CN106349170A - Preparation method of 1,3-dimethyl-5-phenyluracil - Google Patents
Preparation method of 1,3-dimethyl-5-phenyluracil Download PDFInfo
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- CN106349170A CN106349170A CN201610626068.XA CN201610626068A CN106349170A CN 106349170 A CN106349170 A CN 106349170A CN 201610626068 A CN201610626068 A CN 201610626068A CN 106349170 A CN106349170 A CN 106349170A
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- dimethyl
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- phenyl uracils
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- aqueous solution
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
Abstract
The invention relates to a preparation method of 1,3-dimethyl-5-phenyluracil. The preparation method includes mixing phenylamine, water and a fluoboric acid water solution, dropwise adding a water solution of sodium nitrite with stirring for 1-2 hours at 0-5 DEG C and performing suction filtration so as to obtain phenyldiazonium tetrafluoroborate; at the room temperature, adding 1,3-dimethyluracil and a copper salt catalyst into a solvent with stirring and mixing, adding the phenyldiazonium tetrafluoroborate in batches, stirring to react for 8-12 hours after addition is finished, and conducting separation and purification so as to obtain the 1,3-dimethyl-5-phenyluracil. The preparation method has the advantages of simplicity in operation, short reaction route, less reaction time, high product yield and suitability for industrialized production.
Description
Technical field
The invention belongs to the preparation field of uracil compounds, phonetic particularly to a kind of 1,3- dimethyl -5- phenyl urine
The preparation method of pyridine.
Background technology
The uracil compounds that 5- phenyl replaces and its nucleoside derivate have multiple life such as antiviral and antitumor
Thing activity, the uracil that 5- aryl replaces simultaneously is frequently used for nucleotide, oligonucleotide marker and dna answering in bioanalysiss
With.(fukuda,m.；nakamura,m.；takada,t.；yamana,k..tetrahedron letters,2010,51
(13):1732-1735.；jacobsen,m.f.；ferapontova,e.e.；gothelf,k.v..organic&
biomolecular chemistry,2009,7(5):905-908.；pesnot,t.；wagner,g.k..organic&
biomolecular chemistry,2008,6(16):2884-2891.；cahova,h.；havran,l.；brazdilova,
p.；pivonkova,h.；pohl,r.；fojta,m.；hocek,m..angewandte chemie,international
edition,2008,47(11):2059-2062.).In addition, such compound is also important medicinal intermediates.Document
The preparation method of 1, the 3- dimethyl -5- phenyl uracils compound of report mainly has four kinds, method one: with 1,3- dimethyl urine
Pyrimidine and bromination benzene are heated to 130 DEG C of simultaneously nitrogen protection reaction 12 hours for raw material in the presence of palladium is for catalyst and alkali
Obtain 1,3- dimethyl -5- phenyl uracils, yield is 79%.(kim,k.h.；lee,h.s.；kim,j.n.tetrahedron
Letters, 2011,52 (47): 6228-6233.) method two: first with the iodine compound of 5 substituted 1,3- dimethyl uracils
React the iodate zinc compound obtaining 1, the 3- dimethyl uracil that 5- replaces for 3 hours with metallic zinc under oxolane for 70 DEG C,
The iodate zinc compound of the 1,3- dimethyl uracil that 5- is replaced by second step and iodobenzene are raw material tetrahydrochysene furan under palladium catalyst
The middle room temperature reaction 1h that mutters obtains 1,3- dimethyl -5- phenyl uracils, and yield is 83%.(prasad,a.s.b.；
stevenson,t.m.；citineni,j.r.；nyzam,v.；knochel,p..tetrahedron,1997,53(21):
7237-7254.)；The bromo- 1,3- dimethyl uracil of method three: 5- and benzene occur radical reaction to obtain 1,3- under light illumination
Dimethyl -5- phenyl uracils, yield is only 11%.(seki,k.；matsuda,k.；bando,y.；ohkura,
k..chemical&pharmaceutical bulletin,1988,36(12):4737-4748.)；The bromo- 1,3- of method four: 5-
Dimethyl uracil and phenyl trifluoromethanesulfonate potassium borate are heated to 90 with toluene and water (6:1) for solvent under palladium catalyst and alkali effect
The protection reaction of DEG C nitrogen obtains 1,3- dimethyl -5- phenyl uracils, and yield is 88%.(molander,g.a.；
fumagalli,t.journal of organic chemistry,2006,71(15):5743-5747.)
The reaction equation of synthetic method one:
The reaction equation of synthetic method two:
The reaction equation of synthetic method three:
The reaction equation of synthetic method four:
In above-mentioned four kinds of synthetic methods, the catalyst required for method one, two and four costly, increased industry one-tenth
This, be unfavorable for industrialized production.Free radical photoreaction yield used in method three is very low, and about 10% about, be not suitable for industry
Produce.Therefore, 1,3 new dimethyl -5- phenyl uracils synthesis techniques of exploitation have great importance.
Content of the invention
The technical problem to be solved is to provide a kind of preparation method of 1,3- dimethyl -5- phenyl uracils,
The method, with mantoquita as catalyst, 1,3- dimethyl uracil is obtained 1,3- diformazan with phenyldiazonium Tetrafluoroboric acid reactant salt
Base -5- phenyl uracils, easy and simple to handle, improve yield simultaneously.Preparation method initiation material is easy to get simultaneously, low cost, reaction
Simple to operate, reaction scheme short it is easy to industrialized production, have a good application prospect.
One kind 1 of the present invention, the preparation method of 3- dimethyl -5- phenyl uracils, comprising:
(1) aniline, water and fluoborate aqueous solution are mixed, the aqueous solution of Deca sodium nitrite under 0～5 DEG C of stirring, dimension
Hold temperature at 0～5 DEG C, stir 1～2h, sucking filtration, obtain phenyldiazonium tetrafluoroborate；
(2), under room temperature, 1,3- dimethyl uracil, copper salt catalyst are added stirring mixing in solvent, then adds in batches
Enter the phenyldiazonium tetrafluoroborate in step (1), add after finishing, reaction 8-12h, separating-purifying are stirred at room temperature, obtain
1,3- dimethyl -5- phenyl uracils.
In described step (1), aniline, fluoborate aqueous solution, the proportionate relationship of sodium nitrite are 1mol:220～330g (fluorine
The quality of boric acid aqueous solution): 1～1.5mol.
The specification of described fluoborate aqueous solution is 40% fluoborate aqueous solution.
The mol ratio of 1,3- dimethyl uracil, phenyldiazonium tetrafluoroborate and copper salt catalyst in described step (2)
For 1.0:1.0～2.0:0.05～0.2.
Described copper salt catalyst is cucl, cubr or cui.
In described step (2), the ratio of 1,3- dimethyl uracil and solvent is 1.0g:1～20ml.
Described solvent is dmso.
The time used by phenyldiazonium tetrafluoroborate that is dividedly in some parts in described step (2) is 0.5～1h.
In described step (2), the step of separating-purifying is: plus ethyl acetate and water extracted, and merges organic layer, organic
Layer anhydrous sodium sulfate drying, solvent evaporated, it is recrystallized to give product.
The ratio of the consumption of described 1,3- dimethyl uracil and ethyl acetate and anhydrous sodium sulfate is 1g:1～10ml:
0.1～1g；Described recrystallization solvent is 95% (v/v) ethanol.
The present invention, with aniline and 40% fluoborate aqueous solution as raw material, is reacted with sodium nitrite and phenyldiazonium tetrafluoro boron is obtained
Hydrochlorate, then with mantoquitas such as Cu-lyt .s as catalyst, is obtained 1,3- dimethyl -5- phenyl with the reaction of 1,3- dimethyl uracil
Uracil, yield is up to 80%.The synthetic route of 1,3- dimethyl -5- phenyl uracils compound of the present invention:
The structural formula of 1,3- dimethyl -5- phenyl uracils is:
Melting point compound: 146-148 DEG C；
Character: white solid；
The hydrogen nuclear magnetic resonance modal data of 1,3- dimethyl -5- phenyl uracils is as follows:
1h nmr (400mhz, cdcl3) δ 3.46 (s, 3h), 3.50 (s, 3h), 7.32 (s, 1h), 7.37 (d, j=
7.2hz, 1h), 7.42 (t, j=7.3hz, 2h), 7.52 (d, j=7.0hz, 2h).
The carbon-13 nmr spectra data of 1,3- dimethyl -5- phenyl uracils is as follows:
13c nmr(101mhz,cdcl3)δ28.28,37.12,114.44,127.88,128.30,128.46,132.89,
140.41,151.50,162.35.
Beneficial effect
The preparation method of the present invention is simple to operate, and reaction scheme is short, saves the response time, and yield is high, and low cost is suitable to
Industrialized production.
Brief description
Fig. 1 is the proton nmr spectra of compound 1,3- dimethyl -5- phenyl uracils in embodiment 3；
Fig. 2 is the carbon-13 nmr spectra of compound 1,3- dimethyl -5- phenyl uracils in embodiment 3.
Specific embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than restriction the scope of the present invention.In addition, it is to be understood that after having read the content of present invention instruction, people in the art
Member can make various changes or modifications to the present invention, and these equivalent form of values equally fall within the application appended claims and limited
Scope.
Embodiment 1
By aniline 46.5g (0.5mol), water 250m l, 40% fluoborate aqueous solution 220g (1mol), stir in 0～5 DEG C
Lower Deca sodium nitrite 36.5g (0.55mol) and the solution of 100m l water, drip and maintain 0～5 DEG C of continuation stirring reaction 2h after finishing,
Reaction is finished, and sucking filtration obtains white phenyldiazonium tetrafluoroborate 83.1g, yield 86.6%, is directly used in the next step.
Embodiment 2
By aniline 46.5g (0.5mol), water 200m l, 40% fluoborate aqueous solution 300g (1.4mol), stir in 0～5 DEG C
Mix the solution of lower Deca sodium nitrite 53.1g (0.8mol) and 100m l water, drip and after finishing, maintain 0～5 DEG C of continuous stirring reaction 2h, instead
Should finish, sucking filtration, obtain white phenyldiazonium tetrafluoroborate 81.3g, yield 84.7%, be directly used in the next step.
Embodiment 3
1,3- dimethyl uracil 14.1g (0.1mol) and Cu-lyt. 0.5g (0.005mol) is taken to add dmso
100ml, is stirred at room temperature down phenyldiazonium tetrafluoroborate 24.8g (0.13mol) being dividedly in some parts in above-described embodiment 1,1h adds
Complete, addition finishes, and 8h is stirred at room temperature.Reaction finishes, and add water 150ml, plus ethyl acetate 150ml × 2 extraction, and ethyl acetate layer is used
Anhydrous sodium sulfate drying, boils off solvent, and 95% (v/v) ethyl alcohol recrystallization obtains white crystal 15.3g, yield 70.8%, mp:146-
148℃.The proton nmr spectra of 1,3- dimethyl -5- phenyl uracils and carbon are composed as depicted in figs. 1 and 2.
Embodiment 4
1,3- dimethyl uracil 7.1g (0.05mol) and cuprous bromide 1.4g (0.01mol) is taken to add dmso 60ml,
Phenyldiazonium tetrafluoroborate 19.1g (0.1mol) that be dividedly in some parts in above-described embodiment 2 is stirred at room temperature down, 0.5h adds, plus
Enter to finish, 6h is stirred at room temperature.Reaction finishes, and add water 120ml, and with ethyl acetate 100ml × 2 extraction, ethyl acetate layer is with anhydrous
Sodium sulfate is dried, and boils off solvent, ethyl alcohol recrystallization obtains white crystal 4.7g, about 43.5%, mp:145-147 DEG C of yield.
Embodiment 5
1,3- dimethyl uracil 28.2g (0.2mol) and Hydro-Giene (Water Science). 5.7g (0.03mol) is taken to add dmso 200ml,
Phenyldiazonium tetrafluoroborate 49.6g (0.26mol) that be dividedly in some parts in above-described embodiment 1 is stirred at room temperature down, 1h adds, adds
Finish, 8h is stirred at room temperature.Reaction finishes, and add water 200ml, with ethyl acetate 200ml × 2 extraction, the anhydrous sulfur of ethyl acetate layer
Sour sodium is dried, and boils off solvent, 95% (v/v) ethyl alcohol recrystallization obtains white crystal 31.7g, yield about 73.4%, mp:145-148
℃.
Embodiment 6
1,3- dimethyl uracil 14.1g (0.1mol) and Cu-lyt. 2.0g (0.02mol) is taken to add dmso 100ml,
Phenyldiazonium tetrafluoroborate 38.2g (0.2mol) that be dividedly in some parts in above-described embodiment 1 is stirred at room temperature down, 1h adds, adds
Finish, 8h is stirred at room temperature.Reaction finishes, and add water 150ml, with ethyl acetate 150ml × 2 extraction, the anhydrous sulfur of ethyl acetate layer
Sour sodium is dried, and boils off solvent, 95% (v/v) ethyl alcohol recrystallization obtains white crystal 16.7g, yield about 78.4%, mp:146-148
℃.
Embodiment 7
1,3- dimethyl uracil 14.1g (0.1mol) and Cu-lyt. 1.0g (0.01mol) is taken to add dmso 100ml,
Phenyldiazonium tetrafluoroborate 24.8g (0.13mol) that be dividedly in some parts in above-described embodiment 2 is stirred at room temperature down, 1h adds, adds
Finish, 12h is stirred at room temperature.Reaction finishes, and add water 200ml, with ethyl acetate 200ml × 2 extraction, the anhydrous sulfur of ethyl acetate layer
Sour sodium is dried, and boils off solvent, 95% (v/v) ethyl alcohol recrystallization obtains white crystal 14.7g, yield about 68.1%, mp:144-146
℃.
Claims (10)
1. one kind 1, the preparation method of 3- dimethyl -5- phenyl uracils, comprising:
(1) aniline, water and fluoborate aqueous solution are mixed, the aqueous solution of Deca sodium nitrite under 0～5 DEG C of stirring, maintain temperature
Degree, at 0～5 DEG C, stirs 1～2h, sucking filtration, obtains phenyldiazonium tetrafluoroborate；
(2), under room temperature, 1,3- dimethyl uracil, copper salt catalyst are added stirring mixing in solvent, is then dividedly in some parts step
Suddenly the phenyldiazonium tetrafluoroborate in (1), adds after finishing, and reaction 8-12h, separating-purifying are stirred at room temperature, obtain 1,3-
Dimethyl -5- phenyl uracils.
2. a kind of preparation method of 1,3- dimethyl -5- phenyl uracils according to claim 1 is it is characterised in that institute
State aniline in step (1), fluoborate aqueous solution, sodium nitrite proportionate relationship be 1mol:220～330g:1～1.5mol.
3. a kind of 1,3- dimethyl -5- phenyl uracils according to claim 1 and 2 preparation method it is characterised in that
The specification of described fluoborate aqueous solution is 40% fluoborate aqueous solution.
4. a kind of preparation method of 1,3- dimethyl -5- phenyl uracils according to claim 1 is it is characterised in that institute
State 1,3- dimethyl uracil, phenyldiazonium tetrafluoroborate and copper salt catalyst in step (2) mol ratio be 1.0:1.0～
2.0:0.05～0.2.
5. one kind 1 according to claim 1 or 4, the preparation method of 3- dimethyl -5- phenyl uracils it is characterised in that
Described copper salt catalyst is cucl, cubr or cui.
6. a kind of preparation method of 1,3- dimethyl -5- phenyl uracils according to claim 1 is it is characterised in that institute
The ratio stating 1,3- dimethyl uracil and solvent in step (2) is 1.0g:1～20ml.
7. one kind 1 according to claim 1 or 6, the preparation method of 3- dimethyl -5- phenyl uracils it is characterised in that
Described solvent is dmso.
8. a kind of preparation method of 1,3- dimethyl -5- phenyl uracils according to claim 1 is it is characterised in that institute
Stating and being dividedly in some parts time used by phenyldiazonium tetrafluoroborate in step (2) is 0.5～1h.
9. a kind of preparation method of 1,3- dimethyl -5- phenyl uracils according to claim 1 is it is characterised in that institute
The step stating separating-purifying in step (2) is: plus ethyl acetate and water extracted, and merges organic layer, the anhydrous sulfur of organic layer
Sour sodium is dried, and solvent evaporated is recrystallized to give product.
10. a kind of preparation method of 1,3- dimethyl -5- phenyl uracils according to claim 9 is it is characterised in that institute
The ratio stating the consumption of 1,3- dimethyl uracil and ethyl acetate and anhydrous sodium sulfate is 1g:1～10ml:0.1～1g；Tie again
Brilliant solvent is 95% (v/v) ethanol.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109096145A (en) * | 2018-07-13 | 2018-12-28 | 南京卡邦科技有限公司 | A kind of method that multi-substituent aniline prepares diazonium salt |
| CN115611816A (en) * | 2021-07-14 | 2023-01-17 | 中国科学院化学研究所 | Method for efficiently preparing 5-aryl (hetero) ring modified uracil derivative |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105801507A (en) * | 2016-05-26 | 2016-07-27 | 东华大学 | 1-(3-bromophenyl)-1H-tetrazole preparation method |
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2016
- 2016-08-02 CN CN201610626068.XA patent/CN106349170A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105801507A (en) * | 2016-05-26 | 2016-07-27 | 东华大学 | 1-(3-bromophenyl)-1H-tetrazole preparation method |
Non-Patent Citations (3)
| Title |
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| GARY A.MOLANDER ET AL.: "Palladium(0)-Catalyzed Suzuki-Miyaura Cross-Coupling Reactions of Potassium Aryl- and Heteroaryltrifluoroborates with Alkenyl Bromides", 《J.ORG.CHEM.》 * |
| ZHEN-HUA YANG ET AL.: "Selective and tunable synthesis of 3-arylsuccinimides and 3-arylmaleimides from arenediazonium tetrafluoroborates and maleimides", 《RSC ADV.》 * |
| 陈中辉: "苯基重氮盐与马来酰亚胺和磺酰胺的反应研究", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109096145A (en) * | 2018-07-13 | 2018-12-28 | 南京卡邦科技有限公司 | A kind of method that multi-substituent aniline prepares diazonium salt |
| CN115611816A (en) * | 2021-07-14 | 2023-01-17 | 中国科学院化学研究所 | Method for efficiently preparing 5-aryl (hetero) ring modified uracil derivative |
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