CN104109167B - 2,4-carbon-oxo bridge yl pyrimidines cyclisation thing and its preparation method and application - Google Patents
2,4-carbon-oxo bridge yl pyrimidines cyclisation thing and its preparation method and application Download PDFInfo
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- CN104109167B CN104109167B CN201410183022.6A CN201410183022A CN104109167B CN 104109167 B CN104109167 B CN 104109167B CN 201410183022 A CN201410183022 A CN 201410183022A CN 104109167 B CN104109167 B CN 104109167B
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- 150000003230 pyrimidines Chemical class 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 13
- -1 cyclic ethers uracil derivative Chemical class 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 18
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical class O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 17
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 16
- 230000011987 methylation Effects 0.000 claims description 16
- 238000007069 methylation reaction Methods 0.000 claims description 16
- 239000010703 silicon Substances 0.000 claims description 16
- 229910052710 silicon Inorganic materials 0.000 claims description 16
- 238000006555 catalytic reaction Methods 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 238000006266 etherification reaction Methods 0.000 claims description 9
- 239000000376 reactant Substances 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 239000011968 lewis acid catalyst Substances 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 150000004292 cyclic ethers Chemical class 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000011592 zinc chloride Substances 0.000 claims description 4
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 3
- 229940035893 uracil Drugs 0.000 claims description 3
- 229910003074 TiCl4 Inorganic materials 0.000 claims description 2
- 239000003518 caustics Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000001514 detection method Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims 1
- 150000007517 lewis acids Chemical class 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 239000002244 precipitate Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 0 CC(C)(CCO1)Oc2c(*)c(*)nc1n2 Chemical compound CC(C)(CCO1)Oc2c(*)c(*)nc1n2 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- XBCXJKGHPABGSD-UHFFFAOYSA-N methyluracil Natural products CN1C=CC(=O)NC1=O XBCXJKGHPABGSD-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/08—Bridged systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a kind of 2,4-carbon-oxo bridge yl pyrimidines cyclisation thing and its preparation method and application.This compound belongs to the cyclic ethers uracil derivative that a class formation is brand-new, and its structure, such as shown in following formula (I), can be used as nano molecular device and the raw material of nanoassemble parts.
Description
Technical field
The present invention relates to a kind of raw material for nano molecular device and nanoassemble parts and preparation method thereof, be specifically related to 2,4-brand-new carbon of a class formation-oxo bridge class pyrimidine ring compound and its preparation method and application.
Background technology
The 2-position of pyrimidine and 4-position acyclic etherification product individually or simultaneously is often used as the raw material (DrexlerKE of nano molecular device and nanoassemble parts, Natosystems-molecularmachinery, manufacturingandcomputation, WileyInterscience:NewYork, 1992；AmabilinoDB, WilliamsDJ, etal.JAmChemSoc, 1995,117 (45): 11142～11170), and these etherate great majority be all for raw material with 2,4-dihalo-pyrimidines, react with alcohols and prepare under highly basic (such as NaH etc.) acts on, or also prepare under catalyst action for raw material and hydro carbons sulphonic acid ester with uracil.
So far, a class cyclic ethers uracil derivative of the present invention, namely 2,4-carbon-oxo bridge yl pyrimidines cyclisation thing and halogenation hydrogen salt (I) thereof have no bibliographical information.
Summary of the invention
The present invention relates to 2,4-brand-new carbon of a kind of structure-oxo bridge yl pyrimidines cyclisation thing and preparation method thereof, this compound structure is such as shown in following formula (I):
In formula, R is the straight or branched alkyl of H, C1～C4, or the alkylene of C1～C4 and aryl；The straight or branched alkyl etc. that R ' is H, C1～C4；X is Cl or Br；N is 0,1,2 or 3.
As the further optimization of such scheme, wherein R is selected from the straight or branched alkyl of H, C1～C3 or the alkylene of C1～C3 and aryl；The straight or branched alkyl that R ' is H, C1～C3；X is Cl or Br；N is 0,1 or 2.
The systematic naming method of corresponding this kind of 2,4-carbon-oxo bridge yl pyrimidines cyclisation thing is respectively as follows:
As n=0, its called after: 7,8-2,4-dioxa-6 replaced, 9-diazabicylo [3.3.1] ninth of the ten Heavenly Stems-1 (9), 5,7-triolefin；
As n=1, its called after: 8,9-2,5-dioxa-7 replaced, 10-diazabicylo [4.3.1] last of the ten Heavenly stems-1 (10), 6,8-triolefin；
As n=2, its called after: 9,10-2,6-dioxa-8 replaced, 11-diazabicylo [5.3.1] ten one-1 (11), 7,9-triolefin.
The preparation method that the invention allows for above-mentioned formula I compound, it silicon methylation and catalysis ring etherification reaction of including being sequentially carried out raw material uracil derivative according to following reaction equation
Wherein, the condition of described catalysis ring etherification reaction includes: select Lewis acid catalyst, and silicon methylation uracil and formula are XCH in a solvent or under condition of no solvent2(CH2)nX (namely 1, n-dihalo alkane) end halogenated hydrocarbons react, reaction temperature is in the temperature range of room temperature to backflow, reaction regulates reactant liquor to precipitating out precipitation with weak caustic solution after terminating, then through crystallization after filtering and concentrating, cooling, namely preparing target compound, wherein, X selects halogen.
As the further optimization of such scheme, the silicon methylation reagent adopted in the method includes hexamethyldisilane amine (HMDSA), trim,ethylchlorosilane (TMSCl) or bromotrimethylsilane (TMSBr)；The mol ratio of described uracil derivative and silicon methylation reagent is 1:2.2～10；It is highly preferred that described silicon methylation reagent is hexamethyldisilane amine or trim,ethylchlorosilane；The mol ratio of described uracil derivative and silicon methylation reagent is 1:3.5～8.After the silicon methylation of described raw material uracil derivative completes, unnecessary silicon methylation reagent under vacuum condition, is evaporated off, is subsequently adding applicable solvent and dissolves, do not make any purification processes, a step etherification reaction raw material after can be used as.
After a step etherification reaction completes after the present invention, reactant liquor being cooled to 5～10 DEG C, stirring is lower adds saturated NaHCO3Aqueous solution, to neutral, precipitate out precipitation, is precipitated as the metal hydroxides of catalyst, filters out precipitation, then by filtrate reduced in volume, removes the water of reaction dissolvent and half volume.Cooling stands, and precipitates out solid, refilters, finally obtain required cyclic ethers uracil derivative with water recrystallization purifying.
Further, described Lewis acid catalyst includes SnCl4、TiCl4、ZnCl2Or Sn (OTf)2；It is highly preferred that Lewis acid catalyst is SnCl4Or ZnCl2。
Further, make consumption be silicon methylation uracil compounds weight the 10～40% of described Lewis acid catalyst.
Further, described catalysis cyclic ethers reaction dissolvent includes toluene, or does not have reaction dissolvent, now namely with reactants of X CH2(CH2)nX makes solvent, especially with reactants of X CH2(CH2)nX is preferred as solvent.
Further, described catalysis ring etherification reaction temperature is 40 DEG C～reflux temperature, and reflux temperature refers to that steam when reactant liquor seethes with excitement begins at temperature when reactor vessel wall condenses into liquid.
Further, the described catalysis cyclic ethers response time is determined to detect reaction result, and described detection method includes TLC or/and HPLC, and the described response time is generally 4～24 hours.
Above-mentioned 2,4-carbon-oxo bridge yl pyrimidines cyclisation thing is as nano molecular device and the raw-material purposes of nanoassemble parts.
Detailed description of the invention
Below in conjunction with preferred embodiment, the present invention is done more specific detail.
Embodiment 19-methyl-2,5-dioxa-7,10-diazabicylo [4.3.1] last of the ten Heavenly stems-1 (10), the preparation of 6,8-triolefin
Methyl uracil 10.0g (79mmol) is suspended in 102g hexamethyldisilane amine (635mmol), add 0.1g ammonium sulfate post-heating to refluxing, reaction overnight, after clarifying to reactant liquor, removes under reduced pressure and reclaims excessive hexamethyldisilane amine；Residue adds 1,2-dichloroethanes after 80mL drying processes, is cooled to 5 DEG C after dissolving, is slowly added dropwise by 7gSnCl4And the mixed liquor that 10mL1,2-dichloroethanes forms, dripping and finish, by reactant liquor heating to micro-reflux state, completing until detecting reaction with TLC.Reactant liquor is cooled to 5～10 DEG C, and stirring is lower adds saturated NaHCO3Aqueous solution, to neutral, precipitates out precipitation, it is precipitated as the hydroxide of Sn, filters, by filtrate reduced in volume, removing the water of reaction dissolvent and half volume, cooling stands, and precipitates out product solid, filter, then through water recrystallization purifying product, obtain 10.9g (73%) colorless crystalline powder (9-methyl-2,5-dioxa-7,10-diazabicylo [4.3.1] last of the ten Heavenly stems-1 (10), 6,8-triolefin).
Data after the physicochemical properties analysis of the target product of gained are as follows:
Fusing point: > 270 DEG C (undecomposed).
1H-NMR (300MHz, D2O) δ: 7.55 (s, 1H, Ar-H), 4.77 (t, 2H, J=8.60Hz, CH2), 4.31 (t, 2H, J=8.60Hz, CH2), 1.81 (s, 3H, CH3)；
13C-NMR (75MHz, D2O) δ: 175.3,161.4,136.1,116.9,68.0,46.9,12.8；
ES-MSm/z:175.1 [M+Na]+, 151.1 [M-H]-；C7H8N2O2(MW=152.1)；
Elementary analysis: C7H9ClN2O2(MW=188.61)
Value of calculation: C44.58, H4.81, N14.85 (%)
Measured value: C44.32, H4.94, N14.63 (%).
Embodiment 2
On the basis of embodiment 1, apply above-mentioned catalyst SnCl4, proportioning raw materials, reaction condition and operational approach, substituent group on conversion uracil ring and 1, n-dihalo alkane (n=0,1,2), the productivity of 2,4-carbon of gained-oxo bridge yl pyrimidines cyclisation thing is shown in such as table 1 below.
The productivity of the 2,4-carbon that table 1 different substituents is corresponding-oxo bridge yl pyrimidines cyclisation thing
Embodiment 3
On the basis of embodiment 1, application above-mentioned raw materials proportioning, reaction condition and operational approach, transformation catalyst ZnCl2, substituent group on uracil ring and 1, n-dihalo alkane (n=0,1,2), the productivity such as table 2 below of 2,4-carbon of gained-oxo bridge yl pyrimidines cyclisation thing.
The productivity of the 2,4-carbon that table 2 different substituents is corresponding with catalyst-oxo bridge yl pyrimidines cyclisation thing
Claims (11)
1.2,4-carbon-oxo bridge yl pyrimidines cyclisation thing, it is characterised in that there is the structure shown in below formula (I):
In formula, R is the straight or branched alkyl of H, C1～C4, or the alkylene of C1～C4；The straight or branched alkyl that R ' is H, C1～C4；X is Cl or Br；N is equal to 0,1 or 2.
2. 2,4-carbon-oxo bridge yl pyrimidines cyclisation thing according to claim 1, it is characterised in that the alkylene of the R straight or branched alkyl selected from H, C1～C3 or C1～C3；The straight or branched alkyl that R ' is H, C1～C3；N is 0,1, or 2.
3. the preparation method of 2,4-carbon described in claim 1-oxo bridge yl pyrimidines cyclisation thing, it is characterised in that include the silicon methylation and the catalysis ring etherification reaction that are sequentially carried out raw material uracil derivative according to following reaction equation:
Wherein, the condition of described catalysis ring etherification reaction includes: selecting Lewis acid as catalyst, silicon methylation uracil and formula are XCH in a solvent or under condition of no solvent2(CH2)nThe end halogenated hydrocarbons of X reacts, and reaction temperature is in the temperature range of room temperature to backflow, and reaction regulates reactant liquor to precipitating out precipitation with weak caustic solution after terminating, and then through crystallization after filtering and concentrating, cooling, namely prepares target compound, and wherein, X is Cl or Br；N is equal to 0,1 or 2.
4. the preparation method of 2,4-carbon-oxo bridge yl pyrimidines cyclisation thing according to claim 3, it is characterised in that the silicon methylation reagent adopted in the method is hexamethyldisilane amine, trim,ethylchlorosilane or bromotrimethylsilane；The mol ratio of described uracil derivative and silicon methylation reagent is 1:2.2～10.
5. the preparation method of 2,4-carbon-oxo bridge yl pyrimidines cyclisation thing according to claim 4, it is characterised in that described silicon methylation reagent is hexamethyldisilane amine or trim,ethylchlorosilane；The mol ratio of described uracil derivative and silicon methylation reagent is 1:3.5～8.
6. the preparation method of 2,4-carbon-oxo bridge yl pyrimidines cyclisation thing according to claim 3, it is characterised in that described Lewis acid catalyst includes SnCl4、TiCl4、ZnCl2Or Sn (OTf)2。
7. the preparation method of 2,4-carbon-oxo bridge yl pyrimidines cyclisation thing according to claim 3, it is characterised in that make consumption be silicon methylation uracil compounds weight the 10～40% of described Lewis acid catalyst.
8. the preparation method of 2,4-carbon-oxo bridge yl pyrimidines cyclisation thing according to claim 3, it is characterised in that described catalysis cyclic ethers reaction dissolvent is toluene.
9. the preparation method of 2,4-carbon-oxo bridge yl pyrimidines cyclisation thing according to claim 3, it is characterised in that described catalysis ring etherification reaction temperature is 40 DEG C～reflux temperature.
10. the preparation method of 2,4-carbon-oxo bridge yl pyrimidines cyclisation thing according to claim 3, it is characterised in that the described catalysis cyclic ethers response time is determined to detect reaction result, the method that described detection adopts is TLC or/and HPLC.
11. the 2,4-carbon according to any one of claim 1-10-oxo bridge yl pyrimidines cyclisation thing is as nano molecular device and the raw-material purposes of nanoassemble parts.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102633843A (en) * | 2012-03-30 | 2012-08-15 | 江苏笃诚医药科技有限公司 | New method for preparing cytidine |
| CN103333119A (en) * | 2013-05-28 | 2013-10-02 | 中国药科大学 | 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidinecarboxylic acid compound and its preparation method and use |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102633843A (en) * | 2012-03-30 | 2012-08-15 | 江苏笃诚医药科技有限公司 | New method for preparing cytidine |
| CN103333119A (en) * | 2013-05-28 | 2013-10-02 | 中国药科大学 | 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidinecarboxylic acid compound and its preparation method and use |
Non-Patent Citations (2)
| Title |
|---|
| "New Degradable Polyethers Based on the Tautomerism of Pyrimidine Bases in the Main Chain";Seiji Sasaki等，;《imide-Based Degradable Polyethers》;20000121;第38卷(第1期);第198-206页 * |
| "含嘧啶环的双冠醚（I）";陆国元等，;《南京大学学报》;19900430;第26卷(第2期);第348-351页 * |
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Inventor after: Yao Qizheng Inventor after: Li Minquan Inventor after: Wang Duzheng Inventor after: Wang Yuxiang Inventor after: Yao Shining Inventor after: Li Yalin Inventor before: Yao Qizheng Inventor before: Li Minquan Inventor before: Wang Duzheng Inventor before: Wang Yuxiang Inventor before: Yao Shining |
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Effective date of registration: 20180809 Address after: 215000 1 Huayun Road, Suzhou Industrial Park, Jiangsu Co-patentee after: LIANYUNGANG DUXIANG CHEMICALS CO.,LTD. Patentee after: JIANGSU DUCHENG PHARMACEUTICALS Co.,Ltd. Address before: 215000 1 Huayun Road, Suzhou Industrial Park, Jiangsu Patentee before: JIANGSU DUCHENG PHARMACEUTICALS Co.,Ltd. |
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Granted publication date: 20160629 |
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| CF01 | Termination of patent right due to non-payment of annual fee |