2=O Chemical compound CN(c1c(C(N2*)=*)[n]cn1)C2=O 0.000 description 1
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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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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, belong to pharmaceutical synthesis field.
Background technology
Doxofylline (Doxofylline) chemical name is 1,3-dimethyl-7-(1,3-dioxy cyclopentyl-2-base) methyl-3,7-dihydro-1H-purine-2,6-diketone.Doxofylline has stronger antiasthmatic effect, and be the new drug of expansion bronchus, commodity are called Anismar, goes on the market in 1988 in Italy.Its security, apparently higher than theophylline and aminophylline, is the methyl purine derivative of new generation of alternative theophylline class medicine.The treatment of the diseases such as the expiratory dyspnea that doxofylline causes for bronchial asthma, chronic obstructive pulmonary disease and other bronchospasm clinically, its mechanism of action is the release by suppressing inflammation medium, cytokine, controls the development of respiratory tract chronic inflammatory diseases; Suppress phosphodiester ras GTPase activating protein ras-GTP enzyme A and G in asm cell, thus reduce Ca in cell
2+concentration and respiratory tract tension force.In addition, the doxofylline bronchial smooth muscle effect that relaxes is 10 ~ 15 times of aminophylline, and rapid-action, and only need 30min, duration of efficacy reaches 12h.
At present, bibliographical information both at home and abroad in doxofylline synthetic method has: US Patent No. 4187308 with theophylline acetaldehyde for raw material, with ethylene glycol under the katalysis of tosic acid, be that solvent refluxing prepares doxofylline with benzene, this method yield 59.5%, but the toxicity of its solvent benzol is larger.Patent CN1133842A theophylline is under water or organic solvent exist, and obtain theophylline salt with alkali reaction, then prepare doxofylline with the condensation of Haloacetaldehydes condensed ethandiol, productive rate is 75 ~ 85%.Patent CN1044810C adopts theophylline and Haloacetaldehydes condensed ethandiol in polar solvent, does acid absorber with alkali, and single step reaction generates doxofylline, and this method productive rate is 75 ~ 85%.Patent CN1041728C theophylline and 1,1-diethoxy-2-monobromethane are in DMF solvent, make condensing agent with salt of wormwood and prepare intermediate 7-(2,2-dialkoxy ethyl) theophylline, this step yield is 85%, intermediate again with ethylene glycol at N, in dinethylformamide solvent, make condensing agent with alkaline carbonate, under the catalysis of p-methyl benzenesulfonic acid, condensation obtains doxofylline, and this step yield is 89 ~ 91.3%, this method completes reaction in two steps, and total recovery is on the low side.Liu Hongxia etc. adopt vinyl-acetic ester to obtain bromoacetaldehyde methylal through bromination alcoholysis, side chain bromoacetaldehyde condensed ethandiol is obtained again with glycol reaction, and then prepare the method for doxofylline with theophylline condensation, this method has reached pilot scale level, and propose to be moisture content in solvent dimethylformamide on the larger factor of product yield impact in the process, therefore adopt external import solvent, this raw materials technology is not easy to obtain, and cost is higher.
For solving above-mentioned art methods Problems existing, the invention provides a kind of improvement preparation method of doxofylline, the method meets the Atom economy synthesis theory of Green Chemistry, raw material is easy to get, and cost is low, and productive rate is high, concise in technology, economic environmental protection, is conducive to the suitability for industrialized production of this medicine.
Summary of the invention
The invention provides a kind of preparation method of doxofylline, comprise the steps:
Under the existence of alkali and phase-transfer catalyst, the bromoacetaldehyde condensed ethandiol shown in the theophylline shown in formula 3 and formula 2 is made to react with the doxofylline shown in obtained formula 1:
According to the present invention, described alkali can be selected from one or more the mixture in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood;
Described phase-transfer catalyst (PTC) can be selected from one or more the mixture in Tetrabutyl amonium bromide, benzyltriethylammoinium chloride, PEG-400 (poly(oxyethylene glycol) 400).
The molar ratio of described theophylline and bromoacetaldehyde condensed ethandiol is 1:1.0 ~ 1.8, such as 1:1.1 ~ 1.6,1:1.2 ~ 1.5 or 1:1.2 ~ 1.4;
The molar ratio of described theophylline and alkali is 1:1 ~ 3, such as 1:1.2,1:1.3,1:1.5,1:2 or 1:2.5;
Described phase-transfer catalyst be Tetrabutyl amonium bromide or benzyltriethylammoinium chloride time, described theophylline and the molar ratio of phase-transfer catalyst are 1:0.01 ~ 0.1, such as 1:0.03 ~ 0.05;
When described phase-transfer catalyst is PEG-400, material can be thrown in the ratio of every mole of theophylline 10 ~ 30ml (such as 12 ~ 16ml) PEG-400.
Above-mentioned reaction is condensation reaction, and it can carry out in non-protonic solvent or under condition of no solvent.
Described non-protonic solvent can be one or more the mixture in such as acetone, DMF, acetonitrile, methylene dichloride, ethyl acetate.Such as, when described phase-transfer catalyst be Tetrabutyl amonium bromide or benzyltriethylammoinium chloride time, can carry out in described non-protonic solvent or under condition of no solvent; When phase-transfer catalyst is PEG-400, also theophylline first can be made theophylline salt, then under condition of no solvent, carry out condensation reaction with bromoacetaldehyde condensed ethandiol.The preparation of described theophylline salt can adopt methods known in the art to carry out, such as: at water or organic solvent as dehydrated alcohol, N, dinethylformamide or N, under the existence of N-N,N-DIMETHYLACETAMIDE, by theophylline (or Theophylline Anhydrous) and suitable alkali, such as, one or more mixture reaction in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate or saleratus etc., makes theophylline salt.
Described reaction can be carried out in backflow or non-reflow state.Described temperature of reaction is specifically as follows 50 ~ 150 DEG C.Reaction times can be 1 ~ 12h, such as 4 ~ 8h, as 6 ~ 7h.
Described formula 2 compound can add reaction system by the mode dripped after by the mixing of other reaction substrates.
After reaction terminates, can carry out following aftertreatment: frozen water washs, filter, filter residue recrystallization is to obtain target compound.Wherein, recrystallization preferably uses anhydrous or aqueous alcohols solvent, preferred alcohol.In described aqueous alcohols solvent, the volume ratio of water and alcoholic solvent can be (10 ~ 1): 1, and such as (5 ~ 2): 1, as 3:1.
Preferably, the doxofylline purity of formula 1 that preparation method of the present invention obtains is more than 98.5%.
Preparation method of the present invention also provides the preparation method of the bromoacetaldehyde condensed ethandiol shown in formula 2 further, and described method comprises makes ethylene glycol, acetaldehyde and bromine through condensation and bromination reaction with the bromoacetaldehyde condensed ethandiol shown in obtained formula 2:
The preparation method of the bromoacetaldehyde condensed ethandiol according to formula 2 of the present invention:
Preferably, the molar ratio of described ethylene glycol, acetaldehyde and bromine is 1 ~ 5:1:1 ~ 2, as 2 ~ 4:1:1 ~ 1.5.
Preferably, the temperature of reaction of described method can be below room temperature, preferably less than 10 DEG C, such as 0 ~ 10 DEG C, and the reaction times can be such as 1 ~ 5h, preferably 2 ~ 4h.
Described method can be one kettle way (one-potreaction).Described one kettle way refers to, is reacted by reaction raw materials in same reactor, is separated without intermediate, directly obtains the synthetic method of target compound;
Preferably, first in reactor, add ethylene glycol, then under agitation slowly acetaldehyde is added, and in stirred at ambient temperature 0.5 ~ 4h, subsequently to dripping bromine in reaction solution and controlling to drip process temperature lower than below room temperature, preferably less than 10 DEG C, such as 0 ~ 10 DEG C, after dropwising, under described temperature of reaction, react such as 1 ~ 5h, preferably 2 ~ 4h.
Preferably, after the completion of reaction, following post-processing step is carried out: vacuum fractionation is to obtain target compound.
As an example, the invention provides the preparation method of doxofylline, comprise the steps:
Preferably, the bromoacetaldehyde condensed ethandiol purity of formula 2 that the present invention prepares is more than 95%.
The present invention also provides the preparation method of the bromoacetaldehyde condensed ethandiol shown in above-mentioned formula 2 preparing the application in doxofylline.
Beneficial effect of the present invention
The invention provides the synthetic method of the compound shown in formula 2 and doxofylline, comprise and pass through acetaldehyde, ethylene glycol, the side chain bromoacetaldehyde condensed ethandiol of bromine one pot reaction preparation formula 2, and formula 2 compound carries out N-hydrocarbyl reaction with theophylline again and can obtain described doxofylline.Synthetic method raw material of the present invention is easy to get, cost is low, productive rate is high, concise in technology, economic environmental protection, be conducive to this medicine industry extension produce.
Embodiment
By case study on implementation below, the present invention is further described, but scope of the present invention is not confined to following case study on implementation.
Except as otherwise noted, following reaction raw materials and reagent are commercially available prod.Those skilled in the art also can prepare them according to currently known methods.
Embodiment 1
A. the preparation of bromoacetaldehyde condensed ethandiol
12.414Kg ethylene glycol (200mol) is added in retort, slowly add 4.41Kg under agitation and newly steam acetaldehyde (100mol) and in stirring at room temperature 30min, drip bromine 15.98Kg (100mol), controlling to drip process temperature is less than 10 DEG C, after dropwising, 0 ~ 10 DEG C of reaction 3h, vacuum fractionation, collect 80 ~ 82 DEG C of cuts (3.6KPa) 13.126Kg (78.6mol), be 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, slowly add 3.66Kg under agitation and newly steam acetaldehyde (83.185mol) and in stirring at room temperature 30min, drip bromine 14.622Kg (91.504mol), controlling to drip process temperature is less than 10 DEG C, after dropwising, 0 ~ 3 DEG C of reaction 3.5h, vacuum fractionation, collect 80 ~ 82 DEG C of cuts (3.6KPa) 11.002Kg (65.883mol), be bromoacetaldehyde condensed ethandiol, yield is 79.2%, and content is more than 95%.
C. the preparation of doxofylline
Theophylline 13Kg (72.16mol) is added in retort, 8L acetone, 5.77Kg sodium hydroxide (144.32mol), 0.7Kg Tetrabutyl amonium bromide (2.16mol), 14.47Kg bromoacetaldehyde condensed ethandiol (86.64mmol) is dripped after stirring 10min, stirring and refluxing 6.3h, with thin-layer chromatography monitoring reaction end (developping agent is for acetone: methylene dichloride=3:1).After reaction terminates, underpressure distillation solvent evaporated, with saturated common salt water washing 3 times, filter, filter residue dehydrated alcohol recrystallization obtains 17.28Kg doxofylline (64.98mol), and productive rate is 90%, fusing point is 143.5 ~ 145 DEG C, and content is more than 98.5%.
Embodiment 2
Theophylline 12.6Kg (69.94mol) is added in retort, 7.85Kg potassium hydroxide (139.88mol), 0.478Kg benzyltriethylammoinium chloride (2.10mol), 14.02Kg bromoacetaldehyde condensed ethandiol (83.93mol) is dripped after stirring 10min, water-bath temperature control 60 ~ 70 DEG C, stirring reaction 6h, with thin-layer chromatography monitoring reaction end (developping agent is for acetone: methylene dichloride=3:1).After reaction terminates, underpressure distillation solvent evaporated, with saturated common salt water washing 3 times, filter, filter residue dehydrated alcohol recrystallization obtains 16.69Kg doxofylline (62.74mol), and productive rate is 89.7%, fusing point is 143.5 ~ 145 DEG C, and content is more than 98.5%.
Embodiment 3
Theophylline 11.6Kg (64.39mol) is added in retort, 7.3L dehydrated alcohol, 3.35Kg sodium hydroxide (83.71mol), stirring and refluxing 4h, vacuum distillation recovered solvent, gained theophylline salt and 722.68mlPEG-400,12.9Kg bromoacetaldehyde condensed ethandiol (77.27mol) mixes, water-bath temperature control 60 ~ 70 DEG C, stirring reaction 6h, with thin-layer chromatography monitoring reaction end (developping agent is for acetone: methylene dichloride=3:1).After reaction terminates, wash three times with 1000ml frozen water, filter, filter residue water: ethanol=3:1 (v/v) recrystallization obtains 15.24Kg doxofylline (57.31mol), productive rate is 89%, and fusing point is 143.5 ~ 145 DEG C, and content is more than 98.5%.
Embodiment 4
Theophylline 12.5Kg (69.38mol) is added in retort, 3.61Kg sodium hydroxide (90.19mol), 0.671Kg Tetrabutyl amonium bromide (2.08mol), 13.9Kg bromoacetaldehyde condensed ethandiol (83.26mol) mixes, water-bath temperature control 60 ~ 70 DEG C, stirring reaction 6.3h, with thin-layer chromatography monitoring reaction end (developping agent is for acetone: methylene dichloride=3:1).After reaction terminates, wash three times with 1200ml frozen water, filter, filter residue water: ethanol=3:1 (v/v) recrystallization obtains 16.24Kg doxofylline (61.05mol), productive rate is 88%, and fusing point is 143.5 ~ 145 DEG C, and content is more than 98.5%.
Table 1 the present invention synthesizes the cost (calculating with embodiment 4) of 1Kg doxofylline
The cost that the present invention synthesizes 1Kg doxofylline is 139.672 ~ 150.869 yuan.
Claims (10)
1. a preparation method for doxofylline, comprises the steps:
Under the existence of alkali and phase-transfer catalyst, the bromoacetaldehyde condensed ethandiol shown in the theophylline shown in formula 3 and formula 2 is made to react with the doxofylline shown in obtained formula 1:
2. preparation method according to claim 1, wherein:
Described alkali can be selected from one or more the mixture in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood;
Described phase-transfer catalyst (PTC) can be selected from one or more the mixture in Tetrabutyl amonium bromide, benzyltriethylammoinium chloride, PEG-400 (poly(oxyethylene glycol) 400);
The molar ratio of described theophylline and bromoacetaldehyde condensed ethandiol is 1:1.0 ~ 1.8, such as 1:1.1 ~ 1.6,1:1.2 ~ 1.5 or 1:1.2 ~ 1.4;
The molar ratio of described theophylline and alkali is 1:1 ~ 3, such as 1:1.2,1:1.3,1:1.5,1:2 or 1:2.5;
Described phase-transfer catalyst be Tetrabutyl amonium bromide or benzyltriethylammoinium chloride time, described theophylline and the molar ratio of phase-transfer catalyst are 1:0.01 ~ 0.1, such as 1:0.03 ~ 0.05;
When described phase-transfer catalyst is PEG-400, material can be thrown in the ratio of every mole of theophylline 10 ~ 30ml (such as 12 ~ 16ml) PEG-400.
3. the preparation method described in claim 1 or 2, wherein:
Described reaction is condensation reaction, and it can carry out in non-protonic solvent or under condition of no solvent;
Described non-protonic solvent can be one or more the mixture in such as acetone, DMF, acetonitrile, methylene dichloride, ethyl acetate;
Described reaction can be carried out in backflow or non-reflow state;
Described temperature of reaction is specifically as follows 50 ~ 150 DEG C;
Reaction times can be 1 ~ 12h, such as 4 ~ 8h, as 6 ~ 7h.
4. the preparation method described in any one of claim 1-3, wherein:
Formula 2 compound can add reaction system by the mode dripped after by the mixing of other reaction substrates;
Preferably, after reaction terminates, can carry out following aftertreatment: frozen water washs, filter, filter residue recrystallization is to obtain target compound;
Recrystallization preferably uses anhydrous or aqueous alcohols solvent, preferred alcohol; In described aqueous alcohols solvent, the volume ratio of water and alcoholic solvent can be (10 ~ 1): 1, and such as (5 ~ 2): 1, as 3:1.
5. the preparation method of the bromoacetaldehyde condensed ethandiol shown in formula 2, described method comprises makes ethylene glycol, acetaldehyde and bromine through condensation and bromination reaction with the bromoacetaldehyde condensed ethandiol shown in obtained formula 2:
6. preparation method according to claim 5, wherein:
The molar ratio of described ethylene glycol, acetaldehyde and bromine is 1 ~ 5:1:1 ~ 2, as 2 ~ 4:1:1 ~ 1.5;
The temperature of reaction of described method can be below room temperature, preferably less than 10 DEG C, such as 0 ~ 10 DEG C, and the reaction times can be such as 1 ~ 5h, preferably 2 ~ 4h.
7. the preparation method described in claim 5 or 6, wherein:
Described method can be one kettle way;
Preferably, first in reactor, add ethylene glycol, then under agitation slowly acetaldehyde is added, and in stirred at ambient temperature 0.5 ~ 4h, subsequently to dripping bromine in reaction solution and controlling to drip process temperature lower than below room temperature, preferably less than 10 DEG C, such as 0 ~ 10 DEG C, after dropwising, under described temperature of reaction, react such as 1 ~ 5h, preferably 2 ~ 4h.
8. the method described in any one of claim 5-7, wherein:
After the completion of reaction, carry out following post-processing step: vacuum fractionation, to obtain target compound.
9. the method described in any one of claim 1-8, comprises the steps:
10. the method described in any one of claim 5-8 is preparing the application in doxofylline.
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| CN201710147432.9A CN106916156B (en) | 2015-12-23 | 2015-12-23 | A kind of preparation method of doxofylline |
| 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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| CN201710147432.9A Division CN106916156B (en) | 2015-12-23 | 2015-12-23 | A kind of preparation method of doxofylline |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN111233864A (en) * | 2020-03-07 | 2020-06-05 | 安徽恒星制药有限公司 | Novel method for simply, conveniently and industrially producing doxofylline in green |
| CN111995625A (en) * | 2020-08-28 | 2020-11-27 | 开封康诺药业有限公司 | Preparation method of doxofylline |
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| US4255182A (en) * | 1980-03-10 | 1981-03-10 | Velsicol Chemical Corporation | Aminosulfonylthiadiazolylureas |
| CN1133842A (en) * | 1995-04-18 | 1996-10-23 | 绍兴市医药工业研究所 | Preparation method of 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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2015
- 2015-12-23 CN CN201510977332.XA patent/CN105418612B/en active Active
- 2015-12-23 CN CN201710147432.9A patent/CN106916156B/en active Active
- 2015-12-23 CN CN201710147435.2A patent/CN106928226B/en active Active
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| 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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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN111233864A (en) * | 2020-03-07 | 2020-06-05 | 安徽恒星制药有限公司 | Novel method for simply, conveniently and industrially producing doxofylline in green |
| CN111233864B (en) * | 2020-03-07 | 2020-12-22 | 安徽恒星制药有限公司 | Method for industrially producing 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106916156B (en) | 2019-03-26 |
| CN106916156A (en) | 2017-07-04 |
| CN106928226B (en) | 2019-01-08 |
| CN106928226A (en) | 2017-07-07 |
| CN105418612B (en) | 2017-03-22 |
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