CN107417612A - A kind of synthetic method of quinoline - Google Patents

A kind of synthetic method of quinoline Download PDF

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Publication number
CN107417612A
CN107417612A CN201710627093.4A CN201710627093A CN107417612A CN 107417612 A CN107417612 A CN 107417612A CN 201710627093 A CN201710627093 A CN 201710627093A CN 107417612 A CN107417612 A CN 107417612A
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dibromo
methoxyphenyls
methoxyl groups
methoxyl
room temperature
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陈鲲
肖竹平
马祥
樊静
朱海亮
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Guangzhou University
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Guangzhou University
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    • 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

Abstract

The invention discloses a kind of synthetic method of quinoline, comprise the following steps：

Description

A kind of synthetic method of quinoline
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 chloro- bromoquinolines of 5,7- bis- of 3- (4- methoxyphenyls) -6- methoxyl groups -4- are the new tectorigenins found recently Isostere, it can suppress the necrosis of liver cell, prevent the unbalance of intrahepatic fat and protein, make transaminase and glutamyl The active normalization of transferase, it is therefore prevented that the development of liver fibrosis, play a part of protecting liver, recover liver function.With tertiary fourth Base hydrogen peroxide acts on the liver cell of mouse, then takes the compound, it is found that it can protect mouse from t-butyl peroxy Change the infringement of the liver cancer cells of hydrogen induction.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, 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, 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) N- (4- methoxyl group -3,5- dibromo phenyls) 2- (4- methoxyphenyls) -2- carbethoxyl group vinylamines are dissolved in The ethanol CH of 10-20 times of quality3CH2In OH, dense H is slowly added under agitation2SO4, its N- (4- methoxyl group -3,5- dibromobenzene Base) 2- (4- methoxyphenyls) -2- carbethoxyl groups vinylamines and H2SO4The amount ratio of material be 1 ﹕ 0.01-0.1, finish and be heated to 50-60 DEG C, stirring reaction 6-18h, cooling, water is added, stir 30min, white solid 3- (4- methoxyphenyls) -6- of filtering The bromo- 4- quinolinones of methoxyl group -5,7- two；Yield 96%.
(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 chloro- bromoquinolines of 5,7- bis- of white solid 3- (4- methoxyphenyls) -6- methoxyl groups -4-.
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), N- (4- methoxyl groups -3,5- dibromo phenyl) 2- (4- the methoxyphenyls) -2- Carbethoxyl group vinylamine and ethanol CH3CH2OH mass ratio is 1:10, N- (4- methoxyl groups -3, the 5- dibromo phenyl) 2- (4- Methoxyphenyl) -2- carbethoxyl groups vinylamine and H2SO4The amount ratio of material be 1 ﹕ 0.01, the ethanol CH3CH2It is OH, dense H2SO4Volume ratio with water is 30：0.16：80；
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), by N- (4- methoxyl groups -3,5- dibromo phenyl) 2- (4- methoxyphenyls) -2- Carbethoxyl group vinylamine 6mmol 2.90g are dissolved in 30mL ethanol CH3CH2In OH, the dense H of 0.16mL are slowly added under agitation2SO4, Finish and be heated to 50-60 DEG C, stirring reaction 6h, cooling, add 80mL water, stir 30min, white solid 3- (the 4- first of filtering Phenyl) the bromo- 4- quinolinones 2.53g of -6- methoxyl groups -5,7- bis-, yield 96%.
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, white solid 3- (4- methoxyphenyls) -6- methoxyl groups -4- is chloro- 5,7- bis- bromoquinoline 2.26g, yield 99%.Patent CN1850817 also discloses that the preparation method of the compound, but in patent With POCl in CN18508173Solvent is made, high to equipment requirement, 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, above mentioned problem is avoided；
(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) N- (4- methoxyl group -3,5- dibromo phenyls) 2- (4- methoxyphenyls) -2- carbethoxyl group vinylamines are dissolved in 10 The ethanol CH of times quality3CH2In OH, dense H is slowly added under agitation2SO4, its N- (4- methoxyl groups -3,5- dibromo phenyl) 2- (4- methoxyphenyls) -2- carbethoxyl groups vinylamine and H2SO4The amount ratio of material be 1 ﹕ 0.01, the ethanol CH3CH2It is OH, dense H2SO4Volume ratio with water is 30：0.16：80；Finish and be heated to 50 DEG C, stirring reaction 6h, cooling, add water, stir 30min, The two bromo- 4- quinolinones of white solid 3- (4- methoxyphenyls) -6- methoxyl groups -5,7- of filtering；Yield 96%.
(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 chloro- bromoquinolines of 5,7- bis- of white solid 3- (4- methoxyphenyls) -6- methoxyl groups -4-.
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 (4), by N- (4- methoxyl groups -3,5- dibromo phenyl) 2- (4- methoxyphenyls) -2- carbethoxyl group second Enamine is dissolved in the ethanol CH of 20 times of quality3CH2In OH, dense H is slowly added under agitation2SO4, its N- (4- methoxyl group -3,5- bis- Bromophenyl) 2- (4- methoxyphenyls) -2- carbethoxyl groups vinylamines and H2SO4The amount ratio of material be 1 ﹕ 0.1, finish and be heated to 60 DEG C, stirring reaction 12h, cooling, water is added, stir 30min, white solid 3- (4- methoxyphenyls) -6- methoxies of filtering The bromo- 4- quinolinones of base -5,7- two；Yield 96%.
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 chloro- bromoquinolines of 5,7- bis- of white solid 3- (4- methoxyphenyls) -6- methoxyl groups -4-.
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 (4), by N- (4- methoxyl groups -3,5- dibromo phenyl) 2- (4- methoxyphenyls) -2- carbethoxyl group second Enamine is dissolved in the ethanol CH of 15 times of quality3CH2In OH, dense H is slowly added under agitation2SO4, its N- (4- methoxyl group -3,5- bis- Bromophenyl) 2- (4- methoxyphenyls) -2- carbethoxyl groups vinylamines and H2SO4The amount ratio of material be 1 ﹕ 0.06, finish and be heated to 55 DEG C, stirring reaction 18h, cooling, water is added, stir 30min, white solid 3- (4- methoxyphenyls) -6- methoxies of filtering The bromo- 4- quinolinones of base -5,7- two；Yield 96%.
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 chloro- bromoquinolines of 5,7- bis- of white solid 3- (4- methoxyphenyls) -6- methoxyl groups -4-.
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- dibromos methyl phenyl ethers anisole adds 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), N- (4- methoxyl groups -3,5- dibromo phenyl) 2- (4- the methoxyphenyls) -2- carbethoxyl groups Vinylamine and ethanol CH3CH2OH mass ratio is 1:10, N- (4- methoxyl groups -3,5- dibromo phenyl) 2- (the 4- methoxybenzenes Base) -2- carbethoxyl groups vinylamine and H2SO4The amount ratio of material be 1 ﹕ 0.01, the ethanol CH3CH2OH, dense H2SO4With water Volume ratio is 30：0.16：80 (value ranges of the claim 1 without volume ratio)；In step (4), by N- (4- methoxyl groups -3,5- Dibromo phenyl) 2- (4- methoxyphenyls) -2- carbethoxyl group vinylamine 6mmol 2.90g are dissolved in 30mL ethanol CH3CH2In OH, The dense H of 0.16mL are slowly added under stirring2SO4, finish and be heated to 50-60 DEG C, stirring reaction 6h, cooling, add 80mL water, stirring 30min, the bromo- 4- quinolinones 2.53g of white solid 3- (4- methoxyphenyls) -6- methoxyl groups -5,7- bis- of filtering.
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 chloro- bromoquinoline 2.26g of 5,7- bis- of white solid 3- (4- methoxyphenyls) -6- methoxyl groups -4-.
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) N- (4- methoxyl group -3,5- dibromo phenyls) 2- (4- methoxyphenyls) -2- carbethoxyl group vinylamines are dissolved in 10-20 The ethanol CH of times quality3CH2In OH, dense H is slowly added under agitation2SO4, its N- (4- methoxyl groups -3,5- dibromo phenyl) 2- (4- methoxyphenyls) -2- carbethoxyl groups vinylamine and H2SO4The amount ratio of material be 1 ﹕ 0.01-0.1, finish and be heated to 50-60 DEG C, stirring reaction 6-18h, cooling, water is added, stir 30min, white solid 3- (4- methoxyphenyls) -6- methoxies of filtering The bromo- 4- quinolinones of base -5,7- two；
(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 chloro- bromoquinolines of 5,7- bis- of white solid 3- (4- methoxyphenyls) -6- methoxyl groups -4-.
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), the N- (4- methoxyl group -3,5- dibromo phenyls) 2- (4- methoxyphenyls) -2- carbethoxyl groups vinylamines and ethanol CH3CH2OH mass ratio For 1:10, N- (4- methoxyl groups -3,5- dibromo phenyl) 2- (4- the methoxyphenyls) -2- carbethoxyl groups vinylamines and H2SO4's The amount ratio of material is 1 ﹕ 0.01, the ethanol CH3CH2OH, dense H2SO4Volume ratio with water is 30：0.16：80；
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), by N- (4- Methoxyl group -3,5- dibromo phenyls) 2- (4- methoxyphenyls) -2- carbethoxyl group vinylamine 6mmol 2.90g are dissolved in 30mL ethanol CH3CH2In OH, the dense H of 0.16mL are slowly added under agitation2SO4, finish and be heated to 50-60 DEG C, stirring reaction 6h, cooling, add Enter 80mL water, stir 30min, the bromo- 4- quinolinones of white solid 3- (4- methoxyphenyls) -6- methoxyl groups -5,7- bis- of filtering 2.53g。
8. the synthetic method of quinoline according to claim 7, it is characterised in that：, will in step (5) 15mLDMF and 15mLEt2O is placed in flask, is cooled to 0 DEG C under agitation, instills PCl30.85mL, continue to stir 1h, add 3- Room temperature reaction 12h, ice bath are warming up to after the bromo- 4- quinolinones 5mmol 2.19g of (4- methoxyphenyls) -6- methoxyl groups -5,7- bis- Lower addition 50mL water, with AcOEt points of 3 extractions of 300mL, saturated common salt water washing, anhydrous MgSO4Dry, filtering, boil off The chloro- bromoquinoline 2.26g of 5,7- bis- of AcOEt, white solid 3- (4- methoxyphenyls) -6- methoxyl groups -4-.
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