CN106946774B - The preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline - Google Patents
The preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline Download PDFInfo
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- 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
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Abstract
The invention discloses a kind of preparation methods of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline.The described method includes: under anhydrous sulfanilic acid effect, 3- benzyloxy -4- aminoanisole and 3,3- diethoxy ethyl propionate carries out condensation reaction, obtain 3- (3- benzyloxy -4- methoxyphenyl) imido grpup ethyl propionate, purifying is not needed to be separated, it is directly added into higher boiling non-protonic solvent and carries out cyclization reaction, obtain 7- benzyloxy-6-methoxyl-4-hydroxyquinoline, reaction equation is as follows.Whole process, easy to operate, eliminate intermediate steps isolates and purifies link；Preparation method of the invention is easy to operate and safety, reaction condition are mild, high income, consersion unit is required it is low and easy to industrialized production；3- benzyloxy -4- aminoanisole can be restored to obtain by starting material 2- methoxyl group -5- nitrophenol by oxygen atom hydrocarbonylation, nitro, and starting material 2- methoxyl group -5- nitrophenol is cheap and easily-available.
Description
Technical field
The invention belongs to organic compounds to synthesize field, more particularly, to a kind of 7- benzyloxy -6- methoxyl group -4- hydroxyl
The preparation method of base quinoline.
Background technique
The structure of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline is as shown in following Formula I, and wherein Bn is benzyl.It is a variety of
Important intermediate in anti-tumor drug and antibacterials preparation process.
Currently, the preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline mainly include the following types:
The first preparation method: patent document CN104817497, CN102675282 and WO2006108059 disclose 7-
The preparation method of benzyloxy-6-methoxyl-4-hydroxyquinoline, using 4- hydroxy 3-methoxybenzene ethyl ketone as starting material, through benzyl
Change, nitrification, restore, be condensed to yield target product with formic acid esters.This method denitrification step is using the stronger concentrated nitric acid of corrosivity
Nitrating agent, and this method post-processing is cumbersome, and total recovery is low.
Second of preparation method: patent document CN104211686 is former for starting with 3- benzyloxy -4- methoxy nitrobenzene
Material is condensed, last cyclization through nitro reduction, with 5- (methoxymethylene) -2,2- dimethyl -1,3- dioxanes -4,6- diketone
Obtain target product.This method final step cyclization needs under inert gas protection, at 220 DEG C or higher temperature into
Row, severe reaction conditions, side reaction is more, and yield is low.
The third preparation method, patent document CN102030705 are former for starting with 3- methoxyl group -4- benzyloxy acetophenone
Material reacts through nitration reaction, with n,N-Dimethylformamide dimethoxym ethane, finally carries out nitro reduction and is condensed to yield target production
Object.The denitrification step of this method is nitrating agent using the stronger concentrated nitric acid of corrosivity, is required production equipment high；And when reacting
Between it is long, energy consumption is high.
For the defect of above-mentioned each method, the mild easy to operate and safety of one kind, reaction condition, high income are needed, to anti-
Answer equipment requirement low and the novel preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline easy to industrialized production.
Summary of the invention
Therefore, the purpose of the present invention is to provide a kind of easy to operate and safety, reaction condition is mild, high income, to anti-
Answer equipment requirement low and the preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline easy to industrialized production.
Above-mentioned purpose according to the present invention, the present invention provide the preparation side of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline
Method, this method comprises:
3- benzyloxy -4- aminoanisole (i.e. compounds Ⅳ) and 3,3- diethoxy ethyl propionate carry out condensation reaction,
Obtain 3- (3- benzyloxy -4- methoxyphenyl) imido grpup ethyl propionate (i.e. compound V)；Then, in higher boiling aprotic
In the presence of solvent, 3- (3- benzyloxy -4- methoxyphenyl) imido grpup ethyl propionate carries out cyclization reaction, obtains 7- benzyloxy -
6- methoxyl group -4- oxyquinoline (i.e. compound I).Reaction equation is as follows:
Wherein, Bn is benzyl.
The preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline of the invention is described specifically below.
The condensation reaction of the 3- benzyloxy -4- aminoanisole and 3,3- diethoxy ethyl propionate is that solvent free is anti-
It answers.
More specifically, 3- benzyloxy -4- aminoanisole and 3,3- diethoxy ethyl propionate is anhydrous to first in catalyst
In the presence of base benzene sulfonic acid, condensation reaction is carried out.Wherein, the additional amount of anhydrous sulfanilic acid can be 3- benzyloxy -4- first
1wt%~10wt% of oxygroup aniline quality, preferably 3%~5wt% are specifically as follows 3.7wt%.
In the condensation reaction, 3- benzyloxy -4- aminoanisole and 3, the molar ratio of 3- diethoxy ethyl propionate
It can be 1:1~1.5, preferably 1:1；Reaction temperature can be 60 DEG C~120 DEG C, preferably 95 DEG C~105 DEG C；It was reacting
Using lamellae detection reaction carry out degree in journey, fully reacting is usually 2~5 hours, and preferably 3 hours.
Under anhydrous sulfanilic acid effect, 3- benzyloxy -4- aminoanisole and 3,3- diethoxy ethyl propionate
Condensation reaction is carried out, product 3- (3- benzyloxy -4- methoxyphenyl) imido grpup ethyl propionate is obtained, the product is pure without separating
Change, can directly carry out the cyclization reaction of next step.
In the presence of higher boiling non-protonic solvent, 3- (3- benzyloxy -4- methoxyphenyl) imido grpup ethyl propionate into
Row cyclization reaction obtains 7- benzyloxy-6-methoxyl-4-hydroxyquinoline.
The higher boiling non-protonic solvent can be diphenyl ether.In cyclization reaction, the dosage of the solvent is and chemical combination
The volume mass ratio of object V is 3ml/g~10ml/g, can be 6ml/g.
Using lamellae detection reaction carry out degree during cyclization reaction, fully reacting is usually 4~12 hours, excellent
It is selected as 6~8 hours；Cyclization reaction temperature can be 150 DEG C~215 DEG C, preferably 170 DEG C~200 DEG C.
In the preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline of the invention, 3,3- diethoxy propionic acid second
Ester is commercially available to obtain (traditional Chinese medicines reagent).
3- benzyloxy -4- aminoanisole can be adopted to be prepared with the conventional methods in the field.The present invention is preferably following
Method is made: under ammonium chloride effect, 3- benzyloxy -4- methoxy nitrobenzene (i.e. compound III) is restored with reducing agent
Reaction, obtains 3- benzyloxy -4- aminoanisole (i.e. compounds Ⅳ).Specifically, reaction equation is as follows:
Wherein, the molar ratio of ammonium chloride and compound III are 5~2:1, preferably 3:1.
" nitro is reduced to amino " is reacted common reducing agent, preferably iron powder or zinc for this field by the reducing agent
Powder.
In reduction reaction, molar ratio 1:2~6 of compound III and reducing agent, preferably 1:4.6.
The reduction reaction carries out in proton solvent, and proton solvent is this field conventional protic solvent, preferred alcohol-
Aqueous solution, wherein 4~1:1 of volume ratio of ethyl alcohol and water, preferably 2:1.
The volume mass ratio of the solvent and compound III can be 8ml/g~20ml/g, for example, can be 12ml/g.
The reaction temperature of the reduction reaction can be 50~85 DEG C；It is anti-using lamellae detection during reduction reaction
Degree should be carried out, fully reacting is usually 1~4 hour, and preferably 1.5 hours.
3- benzyloxy -4- methoxy nitrobenzene (i.e. compound III) can be adopted to be prepared with the conventional methods in the field.
The preferred following methods of the present invention are made: in the presence of acid binding agent, 2- methoxyl group -5- nitrophenol (i.e. compound ii) and halogenation
Benzyl carries out alkylation reaction, obtains 3- benzyloxy -4- methoxy nitrobenzene.
Wherein, halogenation benzyl is benzyl chloride or cylite, and preferably cylite.
2- methoxyl group -5- nitrophenol is commercially available to obtain (traditional Chinese medicines reagent).
In above-mentioned alkylation reaction, the molar ratio of 2- methoxyl group -5- nitrophenol and halogenation benzyl is 1:1~2, preferably 1:
1.1。
The acid binding agent is the such common acid binding agent of reaction in this field, such as Anhydrous potassium carbonate, natrium carbonicum calcinatum, triethylamine
Or pyridine, preferably Anhydrous potassium carbonate.In above-mentioned alkylation reaction, 2- methoxyl group -5- nitrophenol and Anhydrous potassium carbonate rub
You are than being 1:1~2, preferably 1:1.49.
Above-mentioned alkylation reaction carries out in aprotic solvent, and the aprotic solvent is that the aprotic of this field routine is molten
Agent, preferably n,N-Dimethylformamide or n,N-dimethylacetamide.Wherein, aprotic solvent and 2- methoxyl group -5- nitro
The volume mass ratio of phenol is 5ml/g~15ml/g, for example, can be 10ml/g.
The reaction temperature of above-mentioned alkylation reaction can be 35~45 DEG C；It is anti-using lamellae detection during alkylation reaction
Degree should be carried out, fully reacting is usually 2~7 hours, and preferably 4 hours.
Beneficial effect
Compared with prior art, the preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline of the invention has as follows
Advantage:
In the preparation process in accordance with the present invention, anhydrous sulfanilic acid effect under, 3- benzyloxy -4- aminoanisole with
3,3- diethoxy ethyl propionates react to obtain 3- (3- benzyloxy -4- methoxyphenyl) imido grpup ethyl propionate, reactant compared with
It is completely converted into product, does not need to be separated purifying, higher boiling non-protonic solvent is directly added into and carries out cyclization reaction, is obtained final
Product 7- benzyloxy-6-methoxyl-4-hydroxyquinoline.Whole process, easy to operate, eliminate intermediate steps isolates and purifies ring
Section.
3- benzyloxy -4- aminoanisole can pass through oxygen atom hydrocarbon by starting material 2- methoxyl group -5- nitrophenol
Change, nitro restores to obtain.
Preparation method of the invention, starting material 2- methoxyl group -5- nitrophenol is cheap and easily-available, and operation is easy, right
For consersion unit without particular/special requirement, reagent utilization rate is high, meets environmental requirement, high income (three step total recoverys are up to 80% or more),
Post-processing is simple, application easy to industrialized production.
Specific embodiment
Preparation method of the invention is further illustrated below by embodiment, but the scope of the present invention is not limited to these realities
Apply example.
In embodiment below, using 2- methoxyl group -5- nitrophenol as starting material, also by oxygen atom hydrocarbonylation, nitro
Former, imines prepares (i.e. condensation reaction) and cyclization reaction, obtains target compound 7- benzyloxy -6- methoxyl group -4- hydroxyl quinoline
Quinoline, reaction equation are as follows:
Embodiment 1
The preparation of 3- benzyloxy -4- methoxy nitrobenzene
2- methoxyl group -5- nitrophenol (10.0g, 59.2mmol), Carbon Dioxide are sequentially added in the there-necked flask of 250ml
Cylite (11.1g, 64.9mmol) is added dropwise under stiring in potassium (12.2g, 88.4mmol) and n,N-Dimethylformamide 100ml,
Drop, which finishes, is warming up to 40 DEG C of reactions 4 hours, has been reacted therebetween using thin-layer chromatography (ethyl acetate: petroleum ether (V:V)=2:1) detection
Entirely.After the reaction was completed, reaction solution is poured into 500ml ice water after being cooled to room temperature, is stirred, is filtered, it is dry that 14.1g is light yellow
Solid, yield 93.1%.
1H-NMR(400MHz,DMSO-d6)δ:3.88(s,3H,-CH3)；5.18(s,2H,-CH2)；7.13~7.15 (d,
1H,ArH)；7.33~7.46 (m, 5H, ArH)；7,81~7,82 (d, 1H, ArH)；7.87~7.90 (dd, 1H, ArH)).
The preparation of 3- benzyloxy -4- aminoanisole
3- benzyloxy -4- methoxy nitrobenzene (10.0g, 38.6mmol), chlorination are sequentially added in the there-necked flask of 250ml
Ammonium (6.2g, 115.8mmol), iron powder (9.95g, 177.6mmol) and alcohol-water (V:V=2:1) 120ml.85 DEG C are stirred at reflux
1.5 hours, fully reacting is detected using thin-layer chromatography (ethyl acetate: petroleum ether (V:V)=1:2) therebetween, is then filtered while hot.
80ml boiling water is added into filtrate, then lets cool to room temperature, filters, dry 8.65g dark red powder solid, yield
97.9%.
1H-NMR(400MHz,DMSO-d6)δ:3.60(s,3H,-CH3)；4.65(s,2H,-NH2)；4.95(s,2H,-
CH2)；6.06~6.08 (dd, 1H, ArH)；6.31~6.32 (d, 1H, ArH)；6.64~6.66 (d, 1H, ArH)；7.29~
7.47(m,5H,ArH)。
The preparation of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline
First be added in the there-necked flask of 100ml 3,3- diethoxy ethyl propionate (4.84ml, 25.0mmol), 0.21g without
Water p-methyl benzenesulfonic acid stirs 15 minutes at room temperature, adds 3- benzyloxy -4- aminoanisole (5.73g, 25.0mmol),
It is warming up to 95 DEG C to react 3 hours, fully reacting is detected using thin-layer chromatography (ethyl acetate: petroleum ether (V:V)=1:2) therebetween.
Be cooled to room temperature, obtain 3- (3- benzyloxy -4- methoxyphenyl) imido grpup ethyl propionate, product without isolate and purify can directly into
Row cyclization reaction.
49ml diphenyl ether is added into above-mentioned reaction product, is slowly heated to 180 DEG C of generations cyclization reaction 6 hours, thin layer
Chromatography (ethyl acetate: petroleum ether (V:V)=2:1) detection reaction terminates, and is cooled to room temperature, solid is precipitated, filter, use petroleum ether
(30ml × 2) sufficiently wash filter cake, dry, obtain product 6.33g, yield 90.1%, high performance liquid chromatography detection purity 98.2%.
1H-NMR(400MHz,DMSO-d6)δ:3.81(s,3H,-CH3)；5.35(s,2H,-CH2)；5.92~5.94 (d,
1H,ArH)；7.04(s,1H,ArH)；7.34~7.48 (m, 6H, ArH)；7.74~7.76 (d, 1H, ArH)；11.56(s,1H,-
OH)。
Embodiment 2
Embodiment 1 is pressed in the preparation of 3- benzyloxy -4- methoxy nitrobenzene and 3- benzyloxy -4- aminoanisole.
The preparation of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline
First be added in the there-necked flask of 100ml 3,3- diethoxy ethyl propionate (4.84ml, 25.0mmol), 0.57g without
Water p-methyl benzenesulfonic acid stirs 15 minutes at room temperature, adds 3- benzyloxy -4- aminoanisole (5.73g, 25.0mmol),
It is warming up to 60 DEG C to react 5 hours, fully reacting is detected using thin-layer chromatography (ethyl acetate: petroleum ether (V:V)=1:2) therebetween.
Be cooled to room temperature, obtain 3- (3- benzyloxy -4- methoxyphenyl) imido grpup ethyl propionate, product without isolate and purify can directly into
Row cyclization reaction.
49ml diphenyl ether is added into above-mentioned reaction product, is slowly heated to 180 DEG C of generations cyclization reaction 6 hours, thin layer
Chromatography (ethyl acetate: petroleum ether (V:V)=2:1) detection reaction terminates, and is cooled to room temperature, solid is precipitated, filter, use petroleum ether
(30ml × 2) sufficiently wash filter cake, dry, obtain product 6.39g, yield 91.0%, high performance liquid chromatography detection purity 96.3%.
Embodiment 3
Embodiment 1 is pressed in the preparation of 3- benzyloxy -4- methoxy nitrobenzene and 3- benzyloxy -4- aminoanisole.
The preparation of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline
It is anhydrous that 3,3- diethoxy ethyl propionate (4.84ml, 25.0mmol), 0.1g are first added in the there-necked flask of 100ml
P-methyl benzenesulfonic acid stirs 15 minutes at room temperature, adds 3- benzyloxy -4- aminoanisole (5.73g, 25.0mmol), rises
Temperature to 95 DEG C react 5 hours, therebetween using thin-layer chromatography (ethyl acetate: petroleum ether (V:V)=1:2) detect fully reacting.It is cold
But to room temperature, 3- (3- benzyloxy -4- methoxyphenyl) imido grpup ethyl propionate is obtained, product is without isolating and purifying and can directly carry out
Cyclization reaction.
25ml diphenyl ether is added into above-mentioned reaction product, is slowly heated to 180 DEG C of generations cyclization reaction 6 hours, thin layer
Chromatography (ethyl acetate: petroleum ether (V:V)=2:1) detection reaction terminates, and is cooled to room temperature, solid is precipitated, filter, use petroleum ether
(30ml × 2) sufficiently wash filter cake, dry, obtain product 6.22g, yield 88.6%, high performance liquid chromatography detection purity 96.1%.
Embodiment 4
Embodiment 1 is pressed in the preparation of 3- benzyloxy -4- methoxy nitrobenzene and 3- benzyloxy -4- aminoanisole.
First be added in the there-necked flask of 100ml 3,3- diethoxy ethyl propionate (7.26ml, 37.5mmol), 0.21g without
Water p-methyl benzenesulfonic acid stirs 15 minutes at room temperature, adds 3- benzyloxy -4- aminoanisole (5.73g, 25.0mmol),
It is warming up to 115 DEG C to react 3 hours, fully reacting is detected using thin-layer chromatography (ethyl acetate: petroleum ether (V:V)=1:2) therebetween.
Be cooled to room temperature, obtain 3- (3- benzyloxy -4- methoxyphenyl) imido grpup ethyl propionate, product without isolate and purify can directly into
Row cyclization reaction.
49ml diphenyl ether is added into above-mentioned reaction product, is slowly heated to 180 DEG C of generations cyclization reaction 6 hours, thin layer
Chromatography (ethyl acetate: petroleum ether (V:V)=2:1) detection reaction terminates, and is cooled to room temperature, solid is precipitated, filter, use petroleum ether
(30ml × 2) sufficiently wash filter cake, dry, obtain product 5.93g, yield 84.4%, high performance liquid chromatography detection purity 97.6%.
Embodiment 5
Embodiment 1 is pressed in the preparation of 3- benzyloxy -4- methoxy nitrobenzene and 3- benzyloxy -4- aminoanisole.
First be added in the there-necked flask of 100ml 3,3- diethoxy ethyl propionate (4.84ml, 25.0mmol), 0.21g without
Water p-methyl benzenesulfonic acid stirs 15 minutes at room temperature, adds 3- benzyloxy -4- aminoanisole (5.37g, 25.0mmol),
It is warming up to 95 DEG C to react 3 hours, fully reacting is detected using thin-layer chromatography (ethyl acetate: petroleum ether (V:V)=1:2) therebetween.
Be cooled to room temperature, obtain 3- (3- benzyloxy -4- methoxyphenyl) imido grpup ethyl propionate, product without isolate and purify can directly into
Row cyclization reaction.
80ml diphenyl ether is added into above-mentioned reaction product, is slowly heated to 215 DEG C of generations cyclization reaction 4 hours, thin layer
Chromatography (ethyl acetate: petroleum ether (V:V)=2:1) detection reaction terminates, and is cooled to room temperature, solid is precipitated, filter, use petroleum ether
(30ml × 2) sufficiently wash filter cake, dry, obtain product 5.89g, yield 83.9%, high performance liquid chromatography detection purity 94.8%.
Embodiment 6
Embodiment 1 is pressed in the preparation of 3- benzyloxy -4- methoxy nitrobenzene and 3- benzyloxy -4- aminoanisole.
First be added in the there-necked flask of 100ml 3,3- diethoxy ethyl propionate (4.84ml, 25.0mmol), 0.21g without
Water p-methyl benzenesulfonic acid stirs 15 minutes at room temperature, adds 3- benzyloxy -4- aminoanisole (5.37g, 25.0mmol),
It is warming up to 95 DEG C to react 3 hours, fully reacting is detected using thin-layer chromatography (ethyl acetate: petroleum ether (V:V)=1:2) therebetween.
Be cooled to room temperature, obtain 3- (3- benzyloxy -4- methoxyphenyl) imido grpup ethyl propionate, product without isolate and purify can directly into
Row cyclization reaction.
25ml diphenyl ether is added into above-mentioned reaction product, is slowly heated to 150 DEG C of generations cyclization reaction 12 hours, thin layer
Chromatography (ethyl acetate: petroleum ether (V:V)=2:1) detection reaction terminates, and is cooled to room temperature, solid is precipitated, filter, use petroleum ether
(30ml × 2) sufficiently wash filter cake, dry, obtain product 6.25g, yield 89.0%, high performance liquid chromatography detection purity 98.0%.
Claims (10)
1. a kind of preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline, this method comprises:
3- benzyloxy -4- aminoanisole and 3,3- diethoxy ethyl propionate exist in catalyst anhydrous sulfanilic acid
Under, condensation reaction is carried out, 3- (3- benzyloxy -4- methoxyphenyl) imido grpup ethyl propionate is obtained, which is without molten
Agentization reaction；Then, obtained product 3- (3- benzyloxy -4- methoxyphenyl) imido grpup ethyl propionate does not need to be separated pure
Change, be directly added into higher boiling non-protonic solvent and carry out cyclization reaction, obtain 7- benzyloxy-6-methoxyl-4-hydroxyquinoline,
Wherein, in the condensation reaction, the additional amount of anhydrous sulfanilic acid is 3- benzyloxy -4- aminoanisole quality
1wt%~10wt%；
The higher boiling non-protonic solvent is diphenyl ether；
In the cyclization reaction, the reaction time is 4~12 hours, and cyclization reaction temperature is 150 DEG C~215 DEG C.
2. the preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline according to claim 1, characterized in that in institute
It states in condensation reaction, 3- benzyloxy -4- aminoanisole and 3, the molar ratio of 3- diethoxy ethyl propionate is 1:1~1.5.
3. the preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline according to claim 2, characterized in that in institute
State in condensation reaction, the additional amount of anhydrous sulfanilic acid be 3- benzyloxy -4- aminoanisole quality 3wt%~
5wt%；The molar ratio of 3- benzyloxy -4- aminoanisole and 3,3- diethoxy ethyl propionate is 1:1.
4. the preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline according to any one of claim 1 to 3,
It is characterized in, in the condensation reaction, reaction temperature is 60 DEG C~120 DEG C, and the reaction time is 2~5 hours.
5. the preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline according to claim 4, characterized in that in institute
It states in condensation reaction, reaction temperature is 95 DEG C~105 DEG C.
6. the preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline according to claim 1, characterized in that in ring
It closes in reaction, the dosage of the solvent is the volume mass with 3- (3- benzyloxy -4- methoxyphenyl) imido grpup ethyl propionate
Than for 3ml/g~10ml/g.
7. the preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline according to claim 6, characterized in that in ring
It closes in reaction, the reaction time is 6~8 hours, and cyclization reaction temperature is 170 DEG C~200 DEG C.
8. the preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline according to claim 1, characterized in that described
3- benzyloxy -4- aminoanisole obtains as follows:
Under ammonium chloride effect, 3- benzyloxy -4- methoxy nitrobenzene and reducing agent carry out reduction reaction, obtain 3- benzyloxy -
4- aminoanisole,
Wherein, the reducing agent is iron powder or zinc powder, and reaction dissolvent is ethanol-water solution.
9. the preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline according to claim 8, characterized in that described
3- benzyloxy -4- methoxy nitrobenzene obtains as follows:
In the presence of acid binding agent, 2- methoxyl group -5- nitrophenol and halogenation benzyl carry out alkylation reaction, obtain 3- benzyloxy -4- first
Oxygroup nitrobenzene,
Wherein, the halogenation benzyl is benzyl chloride or cylite；
The acid binding agent is Anhydrous potassium carbonate, natrium carbonicum calcinatum, triethylamine or pyridine；
Solvent for use is N,N-dimethylformamide or DMAC N,N' dimethyl acetamide in the alkylation reaction.
10. the preparation method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline according to claim 9, characterized in that institute
Stating acid binding agent is Anhydrous potassium carbonate.
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| CN102030705A (en) * | 2009-09-30 | 2011-04-27 | 上海睿智化学研究有限公司 | Synthesis method of 7- benzyloxy-6-methoxyl-4-hydroxyquinoline |
| CN104211686A (en) * | 2013-06-03 | 2014-12-17 | 天津隆博基因药物科技有限公司 | Quinoline derivatives and treatment use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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