CN101896484A - Theobromine production process - Google Patents
Theobromine production process Download PDFInfo
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- CN101896484A CN101896484A CN2008801210601A CN200880121060A CN101896484A CN 101896484 A CN101896484 A CN 101896484A CN 2008801210601 A CN2008801210601 A CN 2008801210601A CN 200880121060 A CN200880121060 A CN 200880121060A CN 101896484 A CN101896484 A CN 101896484A
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- 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
- C07D473/10—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 3 and 7, e.g. theobromine
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Abstract
The invention provides a kind of methylating and prepare the novel method of Theobromine by 3-methyl xanthine or its salt (for example its disodium salt).Described novel method comprises: make 3-methyl xanthine or 3-methyl xanthine disodium salt in the presence of yellow soda ash or sodium bicarbonate, the mixture as solvent of acetone or acetone and water is with methyl-sulfate reaction, acidification reaction product again.The present invention has reduced the hydrolysising loss of dimethyl phosphate as solvent with acetone; Yellow soda ash or sodium bicarbonate provide alkaline environment and suitable pH value for methylation reaction.Drip dimethyl phosphate and carry out methylation reaction, have good selectivity and yield and be higher than other advantage of technology more than 10% that methylate.Acetone reclaims and re-uses.This reaction is more complete, caffeine by-product seldom, and efficient liquid phase chromatographic analysis shows that the content of Theobromine in the thick product surpasses 90%.Method of the present invention is fit to industrial-scale production very much.The present invention also provides a kind of novel method of cacao preparate alkali, it is characterized in that the Theobromine crude product solution dissolves by adding alkali such as sodium hydroxide solution, and decolouring is filtered; Reductive agent adds in the filtrate according to circumstances, is acidified to the pH value in 60-80 ℃ again and is 5-6, filters and the dry Theobromine finished product that gets.The refining yield that method of the present invention provides is up to 90%; Make product by present method and have standard color and luster and high product quality; And this law cost is low, is fit to very much commercial scale production.
Description
Technical field
The present invention relates to the synthetic chemistry field, relate in particular to the novel method of a kind of preparation and cacao preparate alkali.
Background technology
Theobromine has another name called 3,7-dihydro-3, and 7-dimethyl-1H-purine-2, the 6-diketone, represent with following structural formula:
Theobromine is an alkaloid main in the cocoa beans, and cocoa beans contains the Theobromine of 1.5-3%, therefore can find it in chocolate.In kola nut and tealeaves, also can find this alkali.Theobromine belongs to xanthine derivative, and xanthine derivative also comprises caffeine and theophylline.Although the title of this compound be " Theobromine " (theobromine) but it does not contain bromine because this title is actually by cocoa (Theobroma), promptly the generic name of cocoa tree is derived.
Theobromine is that a kind of molecular formula is C
7H
8N
4O
2Xln.It is slightly soluble in water (0.5g/l), is partially soluble in boiling water (1g/150ml), is dissolved in EC hardly.Yet Theobromine is dissolved in concentrated acid and moderate is dissolved in ammoniacal liquor.
As a kind of methylated xanthine, Theobromine is a kind of effective cAMP phosphodiesterase inhibitor (cAMP), suppresses the phosphodiesterase this kind of enzyme and is converted into inactive form by active cAMP.CAMP is the second messenger in the various metabolic systems.Theobromine can be used as the initial feed for preparing pentoxifylline, and pentoxifylline is a kind of derivative of methyl xanthine.Pentoxifylline improves blood flow and is usually used in treating intermittent claudication and vascular dementia.
Pentoxifylline
According to Czech patents 279270, Theobromine is by 1-methyl-5-formyl radical methylamino-6-amino uracil preparation, as describing in the following scheme 1:
Scheme 1
1-methyl-5-formyl radical methylamino-6-amino uracil Theobromine
This reaction comprises the compound 1-methyl-5-formyl radical methylamino-6-amino uracil in the ethanolic soln contain KOH that refluxes, and isolates Theobromine sylvite, and it is water-soluble and to be acidified to pH be 6, obtains product with the acetic acid neutralization.Yet aforesaid method is not had a practicality, because initial feed 1-methyl-5-formyl radical methylamino-6-amino uracil is not an industrial raw material.
European patent 0319854 discloses a kind of initial by the 3-methyl xanthine, prepares the method for Theobromine under the pressure of 100bar, in the 1N hydrochloric acid, 170 ℃ of reactions in 2.5 hours by itself and methylcarbonate.European patent 0319854 also discloses a kind of initial by xanthine, prepares the method for Theobromine under the pressure of 160bar, in the 1N hydrochloric acid, 200 ℃ of reactions in 2.5 hours by itself and methylcarbonate.
This method is depicted in the following scheme 2:
Scheme 2
3-methyl xanthine Theobromine
The xanthine Theobromine
Czech patents 281006 discloses a kind of by 3-methyl-2,6-dioxy-1,2,3,6-tetrahydrochysene-1H-purine (3-methyl xanthine) is initial, by starting raw material and methylcarbonate at N, in the dinethylformamide (DMF) in the presence of triethyl benzyl ammonia chloride (TEBAC) method of prepared in reaction Theobromine.This method is depicted in the following scheme 3:
Scheme 3
3-methyl xanthine Theobromine
Other is seen by the initial method for preparing Theobromine of 3-methyl xanthine and is described in, and as in Romanian patent RO 101894, adopts methyl benzenesulfonate (PhSO
3Me) the 3-methyl xanthine that in the presence of NaOH, methylates; As in Czech patents 267100, adopt methyl chloride (MeCl) the 3-methyl xanthine that in methyl alcohol and in the presence of the NaOH, methylates; As in korean patent application KR 2008076146, the 3-methyl xanthine is suspended in tetramethylene sulfone, and is methylated in the presence of alkali.Yet because methyl chloride is extremely inflammable and deleterious, it is disadvantageous using such as the such reagent of methyl chloride.For example tetramethylene sulfone has 284 ℃ very high boiling point, and this solvent of therefore removing residual trace from final product is difficult.
People such as Niegel have described in patent DD 222026 (East Germany) by 3-methyl xanthine and methyl-sulfate in for example water and methanol mixture, there is the synthetic Theobromine (embodiment 1) of reaction down in salt of wormwood, obtaining the Theobromine of 73% yield, but this patent there is no record about the purity of gained Theobromine.When the improved method of retrieval preparation Theobromine, the present inventor has reappeared patent DD 222026 embodiment 1, and the gained Theobromine has low-down purity (adopting the high-efficient liquid phase chromatogram HPLC analysis), as described at comparative example 1.
Obviously, it may not be to be easy to task that those skilled in the art realize obtaining high-purity Theobromine by each method of above describing, and the cacao preparate alkali yield of such gained is easily on the low side.Therefore, starting raw material and the solvent that needs a kind of use to be easy to obtain produced improving one's methods of Theobromine.In addition, this method should be able to high purity and yield isolate product, and foreign matter content wherein is few.
Summary of the invention
The invention provides a kind of novel method for preparing Theobromine, by in solvent, solvent can be the mixture of organic solvent or organic solvent and water, (for example methylates 3-methyl xanthine or its salt in the presence of alkali, disodium salt), to obtain the Theobromine of high yield.
In one embodiment, the invention provides the method that a kind of high yield prepares Theobromine, comprising:
(a) heating 3-methyl xanthine crude product or its salt, the mixture of solvent and alkali;
(b) add methylating reagent and heating; And
(c) the described reaction mixture of acidifying is to produce Theobromine.
According to the present invention, behind acidified reaction mixture, further cooling is to obtain solid, and this solid by filtration and drying obtain.
Preferably, the Theobromine that obtains by the method that provides at this need not any further refining, has at least 99% purity by weight, and perhaps by weight at least 99.5%.
Preferably, the solvent that step (a) is used be organic solvent such as acetone, or the organic solvent mixture of acetone and water for example.
According to preferred embodiment of the present invention, the same as showing at example 2 for example and example 3 respectively, described reaction preferably in the mixture of solvent acetone and water with the 3-methyl xanthine or in the acetone that does not add water usefulness 3-methyl xanthine disodium salt.
In preferred embodiment of the present invention, the method for producing Theobromine can be by in the presence of yellow soda ash, and acetone is made solvent, and 3-methyl xanthine disodium salt and methyl-sulfate react, and acidifying obtains product and realizes again.
According to another preferred embodiment, producing the Theobromine method can be by in the presence of sodium bicarbonate, the mixture as solvent of acetone and water, and 3-methyl xanthine and methyl-sulfate react, and acidifying obtains product and realizes again.
According to the present invention, as shown in table 1, the various combination of solvent and alkali can not produce same good result aspect yield and isolated Theobromine purity.The combination of most these solvents and alkali is inapplicable for the Theobromine that acquisition has essential purity.
According to the present invention, Theobromine can be refining by the method that may further comprise the steps:
(a) Theobromine is mixed with water, add alkali and heat this mixture;
(b) add gac, stir and remove by filter gac;
(c) heating and the described mixture of acidifying; And
(d) the gained solid is filtered in cooling, and washing is also dry.
Preferably, the method for cacao preparate alkali further is included in acidifying mixture and filters and adds reductive agent before.
Embodiment
The invention provides a kind of can be the mixture of organic solvent or organic solvent and water by in solvent, and alkali exists down, the novel method of 3-methyl xanthine or its salt (as its disodium salt) the preparation Theobromine that methylates.
Obviously, it may not be to be easy to task that those skilled in the art will realize obtaining high-purity Theobromine, and the cacao preparate alkali yield of such gained is easily on the low side.Therefore, need a kind ofly with the improving one's methods of high purity and high produced in yields Theobromine, wherein the content of impurity is few.And then, in one embodiment, the invention provides the method that a kind of high yield prepares Theobromine, comprising:
(a) heating 3-methyl xanthine crude product or its salt, the mixture of solvent and alkali;
(b) add methylating reagent and heating; And
(c) the described reaction mixture of acidifying is to produce Theobromine.Term " methylates ", as defined herein, refers to methylation reaction, promptly uses methylating reagent to add a methyl group to molecule.
Term used herein " 3-methyl xanthine crude product " refers to has the 3-methyl xanthine that reaches 98.9% purity by weight, preferably reaches about 98.5% 3-methyl xanthine by weight.
Term used herein " high-purity Theobromine " or " cacao preparate alkali " refer to has the Theobromine of at least 99.0% purity by weight, preferred at least 99.5% or at least 99.8% Theobromine by weight.
According to the present invention, further cooling is to obtain solid behind acidified reaction mixture, and this solid by filtration and drying obtain.
Preferably, further not refining by in the method that this provided, can obtain to have by weight at least 99%, perhaps the Theobromine of at least 99.5% purity by weight.
According to some embodiments of the present invention, methylating reagent is selected from diazomethane, methylcarbonate, Propanal dimethyl acetal, methyl-sulfate, zinc dimethyl, methyl iodide, methyl fluorosulfonate and trifluoromethanesulfonic acid methyl esters.Preferably, methylating reagent is a methyl-sulfate.
According to some other embodiment, the mixture of 3-methyl xanthine crude product, solvent and alkali can be heated to the temperature at least about 55 ℃.Temperature can be about 60 ℃ at least, about at least 65 ℃, about at least 70 ℃, about at least 75 ℃, about at least 80 ℃, about at least 85 ℃, perhaps about at least 90 ℃.The temperature that solution is heated to depends on the physical properties (as boiling point) for preparing the used solvent of this solution and this solvent, and temperature fixes in the correlative technology field personnel ability scope really.
According to some embodiment, used solvent can be to be selected from methyl alcohol in the reaction, ethanol, n-propyl alcohol, Virahol, the n-butanols, the trimethyl carbinol, 1-methoxyl group-2-propyl alcohol, toluene, acetone, methylethylketone, the organic solvent in hexone and the analogue thereof, and their mixture.For example, organic solvent can be the mixture of acetone or this organic solvent and water, for example the mixture of acetone and water.
According to a preferred embodiment of the present invention,, preferably in solvent acetone and water mixture, use the 3-methyl xanthine or in the acetone that does not add water, use 3-methyl xanthine disodium salt to react as the same in example 2 respectively with displaying in the example 3.
According to the present invention, as shown in table 1, the various combination of solvent and alkali can not produce same good result aspect yield and isolated Theobromine purity.The combination of most these solvents and alkali is inapplicable for the Theobromine that acquisition has essential purity.
According to some other embodiment, alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, salt of wormwood, yellow soda ash, Quilonum Retard, cesium carbonate, saleratus, sodium bicarbonate, lithium bicarbonate, cesium bicarbonate and their combination.Preferably, alkali is yellow soda ash or sodium bicarbonate.
In a preferred embodiment of the present invention, the method for producing Theobromine can be by in the presence of yellow soda ash, and acetone is made solvent, and 3-methyl xanthine disodium salt and methyl-sulfate react, and acidifying obtains product and realizes again.
According to another embodiment, the temperature of carrying out the reaction of 3-methyl xanthine disodium salt and methyl-sulfate is 55-60 ℃; Dripped methyl-sulfate 3 to 5 hours, the reaction times is 0.5 to 1.5 hour.
According to another embodiment, 3-methyl xanthine disodium salt: yellow soda ash: the ratio of methyl-sulfate is 1 by weight: 0.3-0.5: 0.95, and 3-methyl xanthine disodium salt: the ratio of solvent is 1g: 4-6ml.
According to another embodiment, after reaction is finished, reduce temperature; It is 4-6 that reactant is acidified to pH, refilters, and washing is also dry to obtain Theobromine.
According to another preferred embodiment, the method for producing Theobromine can be by in the presence of sodium bicarbonate, the mixture as solvent of acetone and water, and 3-methyl xanthine and methyl-sulfate reaction, acidifying acquisition product is realized again.
Preferably, the ratio of 3-methyl xanthine crude product and solvent, i.e. 3-methyl xanthine: solvent ratios, be whenever at least 2 milliliters about 1 gram (g) 3-methyl xanthines of (ml) solvent, preferred every about 5 to the about 1g 3-of about 10ml solvent methyl xanthine.
If solvent is the mixture of organic solvent and water, the mixture of acetone and water for example, acetone: the ratio of water is whenever at least 1 milliliter (ml) water of about 2-12ml acetone; Be preferably about 6ml acetone 1ml water at least whenever.
According to the present invention, Theobromine can be refining by the method that comprises the steps:
(a) Theobromine is mixed with water, add alkali and heat this mixture;
(b) add gac, stir and remove by filter gac;
(c) heating and the described mixture of acidifying; And
(d) the gained solid is filtered in cooling, and washing is also dry.
Preferably, the method for cacao preparate alkali further is included in acidifying mixture and filters and adds reductive agent before.
According to some embodiments of the present invention, alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, salt of wormwood, yellow soda ash, Quilonum Retard, cesium carbonate, saleratus, sodium bicarbonate, lithium bicarbonate, cesium bicarbonate and their combination.Preferably, alkali is sodium hydroxide.
According to a preferred embodiment, by adding 30% aqueous sodium hydroxide solution dissolving Theobromine solution, decolouring, and filtration; Reductive agent is added in the filtrate; Then filtrate is acidified to pH=5-6 under 60-80 ℃, filters also dry to obtain the Theobromine finished product.
According to the present invention, 30% sodium hydroxide adds in the Theobromine crude product makes it be dissolved into sodium salt, and because of the oxidized Vandyke brown that forms of part Theobromine, this causes darkening.Preferably, add a small amount of reductive agent according to circumstances.At a certain temperature, when acidifying was carried out, the oxidized Theobromine of part was reduced into Theobromine, and this makes color become more shallow.
According to another embodiment, reductive agent is S-WAT, sodium bisulfite, Sodium Pyrosulfite, sodium sulphite, Sulfothiorine or hydrogen sulfide.
According to another embodiment, the Theobromine crude product to the weight ratio of reductive agent be 1: 0.01 to 0.03.
According to another embodiment, Theobromine: 30% aqueous sodium hydroxide solution: the ratio of reductive agent is 1: 0.75 by weight: 0.01-0.03.
According to other embodiments of the invention, acid is selected from hydrochloric acid, perchloric acid, Periodic acid, phosphoric acid, sulfurous acid, sodium pyrosulfate and sulfuric acid, preferred hydrochloric acid.
In order to make precipitation easier, can the mixture cooling of Theobromine will be contained.Preferably, mixture is cooled to-10 ℃ to about 25 ℃ approximately.Solution can cool off the enough time to realize the precipitation of Theobromine maximum.
Comparative example 1
This example is showed the preparation of Theobromine according to patent DD 222026 examples 1.
In the 500ml four neck reaction vessels that mechanical stirrer is housed, 8.3g 3-methyl xanthine (0.05mol), 50ml water and 21g salt of wormwood mix down at 85-90 ℃, to obtain solution.This solution is cooled to 70 ℃, and adds 50ml methyl alcohol, form gel, be not easy to stir, next dropwise add 9.45g methyl-sulfate half an hour, temperature rises to 80 ℃ during this period.Continuation was 70-80 ℃ of reaction one hour.Take out sample, filter, dilution is also injected HPLC.The purity of Theobromine is 26.8% when reaction finishes.
Example 2
This examples show the preparation of Theobromine in the mixture of acetone and water in the presence of sodium bicarbonate.
16.6g 3-methyl xanthine (0.1mol) and 100ml acetone are mixed in the 500ml four neck reaction vessels that mechanical stirrer is housed, and add 20ml water.Under agitation the 36g sodium bicarbonate being added and is heated to temperature is 55-60 ℃.The 20g methyl-sulfate dropwise added in 3.5 hours and keeps stirring half an hour down at 55-60 ℃.Then, steaming removes and reclaims acetone.Add 50ml water and this reaction vessel is heated to 80 ℃.Then, 32% salt slow acid is added in the mixture, measure the pH value in the scope of 5-6.Mixture is cooled to 25 ℃, thereby, washes with water and 70 ℃ of dryings by the solid that precipitation obtains forming; Obtain the 15.7g Theobromine with 87% yield, adopt high performance liquid chromatography to detect and have 99.9% purity.
Example 3
This examples show the preparation of Theobromine in the presence of the yellow soda ash in acetone.
In the 500ml four neck reaction vessels that agitator is housed, under continuing to stir, add 3-methyl xanthine disodium salt (63g), acetone (304ml) and yellow soda ash (19.1g).Mixture slowly is heated to about 55 ℃.In 4 hours, dropwise add methyl-sulfate (60g).Then, keep down reacting half an hour at 55 ℃.Under normal pressure, steam and remove acetone, water (50ml) is added.Using 32% hydrochloric acid at 30 ℃ product solution to be neutralized to the pH value is about 5.Then, solution is filtered, with 40 ℃ of warm water (15ml) washing, decompression is filtered to remove down and is anhydrated, and 70 ℃ of dryings, obtains the Theobromine crude product with 86.7% yield.
Example 4
This examples show the preparation of Theobromine in acetone in the presence of yellow soda ash.
In the 500ml four neck reaction vessels that agitator is housed, under agitation add 3-methyl xanthine disodium salt (63g), acetone (304ml) and yellow soda ash (19.1g).With mixture heating up to 55 ℃ and in 3.5 hours, dropwise add methyl-sulfate (60g).Then, keep again reacting half an hour at 55 ℃.Normal pressure steams and removes acetone.Add entry (50ml).Using 32% technical hydrochloric acid at 30 ℃ products therefrom solution to be neutralized to the pH value is about 6.Then, with the solution filtration, with 40 ℃ of warm water (10ml) washing, decompression is filtered down with removal water, and 70 ℃ of dryings, obtains Theobromine with 84.3% yield.
Example 5
This examples show in the presence of yellow soda ash, in acetone, prepare Theobromine.
In the 1000ml four neck reaction vessels that agitator is housed, under agitation add 3-methyl xanthine disodium salt (126g), acetone (610ml) and yellow soda ash (38.5g).Mixture slowly is heated to 55 ℃ and dropwise added methyl-sulfate (120g) in 3.5 hours.Then, keep again reacting half an hour at 57 ℃.Normal pressure steams down and removes acetone.Add entry (100ml), using 32% hydrochloric acid at 30 ℃ products therefrom solution to be neutralized to the pH value is about 6.Then, with the solution filtration, with 40 ℃ of warm water (20ml) washing, decompression is filtered down with removal water, and 70 ℃ of dryings, obtains Theobromine with 84.9% yield.
Example 6-23
These examples have described in detail and have used the combination of different solvents and alkali to prepare Theobromine.
The 3-methyl xanthine is positioned in the 500ml four neck reaction vessels that mechanical stirrer is housed with the solvent and the alkali that describe in detail in the table 1.Under refluxad mix solution, simultaneous temperature rises to the temperature that describes in detail in the table 1 gradually, next dropwise adds methyl-sulfate.Then, continue reaction also basically as progressively carrying out of describing among the embodiment 2.The results are summarized in the table 1.
Table 1
| Example | Solvent | Alkali | Temperature of reaction ℃ | % purity (HPLC) | Remarks |
| 6 | Water/methyl alcohol | Potassium hydroxide/salt of wormwood | 75-80 | 69.5 | Yield only is 48% |
| 7 | Methyl alcohol | Salt of wormwood/Tetramethylammonium hydroxide (TMAOH) | 65-70 | --- | The caffeine of output 92.5% |
| 8 | Water/methyl alcohol | Salt of wormwood | 85-90 | 26.8 | |
| 9 | Methyl alcohol | Potassium hydroxide | Reflux | 26.9 | Splash into alkali |
| 10 | Water/toluene | Sodium bicarbonate/sodium hydroxide | 80 | 92.9 | |
| 11 | Virahol | Sodium bicarbonate | 80-82 | 29.7 | Reaction not exclusively |
| 12 | Virahol | Sodium bicarbonate/sodium hydroxide | 40-45 | 41.5 | |
| 13 | Water | Sodium bicarbonate/sodium hydroxide | 90-95 | 38.3 | |
| 14 | Virahol | 47% sodium hydroxide | Reflux | 76.5 | |
| 15 | Virahol | Solid sodium hydroxide | 82 | ---- | Reactionless |
| 16 | The trimethyl carbinol | Sodium bicarbonate/sodium hydroxide | 82 | 59.5 | |
| 17 | Isopropanol | Sodium bicarbonate/sodium hydroxide | 80-85 | 32 | |
| 18 | Virahol | Salt of wormwood | 78 | 1.7 | |
| 19 | Virahol | Sodium bicarbonate/sodium hydroxide | 75-82 | 60 | |
| 20 | Water | Sodium bicarbonate/sodium hydroxide | 80-85 | 43.6 | |
| 21 | Toluene | Sodium bicarbonate/sodium hydroxide | 100-105 | 34.2 | |
| 22 | Toluene | Salt of wormwood | 100 | 4.5 | |
| 23 | Water/toluene | Sodium bicarbonate/sodium hydroxide | 95 | 31.7 |
TMAOH=Tetramethylammonium hydroxide pentahydrate
Example 24
This example has described the use gac in detail and has come cacao preparate alkali.
The Theobromine of 50g and 500ml water are mixed, and slowly add 47% sodium hydroxide and dissolve fully until Theobromine.Mixture heating up at least 40 ℃ and stirred 30 minutes, is added 2-5g gac (NorritCA1 or SX ultra) simultaneously.Gac filters by pressure filter, with mixture heating up to 80 ℃.Slowly adding 32% hydrochloric acid and measuring pH is 5-6.Mixture is cooled to 25 ℃, and filters out the solid of formation, wash with water and 70 ℃ of dryings.
Example 25
The use gac has been described in detail in detail this example and Sodium Pyrosulfite comes cacao preparate alkali as reductive agent.
In the 250ml four neck reactors that agitator is housed, under agitation add Theobromine crude product (20g), water (120ml) and 30% sodium hydroxide solution (12ml).Reaction vessel is heated to 70-80 ℃ temperature.Add gac (1g), solution decolours half an hour.Leach solution, and Sodium Pyrosulfite (0.2g) is added in the filtrate, under about 65-70 ℃ temperature, stir filtrate.Then, with concentrated hydrochloric acid acidifying filtrate to the pH value in the 5-6 scope.Then, cool the temperature to about 25 ℃.Deionized water wash is filtered and used to the filtrate of handling, dry then, to obtain the 18.5g Theobromine.And then products obtained therefrom is by 2005 editions Chinese Pharmacopoeias (CP 2005), and European Pharmacopoeia 4 (EP 4) and American Pharmacopeia 27 (USP 27) are up to the standards.
Example 26
The use gac has been described in detail in detail this example and sodium bisulfite comes cacao preparate alkali as reductive agent.
In the 250ml four neck reaction vessels that agitator is housed, under agitation add Theobromine crude product (20g), water (120ml) and 30% sodium hydroxide (12ml).It is 70-80 ℃ that reaction vessel is heated to temperature, and adds gac (1g).Solution is decoloured half an hour under 70-80 ℃ of temperature.Leach solution, and in sodium bisulfite (0.3g) the adding filtrate, under 65-70 ℃ of temperature, stir filtrate.Then, with concentrated hydrochloric acid acidifying filtrate to the pH scope in the 5-6 scope.Then, cool the temperature to 25 ℃.The filtrate of handling is leached and uses deionized water wash, dry then, to obtain the 18.6g Theobromine.And then products obtained therefrom is by 2005 editions Chinese Pharmacopoeias, and European Pharmacopoeia 4 and American Pharmacopeia 27 are up to the standards.
Example 27
The use gac has been described in detail in detail this example and Sulfothiorine comes cacao preparate alkali as reductive agent.
In the 250ml four neck reaction vessels that agitator is housed, under agitation add Theobromine crude product (20g), water (120ml) and 30% sodium hydroxide (12ml).It is 70-80 ℃ that reaction vessel is heated to temperature, and adds gac (1g).Solution is decoloured half an hour under 70-80 ℃ of temperature.Leach solution, and Sulfothiorine (0.4g) is added in the filtrate, under 65-70 ℃ of temperature, stir filtrate.Then, with concentrated hydrochloric acid acidifying filtrate to the pH value in the 5-6 scope.Then, cool the temperature to 25 ℃, and the filtrate that will handle leaches, use deionized water wash, and dry, to obtain the 18.2g Theobromine.And then products obtained therefrom is by 2005 editions Chinese Pharmacopoeias, and European Pharmacopoeia 4 and American Pharmacopeia 27 are up to the standards.
Claims (24)
1. the method for a high produced in yields Theobromine comprises:
(a) heating 3-methyl xanthine crude product or its salt, the mixture of solvent and alkali;
(b) add methylating reagent and heating; And
(c) the described reaction mixture of acidifying is to produce Theobromine.
2. the method for claim 1, wherein said methylating reagent is selected from by diazomethane, methylcarbonate, Propanal dimethyl acetal, methyl-sulfate, zinc dimethyl, methyl iodide, the group that methyl fluorosulfonate and trifluoromethanesulfonic acid methyl esters are formed.
3. the method for claim 1, the described solvent that wherein is used for described reaction is to be selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, 1-methoxyl group-2-propyl alcohol, toluene, acetone, methylethylketone, the organic solvent in hexone and their mixture, or the mixture of described organic solvent and water.
4. the method for claim 1, wherein said alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, salt of wormwood, yellow soda ash, Quilonum Retard, cesium carbonate, saleratus, sodium bicarbonate, lithium bicarbonate, cesium bicarbonate, and combination.
5. as the method for the described production Theobromine of claim 1-4, wherein said method is by in the presence of yellow soda ash, and acetone is made solvent, and 3-methyl xanthine disodium salt and methyl-sulfate react, and acidifying obtains described product and realizes again.
6. the method for production Theobromine as claimed in claim 5, after the wherein said reaction mixture acidifying, further cooling is to obtain solid, and this solid by filtration and drying obtain.
7. method as claimed in claim 5, the described temperature of wherein carrying out the described reaction of 3-methyl xanthine disodium salt and methyl-sulfate is 55-60 ℃; Dripped methyl-sulfate 3 to 5 hours, the described reaction times is 0.5 to 1.5 hour.
8. method as claimed in claim 5, wherein 3-methyl xanthine disodium salt: yellow soda ash: the described ratio of methyl-sulfate is 1 by weight: 0.3-0.5: 0.95, and 3-methyl xanthine disodium salt: the described ratio of solvent is 1g: 4-6ml.
9. method as claimed in claim 6, wherein said temperature reduces after reaction is finished; It is 4-6 that described reactant is acidified to pH, filters then, and washing is also dry to obtain Theobromine.
10. as the method for the described production Theobromine of claim 1-4, wherein said method is passed through in the presence of sodium bicarbonate, the mixture as solvent of acetone and water, and 3-methyl xanthine and methyl-sulfate reaction, acidifying realizes to obtain described product again.
11. the method for production Theobromine as claimed in claim 10, wherein said reaction mixture are after acidifying, further cooling is to obtain solid, and this solid by filtration and drying obtain.
12. method as claimed in claim 11, wherein said 3-methyl xanthine crude product is per 5 to the 10ml solvents of about 1g 3-methyl xanthine to the described ratio of described solvent, and described acetone: the water ratio is about 2-12ml acetone at least 1 ml water whenever.
13. the method for a cacao preparate alkali, it comprises a plurality of steps:
(a) Theobromine is mixed with water, add alkali and heat described mixture;
(b) add gac, stir and remove by filter described gac;
(c) heating and the described mixture of acidifying; And
(d) described solid is filtered in cooling, and washing is also dry.
14. method as claimed in claim 13, wherein said alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, salt of wormwood, yellow soda ash, Quilonum Retard, cesium carbonate, saleratus, sodium bicarbonate, lithium bicarbonate, cesium bicarbonate, and combination.
15. method as claimed in claim 14, wherein said alkali are sodium hydroxide.
16. method as claimed in claim 13 further is included in the described mixture of acidifying and filtration adds reductive agent before.
17. as the described method of claim 13-16, wherein said Theobromine solution is by adding the dissolving of 30% aqueous sodium hydroxide solution, decolouring is also filtered; Reductive agent is joined in the filtrate; Described then filtrate is acidified to pH=5-6 at 60-80 ℃, filters also dry to obtain described Theobromine finished product.
18. method as claimed in claim 17, wherein said reductive agent are S-WAT, sodium bisulfite, Sodium Pyrosulfite, sodium sulphite, Sulfothiorine or hydrogen sulfide.
19. method as claimed in claim 17, wherein the Theobromine crude product to the described part by weight of reductive agent be 1: 0.01 to 0.03.
20. method as claimed in claim 17, wherein Theobromine: 30% aqueous sodium hydroxide solution: the described ratio of reductive agent is 1: 0.75 by weight: 0.01-0.03.
21. method as claimed in claim 13, wherein said acidifying is to be selected from hydrochloric acid by use, perchloric acid, and Periodic acid, phosphoric acid, sulfurous acid, the acid in sodium pyrosulfate and the sulfuric acid is carried out.
22. method as claimed in claim 21, wherein said acid are hydrochloric acid.
23. the method for claim 1, the Theobromine that wherein obtains has at least 99% purity by weight.
24. method as claimed in claim 23, wherein the Theobromine of gained has at least 99.5% purity by weight.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200880121060.1A CN101896484B (en) | 2007-12-14 | 2008-12-12 | Theobromine production process |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007101162018A CN101220032B (en) | 2007-12-14 | 2007-12-14 | Novel method for producing theobromine with 3_methylxanthine disodium salt methylating |
| CN200710116201.8 | 2007-12-14 | ||
| CN2007101160008A CN101195619B (en) | 2007-12-14 | 2007-12-14 | Novel method for fine purification of theobromine |
| CN200710116000.8 | 2007-12-14 | ||
| PCT/CN2008/001998 WO2009089677A1 (en) | 2007-12-14 | 2008-12-12 | Theobromine production process |
| CN200880121060.1A CN101896484B (en) | 2007-12-14 | 2008-12-12 | Theobromine production process |
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| CN101896484B CN101896484B (en) | 2013-06-12 |
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| CN (1) | CN101896484B (en) |
| IL (2) | IL206338A0 (en) |
| WO (1) | WO2009089677A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103724348A (en) * | 2013-12-16 | 2014-04-16 | 吉林省舒兰合成药业股份有限公司 | Method for preparing theobromine |
| CN104130259A (en) * | 2014-08-08 | 2014-11-05 | 石药集团新诺威制药股份有限公司 | Ring-closure reaction method of caffeine intermediate 1,3-dimethyl-4-amino-5-formyl aminoureazine (FAU) |
| CN107674032A (en) * | 2017-10-10 | 2018-02-09 | 石药集团新诺威制药股份有限公司 | A kind of new method of caffeine open loop generation theobromine intermediate |
| CN108164530A (en) * | 2018-01-24 | 2018-06-15 | 安徽省百花香料香精有限公司 | A kind of environmentally friendly process for purification of theobromine |
| CN109503585A (en) * | 2018-12-29 | 2019-03-22 | 石药集团新诺威制药股份有限公司 | A kind of refining methd of pentoxifylline recovery article |
| CN112724143A (en) * | 2021-02-07 | 2021-04-30 | 河北工业大学 | Method for preparing theobromine by methylating 3-methylxanthine |
| CN112955138A (en) * | 2018-11-14 | 2021-06-11 | 株式会社德山 | Method for producing ferric citrate hydrate |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294691B (en) * | 2015-11-23 | 2017-03-08 | 青岛科技大学 | A kind of preparation technology of the semi-synthetic caffeine of environment-friendly type |
| CN115710270A (en) * | 2022-09-16 | 2023-02-24 | 安徽恒星制药有限公司 | Recrystallization refining method of pentoxifylline |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD222026A1 (en) * | 1984-02-29 | 1985-05-08 | Dresden Arzneimittel | PROCESS FOR THE PREPARATION OF THEOBROMINE |
| TW225535B (en) * | 1992-11-10 | 1994-06-21 | Hoechst Ag |
-
2008
- 2008-12-12 WO PCT/CN2008/001998 patent/WO2009089677A1/en active Application Filing
- 2008-12-12 CN CN200880121060.1A patent/CN101896484B/en not_active Expired - Fee Related
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103724348A (en) * | 2013-12-16 | 2014-04-16 | 吉林省舒兰合成药业股份有限公司 | Method for preparing theobromine |
| CN103724348B (en) * | 2013-12-16 | 2016-04-27 | 吉林省舒兰合成药业股份有限公司 | A kind of preparation method of Theobromine |
| CN104130259A (en) * | 2014-08-08 | 2014-11-05 | 石药集团新诺威制药股份有限公司 | Ring-closure reaction method of caffeine intermediate 1,3-dimethyl-4-amino-5-formyl aminoureazine (FAU) |
| CN104130259B (en) * | 2014-08-08 | 2016-01-13 | 石药集团新诺威制药股份有限公司 | A kind of ring-closure reaction method of caffeine intermediate 1,3-dimethyl-4-amino-5-formamido group urea piperazine |
| CN107674032A (en) * | 2017-10-10 | 2018-02-09 | 石药集团新诺威制药股份有限公司 | A kind of new method of caffeine open loop generation theobromine intermediate |
| CN108164530A (en) * | 2018-01-24 | 2018-06-15 | 安徽省百花香料香精有限公司 | A kind of environmentally friendly process for purification of theobromine |
| CN112955138A (en) * | 2018-11-14 | 2021-06-11 | 株式会社德山 | Method for producing ferric citrate hydrate |
| CN112955138B (en) * | 2018-11-14 | 2023-08-22 | 株式会社德山 | Method for producing ferric citrate hydrate |
| CN109503585A (en) * | 2018-12-29 | 2019-03-22 | 石药集团新诺威制药股份有限公司 | A kind of refining methd of pentoxifylline recovery article |
| CN109503585B (en) * | 2018-12-29 | 2021-05-14 | 石药集团新诺威制药股份有限公司 | Refining method of pentoxifylline recovered product |
| CN112724143A (en) * | 2021-02-07 | 2021-04-30 | 河北工业大学 | Method for preparing theobromine by methylating 3-methylxanthine |
| CN112724143B (en) * | 2021-02-07 | 2022-04-15 | 河北工业大学 | Method for preparing theobromine by methylating 3-methylxanthine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101896484B (en) | 2013-06-12 |
| IL227837A0 (en) | 2013-09-30 |
| IL206338A0 (en) | 2010-12-30 |
| WO2009089677A1 (en) | 2009-07-23 |
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