CN103012288A - Preparation method of 6-chloro-1,3-dimethyluracil - Google Patents
Preparation method of 6-chloro-1,3-dimethyluracil Download PDFInfo
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- CN103012288A CN103012288A CN2012105711797A CN201210571179A CN103012288A CN 103012288 A CN103012288 A CN 103012288A CN 2012105711797 A CN2012105711797 A CN 2012105711797A CN 201210571179 A CN201210571179 A CN 201210571179A CN 103012288 A CN103012288 A CN 103012288A
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Abstract
The invention provides a preparation method of 6-chloro-1,3-dimethyluracil, which comprises the following steps: carry out reflux reaction on 1,3-dimethylbarbituric acid and a chlorinating agent in a water-insoluble organic solvent to obtain a reaction mixture; and adding water to quench the reaction to obtain the 6-chloro-1,3-dimethyluracil, wherein the chlorinating agent comprises phosphorus oxychloride. The preparation method provided by the invention reduces the consumption of phosphorus oxychloride, and does not need to perform vacuum distillation on the phosphorus oxychloride. Furthermore, additives can be added in the reaction process to enhance the yield of the 6-chloro-1,3-dimethyluracil. The invention also provides a method for synthesizing 1,3-dimethylbarbituric acid, which is implemented by reacting 1,3-dimethylurea, dimethyl malonate and a condensing agent in an organic solvent. The method avoids using abundant malonic acid and acetic anhydride.
Description
Technical field
The invention belongs to technical field of organic synthesis, relate in particular to a kind of 6-chloro-1, the preparation method of 3-FU dimethyl.
Background technology
6-chloro-1, the 3-FU dimethyl has another name called 6-chloro-1, and the 3-dimethyl uracil has formula I structure, is the important intermediate of synthetic Altace Ramipril urapidil and antiarrhythmic drug Nifekalant.
Prior art discloses multiple 6-chloro-1, the synthetic method of 3-FU dimethyl, and in US Patent No. 4659651A, 6-chloro-1, the synthesis step of 3-FU dimethyl is:
At first between 60 ~ 70 ℃, dimethyl urea and propanedioic acid are dissolved in the acetic acid, add aceticanhydride, and with temperature constant temperature to 90 ℃, react after 6 hours again acidifying and make and have 1 of formula II structure, 3-dimethyl barbituric acid;
Then to 1, add a small amount of water in the 3-dimethyl barbituric acid, splash into again a large amount of phosphorus oxychloride and be warming up to back flow reaction, react after 1 ~ 2 hour, cooling, solution decompression is concentrated, add cancellation in a large amount of cold water after removing excessive phosphorus oxychloride, filter and centrifugation after obtain 6-chloro-1, the thick product of 3-FU dimethyl, pass through recrystallization again, obtain the finished product, productive rate is generally about 70%.
Chinese patent CN102617486A also discloses 6-chloro-1, the synthesis step of 3-FU dimethyl: with 6-amino-1, the 3-FU dimethyl makes first 6-hydroxyl-1 through acid hydrolysis, the 3-FU dimethyl; Then mix with a large amount of phosphorus oxychloride solution that splash into a small amount of water, be warming up to again back flow reaction, react after 2 ~ 5 hours, cooling, solution decompression is concentrated, remove excessive phosphorus oxychloride after; Solution after will diluting at last joins cancellation in a large amount of cold water, obtains 6-chloro-1 after filtration and the centrifugation, and the thick product of 3-FU dimethyl passes through recrystallization again, obtains the finished product.
But, prepare 6-chloro-1 at above-mentioned two kinds, in the process of 3-FU dimethyl, the consumption of its chlorination process phosphorus oxychloride is all larger, is generally 10 ~ 15 times of weight of 1,3-dimethyl barbituric acid, not only cost is high, and reaction needs after finishing underpressure distillation to remove excessive phosphorus oxychloride, conversion unit required high, increased operation easier; Also need simultaneously to add a large amount of shrends reaction of going out, produce a large amount of waste acid liquors, still need further to process.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is to provide a kind of 6-chloro-1, and the preparation method of 3-FU dimethyl has reduced the usage quantity of phosphorus oxychloride by preparation method provided by the invention, need not the underpressure distillation phosphorus oxychloride after reaction is finished, reaction conditions is gentle, easy handling.
The invention discloses a kind of 6-chloro-1, the preparation method of 3-FU dimethyl may further comprise the steps:
A) 1,3-dimethyl barbituric acid and chlorizating agent with the immiscible organic solvent of water in carry out back flow reaction, obtain reaction mixture; Described chlorizating agent comprises phosphorus oxychloride;
B) add shrend in the described reaction mixture and go out after the reaction, obtain 6-chloro-1, the 3-FU dimethyl.
Preferably, described steps A) be specially:
A1) 1,3-dimethyl barbituric acid, chlorizating agent and additive with the immiscible organic solvent of water in carry out back flow reaction, obtain reaction mixture, described additive is one or more in water and the alcohol compound.
Preferably, the weight ratio of described chlorizating agent and 1,3-dimethyl barbituric acid is (0.5 ~ 1.5): 1.
Preferably, the described and immiscible organic solvent of water is one or more in benzene kind solvent, ethyl acetate, methyl chloride and the t-butyl methyl ether.
Preferably, described benzene kind solvent is benzene, toluene or dimethylbenzene; Described methyl chloride is methylene dichloride or trichloromethane.
Preferably, described chlorizating agent also comprises one or both in phosphorus trichloride and the phosphorus pentachloride.
Preferably, described alcohol compound is methyl alcohol or ethanol.
Preferably, described steps A 1) be specially:
Mix with 1,3-dimethyl barbituric acid, chlorizating agent with the immiscible organic solvent of water ,-5 ~ 10 ℃ to wherein adding additive, carry out back flow reaction, obtain reaction mixture.
Preferably, described weight ratio with the immiscible organic solvent of water, additive and 1,3-dimethyl barbituric acid is (2 ~ 5): (0.5 ~ 1.2): 1.
Preferably, the time of described back flow reaction is 3 ~ 8 hours, and the time of cancellation reaction is 0.2 ~ 0.8 hour.
Preferably, described 1, the preparation method of 3-dimethyl barbituric acid is:
A) 1,3-dimethyl urea, dialkyl malonate and condensing agent react in alcoholic solvent, obtain 1,3-dimethyl barbituric acid sodium salt; Described condensing agent is sodium methylate or sodium ethylate;
B) described 1,3-dimethyl barbituric acid sodium salt obtains 1,3-dimethyl barbituric acid after acidifying.
Preferably, described dialkyl malonate is propanedioic acid dimethyl esters or propanedioic acid diethyl ester; Described alcoholic solvent is methyl alcohol or ethanol.
Preferably, described acidifying is for to carry out acidifying with concentrated hydrochloric acid.
The invention provides a kind of 6-chloro-1, the preparation method of 3-FU dimethyl, with 1,3-dimethyl barbituric acid and comprise that the chlorizating agent of phosphorus oxychloride is raw material, with the immiscible organic solvent of water in, carry out back flow reaction, at last again after the water cancellation reaction, can obtain 6-chloro-1, the 3-FU dimethyl.Compared with prior art, the present invention with phosphorus oxychloride as chlorizating agent, take with the immiscible organic solvent of water as reaction medium, 1,3-dimethyl barbituric acid and a small amount of phosphorus oxychloride can be reacted obtain 6-chloro-1, the 3-FU dimethyl, reduced the phosphorus oxychloride consumption, the weight ratio that makes phosphorus oxychloride and 1,3-dimethyl barbituric acid is by original (10 ~ 15): 1 is reduced to (0.5 ~ 1.5): 1, reduced cost; Simultaneously, reaction does not need after finishing underpressure distillation to remove excessive phosphorus oxychloride and can add the shrend reaction of going out, reaction conditions gentleness, easy handling; Owing to reduced the consumption of phosphorus oxychloride, need not to use a large amount of shrends reaction of going out, reduced the generation of spent acid, simplified complicated aftertreatment.In addition, the present invention take with the immiscible organic solvent of water as reaction medium, react and be easy to after complete reclaim, can reuse.Further, the present invention has added water or alcohol compound as additive in the reaction process of 1,3-dimethyl barbituric acid and phosphorus oxychloride, so that 6-chloro-1, the productive rate of 3-FU dimethyl is increased to 84% ~ 90%.Further, the present invention with sodium methylate or sodium ethylate as condensing agent, with alcoholic solvent as reaction solvent, make the reaction of 1,3-dimethyl urea and dimethyl malonate obtain 1,3-dimethyl barbituric acid, avoid using a large amount of propanedioic acid and aceticanhydride, reduced cost.Experimental result shows, the present invention is take the phosphorus oxychloride of 0.5 ~ 1.5 times of weight as chlorizating agent, take with the immiscible organic solvent of water as reaction medium, take water or alcohol compound as additive, prepared 6-chloro-1, the 3-FU dimethyl, its productive rate is about more than 80%.
Description of drawings
Fig. 1 be in the embodiment of the invention 1 preparation 1,3-dimethyl barbituric acid nucleus magnetic hydrogen spectrum figure;
Fig. 2 be in the embodiment of the invention 1 preparation 1,3-dimethyl barbituric acid nuclear-magnetism carbon spectrogram;
Fig. 3 is the 6-chloro-1 of preparation in the embodiment of the invention 1,3-FU dimethyl hydrogen nuclear magnetic resonance spectrogram;
Fig. 4 is the 6-chloro-1 of preparation in the embodiment of the invention 1,3-FU dimethyl carbon-13 nmr spectra figure.
Embodiment
In order further to understand the present invention, below in conjunction with embodiment the preferred embodiment of the invention is described, but should be appreciated that these describe just in order to further specify the features and advantages of the present invention, rather than to the restriction of invention claim.
The invention provides a kind of 6-chloro-1, the preparation method of 3-FU dimethyl may further comprise the steps:
A) described 1,3-dimethyl barbituric acid and chlorizating agent with the immiscible organic solvent of water in carry out back flow reaction, obtain reaction mixture; Described chlorizating agent comprises phosphorus oxychloride;
B) add shrend in the described reaction mixture and go out after the reaction, obtain 6-chloro-1, the 3-FU dimethyl.
The present invention is with 1,3-dimethyl barbituric acid and uses the chlorizating agent that comprises phosphorus oxychloride as raw material, with the immiscible organic solvent of water in react, cancellation can obtain 6-chloro-1, the 3-FU dimethyl after reacting.Further, the present invention is 1, in the process of 3-dimethyl barbituric acid and the chlorination reaction that comprises phosphorus oxychloride, take with the immiscible organic solvent of water as reaction medium, can reduce greatly the consumption of phosphorus oxychloride, thereby after reaction is finished, do not need underpressure distillation to remove excessive phosphorus oxychloride and can add the shrend reaction of going out, reaction conditions gentleness, easy handling; Owing to reduced the consumption of phosphorus oxychloride, need not to use a large amount of shrends reaction of going out, reduced the generation of spent acid, simplified complicated aftertreatment.
The present invention is raw material with 1,3-dimethyl barbituric acid, to its source without limits, can buy from the market, also can prepare in accordance with the following methods:
A) 1,3-dimethyl urea, dialkyl malonate and condensing agent react in alcoholic solvent, obtain 1,3-dimethyl barbituric acid sodium salt; Described condensing agent is sodium methylate or sodium ethylate;
B) described 1,3-dimethyl barbituric acid sodium salt obtains 1,3-dimethyl barbituric acid after acidifying.
The present invention at first reacts 1,3-dimethyl urea, dialkyl malonate and condensing agent in alcoholic solvent, obtain 1,3-dimethyl barbituric acid sodium salt; Described dialkyl malonate is preferably propanedioic acid dimethyl esters or propanedioic acid diethyl ester; Described condensing agent is preferably sodium methylate or sodium ethylate; Described alcoholic solvent is preferably methyl alcohol or ethanol.In the present invention, the weight ratio of described condensing agent and 1,3-dimethyl urea is preferably (0.55 ~ 0.68): 1; The weight ratio of described dialkyl malonate and 1,3-dimethyl urea is preferably (1.4 ~ 1.6): 1; The weight ratio of described alcoholic solvent and 1,3-dimethyl urea is preferably (9 ~ 10): 1.
The present invention preferably carries out according to following steps to order of addition(of ingredients) without limits:
At first 1,3-dimethyl urea and condensing agent are mixed in alcoholic solvent, open and stir, churning time is preferably 0.4 ~ 0.7 hour; Add dialkyl malonate, the adding mode is preferably slow adding again; Then heat up and carry out back flow reaction, the reaction times is preferably 5 ~ 7 hours; Cooling, centrifugation obtains 1,3-dimethyl barbituric acid sodium salt.
With described 1,3-dimethyl barbituric acid sodium salt is after acidification, and centrifugation obtains 1,3-dimethyl barbituric acid again; Described acidifying is preferably with concentrated hydrochloric acid carries out acidifying, is that 30% concentrated hydrochloric acid carries out acidifying with concentration more preferably.The present invention preferably will add entry in 1,3-dimethyl barbituric acid sodium salt, add concentrated hydrochloric acid again and carry out acidifying; The weight ratio of described water and 1,3-dimethyl barbituric acid sodium salt is preferably (1.0 ~ 1.2): 1; Described concentrated hydrochloric acid add-on is preferably above-mentioned reaction mixture pH value is adjusted between 1 ~ 2; Centrifugation obtains 1,3-dimethyl barbituric acid more at last.
After obtaining 1,3-dimethyl barbituric acid, it is carried out nuclear magnetic resonance spectroscopy, the result shows that it has formula II structure, shows that method provided by the invention can prepare 1,3-dimethyl barbituric acid.
1,3-dimethyl barbituric acid, chlorizating agent and mix with the immiscible organic solvent of water heat up and carry out back flow reaction, obtain reaction mixture.Described chlorizating agent comprises phosphorus oxychloride, preferably also comprises in phosphorus trichloride or the phosphorus pentachloride one or both.The present invention does not have particular restriction to the weight ratio of phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride, and is well known to those skilled in the art, can get final product with the weight ratio that 1,3-dimethyl barbituric acid reacts.Described as reaction medium with the immiscible organic solvent of water, can be in benzene kind solvent, ethyl acetate, methyl chloride and the t-butyl methyl ether one or more.Wherein, benzene kind solvent is preferably benzene, toluene or dimethylbenzene, and methyl chloride is preferably methylene dichloride or trichloromethane; Described and the immiscible organic solvent of water be benzene,toluene,xylene, ethyl acetate, methylene dichloride, trichloromethane or t-butyl methyl ether more preferably.In the present invention, the weight ratio of described chlorizating agent and 1,3-dimethyl barbituric acid is preferably (0.5 ~ 1.5): 1, more preferably (0.7 ~ 1.3): 1; The weight ratio of organic solvent and 1,3-dimethyl barbituric acid is preferably (2 ~ 5): 1, more preferably (2.5 ~ 3.5): 1.1,3-dimethyl barbituric acid and chlorizating agent react under reflux temperature, preferred 3 ~ 8 hours of reaction times, more preferably 4 ~ 7 hours.
In the back flow reaction process, in order to improve productive rate, the present invention preferably reacts under the existence effect of additive, that is, 1,3-dimethyl barbituric acid, chlorizating agent and additive with the immiscible organic solvent of water in carry out back flow reaction, obtain reaction mixture.Detailed process is preferably:
Mix with 1,3-dimethyl barbituric acid, chlorizating agent with the immiscible organic solvent of water ,-5 ~ 10 ℃ to wherein adding additive, carry out back flow reaction, obtain reaction mixture.
At first with 1,3-dimethyl barbituric acid, chlorizating agent with after the immiscible organic solvent of water mixes, preferably it is cooled to-5 ~ 0 ℃; Slowly add additive, the adding temperature of additive is preferably-5 ~ 10 ℃ again, more preferably-2 ~ 7 ℃; Described additive is one or both in water and the alcohol compound, and wherein alcohol compound is preferably methyl alcohol or ethanol; Described additive is one or more of water, methyl alcohol and ethanol more preferably; The weight ratio of additive and 1,3-dimethyl barbituric acid is preferably (0.5 ~ 1.2) in above-mentioned reaction: 1, more preferably (0.7 ~ 1.0): 1.
Additive add complete after, heat up and carry out back flow reaction, obtain reaction mixture, need not to distill in the situation of phosphorus oxychloride, directly add the shrend reaction of going out in the reaction mixture, the preferred slowly adding of the present invention shrend reaction of going out; The temperature of cancellation reaction is preferably below 60 ℃, and the time of cancellation reaction is preferably 0.2 ~ 0.8 hour, more preferably 0.3 ~ 0.7 hour; After the present invention preferably adds entry, cancellation reaction under the condition that stirs.
React complete after, preferably the reaction mixture that obtains is down to room temperature, after filtration, the aftertreatment such as centrifugation obtains solid crude product 6-chloro-1,3-FU dimethyl and centrifuge mother liquor.
Obtain crude product 6-chloro-1, after the 3-FU dimethyl, preferably comprise that also the crude product to obtaining carries out aftertreatment, described aftertreatment concrete steps are: at first crude product, methyl alcohol and gac are mixed, then pass through reflux decolour, filtration, crystallisation by cooling, carry out again centrifugation, oven dry, obtain at last elaboration 6-chloro-1, the 3-FU dimethyl.In described reflux decolour process, the weight ratio of described methyl alcohol and 1,3-dimethyl barbituric acid is (2 ~ 5): 1, and the weight ratio of activated carbon is (0.03 ~ 1): 1.
Obtain 6-chloro-1, after the 3-FU dimethyl, it is carried out nuclear magnetic resonance spectroscopy, the result shows that it has formula I structure, shows that method provided by the invention can prepare 6-chloro-1, the 3-FU dimethyl.
Obtain 6-chloro-1, after the 3-FU dimethyl, measure its fusing point, the result shows that its fusing point is 113 ~ 114 ℃.
In the present invention, described centrifuge mother liquor is mainly and the immiscible organic solvent of water, recycling after preferably it being reclaimed.The present invention does not have particular restriction to described recovery method, is preferably: will obtain organic solvent after centrifuge mother liquor layering, washing, the drying.
The present invention at first carries out described centrifuge mother liquor layering well known to those skilled in the art and processes, and organic solvent is separated mutually with water, and then preferred water washs the organic layer that obtains, and preferred washing times is 1 ~ 5 time; The preferred anhydrous sodium sulphate that adopts is carried out drying treatment to it after the washing, then remove by filter after the sodium sulfate, obtain pure and the immiscible organic solvent of water, this organic solvent can be used as reaction medium and continues on for 6-chloro-1, the preparation of 3-FU dimethyl, thus greatly reduce cost.Experimental result shows, method provided by the invention can reach 80% ~ 92% with the rate of recovery of the immiscible organic solvent of water.
In order further to understand the present invention, to 6-chloro-1 provided by the invention, the preparation method of 3-FU dimethyl is elaborated below in conjunction with embodiment, and protection scope of the present invention is not limited by the following examples.
Embodiment 1
In 1000L dry reaction still, add 440kg methyl alcohol, 44kg1,3-dimethyl urea and 26kg sodium methylate are opened and are stirred, 0.5 after hour, the dimethyl malonate that slowly adds 66kg, adds complete after, back flow reaction is carried out in intensification, react after 6 hours, be down to room temperature, centrifugation obtains 88kg1,3-dimethyl barbituric acid sodium salt; To obtain 1, add 100kg water in the 3-dimethyl barbituric acid sodium salt, use again 30% concentrated hydrochloric acid with 1, the pH value of the mixed solution of 3-dimethyl barbituric acid sodium salt and water is adjusted to 1 ~ 2, last centrifugation obtains 58.5kg1, and 3-dimethyl barbituric acid product, productive rate are 75%.
1,3-dimethyl barbituric acid is carried out nuclear magnetic resonance spectroscopy, and the result is referring to Fig. 1 and Fig. 2, Fig. 1 be in the embodiment of the invention 1 preparation 1,3-dimethyl barbituric acid hydrogen nuclear magnetic resonance spectrogram, Fig. 2 be in the embodiment of the invention 1 preparation 1,3-dimethyl barbituric acid carbon-13 nmr spectra figure.By Fig. 1 and Fig. 2 as can be known, the product that the present invention obtains is 1,3-dimethyl barbituric acid.
In 100L dry reaction still, add 50kg dimethylbenzene, 10kg by embodiment 1 prepared 1,3-dimethyl barbituric acid and 12kg phosphorus oxychloride, open and stir, said mixture is cooled to-5 ~ 0 ℃, under less than 10 ℃ condition, slowly drip 5kg methyl alcohol, dropwise slow intensification and carry out back flow reaction, react after 5 hours stopped heating, be down to room temperature, under the temperature condition below 40 ℃, slowly to wherein adding 12kg water, add complete, continue to stir after 0.5 hour, be down to room temperature, centrifugal solid crude product and the centrifuge mother liquor of obtaining adds 35kg methyl alcohol to this crude product, 0.5kg activated carbon, through reflux decolour, filter, crystallisation by cooling, centrifugal, oven dry obtains 10.06kg elaboration 6-chloro-1,3-FU dimethyl; Centrifuge mother liquor is carried out layering, with three washings of 30kg moisture, then carries out drying with the 0.5kg anhydrous sodium sulphate,
After removing by filter sodium sulfate, obtain 46kg dimethylbenzene, solvent recovering rate is 92%.
To elaboration 6-chloro-1, the 3-FU dimethyl is measured, and the result shows, its content 99.5%, 113 ~ 114 ℃ of fusing points, yield 90%;
To elaboration 6-chloro-1, the 3-FU dimethyl is carried out nuclear magnetic resonance spectroscopy, the result is referring to Fig. 3 and Fig. 4, Fig. 3 is the 6-chloro-1 of preparation in the embodiment of the invention 1,3-FU dimethyl hydrogen nuclear magnetic resonance spectrogram, Fig. 4 is the 6-chloro-1 of preparation in the embodiment of the invention 1,3-FU dimethyl carbon-13 nmr spectra figure.By Fig. 3 and Fig. 4 as can be known, the final product that the present invention obtains is 6-chloro-1, the 3-FU dimethyl.
Embodiment 3
In 100L dry reaction still, add the 25kg trichloromethane, 10kg commercially available 1,3-dimethyl barbituric acid and 12kg phosphorus oxychloride, open and stir, said mixture is cooled to-5 ~ 0 ℃, under less than 10 ℃ condition, slowly drip 5kg water, dropwise slow intensification and carry out back flow reaction, react after 5 hours stopped heating, be down to room temperature, under the temperature condition below 40 ℃, slowly to wherein adding 12kg water, add complete, continue to stir after 0.5 hour, be down to room temperature, centrifugal solid crude product and the centrifuge mother liquor of obtaining adds 35kg methyl alcohol to this crude product, 0.5kg activated carbon, through reflux decolour, filter, crystallisation by cooling, centrifugal, oven dry obtains 9.39kg elaboration 6-chloro-1,3-FU dimethyl; Centrifuge mother liquor is carried out layering, with three washings of 15kg moisture, then carries out drying with the 0.5kg anhydrous sodium sulphate, remove by filter sodium sulfate after, obtain the 21.3kg trichloromethane, solvent recovering rate is 86%.
To elaboration 6-chloro-1, the 3-FU dimethyl is measured, and the result shows, its content 99.1%, 113 ~ 114 ℃ of fusing points, yield 84%;
To elaboration 6-chloro-1, the 3-FU dimethyl is carried out nuclear magnetic resonance spectroscopy, and the result shows that the final product that the present invention obtains is 6-chloro-1, the 3-FU dimethyl.
Embodiment 4
In 100L dry reaction still, add the 50kg ethyl acetate, 10kg is by embodiment 1 prepared 1,3-dimethyl barbituric acid and 8kg phosphorus oxychloride, open and stir, said mixture is cooled to-5 ~ 0 ℃, under less than 10 ℃ condition, slowly drip 5kg ethanol, dropwise slow intensification and carry out back flow reaction, react after 5 hours stopped heating, be down to room temperature, under the temperature condition below 40 ℃, slowly to wherein adding 12kg water, add complete, continue to stir after 0.5 hour, be down to room temperature, centrifugal solid crude product and the centrifuge mother liquor of obtaining adds 35kg methyl alcohol to this crude product, 0.5kg activated carbon, through reflux decolour, filter, crystallisation by cooling, centrifugal, oven dry obtains 9.49kg elaboration 6-chloro-1,3-FU dimethyl; Centrifuge mother liquor is carried out layering, with three washings of 30kg moisture, then carries out drying with the 0.5kg anhydrous sodium sulphate, remove by filter sodium sulfate after, obtain the 44kg ethyl acetate, solvent recovering rate is 88%.
To elaboration 6-chloro-1, the 3-FU dimethyl is measured, and the result shows, its content 99.3%, 267 ~ 268 ℃ of fusing points, yield 85%;
To elaboration 6-chloro-1, the 3-FU dimethyl is carried out nuclear magnetic resonance spectroscopy, and the result shows that the final product that the present invention obtains is 6-chloro-1, the 3-FU dimethyl.
Embodiment 5
In 100L dry reaction still, add 20kg toluene, 10kg commercially available 1,3-dimethyl barbituric acid and 5kg phosphorus oxychloride, open and stir, slowly heat up and carry out back flow reaction, react after 5 hours stopped heating, be down to room temperature, under the temperature condition below 60 ℃, slowly to wherein adding 5kg water, add complete, continue to stir after 0.5 hour, be down to room temperature, centrifugal solid crude product and the centrifuge mother liquor of obtaining adds 35kg methyl alcohol to this crude product, 0.5kg activated carbon, through reflux decolour, filter, crystallisation by cooling, centrifugal, oven dry obtains 9.17kg elaboration 6-chloro-1,3-FU dimethyl; Centrifuge mother liquor is carried out layering, uses the 10kg water washing, then carry out drying with the 0.5kg anhydrous sodium sulphate, remove by filter sodium sulfate after, obtain 19kg toluene, solvent recovering rate is 95%.
To elaboration 6-chloro-1, the 3-FU dimethyl is measured, and the result shows, its content 99.2%, 113 ~ 114 ℃ of fusing points, yield 82%;
To elaboration 6-chloro-1, the 3-FU dimethyl is carried out nuclear magnetic resonance spectroscopy, and the result shows that the final product that the present invention obtains is 6-chloro-1, the 3-FU dimethyl.
Embodiment 6
In 100L dry reaction still, add the 50kg ethyl acetate, 10kg commercially available 1,3-dimethyl barbituric acid and 12kg phosphorus oxychloride, open and stir, slowly heat up and carry out back flow reaction, react after 5 hours stopped heating, be down to room temperature, under the temperature condition below 40 ℃, slowly to wherein adding 12kg water, add complete, continue to stir after 0.5 hour, be down to room temperature, centrifugal solid crude product and the centrifuge mother liquor of obtaining adds 35kg methyl alcohol to this crude product, 0.5kg activated carbon, through reflux decolour, filter, crystallisation by cooling, centrifugal, oven dry obtains 8.50kg elaboration 6-chloro-1,3-FU dimethyl; Centrifuge mother liquor is carried out layering, with three washings of 30kg moisture, then carries out drying with the 0.5kg anhydrous sodium sulphate, remove by filter sodium sulfate after, obtain the 45kg ethyl acetate, solvent recovering rate is 90%.
To elaboration 6-chloro-1, the 3-FU dimethyl is measured, and the result shows, its content 99.4%, 113 ~ 114 ℃ of fusing points, yield 76%;
To elaboration 6-chloro-1, the 3-FU dimethyl is carried out nuclear magnetic resonance spectroscopy, and the result shows that the final product that the present invention obtains is 6-chloro-1, the 3-FU dimethyl.
Embodiment 7
In 100L dry reaction still, add the 50kg t-butyl methyl ether, 10kg commercially available 1,3-dimethyl barbituric acid and 8kg phosphorus oxychloride, open and stir, slowly heat up and carry out back flow reaction, react after 5 hours stopped heating, be down to room temperature, under the temperature condition below 40 ℃, slowly to wherein adding 8kg water, add complete, continue to stir after 0.5 hour, be down to room temperature, centrifugal solid crude product and the centrifuge mother liquor of obtaining adds 35kg methyl alcohol to this crude product, 0.5kg activated carbon, through reflux decolour, filter, crystallisation by cooling, centrifugal, oven dry obtains 8.38kg elaboration 6-chloro-1,3-FU dimethyl; Centrifuge mother liquor is carried out layering,
With 30kg moisture three times washing, then carry out drying with the 0.5kg anhydrous sodium sulphate, remove by filter sodium sulfate after, obtain the 40kg t-butyl methyl ether, solvent recovering rate is 75%.
To elaboration 6-chloro-1, the 3-FU dimethyl is measured, and the result shows, its content 99.4%, 113 ~ 114 ℃ of fusing points, yield 78%;
To elaboration 6-chloro-1, the 3-FU dimethyl is carried out nuclear magnetic resonance spectroscopy, and the result shows that the final product that the present invention obtains is 6-chloro-1, the 3-FU dimethyl.
Embodiment 8
In 100L dry reaction still, add the 50kg o-Xylol, 10kg is by embodiment 1 prepared 1,3-dimethyl barbituric acid and 12kg phosphorus oxychloride, open and stir, slowly heat up and carry out back flow reaction, react after 5 hours stopped heating, be down to room temperature, under the temperature condition below 60 ℃, slowly to wherein adding 12kg water, add complete, continue to stir after 0.5 hour, be down to room temperature, centrifugal solid crude product and the centrifuge mother liquor of obtaining adds 35kg methyl alcohol to this crude product, 0.5kg activated carbon, through reflux decolour, filter, crystallisation by cooling, centrifugal, oven dry obtains 9.61kg elaboration 6-chloro-1,3-FU dimethyl; Centrifuge mother liquor is carried out layering, with three washings of 30kg moisture, then carries out drying with the 0.5kg anhydrous sodium sulphate, remove by filter sodium sulfate after, obtain the 46kg o-Xylol, solvent recovering rate is 92%.
To elaboration 6-chloro-1, the 3-FU dimethyl is measured, and the result shows, its content 99.1%, 113 ~ 114 ℃ of fusing points, yield 86%;
To elaboration 6-chloro-1, the 3-FU dimethyl is carried out nuclear magnetic resonance spectroscopy, and the result shows that the final product that the present invention obtains is 6-chloro-1, the 3-FU dimethyl.
More than to a kind of 6-chloro-1 provided by the present invention, the preparation method of 3-FU dimethyl is described in detail.Used a concrete example herein principle of the present invention and embodiment are set forth, the explanation of above embodiment just is used for helping to understand method of the present invention and core concept thereof.Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of claim of the present invention.
Claims (13)
1. 6-chloro-1, the preparation method of 3-FU dimethyl may further comprise the steps:
A) 1,3-dimethyl barbituric acid and chlorizating agent with the immiscible organic solvent of water in carry out back flow reaction, obtain reaction mixture; Described chlorizating agent comprises phosphorus oxychloride;
B) add shrend in the described reaction mixture and go out after the reaction, obtain 6-chloro-1, the 3-FU dimethyl.
2. preparation method according to claim 1 is characterized in that, described steps A) be specially:
A1) 1,3-dimethyl barbituric acid, chlorizating agent and additive with the immiscible organic solvent of water in carry out back flow reaction, obtain reaction mixture, described additive is one or more in water and the alcohol compound.
3. the described preparation method of any one according to claim 1 and 2 is characterized in that the weight ratio of described chlorizating agent and 1,3-dimethyl barbituric acid is (0.5 ~ 1.5): 1.
4. the described preparation method of any one according to claim 1 and 2 is characterized in that, described and the immiscible organic solvent of water are one or more in benzene kind solvent, ethyl acetate, methyl chloride and the t-butyl methyl ether.
5. preparation method according to claim 4 is characterized in that, described benzene kind solvent is benzene, toluene or dimethylbenzene; Described methyl chloride is methylene dichloride or trichloromethane.
6. the described preparation method of any one according to claim 1 and 2 is characterized in that described chlorizating agent also comprises one or both in phosphorus trichloride and the phosphorus pentachloride.
7. preparation method according to claim 2 is characterized in that, described alcohol compound is methyl alcohol or ethanol.
8. preparation method according to claim 2 is characterized in that, described steps A 1) be specially:
Mix with 1,3-dimethyl barbituric acid, chlorizating agent with the immiscible organic solvent of water ,-5 ~ 10 ℃ to wherein adding additive, carry out back flow reaction, obtain reaction mixture.
9. preparation method according to claim 2 is characterized in that, described weight ratio with the immiscible organic solvent of water, additive and 1,3-dimethyl barbituric acid is (2 ~ 5): (0.5 ~ 1.2): 1.
10. preparation method according to claim 1 is characterized in that, the time of described back flow reaction is 3 ~ 8 hours, and the time of cancellation reaction is 0.2 ~ 0.8 hour.
11. preparation method according to claim 1 is characterized in that, and is described 1, the preparation method of 3-dimethyl barbituric acid is:
A) 1,3-dimethyl urea, dialkyl malonate and condensing agent react in alcoholic solvent, obtain 1,3-dimethyl barbituric acid sodium salt; Described condensing agent is sodium methylate or sodium ethylate;
B) described 1,3-dimethyl barbituric acid sodium salt obtains 1,3-dimethyl barbituric acid after acidifying.
12. preparation method according to claim 11 is characterized in that, described dialkyl malonate is propanedioic acid dimethyl esters or propanedioic acid diethyl ester; Described alcoholic solvent is methyl alcohol or ethanol.
13. preparation method according to claim 11 is characterized in that, described acidifying is for to carry out acidifying with concentrated hydrochloric acid.
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| CN103288751A (en) * | 2013-06-03 | 2013-09-11 | 四川百利药业有限责任公司 | Preparation method of high-purity nifekalant hydrochloride |
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| CN108586360A (en) * | 2018-06-13 | 2018-09-28 | 峨眉山宏昇药业股份有限公司 | A kind of preparation method of the chloro- 3- methyluracils of 6- |
| CN108586360B (en) * | 2018-06-13 | 2021-07-30 | 峨眉山宏昇药业股份有限公司 | Preparation method of 6-chloro-3-methyl uracil |
| CN109020900A (en) * | 2018-09-17 | 2018-12-18 | 浙江先锋科技股份有限公司 | The preparation method of the chloro- 3- methyluracil of 6- |
| CN109020900B (en) * | 2018-09-17 | 2020-09-04 | 浙江先锋科技股份有限公司 | Preparation method of 6-chloro-3-methyl uracil |
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