CN106046004B - A kind of total synthesis method of 1,3,7,9- tetramethyluric acids - Google Patents
A kind of total synthesis method of 1,3,7,9- tetramethyluric acids Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/14—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with two methyl radicals in positions 1 and 3 and two methyl radicals in positions 7, 8, or 9
Abstract
The present invention relates to a kind of total synthesis method of 1,3,7,9 tetramethyluric acids, including with 6 amino, 1,3 dimethyl uracil for raw material, 61,3 dimethyl of amino of intermediate, 5 nitrosouracil is obtained by nitrozation reaction；61,3 dimethyl of amino, 5 nitrosouracil obtains 1,3 dimethyl of intermediate, 5,6 diaminourea uracil through reduction reaction；1,3 dimethyl, 5,6 diaminourea uracil carries out ring-closure reaction generation 1,3 dimethyl uric acid of intermediate；1,3 dimethyl uric acids and methylating reagent are reacted to obtain product.Tetramethyluric acid is prepared using the method for the present invention, can largely be synthesized in commercial Application, from constraint of the raw material to it；High conversion rate, yield is high, and synthesis is convenient, and post processing is simpler, is adapted to large-scale production, can widely promote and apply；It need not carry out under elevated pressure conditions, it is low for equipment requirements, while reduce the incidence of danger；Target product is prepared using placement is recrystallized, product purity is high.
Description
Technical field
The present invention relates to a kind of synthetic method of the natural products with antidepressant effect in field of pharmaceutical chemistry technology, tool
Body is related to a kind of total synthesis method of natural products 1,3,7,9- tetramethyluric acids.
Background technology
Tetramethyluric acid, the entitled 1,3,7,9-tetramethyluric acid of chemistry, also known as bitter theophylline, are from Yunnan Province of China Honghe
A kind of methyl xanthine Alkaloid extracted in the distinctive Thea section herb mixtures tea in area, the knot with theophylline, caffeine, theobromine etc.
Structure is similar, and concrete structure formula is as follows：
Recently, there is document report tetramethyluric acid (theacrine) that there are a variety of physiological activity, such as anti-inflammatory, analgesia, anti-suppression
Strongly fragrant, tranquilizing soporific etc. acts on, and has certain medicinal application value.
1. antidepression
Thank to fruit etc. and pass through outstanding tail, forced swimming, autonomic activities, yogimbine (yohimbine) toxicity, reserpine
(reserpine) and the animal model such as 5-HTP (5-HTP) inducing mouse whipping behavior evaluates the anti-experimental character of TC
Depressed effect.The result shows that TC improves significantly work for dead time for being produced under the unavoidable desperate environment of mouse
With, and good dose-effect relationship is shown between each dosage.
2. tranquilizing soporific
TC and caffeine differ only by a methyl in structure, both but completely contradict in the effect for nervous centralis.Coffee
Coffee alkali is acted on central excitation, and TC but shows as the effect of tranquilizing soporific.Wang Dongmei etc. observes TC pairs using righting reflex test
The influence of mice sleep.Experiment observes TC high and low dose groups, caffeine high and low dose group, TC and caffeine mixing group respectively
Ith, II, and herb mixtures tea group and the cooperative effect of yellow Jackets.The high and low dose group of the results show TC can substantially increase by penta bar
Than the number that appropriate sodium causes mouse sleep, illustrate that TC has sedative-hypnotic effect, and have association to the CNS inhibition of yellow Jackets
Same-action；In addition, showing sedative-hypnotic effect when TC contents are 3 times of caffeine, do not have when two kinds of component contents are suitable
Obvious hypnosis or excitation, illustrate that TC can be acted on the central excitation of antagonism caffeine.
3. anti-inflammatory and analgesic activities
TC paraxylene causes mice ear, λ carrageenans to cause vascular permeability of the swelling of rat vola and acetic acid induction etc.
Inflammatory model has preferable therapeutic effect, is resisted by suppressing such as performance such as histamine, thrombocytin, bradykinin of relevant inflammatory factor
Scorching effect；TC can substantially suppress acetic acid and cause mouse writhing reaction, and can increase pain threshold of the mouse to hot plate, illustrate TC both
There is Central Analgesic Effect to have Peripheral Analgesic Effect again.
Recent domestic research worker extremely pays close attention to and new antidepression is found from conventional medicament and natural plants
Active medicine, therefore the active ingredient based on TC from natural herb mixtures tea, and with spies such as safe and non-toxic and long edible history
Point, has very positive meaning as drug development and the recycling of herb mixtures tea to TC in theoretical and application.
Tetramethyluric acid initially mainly extract from herb mixtures tea bud-leaf and obtained, but the obtained tetramethyluric acid of extraction contain and
Caffeine similar in its property, and separate cumbersome, cost is higher.Hereafter, the tetramethyluric acid content in herb mixtures tea pericarp is found
Higher, caffeine is less, can conveniently extract, but the limited source of natural herb mixtures tea pericarp, greatly limit product
The market demand.And it is to find a method that can be artificial synthesized to solve the problems, such as this main path.
Therefore, solve source shortage problem to theacrine deeply, extensive research and application be very important.
Application publication number is that the Chinese invention patent of CN 104086550A discloses a kind of synthesis side of tetramethyluric acid
Method, this method are：First, uric acid and methylating reagent are placed in autoclave, protection gas is filled in protective gas displacement afterwards three times
Body to high pressure reacting kettle inner pressure is 0.5MPa~10MPa, is warming up to 84 DEG C~220 DEG C, insulation reaction under stirring condition；2nd,
Cooled down using condensed water to the autoclave after insulation reaction, and open the air outlet valve pressure release of autoclave, treat that high pressure is anti-
Answer kettle pressure to open kettle discharging when being down to 0MPa, the material after reaction is poured into crystallization is stirred in frozen water, obtained after suction filtration thick
Product；3rd, crude product is recrystallized, the tetramethyluric acid that quality purity is not less than 95% is obtained after dry.The invention is with uric acid
For raw material, the exhaustive methylation reaction through nitrogen on purine ring obtains product tetramethyluric acid under high pressure, hot conditions.
The invention needs to carry out under conditions of high temperature and pressure, in process of production, high to equipment requirement, has very high
It is dangerous.Therefore, need to look for another way.
The content of the invention
In view of the above-mentioned problems in the prior art, the defects of it is a primary object of the present invention to solve the prior art,
The present invention provides a kind of total synthesis method of 1,3,7,9-tetramethyluric acid, and this method raw material sources are extensive, in process of production
The features such as, high conversion rate low to temperature requirement, yield are high, production cost is low.
The present invention provides a kind of total synthesis method of 1,3,7,9-tetramethyluric acid, includes the following steps：
S1：Nitrozation reaction：Raw material 6- amino -1,3- dimethyl uracils are to carry out nitroso with nitrosylation reagent
Change reaction and obtain intermediate 6- amino -1,3- dimethyl -5- nitrosouracils；
S2：Reduction reaction：6- amino -1,3- dimethyl -5- nitrosouracils obtain intermediate 1,3- through reduction reaction
Dimethyl -5,6- diaminourea uracil；
S3：Ring-closure reaction：1,3- dimethyl -5,6- diaminourea uracil carries out ring-closure reaction generation intermediate 1,3- diformazans
Base uric acid；
S4：Methylation reaction：1,3- dimethyl uric acids and methylating reagent are reacted to obtain target compound 1,3,7,
9- tetramethyluric acids.
Optionally, the nitrosylation reagent described in step S1 is sodium nitrite, potassium nitrite, isoamyl nitrite and nitrous
One or more in acid butyl ester.
Optionally, the reducing agent that the reduction reaction described in step S2 uses is sodium hydrosulfite, iron powder, zinc powder or in hydrogen
Gas；When select hydrogen for reducing agent when, catalyst is Pd/C or Raney's nickel.
Optionally, the cyclization reagent that the ring-closure reaction described in step S3 uses is selected from N, N- carbonyl dimidazoles, phosgene, three
One or more in phosgene, triethylamine, dimethyl carbonate and diphenyl carbonate.
Optionally, the methylating reagent described in step S4 is dimethyl suflfate, dimethyl carbonate, iodomethane and bromine first
One or more in alkane.
Optionally, reaction dissolvent step S1, used in S2 and S4 is selected from ethanol, methanol, isopropanol, acetonitrile, second
Acetoacetic ester, dichloromethane, dimethyl sulfoxide, tetrahydrofuran, benzene, toluene, chloroform, dimethylbenzene, N,N-dimethylformamide, N, N- bis-
One or more in methylacetamide, water.
Optionally, the reaction dissolvent used in step S3 is selected from acetonitrile, ethyl acetate, dichloromethane, dimethyl sulfoxide, tetrahydrochysene
One or more in furans, benzene, toluene, chloroform, dimethylbenzene, N,N-dimethylformamide and DMAC N,N' dimethyl acetamide.
Optionally, step S1, the reaction temperature of S2, S3 and S4 are -30 DEG C~150 DEG C.
Optionally, the reaction temperature of step S1 is 15 DEG C~40 DEG C；The reaction temperature of step S2 is 15 DEG C~30 DEG C；Step
The reaction temperature of S3 is 20 DEG C~50 DEG C；The reaction temperature of step S4 is 120 DEG C~150 DEG C.
Optionally, the total synthesis method of 1,3,7,9-tetramethyluric acid, includes the following steps：
S1：Nitrozation reaction：Raw material 6- amino -1,3- dimethyl uracils are dissolved in reaction dissolvent, 6- amino -
The mass/volume of 1,3- dimethyl uracils and reaction dissolvent is 1:8~1:20；Nitrosylation reagent is slowly added dropwise, wherein, 6-
The mass ratio of amino -1,3- dimethyl uracils and nitrite acidizing reagent is 3:1~3:5, stirred at room temperature after being added dropwise, mistake
At night, HPLC monitoring reaction process, after completion of the reaction, cools down, filtering, vacuum drying obtains 6- amino -1,3- dimethyl -5- nitrous
Base uracil；
S2：Reduction reaction：Weigh 6- amino -1,3- dimethyl -5- nitrosouracils to be dissolved in reaction dissolvent, 6- ammonia
The mass/volume of base -1,3- dimethyl -5- nitrosouracils and reaction dissolvent is 1:3~1:8；According to 6- amino -1,3- two
The mass ratio of methyl -5- nitrosouracils and reducing agent is 5:3~5:7 add reducing agent, at room temperature fully reaction 12-20h,
HPLC is monitored, after completion of the reaction, concentration；
Distilled water dissolving is added into concentrate, adds organic solvent extraction, repeatedly extraction merging organic phase；
Saturated common salt water washing is added into above-mentioned organic phase, dry, filtering, vacuum distillation removes organic phase, obtains 1,
3- dimethyl -5,6- diaminourea uracils.
S3：Ring-closure reaction：Weigh 1,3- dimethyl -5,6- diaminourea uracils to be dissolved in reaction dissolvent, 1,3- diformazan
The mass/volume of base -5,6- diaminourea uracil and reaction dissolvent is 2:3~2:9；According to cyclization reagent and 1,3- dimethyl-
The mass ratio of 5,6- diaminourea uracils is 2:1~1:2 add cyclization reagent, react 10- under conditions of being 60 DEG C in temperature
20h；Room temperature is cooled the temperature to after completion of the reaction, after addition water fully dissolves, is added organic solvent extraction, is repeatedly extracted
Merge organic phase later；
Above-mentioned organic phase is washed successively, 10% dilute hydrochloric acid pickling, saturated sodium bicarbonate washing, saturated salt solution salt
Organic phase is recycled after washing, 1,3- dimethyl uric acid crude products are obtained after vacuum distillation；
1,3- dimethyl uric acid crude products are recrystallized, it is 1,3- dimethyl uric acids to obtain white solid.
S4：Methylation reaction：Weigh 1,3- dimethyl uric acids, and be dissolved in reaction dissolvent, 1,3- dimethyl uric acid with
The mass/volume of reaction dissolvent is 2:3~2:9；It is 2 according to the mass ratio of 1,3- dimethyl uric acids:3~2:7 add methyl
Change reagent, react 10-20h under the conditions of being 140 DEG C in temperature, cool the temperature to room temperature after completion of the reaction；
Water is added into above-mentioned reactant to be sufficiently stirred, and is added ethyl acetate extraction, is repeatedly associated with after extraction
Machine phase；
Above-mentioned organic phase is washed successively, 10% dilute hydrochloric acid pickling, saturated sodium bicarbonate washing, saturated salt solution salt
Organic phase is recycled after washing, 1,3,7,9-tetramethyluric acid crude product is obtained after vacuum distillation；
1,3,7,9-tetramethyluric acid crude product is recrystallized, it is 1,3,7,9-tetramethyluric acid to obtain white solid.
The present invention has the following advantages and beneficial effect：
1. the present invention, for raw material, tetramethyl is prepared using the method for chemical synthesis with 6- amino -1,3- dimethyl uracil
Base uric acid, can largely synthesize in commercial Application, from constraint of the raw material to it.
2. synthetic method high conversion rate provided by the invention, yield is high, and synthesis is convenient, and post processing is simpler, is adapted to big rule
Mould produces, and can widely promote and apply.
3. the present invention need not carry out under elevated pressure conditions, low for equipment requirements, while reduce the incidence of danger.
4. preparing target product using placement is recrystallized, product purity is high.
Embodiment
The technical solution in the embodiment of the present invention is clearly and completely described below, it is clear that described embodiment
It is part of the embodiment of the present invention, instead of all the embodiments.The detailed description of the embodiment of the present invention presented below is simultaneously
The scope of claimed invention is not intended to be limiting, but is merely representative of the selected embodiment of the present invention.Based in the present invention
Embodiment, those of ordinary skill in the art's all other embodiments obtained without creative efforts,
Belong to the scope of protection of the invention.
The fully synthetic route of the 1,3,7,9- tetramethyluric acids is：
Embodiment 1
A kind of total synthesis method of 1,3,7,9-tetramethyluric acid, includes the following steps：
S1：Nitrozation reaction：With 6- amino -1,3- dimethyl uracil for raw material, as chemical compounds I, chemical combination is weighed
Thing I is dissolved in ethanol, and the mass/volume of chemical compounds I and ethanol is 1:8~1:20；
Nitrosylation reagent is slowly added dropwise, wherein, the mass ratio of chemical compounds I and nitrite acidizing reagent is 3:1~3:5, drop
Add and stirred at room temperature after finishing, overnight, HPLC monitoring reaction process, after completion of the reaction, cools down, filtering, vacuum dryingization
Compound II；
S2：Reduction reaction：Weigh Compound II is dissolved in methanol, and the mass/volume of compound ii and methanol is 1:3~
1:8；It is 5 according to the mass ratio of compound ii and sodium hydrosulfite:3~5:7 take a policy powder, at room temperature fully reaction 12-20h,
HPLC is monitored, after completion of the reaction, concentration；
Distilled water dissolving is added into concentrate, adds DCM extractions, repeatedly extraction merging organic phase；
Saturated common salt water washing is added into above-mentioned organic phase, then is dried with anhydrous sodium sulfate, is filtered, vacuum distillation removes
Organic phase, obtains compound III.
S3：Ring-closure reaction：Weigh Compound III is dissolved in n,N-Dimethylformamide, compound III and N, N- dimethyl
The mass/volume of formamide is 2:3~2:9；According to the quality summation and compound III of triphosgene, triethylamine and carbonyl dimidazoles
Mass ratio be 2:1~1:2 add triphosgene, triethylamine and carbonyl dimidazoles, wherein, two miaow of triphosgene, triethylamine and carbonyl
The mass ratio of azoles is 1:1~1:3, react 10-20h under conditions of being 60 DEG C in temperature；Room temperature is cooled the temperature to after completion of the reaction,
After addition water fully dissolves, ethyl acetate extraction is added, repeatedly merging organic phase after extraction；
Above-mentioned organic phase is washed successively, 10% dilute hydrochloric acid pickling, saturated sodium bicarbonate washing, saturated salt solution salt
Organic phase is recycled after washing, compounds Ⅳ crude product is obtained after vacuum distillation；
IV crude product of recrystallization compound, it is compounds Ⅳ to obtain white solid.
S4：Methylation reaction：Weigh Compound IV is dissolved in NMP, and the mass/volume of compounds Ⅳ and NMP are 2:3~
2:9；Mass ratio according to the quality summation and compounds Ⅳ of dimethyl ester and DBU is 2:3~2:7 add dimethyl carbonate and DBU,
Wherein, the mass ratio of dimethyl carbonate and DBU are 20:1~45:1 reacts 10-20h under the conditions of temperature is 140 DEG C, has reacted
Room temperature is cooled the temperature to after finishing；
Water is added into above-mentioned reactant to be sufficiently stirred, and is added ethyl acetate extraction, is repeatedly associated with after extraction
Machine phase；
Above-mentioned organic phase is washed successively, 10% dilute hydrochloric acid pickling, saturated sodium bicarbonate washing, saturated salt solution salt
Organic phase is recycled after washing, V crude product of compound is obtained after vacuum distillation；
V crude product of recrystallization compound, it is compound V to obtain white solid.
Embodiment 2
A kind of total synthesis method of 1,3,7,9-tetramethyluric acid, includes the following steps：
S1：Prepare compound II
1. weighing 10kg 6- amino -1,3- dimethyl uracils to be dissolved in 120L ethanol, solution A is obtained；
2. weighing 7.82kg isoamyl nitrites, isoamyl nitrite is slowly added drop-wise in solution A, rear chamber is added dropwise
Temperature stirring, overnight；
3. HPLC is monitored, after completion of the reaction, cool down, filtering, is dried in vacuo to obtain red solid 10.5kg, is compound
II, gained yield is 90.0%.
The hydrogen nuclear magnetic resonance modal data of compound ii：1H-NMR(CDCl3,400MHz)：2.72(s,6H),2.12(br,
2H)。
S2：Prepare compound III
1. weighing 10kg compound iis to be dissolved in 50L methanol, 14.1kg sodium hydrosulfites are added, at room temperature fully reaction 12-
20h, HPLC are monitored, after completion of the reaction, concentration；
2. after adding the dissolving of 20L distilled water into above-mentioned reactant, adding 20L DCM extractions, recycling organic phase, repeat to extract
After taking three times, merge organic phase；
3. adding 10L saturated common salt water washings into above-mentioned organic phase, then organic phase is dried with anhydrous sodium sulfate, filtered,
Recycle organic phase；
4. vacuum distillation removes organic phase, crude product 8.0kg, i.e. compound III are obtained, gained yield is 86.9%.
The hydrogen nuclear magnetic resonance modal data of compound III：1H-NMR(DMSO-d6,400MHz):2.68(s,6H),2.16(Br,
4H)。
S3：Prepare compound IV
1. 8.0kg compound IIIs are dissolved in the n,N-Dimethylformamide of 20L, 5.7kg triphosgenes, triethylamine are added
With 9.14kg carbonyl dimidazoles, 10-20h is reacted under conditions of being then 60 DEG C in temperature；
2. cooling the temperature to room temperature after completion of the reaction, after addition 30L water fully dissolves, the extraction of 20L ethyl acetate is added,
Organic phase is recycled, after repeating extraction three times, merges organic phase；
3. being firstly added 10L distillation water washings into above-mentioned organic phase, secondly add 10% dilute hydrochloric acid of 10L and wash, add again
Enter the washing of 10L saturated sodium bicarbonates, organic phase is recycled after being eventually adding 10L saturated common salt water washings；
4. by after the organic phase vacuum distillation in 3. compounds Ⅳ crude product；
5. IV crude product of recrystallization compound, obtains white solid 8.2kg, as compounds Ⅳ, yield 89.1%.
The hydrogen nuclear magnetic resonance modal data of compounds Ⅳ：1H-NMR(DMSO-d6,400MHz):2.68(s,6H),6.06(s,
1H),6.12(s,1H)。
S4：Prepare compound V
1. 8.2kg compounds Ⅳs are dissolved in the NMP of 20L, 18.8kg dimethyl carbonates and 0.64kg DBU are added,
Temperature reacts 10-20h under the conditions of being 140 DEG C, cools the temperature to room temperature after completion of the reaction；
2. adding 30L water into above-mentioned reactant to be sufficiently stirred, the extraction of 20L ethyl acetate is added, recycles organic phase, is repeated
Extraction three times, merges organic phase；
3. adding 10L distillation water washings into above-mentioned organic phase, secondly add 10% dilute hydrochloric acid of 10L and wash, add again
10L saturated sodium bicarbonates wash, and organic phase is recycled after being eventually adding 10L saturated common salt water washings；
4. by after the organic phase vacuum distillation in 3. V crude product of compound；
5. V crude product of recrystallization compound, obtains white solid 8.2kg, as compound V, yield 87.6%.
The hydrogen nuclear magnetic resonance modal data of target compound 1,3,7,9- tetramethyluric acids：1H-NMR(DMSO-d6,
400MHz):3.64(s,3H),3.54(s,3H),3.40(s,3H),3.12(s,3H)。
The mass spectrometric data of target compound 1,3,7,9- tetramethyluric acids：LC/MS:m/z 225.2[M+H].
Embodiment 3
S1：Prepare compound II
1. weighing 10kg 6- amino -1,3- dimethyl uracils to be dissolved in 100L ethyl acetate, solution A is obtained；
2. weighing 9.53kg butyl nitrites, butyl nitrite is slowly added drop-wise in solution A, rear room temperature is added dropwise and stirs
Mix, overnight；
3. HPLC is monitored, after completion of the reaction, cool down, filtering, is dried in vacuo to obtain red solid 10.2kg, is compound
Ⅱ。
S2：Prepare compound III
1. weighing 10kg compound iis to be dissolved in 80L dimethyl sulfoxides, 16kg sodium hydrosulfites are added, at room temperature fully reaction
12-20h, HPLC are monitored, after completion of the reaction, concentration；
2. after adding the dissolving of 20L distilled water into above-mentioned reactant, adding 20L DCM extractions, recycling organic phase, repeat to extract
After taking three times, merge organic phase；
3. adding 10L saturated common salt water washings into above-mentioned organic phase, then organic phase is dried with anhydrous sodium sulfate, filtered,
Recycle organic phase；
4. vacuum distillation removes organic phase, crude product 8.6kg is obtained, is compound III.
S3：Prepare compound IV
1. 8.0kg compound IIIs are dissolved in the benzene of 15L, 15.3kg dimethyl carbonates are added, are then 70 in temperature
10-20h is reacted under conditions of DEG C；
2. cooling the temperature to room temperature after completion of the reaction, after addition 30L water fully dissolves, the extraction of 20L ethyl acetate is added,
Organic phase is recycled, after repeating extraction three times, merges organic phase；
3. being firstly added 10L distillation water washings into above-mentioned organic phase, secondly add 10% dilute hydrochloric acid of 10L and wash, add again
Enter the washing of 10L saturated sodium bicarbonates, organic phase is recycled after being eventually adding 10L saturated common salt water washings；
4. by after the organic phase vacuum distillation in 3. compounds Ⅳ crude product；
It is compounds Ⅳ 5. IV crude product of recrystallization compound, obtains white solid 8.5kg.
S4：Prepare compound V
1. 8kg compounds Ⅳs are dissolved in the acetonitrile of 18L, 26kg iodomethane is added, it is anti-under the conditions of being 130 DEG C in temperature
10-20h is answered, cools the temperature to room temperature after completion of the reaction；
2. adding 30L water into above-mentioned reactant to be sufficiently stirred, the extraction of 20L ethyl acetate is added, recycles organic phase, is repeated
Extraction three times, merges organic phase；
3. adding 10L distillation water washings into above-mentioned organic phase, secondly add 10% dilute hydrochloric acid of 10L and wash, add again
10L saturated sodium bicarbonates wash, and organic phase is recycled after being eventually adding 10L saturated common salt water washings；
4. by after the organic phase vacuum distillation in 3. V crude product of compound；
It is compound V 5. V crude product of recrystallization compound, obtains white solid 8.4kg.
Embodiment 4
4 difference from Example 3 of embodiment is as follows：
S1：1. the middle reaction dissolvent used is 80L isopropanol；2. the middle nitrosification agent used is 8.98kg nitrous acid
Sodium；3. middle gained compound ii is 10.8kg.
S2：1. the middle reaction dissolvent used is 55L dimethyl sulfoxide, the reducing agent used is 10kg hydrogen, catalyst Pd/
C, reaction temperature are 130 DEG C；4. middle gained crude product is 8.5kg.
S3：1. the middle reaction dissolvent used is 15L acetonitrile, the cyclization reagent used is 13.5kg dimethyl carbonate, reaction
Temperature is 35 DEG C；5. middle gained compounds Ⅳ is 8.5kg.
S4：1. the middle reaction dissolvent used is 20L tetrahydrofuran, the methylating reagent used is 30kg dimethyl suflfate；
Reaction temperature is 100 DEG C, and 5. middle gained compound V is 8.7kg.
Embodiment 5
5 difference from Example 3 of embodiment is as follows：
S1：1. the middle reaction dissolvent used is 90L toluene；2. the middle nitrosification agent used is 9.02kg potassium nitrite；
3. middle gained compound ii is 10.9kg.
S2：1. the middle reaction dissolvent used is 60L ethyl acetate, the reducing agent used is for 12kg iron powders, reaction temperature
30℃；4. middle gained crude product is 8.3g.
S3：1. the middle reaction dissolvent used for 18L dichloromethane, the cyclization reagent used for 16.7kg diphenyl carbonates,
Reaction temperature is 85 DEG C；5. middle gained compounds Ⅳ is 8.7kg.
S4：1. the middle reaction dissolvent used is 30L dimethyl sulfoxide, the methylating reagent used is 25kg bromomethane；Reaction
Temperature is 70 DEG C, and 5. middle gained compound V is 8.9kg.
Embodiment 6
6 difference from Example 3 of embodiment is as follows：
S1：1. the middle reaction dissolvent used is 120L dichloromethane；Reaction temperature is 15 DEG C；2. the nitrosation examination of middle use
Agent is 10.3kg isoamyl nitrites；3. middle gained compound ii is 11.0kg.
S2：1. the middle reaction dissolvent used is 60L ethyl acetate, the reducing agent used is for 13kg zinc powders, reaction temperature
50℃；4. middle gained crude product is 8.8g.
S3：1. the middle reaction dissolvent used is 23L dimethylbenzene, the cyclization reagent used is 18.2kg triphosgene, reaction temperature
Spend for 95 DEG C；5. middle gained compounds Ⅳ is 8.9kg.
S4：1. the middle reaction dissolvent used is 26L n,N-Dimethylformamide, the methylating reagent used is 30kg sulphur
Dimethyl phthalate；Reaction temperature is 40 DEG C, and 5. middle gained compound V is 8.8kg.
Embodiment 7
7 difference from Example 3 of embodiment is as follows：
S1：1. the middle reaction dissolvent used is 110L N,N-dimethylformamide；Reaction temperature is 80 DEG C；2. middle use
Nitrosification agent be 13.2kg butyl nitrites；3. middle gained compound ii is 10.7kg.
S2：1. the middle reaction dissolvent used is 55L chloroform, for the reducing agent used for 15kg zinc powders, reaction temperature is 30 DEG C；
4. middle gained crude product is 8.9g.
S3：1. the middle reaction dissolvent used for 20L tetrahydrofurans, the cyclization reagent used for 9.1kg dimethyl carbonates and
6.5kg diphenyl carbonates, reaction temperature are 50 DEG C；5. middle gained compounds Ⅳ is 8.5kg.
S4：1. the middle reaction dissolvent used is 26L ethyl acetate, the methylating reagent used is 25kg dimethyl suflfate；
Reaction temperature is 130 DEG C, and 5. middle gained compound V is 8.4kg.
Embodiment 8
8 difference from Example 3 of embodiment is as follows：
S1：1. the middle reaction dissolvent used is 100L dimethylbenzene；Reaction temperature is 100 DEG C；2. the nitrosation examination of middle use
Agent is 13.2kg butyl nitrites；3. middle gained compound ii is 10.6kg.
S2：1. the middle reaction dissolvent used is 50L ethyl acetate, the reducing agent used is for 15kg iron powders, reaction temperature
60℃；4. middle gained crude product is more than 8.6g.
S3：1. the middle reaction dissolvent used is 20L chloroform, the cyclization reagent used is 13.2kg dimethyl carbonate, reaction
Temperature is 50 DEG C；5. middle gained compounds Ⅳ is 8.3kg.
S4：1. the middle reaction dissolvent used is 20L chloroform, the methylating reagent used is 20kg dimethyl carbonate；Reaction
Temperature is 50 DEG C, and 5. middle gained compound V is 8.5kg.
The foregoing is only a preferred embodiment of the present invention, but protection scope of the present invention be not limited thereto,
Any one skilled in the art the invention discloses technical scope in, the change or replacement that can readily occur in,
It should be covered by the protection scope of the present invention.Therefore, protection scope of the present invention should be with the protection model of claims
Subject to enclosing.
Claims (3)
1. a kind of total synthesis method of 1,3,7,9-tetramethyluric acid, it is characterised in that include the following steps：
S1：Nitrozation reaction：Raw material 6- amino -1,3- dimethyl uracils are dissolved in reaction dissolvent, 6- amino -1,3-
The mass/volume of dimethyl uracil and reaction dissolvent is 1:8~1:20；Nitrosylation reagent is slowly added dropwise, wherein, 6- ammonia
The mass ratio of base -1,3- dimethyl uracils and nitrosylation reagent is 3:1~3:5, stirred at room temperature after being added dropwise, mistake
At night, HPLC monitoring reaction process, after completion of the reaction, cools down, filtering, vacuum drying obtains 6- amino -1,3- dimethyl -5- nitrous
Base uracil；
S2：Reduction reaction：6- amino -1,3- dimethyl -5- nitrosouracils are weighed to be dissolved in reaction dissolvent, 6- amino -
The mass/volume ratio of 1,3- dimethyl -5- nitrosouracils and reaction dissolvent is 1:3~1:8；According to 6- amino -1,3- two
The mass ratio of methyl -5- nitrosouracils and reducing agent is 5:3~5:7 add reducing agent, at room temperature fully reaction 12-20h,
HPLC is monitored, after completion of the reaction, concentration；
Distilled water dissolving is added into concentrate, adds organic solvent extraction, repeatedly extraction merging organic phase；
Saturated common salt water washing is added into above-mentioned organic phase, dry, filtering, vacuum distillation removes organic phase, obtains 1,3- bis-
Methyl -5,6- diaminourea uracil.
S3：Ring-closure reaction：Weigh 1,3- dimethyl -5,6- diaminourea uracils to be dissolved in reaction dissolvent, 1,3- dimethyl -5,
The mass/volume of 6- diaminourea uracil and reaction dissolvent is 2:3~2:9；According to cyclization reagent and 1,3- dimethyl -5,6- bis-
The mass ratio of amino-uracil is 2:1~1:2 add cyclization reagent, react 10-20h under conditions of being 60 DEG C in temperature；Reaction
After cool the temperature to room temperature, add after water fully dissolves, add organic solvent extraction, repeatedly merge after extraction
Organic phase；
Above-mentioned organic phase is washed successively, 10% dilute hydrochloric acid pickling, saturated sodium bicarbonate washing, after saturated salt solution salt is washed
Organic phase is recycled, 1,3- dimethyl uric acid crude products are obtained after vacuum distillation；
1,3- dimethyl uric acid crude products are recrystallized, it is 1,3- dimethyl uric acids to obtain white solid.
S4：Methylation reaction：1,3- dimethyl uric acids are weighed, and are dissolved in reaction dissolvent, 1,3- dimethyl uric acid and reaction
The mass/volume of solvent is 2:3~2:9；It is 2 according to the mass ratio of 1,3- dimethyl uric acids:3~2:7 add the examination that methylates
Agent, reacts 10-20h under the conditions of being 140 DEG C in temperature, cools the temperature to room temperature after completion of the reaction；
Water is added into above-mentioned reactant to be sufficiently stirred, and adds ethyl acetate extraction, organic phase is repeatedly merged after extraction；
Above-mentioned organic phase is washed successively, 10% dilute hydrochloric acid pickling, saturated sodium bicarbonate washing, after saturated salt solution salt is washed
Organic phase is recycled, 1,3,7,9-tetramethyluric acid crude product is obtained after vacuum distillation；
1,3,7,9-tetramethyluric acid crude product is recrystallized, it is 1,3,7,9-tetramethyluric acid to obtain white solid；
Wherein, the reaction temperature of step S1 is 15 DEG C~40 DEG C；The reaction temperature of step S2 is 15 DEG C~30 DEG C；
Nitrosylation reagent described in step S1 is in sodium nitrite, potassium nitrite, isoamyl nitrite and butyl nitrite
It is one or more of；
The reducing agent that reduction reaction described in step S2 uses is sodium hydrosulfite, iron powder, zinc powder or hydrogen；When selection hydrogen for
During reducing agent, catalyst is Pd/C or Raney's nickel；
The cyclization reagent that ring-closure reaction described in step S3 uses is selected from N, N- carbonyl dimidazoles, phosgene, triphosgene, three second
One or more in amine, dimethyl carbonate and diphenyl carbonate；
Methylating reagent described in step S4 is one kind in dimethyl suflfate, dimethyl carbonate, iodomethane and bromomethane
It is or a variety of.
2. the total synthesis method of the 1,3,7,9-tetramethyluric acid according to any one of claim 1, it is characterised in that step
The reaction dissolvent used in rapid S1, S2 and S4 is selected from ethanol, methanol, isopropanol, acetonitrile, ethyl acetate, dichloromethane, two
In first sulfoxide, tetrahydrofuran, benzene, toluene, chloroform, dimethylbenzene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, water
It is one or more of.
3. the total synthesis method of 1,3,7,9-tetramethyluric acid according to claim 1, it is characterised in that adopted in step S3
Reaction dissolvent be selected from acetonitrile, ethyl acetate, dichloromethane, dimethyl sulfoxide, tetrahydrofuran, benzene, toluene, chloroform, dimethylbenzene,
One or more in N,N-dimethylformamide and DMAC N,N' dimethyl acetamide.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103755705A (en) * | 2014-02-17 | 2014-04-30 | 上海佰特因医药科技有限公司 | Total synthesis method for natural product tetramethyl uric acid |
| CN104086550A (en) * | 2014-07-18 | 2014-10-08 | 西安科技大学 | Synthetic method for tetramethyluric acid |
| CN104744469A (en) * | 2014-10-31 | 2015-07-01 | 合肥平光制药有限公司 | Preparation method for theophylline |
| CN104744467A (en) * | 2014-10-31 | 2015-07-01 | 合肥平光制药有限公司 | High-yield synthesis method for theophylline |
-
2016
- 2016-06-06 CN CN201610394488.XA patent/CN106046004B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103755705A (en) * | 2014-02-17 | 2014-04-30 | 上海佰特因医药科技有限公司 | Total synthesis method for natural product tetramethyl uric acid |
| CN104086550A (en) * | 2014-07-18 | 2014-10-08 | 西安科技大学 | Synthetic method for tetramethyluric acid |
| CN104744469A (en) * | 2014-10-31 | 2015-07-01 | 合肥平光制药有限公司 | Preparation method for theophylline |
| CN104744467A (en) * | 2014-10-31 | 2015-07-01 | 合肥平光制药有限公司 | High-yield synthesis method for theophylline |
Non-Patent Citations (1)
| Title |
|---|
| Long-Chain-Substituted Uric Acid and 5,6-Diaminouracil Derivatives as Novel Agents against Free Radical Processes: Synthesis and in Vitro Activity;Laurent Fraisse et al.;《J. Med. Chem.》;19931231;第36卷;1465-1473 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111620872A (en) * | 2020-05-19 | 2020-09-04 | 南京纽邦生物科技有限公司 | Synthetic method of tetramethyluric acid and special catalyst thereof |
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