CN103360393B - The preparation method of theophylline acetic acid - Google Patents
The preparation method of theophylline acetic acid Download PDFInfo
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- CN103360393B CN103360393B CN201310321329.3A CN201310321329A CN103360393B CN 103360393 B CN103360393 B CN 103360393B CN 201310321329 A CN201310321329 A CN 201310321329A CN 103360393 B CN103360393 B CN 103360393B
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- theophylline
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- sodium salt
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- 0 CN(C(N1C)[U])C(N=CC2CC([*-])=O)=C2C1=O Chemical compound CN(C(N1C)[U])C(N=CC2CC([*-])=O)=C2C1=O 0.000 description 1
Abstract
The invention belongs to the field of chemical synthesis, the raw material of existing synthesis theophylline acetic acid all employ highly toxic product Mono Chloro Acetic Acid, and chloroacetic purchasing channel is subject to strict restriction, and therefore the production of theophylline acetic acid is a greater impact.The invention provides a kind of preparation method of theophylline acetic acid, adopt dimethyl FAU and aqueous sodium hydroxide solution to react and generate theophylline sodium salt, then drip the sodium chloroacetate aqueous solution, after reaction solution clarification, by adding 20%Na
2cO
3the aqueous solution makes reaction solution PH remain on 8 ~ 12.The yield of products obtained therefrom of the present invention brings up to more than 90%, and product assay reaches 99.9%, and steady quality, meet States Pharmacopoeia specifications.
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-aceticacid), chemistry 2-(1,3-dimethyl-2 by name, 6-dioxo-2,3,6,7-tetrahydrochysene-1H-purine-7-base) acetic acid, also claim theophylline acetic acids, English name is Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-7-yl) aceticacid, molecular formula: C
9h
10n
4o
4, molecular weight: 238.204, CAS:211-490-2.
Theophylline acetic acid is white powder, slightly water-soluble, and be soluble in dimethyl formamide, chemical structural formula is as follows:
Theophylline acetic acid
Theophylline acetic acid is mainly used in the intermediate of Acefylline Piperazine (Acefyllinepigerazine), and it is that cardiovascular system is unified peripheral vascular system expansion class medicine that Acefylline Piperazine is similar to aminophylline, is mainly used in treatment of relievining asthma, and it is oral and to inject tolerance better.
Current research finds, theophylline acetic acid can be used as HEK-293 human stem cell and transmits A
2Badenosine Receptors has binding activities (Kim, Soon-Ai; Marshall, MelissaA.; Melman, Neli; Kim, HakSung; Mueller, CHristaE.; Linden, Joel; Jacobson, KennethA.; JournalofMedicinalChemistry; 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, application people is L'OREAL, and denomination of invention is Cosmeticcomposition).
Through retrieval, the synthesis technique of theophylline acetic acid mainly mixes latter 90 DEG C by theophylline with aqueous sodium hydroxide solution and reacts 30 minutes, and cooling drips chloroacetic acid solution, and 95 ~ 100 DEG C are reacted about 2.5 hours, add NaOH and maintain pH8 ~ 9, until pH value is constant be reaction end; Cooling, concentrated hydrochloric acid neutralizes, and cooling washing, filtering and drying, obtains 7-theophylline acetic acids, yield 86.5%.(synthesis of aperflavon, Xia Xinqiang, " Chinese Journal of Pharmaceuticals ", 10 phases in 1977,37-38 page, hereinafter referred to as " document 1 ").
The US Patent No. 3562273(of the seventies in last century applies for that people is FERRERLABOR, denomination of invention is TRIS (HYDROXYMETHYL) AMINOMETHANETHEOPHYLLINEACETATE, 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 report and above-mentioned similar synthesis technique.Because the raw material synthesizing theophylline acetic acid all employ highly toxic product Mono Chloro Acetic Acid, chloroacetic purchasing channel is subject to strict restriction, and therefore the production of theophylline acetic acid is a greater impact.
Summary of the invention
Object of the present invention is exactly the synthetic method that will provide a kind of new theophylline acetic acid, and first the method will abandon highly toxic product Mono Chloro Acetic Acid in material choice, the purity of its secondary raising product and yield, and makes chemosynthesis advantageously in environment protection.
In order to solve the chloroacetic use problem of limited highly toxic product, first the present invention replaces Mono Chloro Acetic Acid with sodium chloroacetate, safety when not only using, and is 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 ") reacts with aqueous sodium hydroxide solution, and it is 10 ~ 11 that pH value controls, and drips the sodium chloroacetate aqueous solution, after 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 to monitor reaction, by adding proper amount of sodium carbonate one until detect raw material primitive reaction complete (disappearance of raw material point), makes to react completely; Add sulfuric acid again, separate out white solid, filter, obtain theophylline acetic acid.
The invention provides a kind of preparation method of theophylline acetic acid, the method comprises the following steps:
A dimethyl FAU and sodium hydroxide or potassium hydroxide (mineral alkali) react by () in aqueous, generate theophylline sodium salt or theophylline sylvite;
B (), in theophylline sodium salt or theophylline sylvite, drips the sodium chloroacetate aqueous solution, condensation reaction obtains containing theophylline acetic acid sodium-salt aqueous solution;
C () TLC thin-layer chromatography monitoring reaction, add 20% sodium carbonate or solution of potassium carbonate, until raw material point disappears, control pH is 8 ~ 12.
D () uses mineral acid regulating step pH to pH2 ~ 2.5, the theophylline acetic acid that activated carbon decolorizing obtains.
In described step (a), aqueous sodium hydroxide solution is heated to 40 DEG C, adds dimethyl FAU, and the mol ratio of dimethyl FAU and sodium hydroxide is 1:1.05 ~ 1.10, and reaction generates theophylline sodium salt; Continue to be heated to 90 DEG C, be incubated half an hour at 90 ~ 95 DEG C;
In described step (b), setting-up point is 55 ~ 65 DEG C, and pH value is 10 ~ 11, is preferably 1.00:0.90 ~ 1.20 in molar ratio, and optimum is that 1:1.0 ~ 1.1 drip the sodium chloroacetate aqueous solution in theophylline sodium reactant salt liquid.
In described step (c), described TLC thin-layer chromatography is preferably TLC
254.
In described step (d), described mineral acid preferably sulfuric acid.
Preferably, preparation method of the present invention comprises the following steps:
Aqueous sodium hydroxide solution is heated to 40 DEG C, adds dimethyl FAU, and the mol ratio of dimethyl FAU and sodium hydroxide is 1:1.05 ~ 1.1, and reaction generates theophylline sodium salt; Continue to be heated to 90 DEG C, surveying material liquid PH value is 10 ~ 11,90 ~ 95 DEG C of insulations 0.5 hour, be down to 55 ~ 65 DEG C and drip the sodium chloroacetate aqueous solution in 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 DEG C of condensation reactions 1 ~ 2 hour, TLC monitors reaction, add appropriate 20% aqueous sodium carbonate and make pH theophylline sodium salt raw material point completely dissolve between 8 ~ 12, react complete, obtain the aqueous solution containing theophylline acetic acid sodium; With 50% sulphur acid for adjusting pH to 2 ~ 2.5, crystallisation by cooling, obtains white products and theophylline acetic acid.
In theophylline sodium salt brine solution, drip the sodium chloroacetate aqueous solution, time for adding more preferably controlled at 20 ~ 60 minutes.
After reaction terminates, be cooled to 60 ~ 65 DEG C, then regulate PH to be 2 ~ 2.5 with 50% sulfuric acid, a large amount of white solid is separated out, and stirring repetition measurement pH value half an hour is constant; Then elimination mother liquor, drops into wet product in 1000ml pure water, is heated to 50 ~ 55 DEG C; Filtered while hot, then use appropriate 50 ~ 55 DEG C of pure water, dry.
Under processing condition of the present invention, yield reaches more than 90%, product fusing point 270 ~ 272oC, HPLC detection level 99.9%, single impurity less than 0.05%.
The present invention has following beneficial effect compared with document 1,2,3 technique in background technology:
(1) literature procedures is raw materials used is theophylline; This raw materials technology is theophylline intermediate-dimethyl FAU.One-step synthesis method theophylline acetic acids, simplifies production stage, reduces three waste discharge.
(2) present method is when selecting sodium chloroacetate to do to carry out condensation reaction, avoids employing highly toxic product Mono Chloro Acetic Acid, improves reliability and the security of actual production.
(3) TLC(TLC is adopted
254) monitoring reaction, disappearing to raw material point by adding proper amount of sodium carbonate, making to react completely.
(4) yield of product is brought up to more than 90% by the present invention, and product assay reaches 99.9%, thus reduces costs, and improves the utilization ratio of raw material.
In sum, the inventive method raw material is easy to get, and by product is few, and reaction conditions is gentle and easily control, cost is lower, easily realizes industrialization, and throughput is large, and products obtained therefrom purity is high, steady quality, meets States Pharmacopoeia specifications, provides the route of synthesis of a new theophylline acetic acid.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.These embodiments should be understood only for illustration of the present invention, and be not used in restriction range of application of the present invention.
Embodiment 1:
1500ml pure water and 44g (1.1mol) sheet alkali is dropped in 3L reaction flask.Be heated to 40 DEG C, 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 DEG C, surveying material liquid PH value is 11, is incubated half an hour, sodium chloroacetate 128g(1.1mol at 90 ~ 95 DEG C) be dissolved in 500g pure water solution, be down to 55 ~ 65 DEG C, at the uniform velocity drip the sodium chloroacetate aqueous solution and be about 0.5h, after solution clarification, drip 20%Na
2cO
3the aqueous solution makes reaction solution PH remain on 8 ~ 12, remains on 55 ~ 65 DEG C DEG C during dropping, simultaneously TLC
254detect theophylline sodium salt until raw material point theophylline sodium salt completely dissolve (Rf
theophylline sodium salt=0.7; Rf
theophylline acetic acids=0.4), react and finish for 2 hours, repetition measurement PH:8 ~ 12.
Be cooled to 60 ~ 65 DEG C and add 50% sulfuric acid, regulate PH to be 2 ~ 2.5, a large amount of white solid is separated out, and stirring repetition measurement pH value half an hour is constant.Then elimination mother liquor, drops into wet product in 1000ml pure water, is heated to 50 ~ 55 DEG C.Filtered while hot, then use appropriate 50 ~ 55 DEG C of pure water, dry, obtain theophylline acetic acids finished product 218g, yield 91.5%, HPLC content 99.95%.
Reaction equation of the present invention is as follows:
TLC(TLC
254) thin-layer chromatography detection, concrete grammar is as follows:
TLC thin layer chromatography board (the biochemical plastic molding and processing plant of Taizhou plain road and bridge tetramethyl, silica gel column chromatography plate (3 × 10cm), GF254), developping agent: methylene dichloride: methyl alcohol=10:1,
capillary microcap.
Embodiment 2:
1500ml pure water and 42g(1.05mol is dropped in 3L reaction flask) sheet alkali.Be heated to 40 DEG C, input 198g (1.0mol) dimethyl FAU(Shanghai all ages pharmaceutical Co. Ltd provides).Continue to be heated to 90 DEG C, surveying material liquid PH value is 10, is incubated half an hour, after stirring and dissolving sodium chloroacetate 128g (1.1mol) is dissolved in the solution of 500g pure water at 90 ~ 95 DEG C, at the uniform velocity drip the sodium chloroacetate aqueous solution reaction solution 55 ~ 65 DEG C and be about 1h, after solution clarification, drip 20%Na
2cO
3the aqueous solution makes reaction solution PH remain on 8 ~ 12, and reaction solution remains on 55 ~ 65 DEG C of about 2h and finishes, repetition measurement PH:8 ~ 12.
With 50% sulphur acid for adjusting pH to 2 ~ 2.5, crystallisation by cooling, then use appropriate pure water, dry, obtain theophylline acetic acids finished product 215.1g, yield 90.5%, HPLC content 99.91%.
Table 1: the contrast of embodiment 1,2 and principal reaction condition in document 1,2,3 technique and yield
More than show and describe 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; what describe in above-described embodiment and 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.Application claims protection domain is defined by appending claims and equivalent thereof.
Claims (6)
1. a preparation method for theophylline acetic acid, the method comprises the following steps:
A () aqueous sodium hydroxide solution is heated to 40 DEG C, add 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 theophylline sodium salt; Continue to be heated to 90 DEG C, be incubated half an hour at 90 ~ 95 DEG C;
B (), in theophylline sodium salt, drips the sodium chloroacetate aqueous solution, condensation reaction obtains containing theophylline acetic acid sodium-salt aqueous solution, and setting-up point is 55 ~ 65 DEG C, and pH value is 10 ~ 11, and the mol ratio of theophylline sodium salt and sodium chloroacetate is 1:0.90 ~ 1.20;
(c) TLC thin-layer chromatography monitoring reaction, add 20% sodium carbonate or solution of potassium carbonate, until raw material point disappears, control pH is 8 ~ 12;
D () uses mineral acid regulating step pH to pH2 ~ 2.5, activated carbon decolorizing obtains theophylline acetic acid.
2. the preparation method of a kind of theophylline acetic acid according to claim 1, is characterized in that, the mol ratio of theophylline sodium salt and sodium chloroacetate is 1:1.0 ~ 1.1.
3. the preparation method of a kind of theophylline acetic acid according to claim 1 and 2, is characterized in that, in described step (c), described TLC thin-layer chromatography is TLC
254thin-layer chromatography.
4. the preparation method of a kind of theophylline acetic acid according to claim 1 and 2, is characterized in that, in described step (d), described mineral acid is sulfuric acid.
5. the preparation method of a kind of theophylline acetic acid according to claim 1, it is characterized in that, the method comprises the following steps:
Aqueous sodium hydroxide solution is heated to 40 DEG C, adds N, N-1,3-dimethyl-4-amino-5-formamido group urea piperazine, and the mol ratio of N, N-1,3-dimethyl-4-amino-5-formamido group urea piperazine and sodium hydroxide is 1:1.05 ~ 1.1, and reaction generates theophylline sodium salt; Continue to be heated to 90 DEG C, surveying material liquid pH value is 10 ~ 11,90 ~ 95 DEG C of insulations 0.5 hour, be down to 55 ~ 65 DEG C and drip the sodium chloroacetate aqueous solution in 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 DEG C of condensation reactions 1 ~ 2 hour, TLC monitors reaction, add appropriate 20% aqueous sodium carbonate and make pH theophylline sodium salt raw material point completely dissolve between 8 ~ 12, react complete, obtain the aqueous solution containing theophylline acetic acid sodium; With 50% sulphur acid for adjusting pH to 2 ~ 2.5, crystallisation by cooling, obtains theophylline acetic acid.
6. the preparation method of a kind of theophylline acetic acid according to claim 5, is characterized in that, in theophylline sodium salt brine solution, drip the sodium chloroacetate aqueous solution, time for adding controlled at 20 ~ 60 minutes.
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Citations (7)
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|---|---|---|---|---|
| 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 |
|---|
| Effects of Alkyl Substitutions of Xanthine Skeleton on Bronchodilation;Ryosuke Sakai 等;《J. Med. Chem.》;19921130;第35卷(第22期);第4039-4044页 * |
| New Syntheses of Caffeine and Theophylline;BOGUSLAW BOBRANSKI 等;《Journal of the American Pharmaceutical Association》;19481231;第37卷(第2期);第62-62页，尤其第64页右栏第2段 * |
| 茶胺黄酮的合成;夏莘强;《中国医药工业杂志》;19771031(第10期);第37-38页，尤其第38页操作方法中7-乙酸茶碱的制备 * |
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