CN101560210A - Method for synthesizing diprophylline - Google Patents
Method for synthesizing diprophylline Download PDFInfo
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- CN101560210A CN101560210A CNA2009101469932A CN200910146993A CN101560210A CN 101560210 A CN101560210 A CN 101560210A CN A2009101469932 A CNA2009101469932 A CN A2009101469932A CN 200910146993 A CN200910146993 A CN 200910146993A CN 101560210 A CN101560210 A CN 101560210A
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- theophylline
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Abstract
The invention relates to a method for preparing diprophylline, which comprises the step of: converting theophylline into a theophylline salt by strong alkali selected from sodium hydroxide and potassium hydroxide and the steps of condensing the theophylline salt and dichlorohydrin; the method is characterized in that the mole ratio of the theophylline, the strong alkali and the dichlorohydrin is 1:1.05 to 2.0:1.05 to 2.0; in addition, the temperature for converting and salinization is 80 to 130 DEG C and the temperature for condensation is 90 to 110 DEG C. The method can obtain relatively high product yield and purity, shorten condensation reaction time and simplify the subsequent fining technique of finished products.
Description
Technical field
The present invention relates to a kind of synthetic method of medical compounds, relate more specifically to a kind of synthetic method of theophylline derivative.
Background technology
Diprophylline has another name called dihydroxypropyltheo-pylline, dihydroxypropyltheophylline, and chemistry is called 1,3-dimethyl-7-(2, the 3-dihydroxypropyl)-3,7-dihydro-1H-purine-2,6-diketone.Diprophylline is the derivative of theophylline, is a kind of smooth muscle relaxant, can promote the release of endogenous adrenin material.Its effect is basic similar to aminophylline, segmental bronchus expansion effect than aminophylline a little less than, only be 10%～20% of aminophylline.Untoward reaction is little, and its toxicity is 20%～25% of aminophylline, and is less to heart and neural influence, is particularly useful for accompanying tachycardic asthmatic patient.Be used for bronchial asthma and cardiac asthma etc. clinically, especially be suitable for because of gastrointestinal irritation obviously can not tolerate aminophylline or with tachycardic should not be with the patient of aminophylline.
Diprophylline is prepared by condensation reaction by theophylline sodium and glycerine monochlorohydrin usually, and existing processes preparation method mainly was divided into for two steps:
Step 1 salinization
Step 2 condensation
This processing method is owing to adopt water as reaction medium, and it is cheap to have a raw material, the avirulent advantage of production process.But the product yield that these methods obtained is all lower, all below 70%.Therefore, need the concrete operations condition of this synthesis technique of research, so that obtain the sintetics of steady quality, high yield.
Summary of the invention
The purpose of this invention is to provide a kind of yield height, diprophylline synthetic method that cost is low.
In the method that is used for preparing diprophylline according to the present invention, comprise the step that theophylline is changed into theophylline salt with the highly basic that is selected from sodium hydroxide and potassium hydroxide, and the step that makes theophylline salt and glycerine monochlorohydrin carry out condensation, it is characterized in that, the mol ratio of theophylline, highly basic and glycerine monochlorohydrin is 1: 1.05-2.0: 1.05-2.0, and the temperature that transforms salinization is 80～130 ℃, and condensation temp is 90-110 ℃.
The mol ratio of theophylline and oxyhydroxide is preferably 1: between the 1.25-2.0, further preferably 1: between the 1.5-1.71, wherein most preferably be 1: 1.62.Employed oxyhydroxide is preferably sodium hydroxide.
The salinization reaction of theophylline is preferably carried out at 90-120 ℃, and more preferably 100-120 ℃, most preferably 110-120 ℃.
In the method for the invention, the mol ratio of theophylline and glycerine monochlorohydrin is preferably 1.0: between the 1.05-1.5, more preferably 1.0: between the 1.05-1.25, more preferably 1.0: between the 1.10-1.20, most preferably be 1: 1.15.
In the method for the invention, condensation temp is preferably between 90 ℃-110 ℃, more preferably between 100-105 ℃.
Method of the present invention can obtain higher product yield and purity, and can shorten the reaction times, has simplified the follow-up process for refining of finished product.
Embodiment
In a kind of embodiment of the present invention, the method according to this invention may further comprise the steps:
1. the salinization of theophylline
In this step, theophylline and sodium hydroxide or potassium hydroxide are dissolved in the water, under heating condition, keep for some time.In the method for the invention, preferably use purified water, this purified water can obtain by distillation, also can make through ion-exchange resin purification or reverse osmosis.
Characteristics of the inventive method are that the mol ratio of theophylline and oxyhydroxide is 1: between the 1.05-2.0, preferably 1: between the 1.25-2.0, further preferably 1: between the 1.5-1.71, wherein most preferably be 1: 1.62.Employed oxyhydroxide is preferably sodium hydroxide.The contriver finds, carries out the salinization reaction in above-mentioned scope, and its reaction times protects and is shortened, and transformation efficiency obviously improves.
Normally, earlier with alkali fully water-soluble after, theophylline is joined alkaline solution.Characteristics of the present invention are that the salinization of theophylline is reflected at 80-130 ℃ to be carried out, preferably carry out at 90-120 ℃, and more preferably 100-120 ℃, most preferably 110-120 ℃.110-120 ℃ condition, reaction only need can thoroughly be finished in 30min.If temperature is lower than 75 ℃, then is reflected at and also is difficult in the long time fully.If reaction surpasses 130 ℃, the yield of final sintetics (diprophylline) can reduce, and may be that the too high meeting of temperature causes the cracking of theophylline ring structure because in the presence of highly basic.Theophylline listed by table 2 and the sodium hydroxide mol ratio is 1: 1.5 o'clock needed reaction times under differing temps.
Table 1 temperature is to the influence of salinization effect
| The salinization temperature (℃) | 75 | 80 | 85 | 90 | 100 | 110 | 120 | 130 | 140 |
| Reaction times (min) | 100 | 80 | 65 | 57 | 42 | 25 | 25 | 25 | 25 |
| Transformation efficiency | 91％ | 98％ | 100％ | 100％ | 100％ | 100％ | 100％ | 100％ | *100％ |
*There is by product to produce
2. condensation
In the method for the invention, the mol ratio of diprophylline and glycerine monochlorohydrin is preferably less than 1, preferably 1.0: between the 1.05-2.0, more preferably 1.0: between the 1.05-1.5, more preferably 1.0: between the 1.05-1.25, more preferably 1.0: between the 1.10-1.20, most preferably be 1: 1.15.Condensation reaction is preferably carried out under more than or equal to 90 ℃ temperature, more preferably 100 ℃-105 ℃.The contriver finds, condensation under this temperature, and not only the reaction times can shorten greatly, and can obtain higher product yield.
In step of condensation, the temperature that adds glycerine monochlorohydrin should be controlled at below 90 ℃.If surpass this temperature, can temporarily stop to feed in raw material, so that temperature falls back to below 90 ℃.After adding, temperature can be risen to the reservation value.In the present invention, rise to usually between 90-110 ℃, preferably between 100-105 ℃.Condensation temp is also unsuitable too high, if be higher than 110 ℃, glycerine monochlorohydrin and sodium hydroxide reacted generate the by product glycerol, reduces the yield of diprophylline.Under said temperature, reaction generally can be finished in 40min, under 100-105 ℃ situation, only needs 20-30min to finish, and analysis revealed, does not have by product to generate in reaction system.
3. aftertreatment
After condensation reaction is finished, remove most of water by underpressure distillation usually, preferably be distilled to the state that resistates is a pasty state.Then resistates is stirred in organic solvent, with the dissolving final product.Leach the inorganic salt in the mixture then---sodium-chlor or Repone K.Filtrate slowly cools to 0 ℃ and leave standstill.In cooling with leave standstill in the process and can produce a large amount of crystal.By filtering or the centrifugal crystal of telling, final drying gets final product.Can be used to make product crystalline organic solvent need have certain polarity, finished product is had higher solubleness, and solubility with temperature and change bigger.Operable solvent includes but not limited to acetone, methyl alcohol, ethanol, methylene dichloride, acetonitrile, N, dinethylformamide.In above-mentioned solvent, ethanol and acetone are most preferred.Fig. 1 shows the schema of a kind of embodiment of the inventive method.
Embodiment
According to following operation steps, listed operational condition is carried out the synthetic of diprophylline in the employing table 2.
Put into the 400ml pure water in the 1000ml there-necked flask that agitator, condenser and dropping funnel are housed, start and stir, add sodium hydroxide, add 181g (1mol) theophylline again after the dissolving fully, heat temperature raising is to 110-120 ℃ of insulation reaction 30min.Temperature is controlled at 75～90 ℃ then, slowly adds glycerine monochlorohydrin.Stirring reaction for some time under condensation temp then.Stirring reaction fully after, control vacuum tightness-be distilled to material more than the 0.085Mpa to be white in color till the thick thing.After the underpressure distillation to terminal, slowly add ethanol 550ml, insulation backflow 30min makes that product dissolves fully in the material, press filtration, and growing the grain, centrifugal, get product after the drying and crushing.
The operating parameters of table 2 embodiment 1-11
| Implement numbering | NaOH consumption/mol | Glycerine monochlorohydrin consumption/mol | Condensation temp/℃ | Condensation time/min | Product purity/% | Yield/% |
| 1 | 1.25 | 1.05 | 90 | 40 | 98.1 | 74.58 |
| 2 | 2.0 | 1.25 | 110 | 40 | 97.9 | 73.72 |
| 3 | 1.5 | 1.15 | 105 | 30 | 98.3 | 76.00 |
| 4 | 1.71 | 1.15 | 105 | 25 | 98.3 | 76.31 |
| 5 | 1.62 | 1.15 | 100-105 | 25 | 98.3 | 78.46 |
| 6 | 2.2 | 1.00 | 78 | 30 | 96.3 | 67.6 |
| 7 | 2.5 | 1.25 | 110 | 30 | 94.7 | 71.6 |
| 8 | 1.5 | 1.25 | 78 | 30 | 98.1 | 71.5 |
| 9 | 1.71 | 1.00 | 105 | 25 | 98.3 | 71.50 |
| 10 | 1.0 | 1.15 | 105 | 30 | 97.8 | 67.00 |
| 11 | 1.71 | 1.15 | 130 | 25 | 95.5 | 70.25 |
In table 2, the processing parameter that embodiment 1-5 is adopted drops in the scope according to the inventive method, and they have obtained good yield, all more than 73.5%.Embodiment 6-11 does not adopt processing parameter of the present invention, and as can be seen from Table 2, they are not so good as embodiment 1-5 aspect yield or product purity.
The method according to this invention has the following advantages:
1, product quality and yield have significantly raising. Because having carried out adjusting to the proportioning of raw material theophylline, NaOH and glycerine monochlorohydrin in the main reaction, new technology improves, optimized reaction temperature, thereby raw material is fully reacted in synthetic, less residue, reach utmost point low value even trace through the content of leaving over that can make it in product after the follow-up refinement treatment, the unit consumption (the consumption of raw materials amount of production unit product) of product is reduced, improved the yield of product, reduced production cost.
2, production operation is simplified, and shortens man-hour, reduces energy consumption. Because the optimization of raw material proportioning and technological operation temperature is carried out fully synthetic reaction, slightly the quality of finished product is greatly improved, thereby the simple follow-up process for refining of finished product has shortened production cycle of technique, has reduced energy consumption.
3, environmental pollution is little. The solvent that uses in the production process mainly is water and ethanol (preferred situation), and used ethanol remains the light waste liquid of environmental pollution and processes rear discharging up to standard, environmentally safe by Sewage Disposal by rear recyclable the applying mechanically of distillation processing.
Claims (10)
1. method for preparing diprophylline, comprise the step that makes the theophylline salinization with the highly basic that is selected from sodium hydroxide and potassium hydroxide, and the step that makes gained theophylline salt and glycerine monochlorohydrin condensation, it is characterized in that, the mol ratio of theophylline, described highly basic and glycerine monochlorohydrin is 1: 1.05-2.0: 1.05-2.0, and the temperature of described salinization step is 80-130 ℃, and condensation temp is 90-110 ℃.
2. method according to claim 1, wherein, theophylline and described alkaline mol ratio are 1: 1.25-2.0.
3. method according to claim 2, wherein, theophylline and described alkaline mol ratio are 1: 1.5-1.71.
4. method according to claim 3, wherein, theophylline and described alkaline mol ratio are 1: 1.62.
5. according to each described method of claim 1 to 4, wherein, the salinization of theophylline is reflected at 110-120 ℃ and carries out.
6. according to each described method of claim 1 to 4, wherein, the mol ratio of theophylline and glycerine monochlorohydrin is 1: 1.05-1.50.
7. method according to claim 6, wherein, the mol ratio of theophylline and glycerine monochlorohydrin is 1.0: 1.10-1.20.
8. method according to claim 7, wherein, the mol ratio of theophylline and glycerine monochlorohydrin is 1.0: 1.15.
9. according to each described method of claim 1 to 4, wherein, the temperature of described condensation is 100-105 ℃.
10. according to claim 6 or 7 described methods, wherein, the temperature of described condensation is 100-105 ℃.
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| CN2009101469932A CN101560210B (en) | 2009-06-09 | 2009-06-09 | Method for synthesizing diprophylline |
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| CN2009101469932A CN101560210B (en) | 2009-06-09 | 2009-06-09 | Method for synthesizing diprophylline |
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| CN101560210B CN101560210B (en) | 2011-11-09 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098567A (en) * | 2013-04-09 | 2014-10-15 | 中国医学科学院药物研究所 | Diprophylline crystal II material, preparation method, pharmaceutical composition and use |
| CN110256434A (en) * | 2019-06-03 | 2019-09-20 | 上海万巷制药有限公司 | A method of preparing high-purity diprophylline |
| CN112110921A (en) * | 2020-07-02 | 2020-12-22 | 江苏顺丰化工有限公司 | Synthesis method of diprophylline |
| CN115850278A (en) * | 2022-11-30 | 2023-03-28 | 广州合和医药有限公司 | Dihydroxypropyltheophylline new crystal form solid substance and preparation method thereof, and injection and preparation method thereof |
| CN115850278B (en) * | 2022-11-30 | 2024-06-07 | 广州合和医药有限公司 | Novel crystal form solid substance of dihydroxypropehylline, preparation method thereof, injection and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2575344A (en) * | 1946-03-01 | 1951-11-20 | State Of Iowa | Dihydroxypropyl theophylline |
-
2009
- 2009-06-09 CN CN2009101469932A patent/CN101560210B/en active Active
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098567A (en) * | 2013-04-09 | 2014-10-15 | 中国医学科学院药物研究所 | Diprophylline crystal II material, preparation method, pharmaceutical composition and use |
| CN110256434A (en) * | 2019-06-03 | 2019-09-20 | 上海万巷制药有限公司 | A method of preparing high-purity diprophylline |
| CN110256434B (en) * | 2019-06-03 | 2020-11-10 | 上海万巷制药有限公司 | Method for preparing high-purity diprophylline |
| CN112110921A (en) * | 2020-07-02 | 2020-12-22 | 江苏顺丰化工有限公司 | Synthesis method of diprophylline |
| CN115850278A (en) * | 2022-11-30 | 2023-03-28 | 广州合和医药有限公司 | Dihydroxypropyltheophylline new crystal form solid substance and preparation method thereof, and injection and preparation method thereof |
| CN115850278B (en) * | 2022-11-30 | 2024-06-07 | 广州合和医药有限公司 | Novel crystal form solid substance of dihydroxypropehylline, preparation method thereof, injection and preparation method thereof |
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| CN101560210B (en) | 2011-11-09 |
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