CN109369520A - A novel dinitroquinoline compound and its preparation method and application - Google Patents
A novel dinitroquinoline compound and its preparation method and application Download PDFInfo
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- CN109369520A CN109369520A CN201811073988.9A CN201811073988A CN109369520A CN 109369520 A CN109369520 A CN 109369520A CN 201811073988 A CN201811073988 A CN 201811073988A CN 109369520 A CN109369520 A CN 109369520A
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- dinitroquinoline
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- compound
- quinolines
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- -1 dinitroquinoline compound Chemical class 0.000 title claims description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- RRBUKOWICXHUHD-UHFFFAOYSA-N 2,3-dinitroquinoline Chemical class C1=CC=C2N=C([N+]([O-])=O)C([N+](=O)[O-])=CC2=C1 RRBUKOWICXHUHD-UHFFFAOYSA-N 0.000 claims abstract description 23
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000003248 quinolines Chemical class 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- KUDYKIJCJSRIBX-UHFFFAOYSA-N 2,5,7-trimethylquinoline Chemical compound C1=CC(C)=NC2=CC(C)=CC(C)=C21 KUDYKIJCJSRIBX-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 229930195733 hydrocarbon Natural products 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 2
- 125000001188 haloalkyl group Chemical group 0.000 claims 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 abstract description 11
- 239000003054 catalyst Substances 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 3
- 238000011017 operating method Methods 0.000 abstract description 3
- 125000001072 heteroaryl group Chemical group 0.000 abstract 2
- 150000001335 aliphatic alkanes Chemical class 0.000 abstract 1
- 238000005804 alkylation reaction Methods 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 238000006884 silylation reaction Methods 0.000 abstract 1
- 125000003107 substituted aryl group Chemical group 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000006396 nitration reaction Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 4
- 230000002459 sustained effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 2
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- QCDFBFJGMNKBDO-UHFFFAOYSA-N Clioquinol Chemical compound C1=CN=C2C(O)=C(I)C=C(Cl)C2=C1 QCDFBFJGMNKBDO-UHFFFAOYSA-N 0.000 description 2
- 206010039966 Senile dementia Diseases 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- YZPOQCQXOSEMAZ-UHFFFAOYSA-N pbt2 Chemical compound ClC1=CC(Cl)=C(O)C2=NC(CN(C)C)=CC=C21 YZPOQCQXOSEMAZ-UHFFFAOYSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical compound C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004922 2-methyl-3-pentyl group Chemical group CC(C)C(CC)* 0.000 description 1
- MHNNAWXXUZQSNM-UHFFFAOYSA-N 2-methylbut-1-ene Chemical compound CCC(C)=C MHNNAWXXUZQSNM-UHFFFAOYSA-N 0.000 description 1
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 1
- 125000004921 3-methyl-3-pentyl group Chemical group CC(CC)(CC)* 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960005228 clioquinol Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000007684 eye toxicity Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- SFDJOSRHYKHMOK-UHFFFAOYSA-N nitramide Chemical compound N[N+]([O-])=O SFDJOSRHYKHMOK-UHFFFAOYSA-N 0.000 description 1
- 231100000327 ocular toxicity Toxicity 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention belongs to synthesising chemical technology field, a kind of novel dinitro quinolines and its preparation method and application are disclosed, the general formula of the chemical structure of the dinitro quinolines is as follows:
Description
Technical field
The invention belongs to synthesising chemical technology field, more particularly, to a kind of novel dinitro quinolines and
Preparation method and application.
Background technique
It has increased significantly in information and today of science and technology rapid development, the healthy and safe consciousness of the mankind.Phase
Ying Di, for producing not only efficiently but also safe drugs demand or higher and higher.To accelerate pharmaceuticals industry research and development cost performance
The paces of higher drug.Studies have shown that nitrogenous heterocyclic compounds have good drug and bioactivity.Moreover,
Because nitrogenous heterocyclic compounds and its being easy to carry out structural modification, it is easy to introduce different functional groups to realize structure
Derivative and structure-activity relationship research.So it is widely used in field of medicaments, precursor and centre as many drugs
Body.Quinoline and its derivates are important nitrogenous heterocyclic compounds, are the important skeletons of a variety of organic compounds and a variety of
The important intermediate of synthetic drug.Currently, existing substantial quinoline class compound is used in the research direction of new target drone enzyme, and
And as a kind of metal ion chelation agent de-regulation with the disorder ion in patients of senile dementia brain, research-on-research
Person Bush and his team have developed enteroquinol (Clioquinol, CQ), PBT2 etc., but because
The two all do not reach one very well treatment and relaxation effect (CQ dies young because it is with eye toxicity, PBT2 because its to copper from
None good selectivity of son and zinc ion is died without known cause) and end up with nothing definite.But they are but anti senile dementia drug
Research and development provide solid theoretical foundation with the research that metal ion is adjusted to target spot.
It is related to multiple reaction steps and a variety of reaction intermediates during synthesizing activity quinolines.Wherein,
The preparation of intermediate 2,5,7- trimethyl -6,8- dinitro quinolines is by its precursor 2,5,7- trimethylquinoline class
It closes object and reacts obtained with the nitration mixture that the concentrated sulfuric acid and concentrated nitric acid form, do not need combined catalyst not only and carry out catalysis reaction, but also
The Product Byproduct of synthesis is few.In synthesis chemistry, have property, the halogenation examination of substituent group in the generation of reaction product and substrate
Agent has much relations, therefore, finds the quinolines that a kind of side reaction is few, synthesis step is simple, reaction product is controllable
Preparation method will have great meaning to the application study in the fields such as pharmaceutical chemistry, biomedicine.
Summary of the invention
In order to solve above-mentioned the shortcomings of the prior art and disadvantage, it is an object of that present invention to provide a kind of novel dinitros
Quinolines.
Another object of the present invention is to provide the preparation method of above-mentioned novel dinitro quinolines.This method passes through
Dinitro quinolines are made in quinolines and concentrated nitric acid and concentrated sulfuric acid hybrid reaction, reaction condition is mild, nothing
Other catalyst need to be added, operating procedure is simple, securely and reliably；This method is suitble to a variety of quinolines reaction substrates, synthetic yield
80% is reached as high as, by optimizing and adjusting to reaction substrate, polysubstituted and various structures dinitro quinolines can be synthesized
Quinoline class compound, be suitble to industrialized production for the later period deeper into research reference frame is provided.
Still a further object of the present invention is to provide the application of above-mentioned novel dinitro quinolines.
The purpose of the present invention is realized by following technical proposals:
A kind of novel dinitro quinolines, the general formula of the chemical structure of the dinitro quinolines are as follows:
Wherein, X is selected from hydro carbons alkyl；R2And R4For nitro；R1And R3Selected from alkyl, halogen, halogenated alkyl, nitro, ammonia
Base, cyano, alkynyl, aldehyde radical or ester group.
Preferably, the substituent group in the hydro carbons alkyl is halogen, alkyl, halogenated alkyl, alkoxy, nitro, hydroxyl, cyanogen
Base, ester group, carbonyl or amide groups.
Preferably, the dinitro quinolines are as follows:
The preparation method of the novel dinitro quinolines, comprising the following specific steps
The concentrated sulfuric acid is added dropwise under ice bath stirring in quinolines, nitration mixture is added after mixing, after stirring under ice bath
It is warmed to room temperature sustained response, TLC tracking reaction to raw material point disappears, and obtains reaction system A；Reaction system A adjusts pH through ammonium hydroxide,
It is extracted with organic solvent, crude product obtains dinitro quinolines after isolating and purifying.
Preferably, the quinolines are 2,5,7- trimethylquinolines or 2- methyl -5,7- phenodiazine nitrogen dimethyl quinoline
Quinoline.
Preferably, the nitration mixture is the concentrated sulfuric acid and concentrated nitric acid, and the volume ratio of the concentrated sulfuric acid and concentrated nitric acid is (0.4~1):
(0.2~0.5)；The concentrated nitric acid: the molar ratio of quinolines is (0.2~0.8): 1.
Preferably, the organic solvent is acetonitrile, methanol, ethyl alcohol, methylene chloride, chloroform, benzene, toluene, tetrahydrofuran, second
Ether, dimethylformamide, dimethyl acetamide, dimethyl Asia or ethyl acetate.
Preferably, the pH is 10~12, and the time of the reaction is 1~21h.
Preferably, the time of the stirring is 15~20min, and the revolving speed of the stirring is 500~1000r/min.
Preferably, the volume ratio of the reaction system A and water is 1:(100~200), the concentration of the ammonia spirit is 25
~28wt%.
Application of the novel dinitro quinolines in drug field.
Further, the drug include the described in any item novel dinitro quinolines of claim 1-3 with
And pharmaceutically acceptable auxiliary material.
Alkyl or alkyl group (halogenated alkyl, alkoxy) of the present invention indicate the saturation for containing 1~20 carbon atom
Straight chain, ring-type or branch monovalence hydrocarbon atomic group.Alkyl contains 1~20 carbon atom, it is preferable that and alkyl contains 1~
10 carbon atoms, it is further preferable that alkyl contains 1~4 carbon atom；Alkoxy contains 1~20 carbon atom, it is preferable that alkane
Oxygroup contains 1~10 carbon atom, it is further preferable that alkoxy contains 1~4 carbon atom；Halogenated alkyl contains 1~20 carbon
Atom, it is preferable that halogenated alkyl contains 1~10 carbon atom, it is further preferable that halogenated alkyl contains 1~4 carbon atom.
Alkyl or alkyl group of the present invention include but are not limited to methyl (Me ,-CH3), ethyl (Et ,-
CH2CH3), n-propyl (n-Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-
CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tert-butyl (t-
Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl (- CH (CH3)CH2CH2CH3), 3- amyl (- CH
(CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl-
1- butyl (- CH2CH2CH(CH3)2), 2-methyl-1-butene base (- CH2CH(CH3)CH2CH3), n-hexyl (-
CH2CH2CH2CH2CH2CH3), 2- hexyl (- CH (CH3)CH2CH2CH2CH3), 3- hexyl (- CH (CH2CH3)(CH2CH2CH3)), 2-
Methyl -2- amyl (- C (CH3)2CH2CH2CH3), 3- methyl -2- amyl (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- penta
Base (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- amyl (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl (- CH
(CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)
C(CH3)3), n-heptyl, n-octyl etc..
Reaction formula of the invention is shown below:
Compared with prior art, the invention has the following advantages:
1. novel dinitro quinolines of the invention are mixed by quinolines and concentrated nitric acid and the concentrated sulfuric acid
It closes to react and dinitro quinolines is made.
2. the reaction condition of method of the invention is mild, without adding other catalyst, operating procedure is simple, safely may be used
It leans on, by-product is few.
3. method of the invention is suitble to a variety of quinolines reaction substrates, synthetic yield reaches as high as 80%, by reaction
Substrate is optimized and is adjusted, and can be synthesized polysubstituted and various structures dinitro quinolines and is suitble to industrial metaplasia
It produces.
Specific embodiment
The contents of the present invention are further illustrated combined with specific embodiments below, but should not be construed as limiting the invention.
Unless otherwise specified, the conventional means that technological means used in embodiment is well known to those skilled in the art.Except especially saying
Bright, reagent that the present invention uses, method and apparatus is the art conventional reagents, method and apparatus.
Embodiment 1
1. preparation: 2,5,7- trimethylquinolines (200mg, 1.168mmol) being added in round-bottomed flask, delay under ice bath stirring
It is slow that the 3mL concentrated sulfuric acid is added dropwise, be added dropwise again after being added dropwise 0.6mL nitration mixture (concentrated sulfuric acid: volume ratio=4:5 of concentrated nitric acid, concentrated nitric acid:
2,5,7- trimethylquinolines=0.8mol:1.0mol), stirring 15 under ice bath~be warmed to room temperature after twenty minutes, after sustained response 1h,
TLC tracking reaction to raw material point disappears.Reaction is stopped into stirring, 300mL water is added into beaker, then by reaction system whole
It is poured into beaker, the ammonium hydroxide of 27wt% is added to it, regulation system pH value is 12.Make to be extracted with ethyl acetate three times, merges extraction
Organic phase is taken, depressurizes to obtain concentrate using Rotary Evaporators, 100~200 mesh chromatographic silica gels are added and stir evenly, with acetic acid second
Ester and hexane solution are eluant, eluent, and sample is carried out silica gel column chromatography, obtains 2,5,7- trimethyl -6,8- dinitro quinoline
40mg, yield 83%.
2. Structural Identification: the structure of gained compound through nuclear magnetic resonance (1H-NMR) characterization result are as follows:1H NMR(400MHz,
CDCl3): δ=8.21 (d, J=8.8Hz, 1H), 7.41 (d, J=8.8Hz, 1H), 2.67 (s, 3H), 2.54 (s, 3H), 2.32
(s,3H)。
Embodiment 2
1. preparation: 2,5,7- trimethylquinolines (200mg, 1.168mmol) being added in round-bottomed flask, delay under ice bath stirring
It is slow that the 3mL concentrated sulfuric acid is added dropwise, the 1.4mL nitration mixture (concentrated sulfuric acid: concentrated nitric acid=2:1, concentrated nitric acid: 2,5,7- tri- is added dropwise after being added dropwise again
Methylquinoline=0.4mol:1.0mol), stirring 15 under ice bath~be warmed to room temperature after twenty minutes, after sustained response 21h, TLC tracking
Reaction to raw material point disappears.Reaction is stopped into stirring, 300mL water is added into beaker, then reaction system is all poured into burning
In cup, the ammonia spirit of 25wt% is added to it, regulation system pH value is 10.Three times using dichloromethane solution extraction, merge
Organic phase is extracted, depressurizes to obtain concentrate using Rotary Evaporators, 100~200 mesh chromatographic silica gels are added and stir evenly, use acetic acid
Ethyl ester and hexane solution are eluant, eluent, and sample is carried out silica gel column chromatography, obtains 2,5,7- trimethyl -6,8- dinitro quinoline
244.2mg, yield 80%.
2. Structural Identification: gained compound structure characterizes qualification result through nuclear magnetic resonance (1H-NMR) are as follows:1H NMR
(400MHz, CDCl3): δ=8.21 (d, J=8.8Hz, 1H), 7.41 (d, J=8.8Hz, 1H), 2.67 (s, 3H), 2.54 (s,
3H),2.32(s,3H)。
Embodiment 3
1. preparation: 2,5,7- trimethylquinolines (200mg, 1.168mmol) being added in round-bottomed flask, delay under ice bath stirring
It is slow that the 3mL concentrated sulfuric acid is added dropwise, be added dropwise again after being added dropwise 1.05mL nitration mixture (concentrated sulfuric acid: volume ratio=5:1 of concentrated nitric acid, concentrated nitric acid:
2,5,7- trimethylquinolines=0.6mol:1.0mol), stirring 15 under ice bath~be warmed to room temperature after twenty minutes, sustained response 21h
Afterwards, TLC tracking reaction to raw material point disappears.Reaction is stopped into stirring, 300mL water is added into beaker, then by reaction system
It is all poured into beaker, the ammonia spirit of 28wt% is added to it, regulation system pH value is 11.It is extracted using dichloromethane solution
Three times, merge extraction organic phase, depressurize to obtain concentrate using Rotary Evaporators, it is equal that the stirring of 100-200 mesh chromatographic silica gel is added
It is even, it is eluant, eluent with ethyl acetate and hexane solution, sample is subjected to silica gel column chromatography, obtains 2,5,7- trimethyls -6,8-
Dinitro quinoline 192.3mg, yield 73%.
2. Structural Identification: gained compound structure is through nuclear magnetic resonance (1H-NMR) characterization result are as follows:1H NMR(400MHz,
CDCl3): δ=8.21 (d, J=8.8Hz, 1H), 7.41 (d, J=8.8Hz, 1H), 2.67 (s, 3H), 2.54 (s, 3H), 2.32
(s,3H)。
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes made without departing from the spirit and principles of the present invention, modification, alternative combinations and simplification,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (10)
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110275643A1 (en) * | 2010-05-06 | 2011-11-10 | National Health Research Institutes | Aroylquinoline compounds |
| CN106674102A (en) * | 2016-12-26 | 2017-05-17 | 广东工业大学 | Halogenated quinoline compound and preparation method thereof |
-
2018
- 2018-09-14 CN CN201811073988.9A patent/CN109369520A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110275643A1 (en) * | 2010-05-06 | 2011-11-10 | National Health Research Institutes | Aroylquinoline compounds |
| CN106674102A (en) * | 2016-12-26 | 2017-05-17 | 广东工业大学 | Halogenated quinoline compound and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| 李润莱 等: "5,7-二硝基-8-羟基喹哪啶合成工艺研究", 《化工时刊》 * |
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