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.
You will get efficient and thoughtful service from Guangxing.
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.
Chinese patent CNA 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.
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%.
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;
Prior art discloses multiple 6-chloro-1, the synthetic method of 3-FU dimethyl, and in US Patent No. A, 6-chloro-1, the synthesis step of 3-FU dimethyl is:
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.
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%.
Preferably, the time of described back flow reaction is 3 ~ 8 hours, and the time of cancellation reaction is 0.2 ~ 0.8 hour.
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 chlorizating agent also comprises one or both in phosphorus trichloride and the phosphorus pentachloride.
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.
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.
B) add shrend in the described reaction mixture and go out after the reaction, obtain 6-chloro-1, the 3-FU dimethyl.
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;
The invention discloses a kind of 6-chloro-1, the preparation method of 3-FU dimethyl may further comprise the steps:
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.
Fig. 4 is the 6-chloro-1 of preparation in the embodiment of the invention 1,3-FU dimethyl carbon-13 nmr spectra figure.
Fig. 3 is the 6-chloro-1 of preparation in the embodiment of the invention 1,3-FU dimethyl hydrogen nuclear magnetic resonance spectrogram;
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 L 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.
Embodiment 2
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
The company is the world’s best 1,3-dimethyl-6-aminouracil raw materials supplier. We are your one-stop shop for all needs. Our staff are highly-specialized and will help you find the product you need.
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.
The influence of solvents on intramolecular interactions in 5- or 6-substituted nitro and amino derivatives of six tautomeric forms of uracil was investigated. For this purpose, the density functional theory (B97-D3/aug-cc-pVDZ) calculations were performed in ten environments (1 > ε > 109) using the polarizable continuum model (PCM) of solvation. The substituents were characterized by electronic (charge of the substituent active region, cSAR) and geometric parameters. Intramolecular interactions between non-covalently bonded atoms were investigated using the theory of atoms in molecules (AIM) and the non-covalent interaction index (NCI) method, which allowed discussion of possible interactions between the substituents and N/NH endocyclic as well as =O/&#;OH exocyclic groups. The nitro group was more electron-withdrawing in the 5 than in the 6 position, while the opposite effect was observed in the case of electron donation of the amino group. These properties of both groups were enhanced in polar solvents; the enhancement depended on the ortho interactions. Substitution or solvation did not change tautomeric preferences of uracil significantly. However, the formation of a strong NO&#;&#;&#;HO intramolecular hydrogen bond in the 5-NO 2 derivative stabilized the dienol tautomer from +17.9 (unsubstituted) to +5.4 kcal/mol (substituted, energy relative to the most stable diketo tautomer).
It should be emphasized that the &#;OH and =O groups have opposite electronic properties: the &#;OH group is an electron-donating substituent, whereas =O is an electron-withdrawing substituent. Therefore, the tautomeric form should be important for the intramolecular interactions in uracil derivatives.
Regarding the through-bond interactions, the 5 position is meta-related towards two endocyclic N/NH groups and ortho- and para-related towards two exocyclic &#;OH/=O groups. Conversely, the 6 position is meta-related to the &#;OH/=O and ortho- and para-related towards N/NH. Here, it is important to mention that in pyrimidines, the position of the substituent in relation to the endocyclic N atoms has a profound influence on the substituent&#;substituted system interaction, which affects the electron-withdrawing/donating strength of substituents. This topic is discussed in our recent paper [ 33 ].
Two substitution positions, 5 and 6, differ in through-space ortho interactions and through-bond interactions with endocyclic N atoms/NH groups as well as &#;OH/=O groups. In position 5, depending on the tautomeric form, the substituent can interact through-space with the C4=O or C4&#;OH group. In turn, the substituent in position 6 can interact through-space with the N or NH group in the 1 position. Regarding the through-space interactions, in some cases, formation of an intramolecular hydrogen bond is possible. Thus, the question arises whether it can alter tautomeric preferences.
For this study, we selected the 5- and 6-substituted nitro and amino derivatives of the six tautomeric forms of uracil ( ). The nitro and amino groups represent model electron-withdrawing and electron-donating substituents, respectively. In addition, the nitro group rotated by 90 degrees from the plane of the ring was taken into account. This group interacts with the substituted system only inductively, as opposed to the planar NO 2 group, which acts through induction and resonance.
The aim of the research is to investigate both the intramolecular interactions in uracil derivatives and their sensitivity to solvent change, as well as their ability to change tautomeric preferences. Similar studies on adenine and purine derivatives were recently carried out [ 31 , 32 ]; our computational results were in agreement with the experimental NMR data of 8-halopurines obtained by other groups [ 19 , 20 ].
Uracil consists of a pyrimidine ring and two attached &#;OH groups at the 2 and 4 positions. However, the most stable tautomeric form has both hydrogen atoms of the &#;OH groups attached to the nitrogen atoms in the pyrimidine ring. The four most stable uracil tautomers ( u1 &#; u4 ) and their two rotamers ( u5 , u6 ), along with their relative stabilities, are shown in . Based on calorimetric experiments [ 29 ], it was found that the dienol form is 20 ± 10 kcal/mol less stable than u1 , while u3 by 19 ± 6 kcal/mol. In addition, both diketo ( u1 ) and keto-enol tautomers ( u2 , u3 ) were identified using the dispersed fluorescence spectra, although the precise structure of the latter was not determined [ 30 ]. The most stable keto-enol tautomer was estimated to have about 9.6 kcal/mol higher energy than the diketo form ( u1 ).
An important issue regarding nucleic acid bases is tautomerism. Each of the bases can exist in several forms that differ in the position of the labile hydrogen atom. In general, one of these forms is more stable than the others, and most of the molecules exist in that form [ 16 , 17 , 18 ]. For this reason, RNA and DNA base pairs are built only from N9H tautomer of purine bases and N1H of pyrimidine bases [ 1 ]. However, relative stability of the tautomers can significantly change upon oxidation, reduction [ 17 ], substitution of the nucleobase [ 19 , 20 ], polarity of the environment [ 17 ] and even interaction with a metal cation [ 21 , 22 ]. Tautomerism of nucleobases is of interest in knowledge of biochemical processes. Importantly, it has been proposed that the existence of rare tautomeric forms can cause mutations of genetic code recorded in the DNA or alter functions performed by different variants of RNA [ 23 , 24 , 25 , 26 , 27 ]. Therefore, much effort has been put into studying the properties of uracil and its tautomers, including both theoretical and experimental studies ([ 16 , 28 ] and references therein). As mentioned above, various uracil derivatives are used or currently being studied for medical applications, where they are introduced into the human body. For this reason, investigating which factors can affect the tautomeric equilibria of uracil (and how) is a relevant research topic.
Uracil is a common and naturally occurring pyrimidine derivative. The best known occurrences of uracil are probably nucleic acids, as it is one of the five bases of the nucleic acid. In RNA, uracil forms a complementary base pair with adenine, while its 5-methylated derivative, called thymine, is an equivalent base in DNA [ 1 ]. Uracil and its derivatives have also found applications in other branches of biochemistry. For example, 5-fluorouracil is used in treatment of several cancer types by chemotherapy [ 2 , 3 ], while 5-bromo and iodo uracil derivatives are studied as radiosensitizers for radiotherapy [ 4 , 5 , 6 , 7 ]. In , a computational study of various 5-substituted uracil derivatives (X = CN, SCN, NCS, NCO, OCN, SH, N 3 , NO 2 ) was performed in order to identify the most suitable radiosensitizers for experimental studies [ 8 ]. The most promising derivatives with high electron affinities, 5-(N-Trifluoromethylcarboxy)aminouracil [ 9 ], 5-thiocyanatouracil [ 10 ] and 5-selenocyanatouracil [ 11 ], were synthesized. Among them, 5-thiocyanatouracil has already been tested against prostate cancer cells with promising results [ 12 ]. Some uracil derivatives show antifungal and antimicrobial properties, whereas others act as inhibitors of specific enzymes [ 13 ]. On the other hand, some of them are mutagenic, for example, 5-hydroxyuracil [ 14 ]. An interesting novel class of compounds that are derived from nucleic acid base molecules, including uracil, are ferrocene-like complexes in which the nitrogen base molecule is attached to one of the cyclopentadienyl ligands [ 15 ]. It is a relatively new class of compounds that may find applications in pharmacy, biology and electrochemistry.
Intramolecular interactions between non-covalently bonded atoms were also investigated using the non-covalent interaction index (NCI) method [ 49 ]. The nature of a given interaction was assigned and color-coded according to the value of sgn(λ 2 ) &#; ρ(r), where λ 2 is the second eigenvalue of the Hessian matrix of electron density (ρ(r)). Points on reduced density gradient isosurfaces with a value of sgn(λ 2 )&#;ρ(r) > 0 indicate non-bonding (steric) contacts (in red), with sgn(λ 2 )&#;ρ(r)~0 indicating weakly attractive interactions (e.g., van der Waals, in green) and sgn(λ 2 )&#;ρ(r) < 0 indicating strongly attractive interactions (e.g., hydrogen and halogen bonding, in blue). For more information on the NCI analysis, see Johnson et al. [ 49 ]. In our case, NCI calculations were performed in Multiwfn 3.8 software [ 50 ] and the visualization in the VMD program [ 51 ].
Analysis of electron density using the atoms in molecules (AIM) theory [ 45 ] was performed in the AIMAII program [ 46 ]. The main goal of this analysis was the search for possible bond critical points (BCPs) of non-covalent intramolecular interactions. When such a BCP was present, we estimated the interaction energy according to the formula of Afonin et al. (Equation (1)) [ 47 ], derived from the Espinosa equation [ 48 ].
In order to study solvent effects, the IEF-PCM implicit model of solvation was used [ 41 , 42 , 43 ]. Calculations were performed in ten media, listed in along with their dielectric constants. It should be mentioned that the PCM has been used many times in computational studies of nucleic acid bases [ 6 , 17 , 19 ]. In the AT and GC base pairs, the molecular geometries obtained with the PCM were in good agreement with the experimental data and the calculations using the H 2 O microsolvation model [ 44 ].
Electronic properties of substituents were evaluated using the charge of the substituent active region (cSAR) parameter [ 38 , 39 ]. Its definition is presented in . Positive cSAR values indicate the deficit of electrons in the substituent active region, i.e., the substituent is electron-donating. Negative values represent an excess of electrons in the active region of the substituent, indicating its electron-withdrawing properties. To allow comparison with our other results, the atomic charges used to calculate cSAR were obtained by the Hirshfeld method [ 40 ].
Quantum chemical DFT calculations [ 34 , 35 ] were performed in the Gaussian 16 program [ 36 ]. We used the B97-D3/aug-cc-pVDZ method, in accordance with our recent research regarding purine and adenine derivatives [ 31 , 32 , 37 ]. The optimized geometries correspond to the minima on the potential energy surface since no imaginary vibrational frequencies were found. In the constrained optimization cases, i.e., systems with the NO 2 group rotated by 90 degrees, one imaginary frequency corresponding to the rotation along the C-N bond was found.
The raw data generated in this study and used in statistical analyses are available in the Supplementary Materials. presents the cSAR values of the substituents in all studied systems. In the case of amino derivatives, the NH2 substituent in position 6 has more than twice, in the cSAR scale, stronger electron-donating properties than in position 5. In nitro derivatives, the NO2 group in position 5 is more electron-withdrawing than in position 6. Therefore, the substitution position, i.e., the position in relation to the nitrogen atoms in the ring, has a decisive influence on the properties of the substituent. In contrast, the effect of the tautomeric form of uracil is clearly less significant. It is also worth noting that in polar solvents, the characteristic properties of both NO2 and NH2 groups are enhanced, as shown by the difference between cSAR(X) values in the water and gas phase (Δ).
In 5-NH2 derivatives, electron-donating strength of the amino group decreases in the sequence: u2 > u5~u4~u1 > u3 > u6. The clearly lower cSAR(X) for u6 is a consequence of the rotation of the NH2 group by 90 degrees and the formation of the hydrogen bond, H2N&#;&#;&#;HO, which is discussed in more detail later in the paper. In this case, the large influence of the solvent on the cSAR(NH2) value is due to the rotation of the NH2 group to more planar conformation with respect to the ring in polar solvents. This strengthens the resonance effect.
In 6-NH2 derivatives, electron-donating strength of the amino group decreases in the sequence: u3 > u1~u5 > u6~u4 > u2. Two systems containing the NH endocyclic group at the ortho position, u3 and u1, have the greatest electron-donating properties. An interesting difference is present between the u5 form and its rotamers: u4 and u6. Among them, the highest cSAR(NH2) value and the lowest Δ occur in u5, where the two OH groups are facing in the same direction. When they are in opposite directions, as in u4 and u6, the value of cSAR(X) is lower, while Δ is higher. This may be due to the differences in the dipole moments in these two cases, as the conformation of the OH groups has a significant impact on the value and direction of molecular dipole moment (Table S1). By far the strongest solvent effect on cSAR(X) among the 6-NH2 derivatives occurs in u1 and u3 (highest Δ). These systems also have the highest values of the dipole moment (Table S1). All cSAR(NH2) values in 5-NH2 derivatives are lower than in aniline (0.094), while in 6-NH2 they are higher.
Generally, in all 5-NO2 tautomers, the NO2 group is withdrawing electrons more strongly than in nitrobenzene, where the cSAR(X) is higher, &#;0.140. Its rotation by 90 degree increases cSAR(NO2) by about 0.4 units. The only exception is u6, where a decrease in cSAR is observed; however, this is caused by the hydrogen bonding between the NO2 and ortho OH groups. In 5-NO2 systems, electron-withdrawing strength of the nitro group decreases in the sequence: u3 > u4~u5 > u2 > u1 > u6. The systems with the strongest electron-withdrawing NO2 groups (u3, u4 and u5) have an electron-donating OH group in the ortho position, but its hydrogen atom is directed to the endocyclic N atom, so that NO&#;&#;&#;OH interaction can be expected. When NO&#;&#;&#;HO interaction is present (5-NO2 u6), the electron-withdrawing ability of the NO2 group is the weakest. Again, the greatest variability of cSAR(X) due to solvation occurs in the derivatives with the highest values of the dipole moments (u1 and u2).
In the 6-NO2 derivatives, the cSAR(NO2) values are high, indicating weak electron-withdrawing properties. This is caused by the disturbance of the resonance interactions by ring nitrogen atoms in ortho and para positions. Weak resonance is also evidenced by a smaller increase in cSAR due to the rotation of NO2 by 90° as compared to the 5-NO2 derivatives. This increase is by about 0.2 units, with the exception of u1 and u3 where cSAR(NO2) is positive and its change due to rotation is smaller. Electron-withdrawing strength decreases in the sequence: u2 > u4 > u6~u5 > u1 > u3. The loss of electron-withdrawing properties (cSAR close to 0.0) of the 6-NO2 group occurs in the u1 and u3 derivatives, where the NH group is in the ortho position. Thus, apart from the relative position of the endo N atoms and the substituent, the NO&#;&#;&#;HN through-space interaction has an effect as well. The summary of the cSAR analysis in the form of a bar chart is shown in .
Open in a separate windowIn most cases, the dependences of cSAR(X) on 1/ε are well approximated by a linear function. The parameters of resulting cSAR (X) = a&#;(1/ε) + b functions are summarized in . The slope value, a, informs about the sensitivity of the electronic properties of the substituent in a given derivative to the solvent effect. In general, except for u6 5-NH2, large absolute values of the coefficient occur in systems with a large dipole moment, and small ones in systems with a small dipole moment ( and Table S1). In 6-substituted systems (6-NO2 and 6-NH2), the values of a in u1 and u3 (ortho NH) clearly differ from other tautomers (ortho N). This can be attributed to the influence of ortho interactions with endocylic N/NH groups. It can be concluded that the repulsive ortho interaction, NH&#;&#;&#;HN for 6-NH2 and NO&#;&#;&#;N for 6-NO2, causes high sensitivity of the substituent properties to the solvent effect, whereas the attractive interaction causes low sensitivity. A similar effect was observed in adenine and purine derivatives [29,30].
Properties of the =O/&#;OH groups of all studied forms of uracil, quantified by cSAR, are shown in . Negative values correspond to the electron-withdrawing =O group, whereas positive values to the electron-donating &#;OH. Both the interactions with the substituent and the type of tautomer can affect the electron-donating (&#;OH) or -withdrawing (=O) properties of these groups. The electron-withdrawing properties of the =O groups are greater in the amino derivatives than in the nitro derivatives, which is shown by the more negative cSAR(=O) values in the 5-NH2 and 6-NH2 derivatives. In turn, the electron-donating properties of the &#;OH groups are greater in the nitro than in the amino derivatives. This is due to charge transfer between groups with opposite electronic properties. Global ranges of variation of cSAR are 0.143 for the =O group and 0.107 for the &#;OH group. The ranges for the =O group in C4 and C2 positions are 0.096 and 0.078, respectively, while the average values are &#;0.134 for C4 and &#;0.115 for C2. In the case of the &#;OH group, the ranges are 0.099 for C4 and 0.103 for C2 positions; the average values are 0.159 for C4 and 0.199 for C2. Thus, the characteristic electronic properties of the &#;OH group are on average stronger in the C2 position, while those of the =O group are stronger in the C4 position. Stronger electronic properties are accompanied by higher ranges of their variability.
Open in a separate windowThe C2 position of the uracil ring is double ortho with respect to the two endo N/NH atoms/groups, while the C4 position is ortho and para. So, two electronegative atoms in the ortho position of the &#;OH group might enhance its electron-donating properties, while diminishing the electron-withdrawing by the =O group. A similar effect of ortho N atoms on the substituent properties was observed in our recent studies on nitro and amino derivatives of pyridine, pyrimidine, pyrazine and triazine [33].
Analysis of geometry will be focused on the lengths of CN bonds connecting the NO2 and NH2 substituents and the substituted system. As shown in a, they vary depending on the substitution position and the tautomeric form. In the case of 5-NH2 derivatives, the shortest CN bond occurs in the u2 tautomer and the longest in u6. The u2 tautomer is also characterized by the highest electron-donating strength of the NH2 group among 5-NH2 derivatives ( and ). In the case of the u6 tautomer in the gas phase, the NH2 group is rotated by 90 degrees in order to form a H2N&#;&#;&#;HO hydrogen bond with the OH group in the ortho position. This is accompanied by a significant extension of the CN bond, which reaches the length observed for the 5-NO2 group in u6. In 6-NH2 derivatives, CN bonds are shorter than in 5-NH2, which is connected with the strong electron-donating 6-NH2 group. A slightly longer bond relative to other tautomers occurs in u1 and u3. This may be due to the presence of the NH group in the ortho position resulting in NH&#;&#;&#;HN steric interaction.
Open in a separate windowIn NO2 derivatives, shorter CN bonds are found in 5-NO2 than in 6-NO2 systems. This is in line with the electron-withdrawing strength of the 5-NO2 and 6-NO2 groups. In position 5, the shortest bond occurs in u6, where a strong NO&#;&#;&#;HO hydrogen bond is formed, while the second shortest is in u3, in which the NO2 group has the strongest electron-accepting properties among all systems. For 6-NO2 tautomers, clearly the shortest bonds occur in u1 and u3, where the NH group is in the ortho position. This results from the attractive NO&#;&#;&#;HN interaction.
The rotation of the NO2 group in 5-NO2 derivatives causes the elongation of CN bonds, which is related to the disturbance of the resonance effect of the NO2 group. The largest elongation occurs in the u6 5-NO2 derivative. It is caused by breaking of the NO&#;&#;&#;HO hydrogen bond as a result of NO2 rotation. In the 6-NO2 systems, in four tautomers: u2, u4, u5 and u6 (ortho N), the NO2 rotation clearly shortens the CN bond. This is caused by the weakening of through-space repulsive interactions with the ortho endocyclic N atom. Thus, the main factor determining the CN bond lengths in the 5-NO2 derivatives is the resonance between the NO2 group and the substituted system, while in the 6-NO2 derivatives it is the ortho interaction.
The solvation effect is also reflected in the CN bond lengths. b shows the difference in CN bond lengths between the values obtained in the aqueous solution and the gas phase. In NH2 derivatives, a stronger solvent effect occurs in 6-NH2 systems, while in the case of NO2 derivatives, in 5-NO2 systems. This is connected with the greater variability of the substituent&#;s electronic properties in these systems (see, for example, ). Thus, the bond shortening is related to an increase in the characteristic electronic properties of a given substituent, due to the increase in the solvent polarity.
An important aspect of the interaction between the substituent and the substituted system are through-space ortho interactions, which in some cases could already be seen by the cSAR(X) values and CN bond lengths. In order to identify these interactions, the lengths of two NH/NO bonds of the NH2/NO2 groups were plotted against each other ( ). Deviations from the equal length of these two bonds may indicate the existence of an asymmetric through-space interaction. Such plots also provide information about the attractive/repulsive nature of these interactions, based on the location of a point above or below the y = x line.
Open in a separate windowFirst of all, it should be noticed that the asymmetry in the bond lengths of the NO2 group is about four times greater than that of the NH2 group. Moreover, for the nitro group, the obtained results indicate greater variability of interactions, but as expected in systems with rotated groups, the lengths of both NO bonds are similar. Both repulsive and attractive interactions as well as hydrogen bonds are observed. In the latter case, the systems in which the interaction meets the Koch&#;Popelier criteria for hydrogen bonding [52] are depicted as H-bonds in . Only one system (in the gas phase), visible in the plot, u6 5-NO2, fulfills the criteria. Additionally, an increase in the polarity of the solvent weakens the through-space interactions&#;an increase in the O&#;&#;&#;H distance and a decrease in O&#;&#;&#;HO angle, as shown in . An interesting system in which, despite the symmetry between NH bonds, there is a strong H-bond is u6 5-NH2. In this case, the NH2 group rotates by 90°, and forms a H2N&#;&#;&#;HO hydrogen bond. Moreover, the NH2 group in the formamide solution rotates slightly towards the coplanar conformation (76.7° dihedral angle) and the H-bond is weakened. This rotation is an interesting example of competition of attractive through-space interactions and the resonance between the group and the substituted system. In the gas phase, the H-bond has a greater influence on the structure, but in the polar solvent, due to the weakening of the H-bond, stabilization by resonance forces the group to be coplanar. The structures of u6 5-NO2 and u6 5-NH2 are shown in .
Open in a separate windowBased on the potential energy density at the critical point of each hydrogen bond, their energy was calculated from the Afonin equation (Equation (1)). For comparison, the hydrogen bond energy was also calculated using the rotational method [53], i.e., the difference between u6 and u5 rotamers. Both methods give similar results ( ), especially in the case of stronger hydrogen bonding in u6 5-NO2.
shows the energy scan along the dihedral angle between the amino group and the uracil ring plane. The global minimum corresponds to the conformer shown in , the minimum near scan coordinate 300 corresponds to the form rotated by 180° from the global minimum, so that NH2&#;&#;&#;HO bifurcated contact is present. Two maxima correspond to forms with close NH&#;&#;&#;HO contacts (1.956 Å). Rotational barrier height is 5.08 kcal/mol, while the difference in energy between the two minima is 4.16 kcal/mol.
Open in a separate windowThe NCI analysis, shown in , was performed to visualize all non-covalent interactions. In most cases, only weak interactions (green-shaded isosurfaces) are present. However, in systems where the asymmetry of two NH/NO bonds ( ) was high, a blue color can be noticed on the isosurfaces between the interacting atoms. This indicates a stronger attractive character of these interaction. The u1 5-NH2 system, which has the highest bond length asymmetry ( ) among the amino derivatives, has very slight blue features on the isosurface between NH and =O, which indicated stronger attractive interaction than in u2&#;u5 5-NH2 systems. The intramolecular H-bond in u6 5-NH2, discussed earlier, appears as a mostly blue isosurface between H2N and HO. The H-bond in the u6 5-NO2 system is so strong that the NCI analysis treats it as a partially covalent interaction, as the hole is pierced through the isosurface along the H&#;&#;&#;O line. In u1 and u3 6-NO2 systems, some blue accents are noticeable on the isosurface corresponding to the NO&#;&#;&#;HN contact. Bond critical points of non-covalent interactions were found only in u6 5-NH2 and u6 5-NO2.
Open in a separate windowInterestingly, in several nitropurines, NO&#;&#;&#;HN interactions have a bond critical point [30]. It is possible that this interaction is on the edge of being classified as H-bonding. The reasons are probably low values of O&#;&#;&#;HN angles (105.6° in 1H 6-nitropurine vs. 101.4° in u1 6-NO2 uracil), which are close to the limit of 110° proposed by Desiraju [54], and rather high O&#;&#;&#;H distances (2.107 Å in 1H 6-nitropurine vs. 2.200 Å in u1 6-NO2 uracil).
The last section is devoted to the effects of substitution and solvation on the stability of uracil tautomers. presents electronic energies of each system relative to the u1 tautomer. In all cases, this tautomer remains the most stable, irrespective of substitution and solvation. Considering the 5-NO2 substitution, the u6 5-NO2 derivative is a particularly interesting case. Formation of a strong NO&#;&#;&#;HO H-bond results in a large stabilization relative to the unsubstituted u6 tautomer (by 12.5 kcal/mol). Consequently, among the 5-NO2 tautomers, u6 becomes the second most stable tautomer after u1, despite the fact that u6 is the least stable tautomer for unsubstituted uracil. Rotating the 5-NO2 group by 90 degrees and breaking the hydrogen bond increases the relative energy of u6 by 10.4 kcal/mol and in 5-NO2 (90°), u6 is again the least stable tautomer.
In the case of 5-NH2 substitution, the energy difference between the u1 and u2 tautomers decreases compared to the unsubstituted systems, while between u1 and others it increases. In 6-NH2, the relative energies are smaller than for unsubstituted systems. A noteworthy increase in stability relative to u1 is observed for u2, u4, u5 and u6 tautomers (between 5 and 6 kcal/mol), while much less for u3 (1.1 kcal/mol). In the case 6-NO2 tautomers, apart from u3, the relative energies decrease slightly, but not as much as in 6-NH2. In all cases, the relative energies between the u1 tautomer and the second most stable one are above 5.4 kcal/mol; therefore, it is unlikely that substitution with NH2 or NO2 groups can significantly affect the tautomeric equilibrium. Solvation. in most cases, further increases the difference between u1 and the other forms, as evidenced by the positive values of Δ (apart of two cases) in . The only cases where Δ is negative are the two NH2 derivatives of the u3 tautomer: u3 5-NH2 (Δ = &#;2.2 kcal/mol) and u3 6-NH2 (Δ = &#;0.6 kcal/mol).
Similarly to the cSAR (X), electronic energy can be plotted against 1/ε and relations approximated with straight lines can be obtained ( ). In this case, the slopes (a) inform about the sensitivity of the energy of a given system to the solvent effect. In most cases, the u1 and u3 tautomers are the most sensitive, these two tautomers have an endo NH group in the 1 position of the uracil ring. The only exception is the 6-NO2 substitution, where the u2 and u6 tautomers are most sensitive to the solvent effect. The u4 and u5 tautomers are in all but one case (H-bond forming u6 5-NO2) the least sensitive. In amino derivatives, the sensitivity to the solvent effect seems to be correlated with the dipole moments of the molecules, i.e., a large dipole moment is associated with a large value of a. However, no such relation can be observed in the case of nitro derivatives.
Plotting the relative energy, Erel, against the cSAR(X) for all systems in all solvents ( ) reveals linearly correlated groups of points for each tautomer. The linearity comes from the fact that both Erel and cSAR change linearly with 1/ε (see and ). The ranges on the y and x axes for particular tautomers are a visual representation of the strength of the solvent effect on Erel and cSAR, respectively. It is clearly visible that, in general, the greatest changes in both parameters occur for the 5-NO2 and 6-NH2 derivatives.
Open in a separate windowWant more information on 1,3-dimethyl-6-aminouracil wholesale? Feel free to contact us.