CN107501174A - A kind of synthetic method of quinoline - Google Patents
A kind of synthetic method of quinoline Download PDFInfo
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- CN107501174A CN107501174A CN201710610704.4A CN201710610704A CN107501174A CN 107501174 A CN107501174 A CN 107501174A CN 201710610704 A CN201710610704 A CN 201710610704A CN 107501174 A CN107501174 A CN 107501174A
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- Prior art keywords
- dibromo
- methoxyl groups
- room temperature
- methoxyphenyls
- synthetic method
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- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 238000010189 synthetic method Methods 0.000 title claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 65
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 64
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 63
- -1 4- nitro -2,6- dibromo methyl phenyl ethers anisoles Chemical class 0.000 claims description 38
- 239000007787 solid Substances 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 26
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 24
- 239000000463 material Substances 0.000 claims description 24
- 239000007864 aqueous solution Substances 0.000 claims description 21
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 20
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- 229910004878 Na2S2O4 Inorganic materials 0.000 claims description 17
- FZHFNYMWBPLKPO-UHFFFAOYSA-N 2-bromo-3H-quinolin-4-one Chemical class C1=CC=C2C(=O)CC(Br)=NC2=C1 FZHFNYMWBPLKPO-UHFFFAOYSA-N 0.000 claims description 16
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 16
- UYMKPFRHYYNDTL-UHFFFAOYSA-N ethenamine Chemical class NC=C UYMKPFRHYYNDTL-UHFFFAOYSA-N 0.000 claims description 16
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 16
- 238000005406 washing Methods 0.000 claims description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 15
- NRPFNQUDKRYCNX-UHFFFAOYSA-N 4-methoxyphenylacetic acid Chemical class COC1=CC=C(CC(O)=O)C=C1 NRPFNQUDKRYCNX-UHFFFAOYSA-N 0.000 claims description 14
- 238000000605 extraction Methods 0.000 claims description 14
- 238000010792 warming Methods 0.000 claims description 14
- 238000013019 agitation Methods 0.000 claims description 9
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 9
- 239000003208 petroleum Substances 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 6
- 150000002170 ethers Chemical class 0.000 claims description 6
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- 238000003760 magnetic stirring Methods 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- HETSDWRDICBRSQ-UHFFFAOYSA-N 3h-quinolin-4-one Chemical class C1=CC=C2C(=O)CC=NC2=C1 HETSDWRDICBRSQ-UHFFFAOYSA-N 0.000 claims description 3
- 238000000658 coextraction Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- IWRCWERCDOHTHB-UHFFFAOYSA-N C(=O)=NC=C.[O] Chemical compound C(=O)=NC=C.[O] IWRCWERCDOHTHB-UHFFFAOYSA-N 0.000 claims 1
- 241000254173 Coleoptera Species 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 9
- 230000007613 environmental effect Effects 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 4
- 238000011084 recovery Methods 0.000 abstract description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- 229910019213 POCl3 Inorganic materials 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- JLIDRDJNLAWIKT-UHFFFAOYSA-N 1,2-dimethyl-3h-benzo[e]indole Chemical compound C1=CC=CC2=C(C(=C(C)N3)C)C3=CC=C21 JLIDRDJNLAWIKT-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DULCUDSUACXJJC-UHFFFAOYSA-N benzeneacetic acid ethyl ester Natural products CCOC(=O)CC1=CC=CC=C1 DULCUDSUACXJJC-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- OBBCRPUNCUPUOS-UHFFFAOYSA-N tectorigenin Chemical compound O=C1C2=C(O)C(OC)=C(O)C=C2OC=C1C1=CC=C(O)C=C1 OBBCRPUNCUPUOS-UHFFFAOYSA-N 0.000 description 2
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000004568 cement Substances 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000010808 liquid waste Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UYLQOGTYNFVQQX-UHFFFAOYSA-N psi-tectorigenin Natural products COC1=C(O)C=C(O)C(C2=O)=C1OC=C2C1=CC=C(O)C=C1 UYLQOGTYNFVQQX-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 238000010563 solid-state fermentation Methods 0.000 description 1
- 229940071182 stannate Drugs 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- OYUJPVCKGSEYDD-UHFFFAOYSA-N tectorigenin Natural products COc1c(O)cc2OCC(C(=O)c2c1O)c1ccc(O)cc1 OYUJPVCKGSEYDD-UHFFFAOYSA-N 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
- C07D215/20—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Quinoline Compounds (AREA)
Abstract
The invention discloses a kind of synthetic method of quinoline, comprise the following steps：
Description
Technical field
The present invention relates to technical field of medicine synthesis, more particularly, to a kind of synthetic method of quinoline.
Background technology
The synthetic method of quinoline is the isostere of the new tectorigenin found recently, and it is thin that it can suppress liver
The necrosis of born of the same parents, the unbalance of intrahepatic fat and protein is prevented, makes transaminase and the active normalization of glutamyl transferase, prevents
The development of liver fibrosis, play a part of protecting liver, recover liver function.The liver of mouse is acted on TBHP
Cell, the compound is then taken, find the infringement for the liver cancer cells that it can protect mouse to be induced from TBHP.
The compound has the function that fine anti-hepatic fibrosis.
The present inventor is in patent CN1850817 and CN100999492, and paper ChemMedChem 2008,3 (7),
1077-1083 and ChemMedChem 2008,3 (10), 1516-1519 disclose the preparation method of the compound, and the present inventor is herein
On the basis of, it is proposed that new synthesis technique, make it more green, more suitable for industrialized production.
The content of the invention
The purpose of the present invention is in view of the shortcomings of the prior art, there is provided a kind of synthetic method of the quinoline of high income.
To reach above-mentioned purpose, present invention employs following technical proposal：The invention provides a kind of quinoline
Synthetic method, comprise the following steps：
(1) at room temperature, 4- nitro -2,6- dibromo methyl phenyl ethers anisoles are dissolved in the ethanol CH3CH2OH of 10-20 times of quality,
10-30% Na is added under magnetic agitation2S2O4The aqueous solution, 4- nitro -2,6- dibromo methyl phenyl ethers anisoles and Na2S2O4Material amount it
Than for 1 ﹕ 2-6,3-7h is reacted between being gradually heating to 50-60 DEG C, cool down, with the ethyl acetate AcOEt of 2-4 times of aqueous solution volume
Extraction, coextraction 3 times, saturated common salt water washing, anhydrous MgSO4Dry, filtering, boil off AcOEt, white solid 4- methoxyl groups-
3,5- dibromo anilines, yield 97%；
(2) 4- methoxyl group -3,5- dibromo anilines are dissolved in the CH (OMe) of 10-20 times of quality3In, stirring reaction at room temperature
6-20h, reaction finish, and boil off excessive CH (OMe)3, obtain white solid N- (4- methoxyl groups -3,5- dibromo phenyl) methoxy phosphinylidyne
Imines, yield 99%.
(3) N- (4- methoxyl group -3,5- dibromo phenyls) methoxy carbimide is dissolved in the absolute methanol of 15-30 times of quality
In, 15-45min is stirred at room temperature after adding sodium methoxide NaOMe, adds 4- methoxyphenylacetates, N- (4- methoxyl groups-
3,5- dibromo phenyls) methoxy carbimide, the ratio between the amount of sodium methoxide NaOMe and 4- methoxyphenylacetate material be 1 ﹕ 1-4 ﹕
1-3, continue to react at room temperature, 4-10h, boil off methanol, add the water equal with methanol volume, stir 10-20min, filter, do
It is dry, obtain white solid N- (4- methoxyl groups -3,5- dibromo phenyl) 2- (4- methoxyphenyls) -2- carbethoxyl group vinylamines；Yield
99%.
(4) diphenyl ether is taken in there-necked flask, addition N- (4- methoxyl groups -3,5- dibromo phenyl) 2- (4- methoxyphenyls) -
2- carbethoxyl group vinylamines, 250 DEG C of reaction 10min are warming up to, cooling, petroleum ether is added, separates out precipitation, filter, be dried in vacuo
Obtain faint yellow solid；
(5) by isometric DMF and Et2O is placed in flask, is cooled to 0 DEG C under agitation, instills PCl3, continue to stir
1h, after adding the bromo- 4- quinolinones of 3- (4- methoxyphenyls) -6- methoxyl groups -5,7- bis-, 3- (4- methoxyphenyls) -6- methoxies
The bromo- 4- quinolinones of base -5,7- two, PCl3Amount ratio with DMF materials is 1 ﹕ 1-2 ﹕ 12-24, is warming up to room temperature reaction 8-12h, ice
Bath is lower to add water, with AcOEt points of 3 extractions of ethyl acetate of 2-4 times of aqueous solution volume, saturated common salt water washing, anhydrous MgSO4
Dry, filtering, boil off AcOEt, the synthetic method of white solid quinoline.
Further, in step (1), 4- nitros -2,6- dibromo methyl phenyl ethers anisole and ethanol CH3CH2OH mass ratio is
1:10,4- nitros -2,6- dibromo methyl phenyl ethers anisole and Na2S2O4The amount ratio of material is 1：2；
In step (2), 4- methoxyl group -3,5- dibromo anilines：CH(OMe)3Mass ratio 1:10；
In step (3), N- (4- methoxyl groups -3,5- dibromo phenyl) methoxy carbimide, sodium methoxide NaOMe and 4- methoxy
The amount ratio of the material of base ethyl phenylacetate is 1:1：1, N- (4- methoxyl groups -3,5- dibromo phenyl) the methoxy carbimides and nothing
The mass ratio of water methanol is 1：15.
Further, in step (4), diphenyl ether：N- (4- methoxyl group -3,5- dibromo phenyls) 2- (4- methoxybenzenes
Base) -2- carbethoxyl group vinylamines：The solid-to-liquid ratio of petroleum ether is 50g：2.9g：50ml；
In step (5), the bromo- 4- quinolinones of 3- (4- methoxyphenyls) -6- methoxyl groups -5,7- bis-, PCl3With DMF materials
Amount ratio be the ﹕ 12 of 1 ﹕ 1；The volume ratio of 3- (4- methoxyphenyls) -6- methoxyl groups -5,7- two bromo- the 4- quinolinones and water is
1:2。
Further, in step (1), at room temperature, by 10mmol 3.10g 4- nitro -2,6- dibromo methyl phenyl ethers anisoles
20mL ethanol CH3CH2In OH, 20mL Na are added under magnetic stirring2S2O4The aqueous solution, the Na2S2O4The aqueous solution in contain
Na2S2O46.96g, 3h is reacted between being gradually heating to 50-60 DEG C, cooled down, with AcOEt points of 3 extractions of 300mL, saturated common salt
Water washing, anhydrous MgSO4Dry, filtering, boil off AcOEt, white solid 4- methoxyl group -3,5- dibromo aniline 2.72g, yield
97%.4- methoxyl groups -3,5- dibromo aniline discloses its preparation method, but the 4- in patent CN1850817 in patent CN1850817
Nitro -2,6- dibromo methyl phenyl ethers anisole is reduced using Sn powder in watery hydrochloric acid, and product is the ammonium salt of chlordene stannate, rear
Substantial amounts of Sn (OH) can be produced in continuous reaction4, post processing trouble, increase extra processing cost, and serious ring can be brought
Border problem, this method energy consumption is lower by contrast, also more green.
Further, in step (2), 4- methoxyl group -3,5- dibromo aniline 8mmol 2.25g are dissolved in 30mL CH
(OMe)3In, stirring reaction 10h, reaction at room temperature finishes, and boils off excessive CH (OMe)3, obtain white solid N- (4- methoxyl groups-
3,5- dibromo phenyls) methoxy carbimide 2.56g.
Further, in step (3), N- (4- methoxyl groups -3,5- dibromo phenyl) methoxy carbimide is dissolved in anhydrous
In methanol, the sodium methoxide NaOMe of equimolar amounts is added, stirs 30min at room temperature, add the 4- methoxyphenylacetic acids of equimolar amounts
Ethyl ester, continue to react at room temperature 6h, boil off methanol, add water 40mL, filter, dry, obtain white solid N- (4- methoxyl groups -3,5- bis-
Bromophenyl) 2- (4- methoxyphenyls) -2- carbethoxyl group vinylamine 2.88g, yield 99%.
Further, in step (4), 50g diphenyl ether is taken in there-necked flask, addition 2.90g N- (4- methoxyl group -3,
5- dibromo phenyls) 2- (4- methoxyphenyls) -2- carbethoxyl group vinylamines, 250 DEG C of reaction 10min are warming up to, cools down, adds
50mL petroleum ethers, precipitation is separated out, filters, is dried in vacuo to obtain faint yellow solid 1.45g.Yield 55%.
Further, in step (5), by 15mL DMF and 15mLEt2O is placed in flask, is cooled to 0 under agitation
DEG C, instill PCl30.85mL, continue to stir 1h, add the bromo- 4- quinolinones of 3- (4- methoxyphenyls) -6- methoxyl groups -5,7- bis-
Room temperature reaction 12h is warming up to after 5mmol2.19g, 50mL water is added under ice bath, with AcOEt points of 3 extractions of 300mL, saturation food
Salt water washing, anhydrous MgSO4Dry, filtering, boil off AcOEt, the synthetic method 2.26g of white solid quinoline, yield
99%.Patent CN1850817 also discloses that the preparation method of the compound, but with POCl in patent CN18508173Solvent is made, it is right
Equipment requirement is high, and corrosivity is big, and reaction temperature is high, and energy consumption is big.
Beneficial effect：The high income of the present invention, safety and environmental protection, energy-saving and emission-reduction, total recovery 90.4%, with prior art
(38.7%) compared to improving 51.7%, the generation of discarded object in course of reaction is greatly reduced, is process route more ring
Protect.
Compared with prior art, the invention has the advantages that：
(1) prior art iron powder reducing, a large amount of iron cements can be produced, it is difficult to handle, and the environmental protection such as Solid state fermentation be present and ask
Topic, existing process byproducts are Na2SO4, cost can be reduced with coproduction；
(2) prior art uses polyphosphoric acids PPA as reaction medium, sticky, influences mass transfer and heat transfer, and post-process
Add water, produce a large amount of phosphoric acid, bring the environmental issues such as serious liquid waste processing, existing technique avoids these problems；
(3) prior art uses POCl3Make solvent and reactant, POCl3Though can reclaim, come to equipment belt serious rotten
Erosion, HCl easily is produced with the vapor effect in air, brings the environmental issues such as exhaust-gas treatment, existing technique changes POCl3For
PCl3, and dosage greatly reduces, and avoids above mentioned problem；
(4) H of catalytic amount is used2SO4Instead of playing the polyphosphoric acids of solvent action, with the PCl of stoichiometry3Instead of playing solvent
The POCl of effect3, it is that process route is more environmentally friendly, and closing with the generation for greatly reducing discarded object in course of reaction
During into N- (4- methoxyl groups -3,5- dibromo phenyl) 2- (4- methoxyphenyls) -2- carbethoxyl group vinylamines, N- (4- methoxies are used instead
Base -3,5- dibromo phenyl) methoxy carbimide is condensed with 4- methoxyphenylacetates, avoids using unstable
NaH, it is physically easier to perform reaction, new technology not only substantially increases the Atom economy of reaction, also more green.
Embodiment
Following examples only exist in illustrative purpose, without being intended to limit the scope of the present invention.
Embodiment 1
The invention provides a kind of synthetic method of quinoline, it is characterised in that comprises the following steps：
(1) at room temperature, 4- nitro -2,6- dibromo methyl phenyl ethers anisoles are dissolved in the ethanol CH of 10 times of quality3CH2In OH, in magnetic force
The Na of the lower addition 10% of stirring2S2O4The aqueous solution, 4- nitro -2,6- dibromo methyl phenyl ethers anisoles and Na2S2O4The ratio between the amount of material be 1 ﹕
2,3h is reacted between being gradually heating to 55 DEG C, is cooled down, is extracted with the ethyl acetate AcOEt of 2 times of aqueous solution volumes, coextraction 3 times,
Saturated common salt water washing, anhydrous MgSO4Dry, filtering, boil off AcOEt, white solid 4- methoxyl group -3,5- dibromo anilines, production
Rate 97%；
(2) 4- methoxyl group -3,5- dibromo anilines are dissolved in the CH (OMe) of 10 times of quality3In, stirring reaction 6h at room temperature,
Reaction finishes, and boils off excessive CH (OMe)3, white solid N- (4- methoxyl groups -3,5- dibromo phenyl) methoxy carbimide is obtained,
Yield 99%；
(3) N- (4- methoxyl groups -3,5- dibromo phenyl) methoxy carbimide is dissolved in the absolute methanol of 15 times of quality, added
15min is stirred at room temperature after entering sodium methoxide NaOMe, adds 4- methoxyphenylacetates, N- (4- methoxyl group -3,5- dibromos
Phenyl) methoxy carbimide, the ratio between the amount of sodium methoxide NaOMe and 4- methoxyphenylacetate material be the ﹕ 1 of 1 ﹕ 1, continue room temperature
Reaction, 4h, methanol is boiled off, add the water equal with methanol volume, stir 10min, filtered, dried, obtain white solid N- (4- first
Epoxide -3,5- dibromo phenyls) 2- (4- methoxyphenyls) -2- carbethoxyl group vinylamines；Yield 99%；
(4) diphenyl ether is taken in there-necked flask, addition N- (4- methoxyl groups -3,5- dibromo phenyl) 2- (4- methoxyphenyls) -
2- carbethoxyl group vinylamines, 250 DEG C of reaction 10min are warming up to, cooling, petroleum ether is added, separates out precipitation, filter, be dried in vacuo
Obtain faint yellow solid；Diphenyl ether：N- (4- methoxyl group -3,5- dibromo phenyls) 2- (4- methoxyphenyls) -2- carbethoxyl group ethene
Amine：The solid-to-liquid ratio of petroleum ether is 50g：2.9g：50ml；Yield 55%；
(5) by isometric DMF and Et2O is placed in flask, is cooled to 0 DEG C under agitation, instills PCl3, continue to stir
1h, after adding the bromo- 4- quinolinones of 3- (4- methoxyphenyls) -6- methoxyl groups -5,7- bis-, 3- (4- methoxyphenyls) -6- methoxies
The bromo- 4- quinolinones of base -5,7- two, PCl3Amount ratio with DMF materials is the ﹕ 12 of 1 ﹕ 1, is warming up to room temperature reaction 8h, is added under ice bath
Water, with AcOEt points of 3 extractions of ethyl acetate of 2 times of aqueous solution volumes, saturated common salt water washing, anhydrous MgSO4Dry, filtering,
Boil off AcOEt, the synthetic method of white solid quinoline.
Embodiment 2
The difference of embodiment 2 and embodiment 1 is：The invention provides a kind of synthetic method of quinoline, and it is special
Sign is to comprise the following steps：
In step (1), at room temperature, 4- nitro -2,6- dibromo methyl phenyl ethers anisoles are dissolved in the ethanol CH of 20 times of quality3CH2OH
In, under magnetic stirring add 30% Na2S2O4The aqueous solution, 4- nitro -2,6- dibromo methyl phenyl ethers anisoles and Na2S2O4Material amount
The ratio between be 1 ﹕ 6,7h is reacted between being gradually heating to 50 DEG C, is cooled down, is extracted with the ethyl acetate AcOEt of 4 times of aqueous solution volumes, altogether
Extraction 3 times, saturated common salt water washing, anhydrous MgSO4Dry, filtering, boil off AcOEt, white solid 4- methoxyl group -3,5- dibromos
Aniline, yield 97%.
In step (2), 4- methoxyl group -3,5- dibromo anilines are dissolved in the CH (OMe) of 20 times of quality3In, stir at room temperature
Reaction 20h is mixed, reaction finishes, and boils off excessive CH (OMe)3, obtain white solid N- (4- methoxyl groups -3,5- dibromo phenyl) methoxy
Carbimide, yield 99%.
In step (3), N- (4- methoxyl groups -3,5- dibromo phenyl) methoxy carbimide is dissolved in the anhydrous of 30 times of quality
In methanol, 45min is stirred at room temperature after adding sodium methoxide NaOMe, adds 4- methoxyphenylacetates, N- (4- methoxyl groups-
3,5- dibromo phenyls) methoxy carbimide, the ratio between the amount of sodium methoxide NaOMe and 4- methoxyphenylacetate material be the ﹕ 3 of 1 ﹕ 4,
Continue to react at room temperature, 10h, boil off methanol, add the water equal with methanol volume, stir 20min, filter, dry, obtain white solid
Body N- (4- methoxyl group -3,5- dibromo phenyls) 2- (4- methoxyphenyls) -2- carbethoxyl group vinylamines；Yield 99%.
In step (5), by isometric DMF and Et2O is placed in flask, is cooled to 0 DEG C under agitation, instills PCl3,
Continue to stir 1h, after adding the bromo- 4- quinolinones of 3- (4- methoxyphenyls) -6- methoxyl groups -5,7- bis-, 3- (4- methoxybenzenes
Base) two bromo- 4- quinolinones of -6- methoxyl groups -5,7-, PCl3Amount ratio with DMF materials is the ﹕ 24 of 1 ﹕ 2, is warming up to room temperature reaction 12h,
Water is added under ice bath, with AcOEt points of 3 extractions of ethyl acetate of 4 times of aqueous solution volumes, saturated common salt water washing, anhydrous MgSO4
Dry, filtering, boil off AcOEt, the synthetic method of white solid quinoline.
Embodiment 3
The difference of embodiment 3 and embodiment 1 is：
A kind of synthetic method of quinoline of the present invention, comprises the following steps：
In step (1), at room temperature, 4- nitro -2,6- dibromo methyl phenyl ethers anisoles are dissolved in the ethanol CH of 15 times of quality3CH2OH
In, under magnetic stirring add 20% Na2S2O4The aqueous solution, 4- nitro -2,6- dibromo methyl phenyl ethers anisoles and Na2S2O4Material amount
The ratio between be 1 ﹕ 4,5h is reacted between being gradually heating to 60 DEG C, is cooled down, is extracted with the ethyl acetate AcOEt of 3 times of aqueous solution volumes, altogether
Extraction 3 times, saturated common salt water washing, anhydrous MgSO4Dry, filtering, boil off AcOEt, white solid 4- methoxyl group -3,5- dibromos
Aniline, yield 97%；
In step (2), 4- methoxyl group -3,5- dibromo anilines are dissolved in the CH (OMe) of 15 times of quality3In, stir at room temperature
Reaction 16h is mixed, reaction finishes, and boils off excessive CH (OMe)3, obtain white solid N- (4- methoxyl groups -3,5- dibromo phenyl) methoxy
Carbimide, yield 99%.
In step (3), N- (4- methoxyl groups -3,5- dibromo phenyl) methoxy carbimide is dissolved in the anhydrous of 25 times of quality
In methanol, 25min is stirred at room temperature after adding sodium methoxide NaOMe, adds 4- methoxyphenylacetates, N- (4- methoxyl groups-
3,5- dibromo phenyls) methoxy carbimide, the ratio between the amount of sodium methoxide NaOMe and 4- methoxyphenylacetate material be the ﹕ 2 of 1 ﹕ 3,
Continue to react at room temperature, 7h, boil off methanol, add the water equal with methanol volume, stir 15min, filter, dry, obtain white solid
Body N- (4- methoxyl group -3,5- dibromo phenyls) 2- (4- methoxyphenyls) -2- carbethoxyl group vinylamines；Yield 99%.
In step (5), by isometric DMF and Et2O is placed in flask, is cooled to 0 DEG C under agitation, instills PCl3,
Continue to stir 1h, after adding the bromo- 4- quinolinones of 3- (4- methoxyphenyls) -6- methoxyl groups -5,7- bis-, 3- (4- methoxybenzenes
Base) two bromo- 4- quinolinones of -6- methoxyl groups -5,7-, PCl3Amount ratio with DMF materials is the ﹕ 18 of 1 ﹕ 1.5, is warming up to room temperature reaction
10h, water is added under ice bath, it is anhydrous with AcOEt points of 3 extractions of ethyl acetate of 3 times of aqueous solution volumes, saturated common salt water washing
MgSO4Dry, filtering, boil off AcOEt, the synthetic method of white solid quinoline.
Embodiment 4
The difference of embodiment 4 and embodiment 1 is：A kind of synthetic method of quinoline of the present invention, including it is as follows
Step：
In step (1), 4- nitros -2,6- dibromo methyl phenyl ethers anisole and ethanol CH3CH2OH mass ratio is 1:10, it is described
4- nitros -2,6- dibromos methyl phenyl ethers anisole and Na2S2O4The amount ratio of material is 1：2；At room temperature, by 10mmol 3.10g, 4- nitros-
2,6- dibromo methyl phenyl ethers anisole 20mL ethanol CH3CH2In OH, 20mL Na are added under magnetic stirring2S2O4The aqueous solution, it is described
Na2S2O4The aqueous solution in contain Na2S2O46.96g, 3h is reacted between being gradually heating to 50-60 DEG C, cooled down, with 300mL AcOEt
Divide 3 extractions, saturated common salt water washing, anhydrous MgSO4Dry, filtering, boil off AcOEt, white solid 4- methoxyl groups -3,5- bis-
Bromaniline 2.72g.
In step (2), 4- methoxyl group -3,5- dibromo anilines：CH(OMe)3Mass ratio 1:10；, will in step (2)
4- methoxyl group -3,5- dibromo aniline 8mmol 2.25g are dissolved in 30mL CH (OMe)3In, stirring reaction 10h, has reacted at room temperature
Finish, boil off excessive CH (OMe)3, obtain white solid N- (4- methoxyl groups -3,5- dibromo phenyl) methoxy carbimide 2.56g.
In step (3), N- (4- methoxyl groups -3,5- dibromo phenyl) methoxy carbimide, sodium methoxide NaOMe and 4- methoxy
The amount ratio of the material of base ethyl phenylacetate is 1:1：1, N- (4- methoxyl groups -3,5- dibromo phenyl) the methoxy carbimides and nothing
The mass ratio of water methanol is 1：15.N- (4- methoxyl groups -3,5- dibromo phenyl) methoxy carbimide is dissolved in absolute methanol, added
Enter the sodium methoxide NaOMe of equimolar amounts, stir 30min at room temperature, add the 4- methoxyphenylacetates of equimolar amounts, continue
6h is reacted at room temperature, methanol is boiled off, adds water 40mL, is filtered, dries, obtains white solid N- (4- methoxyl groups -3,5- dibromo phenyl) 2-
(4- methoxyphenyls) -2- carbethoxyl group vinylamines 2.88g.
In step (4), 50g diphenyl ether is taken in there-necked flask, adds 2.90g N- (4- methoxyl groups -3,5- dibromo phenyl)
2- (4- methoxyphenyls) -2- carbethoxyl group vinylamines, 250 DEG C of reaction 10min are warming up to, cooling, add 50mL petroleum ethers, analysis
Go out precipitation, filter, be dried in vacuo to obtain faint yellow solid 1.45g.
In step (5), the bromo- 4- quinolinones of 3- (4- methoxyphenyls) -6- methoxyl groups -5,7- bis-, PCl3With DMF materials
Amount ratio be the ﹕ 12 of 1 ﹕ 1；The volume ratio of 3- (4- methoxyphenyls) -6- methoxyl groups -5,7- two bromo- the 4- quinolinones and water is
1:2.By 15mL DMF and 15mLEt2O is placed in flask, is cooled to 0 DEG C under agitation, instills PCl30.85mL, continue to stir
1h, room temperature reaction is warming up to after adding the bromo- 4- quinolinones 5mmol 2.19g of 3- (4- methoxyphenyls) -6- methoxyl groups -5,7- bis-
12h, 50mL water is added under ice bath, with AcOEt points of 3 extractions of 300mL, saturated common salt water washing, anhydrous MgSO4Dry, mistake
Filter, boils off AcOEt, the synthetic method 2.26g of white solid quinoline.
Specific embodiment described herein is only to spirit explanation for example of the invention.Technology belonging to the present invention is led
The technical staff in domain can be made various modifications or supplement to described specific embodiment or be replaced using similar mode
Generation, but without departing from the spiritual of the present invention or surmount scope defined in appended claims.
Claims (8)
1. a kind of synthetic method of quinoline, it is characterised in that comprise the following steps：
(1) at room temperature, 4- nitro -2,6- dibromo methyl phenyl ethers anisoles are dissolved in the ethanol CH of 10-20 times of quality3CH2In OH, in magnetic force
The lower Na for adding 10-30% of stirring2S2O4The aqueous solution, 4- nitro -2,6- dibromo methyl phenyl ethers anisoles and Na2S2O4The ratio between the amount of material be
1 ﹕ 2-6,3-7h is reacted between being gradually heating to 50-60 DEG C, cooled down, extracted with the ethyl acetate AcOEt of 2-4 times of aqueous solution volume
Take, coextraction 3 times, saturated common salt water washing, anhydrous MgSO4Dry, filtering, boil off AcOEt, white solid 4- methoxyl group -3,
5- dibromo anilines；
(2) 4- methoxyl group -3,5- dibromo anilines are dissolved in the CH (OMe) of 10-20 times of quality3In, stirring reaction 6-20h at room temperature,
Reaction finishes, and boils off excessive CH (OMe)3, obtain white solid N- (4- methoxyl groups -3,5- dibromo phenyl) methoxy carbimide；
(3) N- (4- methoxyl groups -3,5- dibromo phenyl) methoxy carbimide is dissolved in the absolute methanol of 15-30 times of quality, added
15-45min is stirred at room temperature after entering sodium methoxide NaOMe, adds 4- methoxyphenylacetates, N- (4- methoxyl groups -3,5- bis-
Bromophenyl) methoxy carbimide, the ratio between the amount of sodium methoxide NaOMe and 4- methoxyphenylacetate material be 1 ﹕ 1-4 ﹕ 1-3, after
Continuous room temperature reaction, 4-10h, boils off methanol, adds the water equal with methanol volume, stirs 10-20min, filters, and dries, obtains white
Color solid N- (4- methoxyl group -3,5- dibromo phenyls) 2- (4- methoxyphenyls) -2- carbethoxyl group vinylamines；
(4) diphenyl ether is taken in there-necked flask, adds N- (4- methoxyl groups -3,5- dibromo phenyl) 2- (4- methoxyphenyls) -2- second
Oxygen carbonyl vinylamine, 250 DEG C of reaction 10min are warming up to, cooling, petroleum ether is added, separates out precipitation, filter, be dried in vacuo light
Yellow solid；
(5) by isometric DMF and Et2O is placed in flask, is cooled to 0 DEG C under agitation, instills PCl3, continue to stir 1h, add
After entering the bromo- 4- quinolinones of 3- (4- methoxyphenyls) -6- methoxyl groups -5,7- bis-, 3- (4- methoxyphenyls) -6- methoxyl group -5,
The bromo- 4- quinolinones of 7- bis-, PCl3Amount ratio with DMF materials is 1 ﹕ 1-2 ﹕ 12-24, is warming up to room temperature reaction 8-12h, adds under ice bath
Enter water, with AcOEt points of 3 extractions of ethyl acetate of 2-4 times of aqueous solution volume, saturated common salt water washing, anhydrous MgSO4Dry,
Filtering, boils off AcOEt, the synthetic method of white solid quinoline.
2. the synthetic method of quinoline according to claim 1, it is characterised in that：In step (1), the 4- nitre
Base -2,6- dibromos methyl phenyl ethers anisole and ethanol CH3CH2OH mass ratio is 1:10,4- nitros -2,6- dibromo methyl phenyl ethers anisole with
Na2S2O4The amount ratio of material is 1：2；
In step (2), 4- methoxyl group -3,5- dibromo anilines：CH(OMe)3Mass ratio 1:10；
In step (3), N- (4- methoxyl groups -3,5- dibromo phenyl) methoxy carbimide, sodium methoxide NaOMe and 4- methoxybenzene
The amount ratio of the material of ethyl acetate is 1:1：1, N- (4- methoxyl groups -3,5- dibromo phenyl) the methoxy carbimides with without water beetle
The mass ratio of alcohol is 1：15.
3. the synthetic method of quinoline according to claim 2, it is characterised in that：In step (4), diphenyl ether：
N- (4- methoxyl group -3,5- dibromo phenyls) 2- (4- methoxyphenyls) -2- carbethoxyl group vinylamines：The solid-to-liquid ratio of petroleum ether is
50g：2.9g：50ml；
In step (5), the bromo- 4- quinolinones of 3- (4- methoxyphenyls) -6- methoxyl groups -5,7- bis-, PCl3With the amount of DMF materials
Than for the ﹕ 12 of 1 ﹕ 1；The volume ratio of 3- (4- methoxyphenyls) -6- methoxyl groups -5,7- two bromo- the 4- quinolinones and water is 1:2.
4. the synthetic method of quinoline according to claim 1, it is characterised in that：In step (1), in room temperature
Under, by 10mmol 3.10g 4- nitro -2,6- dibromo methyl phenyl ethers anisole 20mL ethanol CH3CH2In OH, 20mL is added under magnetic stirring
Na2S2O4The aqueous solution, the Na2S2O4The aqueous solution in contain Na2S2O46.96g, reacted between being gradually heating to 50-60 DEG C
3h, cooling, with AcOEt points of 3 extractions of 300mL, saturated common salt water washing, anhydrous MgSO4Dry, filtering, boil off AcOEt, in vain
Color solid 4- methoxyl group -3,5- dibromo anilines 2.72g.
5. the synthetic method of quinoline according to claim 4, it is characterised in that：In step (2), by 4- methoxies
Base -3,5- dibromo aniline 8mmol 2.25g are dissolved in 30mL CH (OMe)3In, stirring reaction 10h, reaction at room temperature finishes, and boils off
Excessive CH (OMe)3, obtain white solid N- (4- methoxyl groups -3,5- dibromo phenyl) methoxy carbimide 2.56g.
6. the synthetic method of quinoline according to claim 5, it is characterised in that：In step (3), by N- (4-
Methoxyl group -3,5- dibromo phenyl) methoxy carbimide is dissolved in absolute methanol, add the sodium methoxide NaOMe of equimolar amounts, room temperature
Lower stirring 30min, the 4- methoxyphenylacetates of equimolar amounts are added, continue to react at room temperature 6h, boil off methanol, add water
40mL, filter, dry, obtain white solid N- (4- methoxyl groups -3,5- dibromo phenyl) 2- (4- methoxyphenyls) -2- carbethoxyl groups
Vinylamine 2.88g.
7. the synthetic method of quinoline according to claim 6, it is characterised in that：In step (4), 50g bis- is taken
Phenylate adds 2.90g N- (4- methoxyl groups -3,5- dibromo phenyl) 2- (4- methoxyphenyls) -2- carbethoxyl groups in there-necked flask
Vinylamine, 250 DEG C of reaction 10min are warming up to, cooling, 50mL petroleum ethers is added, separates out precipitation, filter, be dried in vacuo yellowish
Color solid 1.45g.
8. the synthetic method of quinoline according to claim 7, it is characterised in that：In step (5), by 15mL
DMF and 15mLEt2O is placed in flask, is cooled to 0 DEG C under agitation, instills PCl30.85mL, continue to stir 1h, add 3- (4-
Methoxyphenyl) be warming up to room temperature reaction 12h after the bromo- 4- quinolinones 5mmol 2.19g of -6- methoxyl groups -5,7- bis-, under ice bath plus
Enter 50mL water, with AcOEt points of 3 extractions of 300mL, saturated common salt water washing, anhydrous MgSO4Dry, filtering, boil off AcOEt,
The synthetic method 2.26g of white solid quinoline.
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