CN103360393A - Preparation method of theophylline-7-acetic acid - Google Patents
Preparation method of theophylline-7-acetic acid Download PDFInfo
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- CN103360393A CN103360393A CN2013103213293A CN201310321329A CN103360393A CN 103360393 A CN103360393 A CN 103360393A CN 2013103213293 A CN2013103213293 A CN 2013103213293A CN 201310321329 A CN201310321329 A CN 201310321329A CN 103360393 A CN103360393 A CN 103360393A
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Abstract
The invention belongs to the field of chemical synthesis. In the prior art, the raw materials for synthesis of theophylline-7-acetic acid all contain chloroacetic acid, which has a strong toxicity, purchase channels of chloroacetic acid are strictly restricted, so the production of theophylline-7-acetic acid is largely affected. The invention provides a preparation method of theophylline-7-acetic acid, the preparation method comprises following steps: subjecting dimethyl FAU to react with sodium hydroxide water solution to form theophylline sodium salt, adding sodium chloroacetate water solution drop by drop, after the reaction solution is clear, maintaining the reactant pH in the range of 8 to 12 by adding Na2CO3 water solution. The yield of the product prepared by the preparation method provided by the invention has been improved to 90% or more, the content of the product reaches 99.9%, the quality of the product is stable and meets the requirement of pharmacopeia.
Description
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to a kind of preparation method of theophylline acetic acid.
Background technology
Theophylline acetic acid (Theophylline-7-acetic acid), chemistry 2-(1,3-dimethyl-2 by name, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-7-yl) acetic acid, also claim the acetic acid theophylline, English name is Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-7-yl) acetic acid, molecular formula: C
9H
10N
4O
4, molecular weight: 238.204, CAS:211-490-2.
Theophylline acetic acid is white powder, and is slightly water-soluble, is soluble in dimethyl formamide, and chemical structural formula is as follows:
Theophylline acetic acid
Theophylline acetic acid is mainly used in the intermediate of Acefylline Piperazine (Acefylline pigerazine), and it is the cardiovascular system peripheral vascular system expansion class medicine of unifying that Acefylline Piperazine is similar to aminophylline, the treatment that is mainly used in relievining asthma, and it is oral and to inject tolerance better.
The current research discovery, theophylline acetic acid can be used as the HEK-293 human stem cell and transmits A
2BAdenosine Receptors has in conjunction with active (Kim, Soon-Ai; Marshall, Melissa A.; Melman, Neli; Kim, Hak Sung; Mueller, CHrista E.; Linden, Joel; Jacobson, Kenneth A.; Journal of Medicinal Chemistry; Vol.45; Nb.11; (2002); P.2131-2138).Theophylline acetic acid also can be used for control fat or " orange peel " skin as effective constituent, show makeup performance (the U.S. Patent application US2006134234A1 of good flexibility and Abherent, the application people is L'OREAL, and denomination of invention is Cosmetic composition).
Through retrieval, the synthesis technique of theophylline acetic acid mainly is to mix rear 90 ℃ of reactions 30 minutes with aqueous sodium hydroxide solution by theophylline, and cooling drips chloroacetic acid solution, and 95～100 ℃ were reacted approximately 2.5 hours, add NaOH and keep pH8～9, until the constant reaction end that is of pH value; Cooling, the concentrated hydrochloric acid neutralization, the cooling washing, filtering and drying obtains 7-acetic acid theophylline, yield 86.5%.(synthesizing of aperflavon, Xia Xinqiang, " Chinese Journal of Pharmaceuticals ", 10 phases in 1977, the 37-38 page or leaf is hereinafter referred to as " document 1 ").
The US Patent No. 3562273(application people of the seventies in last century is FERRER LABOR, denomination of invention is TRIS (HYDROXYMETHYL) AMINOMETHANE THEOPHYLLINE ACETATE, hereinafter referred to as " document 2 "), Chinese patent application CN101407517A(applicant: Moer Biological Medicine Co., Ltd., Chengdu City, denomination of invention: the preparation method of ambroxol theophylline-7-acetate, hereinafter referred to as " document 3 ") all reported and above-mentioned similar synthesis technique.Because the raw material of synthetic theophylline acetic acid has all used the highly toxic product Mono Chloro Acetic Acid, chloroacetic purchasing channel is subject to strict restriction, so the production of theophylline acetic acid is a greater impact.
Summary of the invention
Purpose of the present invention is exactly the synthetic method that a kind of new theophylline acetic acid will be provided, and the method at first will be abandoned the highly toxic product Mono Chloro Acetic Acid on material choice, the purity of its less important raising product and yield, and make chemosynthesis more be conducive to environment protection.
In order to solve the chloroacetic use problem of limited highly toxic product, the present invention at first replaces Mono Chloro Acetic Acid with sodium chloroacetate, safety when not only using, and be convenient to preserve.
Secondly, the present invention improves processing condition further, adopt theophylline intermediate-N, N-1,3-dimethyl-4-amino-5-formamido group urea piperazine (being called for short " dimethyl FAU ") and aqueous sodium hydroxide solution reaction, pH value is controlled to be 10～11, drips the sodium chloroacetate aqueous solution, after the reaction solution clarification, by adding 20%Na
2CO
3The aqueous solution makes reaction solution PH remain on 8～12.
In addition, the present invention also adopts TLC monitoring reaction,, makes to react completely until detect raw material primitive reaction complete (disappearance of raw material point) by adding an amount of yellow soda ash one; Add again sulfuric acid, separate out white solid, filter, get theophylline acetic acid.
The invention provides a kind of preparation method of theophylline acetic acid, the method may further comprise the steps:
(a) in the aqueous solution with dimethyl FAU and sodium hydroxide or potassium hydroxide (mineral alkali) reaction, generate theophylline sodium salt or theophylline sylvite;
(b) in theophylline sodium salt or theophylline sylvite, drip the sodium chloroacetate aqueous solution, condensation reaction obtains containing the theophylline acetic acid sodium salt aqueous solution;
(c) 20% yellow soda ash or solution of potassium carbonate are added in TLC thin-layer chromatography monitoring reaction, until raw material point disappears, control pH is 8～12.
(d) with mineral acid regulating step pH to pH2～2.5, the theophylline acetic acid that activated carbon decolorizing obtains.
In the described step (a), aqueous sodium hydroxide solution is heated to 40 ℃, adds dimethyl FAU, and the mol ratio of dimethyl FAU and sodium hydroxide is 1:1.05～1.10, and reaction generates the theophylline sodium salt; Continue to be heated to 90 ℃, be incubated half an hour at 90～95 ℃;
In the described step (b), setting-up point is 55～65 ℃, and the pH value is 10～11, is preferably in molar ratio 1.00:0.90～1.20, and optimum is that 1:1.0～1.1 drip the sodium chloroacetate aqueous solution in theophylline sodium reactant salt liquid.
In the described step (c), described TLC thin-layer chromatography is preferably TLC
254
In the described step (d), described mineral acid preferably sulfuric acid.
More excellent, preparation method of the present invention may further comprise the steps:
Aqueous sodium hydroxide solution is heated to 40 ℃, adds dimethyl FAU, and the mol ratio of dimethyl FAU and sodium hydroxide is 1:1.05～1.1, and reaction generates the theophylline sodium salt; Continue to be heated to 90 ℃, surveying material liquid PH value is 10～11,90～95 ℃ of insulations 0.5 hour, be down to 55～65 ℃ and drip the sodium chloroacetate aqueous solution in the theophylline sodium salt brine solution, the mol ratio that theophylline sodium salt and sodium chloroacetate carry out condensation reaction is 1:1.0～1.1,55～65 ℃ condensation reaction 1～2 hour, TLC monitors reaction, add an amount of 20% aqueous sodium carbonate and make pH theophylline sodium salt raw material point completely dissolve between 8～12, react complete, obtain containing the aqueous solution of theophylline sodium acetate; With 50% sulphur acid for adjusting pH to 2～2.5, crystallisation by cooling, obtaining white products is theophylline acetic acid.
Drip the sodium chloroacetate aqueous solution in the theophylline sodium salt brine solution, time for adding more preferably is controlled at 20～60 minutes.
Reaction is cooled to 60～65 ℃ after finishing, and regulating PH with 50% sulfuric acid again is 2～2.5, and a large amount of white solids are separated out, and stirring repetition measurement pH value half an hour is constant; Then the elimination mother liquor in the product that will the wet input 1000ml pure water, is heated to 50～55 ℃; Filtered while hot is again with an amount of 50～55 ℃ of pure water washing, oven dry.
Under the processing condition of the present invention, yield has reached more than 90%, product fusing point 270～272oC, and HPLC detection level 99.9%, single impurity is below 0.05%.
The present invention compares with document 1,2,3 techniques in the background technology has following beneficial effect:
(1) document technique is raw materials used is theophylline; This raw materials technology is theophylline intermediate-dimethyl FAU.Single stage method synthesis of acetic acid theophylline is simplified production stage, reduces three waste discharge.
(2) present method avoids having used the highly toxic product Mono Chloro Acetic Acid when selecting sodium chloroacetate to do to carry out condensation reaction, has improved reliability and the security of actual production.
(3) adopt TLC(TLC
254) the monitoring reaction, disappear by adding an amount of yellow soda ash to raw material point, make to react completely.
(4) the present invention brings up to the yield of product more than 90%, and product content reaches 99.9%, thereby reduces cost, has improved the utilization ratio of raw material.
In sum, the inventive method raw material is easy to get, and by product is few, the gentle and easy control of reaction conditions, cost is lower, easily realizes industrialization, and throughput is large, and products obtained therefrom purity is high, steady quality meets the pharmacopeia regulation, and the route of synthesis of a new theophylline acetic acid is provided.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should understand these embodiment and only be used for explanation the present invention, and be not used in restriction range of application of the present invention.
Embodiment 1:
Drop into 1500ml pure water and 44g (1.1mol) sheet alkali in the 3L reaction flask.Be heated to 40 ℃, drop into 198g(1.0mol) N, N-1,3-dimethyl-4-amino-5-formamido group urea piperazine (be called for short dimethyl FAU, Shanghai all ages pharmaceutical Co. Ltd provides).Continue to be heated to 90 ℃, surveying material liquid PH value is 11, is incubated half an hour, sodium chloroacetate 128g(1.1mol at 90～95 ℃) be dissolved in the 500g pure water solution, be down to 55～65 ℃, at the uniform velocity drip approximately 0.5h of the sodium chloroacetate aqueous solution, drip 20%Na after the solution clarification
2CO
3The aqueous solution makes reaction solution PH remain on 8～12, remains on 55～65 ℃ ℃ during dropping, simultaneously TLC
254Detect the theophylline sodium salt until raw material point theophylline sodium salt completely dissolve (Rf
The theophylline sodium salt=0.7; Rf
The acetic acid theophylline=0.4), reacts and finished in 2 hours, repetition measurement PH:8～12.
Be cooled to 60～65 ℃ and add 50% sulfuric acid, regulating PH is 2～2.5, and a large amount of white solids are separated out, and stirring repetition measurement pH value half an hour is constant.Then the elimination mother liquor in the product that will the wet input 1000ml pure water, is heated to 50～55 ℃.Filtered while hot, with an amount of 50～55 ℃ of pure water washing, oven dry gets acetic acid theophylline finished product 218g, yield 91.5%, HPLC content 99.95% again.
Reaction equation of the present invention is as follows:
TLC(TLC
254) the thin-layer chromatography detection, concrete grammar is as follows:
The TLC thin layer chromatography board (the biochemical plastic molding and processing plant of Taizhou plain road and bridge tetramethyl, and the silica gel column chromatography plate (3 * 10cm), GF254), developping agent: methylene dichloride: methyl alcohol=10:1,
The capillary microcap.
Embodiment 2:
Drop into 1500ml pure water and 42g(1.05mol in the 3L reaction flask) sheet alkali.Be heated to 40 ℃, input 198g (1.0mol) dimethyl FAU(Shanghai all ages pharmaceutical Co. Ltd provides).Continue to be heated to 90 ℃, surveying material liquid PH value is 10, is incubated half an hour at 90～95 ℃, after stirring and dissolving sodium chloroacetate 128g (1.1mol) is dissolved in the solution of 500g pure water, at the uniform velocity drip approximately 1h of the sodium chloroacetate aqueous solution 55～65 ℃ of reaction solutions, drip 20%Na after the solution clarification
2CO
3The aqueous solution makes reaction solution PH remain on 8～12, and reaction solution remains on 55～65 ℃, and approximately 2h is complete, repetition measurement PH:8～12.
With 50% sulphur acid for adjusting pH to 2～2.5, crystallisation by cooling, with an amount of pure water washing, oven dry gets acetic acid theophylline finished product 215.1g, yield 90.5%, HPLC content 99.91% again.
The contrast of principal reaction condition and yield in table 1: embodiment 1,2 and document 1,2,3 techniques
Above demonstration and described ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in above-described embodiment and the specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (9)
1. the preparation method of a theophylline acetic acid, the method may further comprise the steps:
(a) in the aqueous solution with N, N-1, the reaction of 3-dimethyl-4-amino-5-formamido group urea piperazine and sodium hydroxide or potassium hydroxide generates theophylline sodium salt or theophylline sylvite;
(b) in theophylline sodium salt or theophylline sylvite, drip the sodium chloroacetate aqueous solution, condensation reaction obtains containing the theophylline acetic acid sodium salt aqueous solution;
(c) 20% yellow soda ash or solution of potassium carbonate are added in TLC thin-layer chromatography monitoring reaction, until raw material point disappears, control pH is 8～12;
(d) with mineral acid regulating step pH to pH2～2.5, the theophylline acetic acid that activated carbon decolorizing obtains.
2. the preparation method of a kind of theophylline acetic acid according to claim 1, it is characterized in that, in the described step (a), aqueous sodium hydroxide solution is heated to 40 ℃, adds N, N-1,3-dimethyl-4-amino-5-formamido group urea piperazine, N, N-1, the mol ratio of 3-dimethyl-4-amino-5-formamido group urea piperazine and sodium hydroxide is 1:1.05～1.10, and reaction generates the theophylline sodium salt; Continue to be heated to 90 ℃, be incubated half an hour at 90～95 ℃.
3. the preparation method of a kind of theophylline acetic acid according to claim 1 and 2 is characterized in that, in the described step (b), setting-up point is 55～65 ℃, and the pH value is 10～11, and the mol ratio of theophylline sodium salt and sodium chloroacetate is 1:0.90～1.20.
4. the preparation method of a kind of theophylline acetic acid according to claim 3 is characterized in that, the mol ratio of theophylline sodium salt and sodium chloroacetate is 1:1.0～1.1.
5. the preparation method of a kind of theophylline acetic acid according to claim 1 and 2 is characterized in that, in the described step (c), described TLC thin-layer chromatography is TLC
254Thin-layer chromatography.
6. the preparation method of a kind of theophylline acetic acid according to claim 1 and 2 is characterized in that, in the described step (d), described mineral acid is sulfuric acid.
7. the preparation method of a kind of theophylline acetic acid according to claim 1 is characterized in that, the method may further comprise the steps:
Aqueous sodium hydroxide solution is heated to 40 ℃, adds N, N-1, and 3-dimethyl-4-amino-5-formamido group urea piperazine, N, N-1, the mol ratio of 3-dimethyl-4-amino-5-formamido group urea piperazine and sodium hydroxide is 1:1.05～1.1, reaction generates the theophylline sodium salt; Continue to be heated to 90 ℃, surveying material liquid PH value is 10～11,90～95 ℃ of insulations 0.5 hour, be down to 55～65 ℃ and drip the sodium chloroacetate aqueous solution in the theophylline sodium salt brine solution, the mol ratio that theophylline sodium salt and sodium chloroacetate carry out condensation reaction is 1:1.0～1.1,55～65 ℃ condensation reaction 1～2 hour, TLC monitors reaction, add an amount of 20% aqueous sodium carbonate and make pH theophylline sodium salt raw material point completely dissolve between 8～12, react complete, obtain containing the aqueous solution of theophylline sodium acetate; With 50% sulphur acid for adjusting pH to 2～2.5, crystallisation by cooling namely gets theophylline acetic acid.
8. the preparation method of a kind of theophylline acetic acid according to claim 7 is characterized in that, drips the sodium chloroacetate aqueous solution in the theophylline sodium salt brine solution, and time for adding is controlled at 20～60 minutes.
9. the preparation method of a kind of theophylline acetic acid according to claim 7 is characterized in that, reaction is cooled to 60～65 ℃ after finishing, and is 2～2.5 with 50% sulphur acid for adjusting pH again, and a large amount of white solids are separated out, and stirring repetition measurement pH value half an hour is constant; Then the elimination mother liquor in the product that will the wet input 1000ml pure water, is heated to 50～55 ℃; Filtered while hot is again with an amount of 50～55 ℃ of pure water washing, oven dry.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3562273A (en) * | 1966-02-17 | 1971-02-09 | Ferrer Labor | Tris (hydroxymethyl) aminomethane theophylline acetate |
| US6066641A (en) * | 1994-12-13 | 2000-05-23 | Euro-Celtique S.A. | Aryl thioxanthines |
| WO2003024965A2 (en) * | 2001-09-19 | 2003-03-27 | Novo Nordisk A/S | Heterocyclic compounds that are inhibitors of the enzyme dpp-iv |
| CN101384261A (en) * | 2005-12-22 | 2009-03-11 | 海德拉生物科学公司 | Method and composition for treating pain |
| CN101407517A (en) * | 2008-11-26 | 2009-04-15 | 成都摩尔生物医药有限公司 | Preparation of ambroxol theophylline-7-acetate |
| WO2011156632A2 (en) * | 2010-06-09 | 2011-12-15 | Georgetown University | Compositions and methods of treatment for tumors in the nervous system |
| CN102796102A (en) * | 2012-06-13 | 2012-11-28 | 广州万孚生物技术股份有限公司 | Caffeine hapten, conjugate, applications of caffeine hapten and conjugate, and method for detecting or determining caffeine |
-
2013
- 2013-07-29 CN CN201310321329.3A patent/CN103360393B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3562273A (en) * | 1966-02-17 | 1971-02-09 | Ferrer Labor | Tris (hydroxymethyl) aminomethane theophylline acetate |
| US6066641A (en) * | 1994-12-13 | 2000-05-23 | Euro-Celtique S.A. | Aryl thioxanthines |
| WO2003024965A2 (en) * | 2001-09-19 | 2003-03-27 | Novo Nordisk A/S | Heterocyclic compounds that are inhibitors of the enzyme dpp-iv |
| CN101384261A (en) * | 2005-12-22 | 2009-03-11 | 海德拉生物科学公司 | Method and composition for treating pain |
| CN101407517A (en) * | 2008-11-26 | 2009-04-15 | 成都摩尔生物医药有限公司 | Preparation of ambroxol theophylline-7-acetate |
| WO2011156632A2 (en) * | 2010-06-09 | 2011-12-15 | Georgetown University | Compositions and methods of treatment for tumors in the nervous system |
| CN102796102A (en) * | 2012-06-13 | 2012-11-28 | 广州万孚生物技术股份有限公司 | Caffeine hapten, conjugate, applications of caffeine hapten and conjugate, and method for detecting or determining caffeine |
Non-Patent Citations (3)
| Title |
|---|
| BOGUSLAW BOBRANSKI 等: "New Syntheses of Caffeine and Theophylline", 《JOURNAL OF THE AMERICAN PHARMACEUTICAL ASSOCIATION》 * |
| RYOSUKE SAKAI 等: "Effects of Alkyl Substitutions of Xanthine Skeleton on Bronchodilation", 《J. MED. CHEM.》 * |
| 夏莘强: "茶胺黄酮的合成", 《中国医药工业杂志》 * |
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