CN108101842A - A kind of preparation method of 2- hydroxyls -4- carboxyl quinolines - Google Patents
A kind of preparation method of 2- hydroxyls -4- carboxyl quinolines Download PDFInfo
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- CN108101842A CN108101842A CN201711469792.7A CN201711469792A CN108101842A CN 108101842 A CN108101842 A CN 108101842A CN 201711469792 A CN201711469792 A CN 201711469792A CN 108101842 A CN108101842 A CN 108101842A
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- acetic acid
- carboxyl
- glacial acetic
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- quinolines
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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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
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Abstract
The invention belongs to chemosynthesis technical fields, are specifically related to a kind of preparation method of 2 hydroxyl of cinchocaine hydrochloride intermediate, 4 carboxyl quinoline.This method comprises the following steps:(1) glacial acetic acid is inserted in reaction kettle, is added with stirring isatin, malonic acid, sodium acetate；(2) solution in step (1) is heated to reflux, has flowed back and be down to room temperature；(3) material carries out removing glacial acetic acid under reduced pressure in step (2)（Recovery）；(4) it is evaporated off adding in deionized water stirring and crystallizing in the material after glacial acetic acid in step (3), rejection filter after crystallization, is first eluted with glacial acetic acid, again with methanol elution, wet product baking material obtains 2 hydroxyl, 4 carboxyl quinoline.This synthetic method is obtained target product, is simplified operation, shorten the production cycle, reduce production cost using the technique of " cooking all things in one pot "；Products obtained therefrom purity is high, high income, is suitable for large-scale production.
Description
Technical field
The invention belongs to chemosynthesis technical fields, are specifically related to a kind of cinchocaine hydrochloride intermediate 2- hydroxyls -4-
The preparation method of carboxyl quinoline.
Background technology
2- hydroxyl -4- carboxyl quinolines are the important intermediates of cinchocaine hydrochloride, and in catalysis, molecular conductor, luminous material
The fields such as material, molecular magnet, nonlinear optics have broad application prospects.
Synthesis route is mainly isatin at present and aceticanhydride back flow reaction obtains acetylisatin, and N- acetylisatins are again in hydrogen
Hydrolysis, rearrangement obtain product in aqueous solution of sodium oxide, to obtain the high product of liquid phase purity and also need to refine.Its N- acetylisatin
It gets rid of that material process smell is very big during preparation, is unsuitable for present safety and environmental protection situation.And it is used in hydrolysis, rearrangement process substantial amounts of
Water, so as to generate a large amount of waste liquids.The method is of high cost, cumbersome, the amount of labour is big, the cycle is long, yield is low, safety and environmental protection pressure
The shortcomings of big.Once document mentions isatin, malonic acid obtains 2- hydroxyl -4- carboxyl quinolines under microwave irradiation, but this scheme
It is not suitable for mass producing.
Patent CN106966975A is disclosed a kind of improved synthesizes chloro- 1 hydrogen of 4--quinoline-2-one -3- carboxylics by isatoic anhydride
The method of sour methyl esters.It is acidified again after being reacted in this method using isatoic anhydride in DMF with dimethyl malenate by first filtering
Mode purified, hence it is evident that reduce the dosage of water and hydrochloric acid, reduce the generation of waste water.In this method, using danger during preparation
Dangerous chemical substance sodium hydride, it is flammable, explosive that sodium hydride meets water, humid air releasing hydrogen.Therefore, security risk is high in production.
The content of the invention
The purpose of the present invention provides a kind of preparation side of 2- hydroxyls -4- carboxyl quinolines aiming at above-mentioned defect
Method.This method is reacted using isatin, malonic acid, sodium acetate, glacial acetic acid, direct back flow reaction, and reaction finishes recycling design
, organic solvent emission amount is few, environmentally friendly；Reaction is simple, safe operation.Using the technical program prepare 2- hydroxyls-
4- carboxyl quinolines not only can significantly shorten the production cycle, reduce cost and labor intensity, moreover it is possible to improve the yield of product.
The present invention is achieved by the following technical solution：
A kind of preparation method of 2- hydroxyls -4- carboxyl quinolines, which is characterized in that comprise the following steps:
(1) glacial acetic acid is inserted in reaction kettle, is added with stirring isatin, malonic acid, sodium acetate；
(2) solution in step (1) is heated to reflux, has flowed back and be down to room temperature；
(3) material carries out removing glacial acetic acid under reduced pressure in step (2)；
(4) it is evaporated off adding in deionized water stirring and crystallizing in the material after glacial acetic acid in step (3), rejection filter after crystallization, first
It eluted with cold glacial acetic acid, eluted again with cold methanol, wet product baking material obtains 2- hydroxyl -4- carboxyl quinolines.
Reaction equation is as follows：
In the preparation method of above-mentioned 2- hydroxyl -4- carboxyl quinolines, sodium acetate can use sodium carbonate, bicarbonate in the step (1)
Sodium substitutes.
In the preparation method of above-mentioned 2- hydroxyl -4- carboxyl quinolines, in the step (1), to isatin, malonic acid, acetic acid
Sodium, the weight ratio of glacial acetic acid are:1:1.3-2:0.1-0.3:3-8.
Preferably, in the preparation method of above-mentioned 2- hydroxyl -4- carboxyl quinolines, in the step (1), to isatin, the third two
Acid, sodium acetate, the weight ratio of glacial acetic acid are:1:1.6:0.15:4.
In the preparation method of above-mentioned 2- hydroxyl -4- carboxyl quinolines, reflux time is small for 3-9 in the step (2)
When.
In the preparation method of above-mentioned 2- hydroxyl -4- carboxyl quinolines, in the step (4) in deionized water and step (1)
The weight ratio of isatin is 2-7:1.
Preferably, in the preparation method of above-mentioned 2- hydroxyl -4- carboxyl quinolines, deionized water and step in the step (4)
Suddenly the weight ratio of isatin is 3 in (1):1.
In the preparation method of above-mentioned 2- hydroxyl -4- carboxyl quinolines, in the step (4), the weight of glacial acetic acid and isatin
Than for 0.25-0.5:1, the weight ratio of methanol and isatin is 0.25-0.5:1.
Preferably, in the preparation method of above-mentioned 2- hydroxyl -4- carboxyl quinolines, in the step (4), glacial acetic acid and isatin
Weight ratio be 0.4:1, the weight ratio of methanol and isatin is 0.4:1.
Preferably, the preparation method of above-mentioned 2- hydroxyl -4- carboxyl quinolines, including as follows:
(1) 300-800kg glacial acetic acid is inserted in 1000L reaction kettles, is added with stirring 100kg isatin, 130-200kg the third two
Acid, 10-30kg sodium acetates or sodium carbonate or sodium acid carbonate, obtain mixed liquor；
(2) solution in step (1) is heated to reflux, when back flow reaction 3-9 is small, has reacted and be down to room temperature；
(3) material carries out removing glacial acetic acid under reduced pressure in step (2)（It can apply mechanically）；
(4) it is evaporated off adding in 200-700kg deionized water stirring and crystallizings in the material after glacial acetic acid in step (3), first with cold
The elution of 25-50kg glacial acetic acid is eluted again with cold 25-50kg methanol, is obtained 2- hydroxyl -4- carboxyl quinoline wet products, is dried after rejection filter
It is dry, obtain 2- hydroxyl -4- carboxyl quinolines.
It is furthermore preferred that the preparation method of above-mentioned 2- hydroxyl -4- carboxyl quinolines, detailed step are as follows：
(1) 400kg glacial acetic acid is inserted in 1000L reaction kettles, is added with stirring 100kg isatin, 160kg malonic acid, 15kg vinegar
Sour sodium, obtains mixed liquor；
(2) solution in step (1) is heated to reflux, when back flow reaction 6 is small, has reacted and be down to room temperature；
(3) material carries out removing glacial acetic acid under reduced pressure in step (2)（It can apply mechanically）；
(4) it is evaporated off adding in 300kg deionized water stirring and crystallizings in the material after glacial acetic acid in step (3), solid is first after filtering
It is eluted with cold 40kg glacial acetic acid, again with cold 4kg methanol elution, obtains 2- hydroxyl -4- carboxyl quinoline wet products, 45- after rejection filter
When 70 DEG C of baking materials 24 are small, 2- hydroxyl -4- carboxyl quinolines are obtained.
In the preparation method of the 2- hydroxyl -4- carboxyl quinolines of the present invention, the glacial acetic acid that step (3) is steamed out can be applied mechanically.
In the present invention, refer in particular to as non-, all amounts, part is unit of weight, and all raw material, equipment can be from
Market is bought.
Compared with prior art, the present invention is beneficial in that：
1st, this synthetic method is obtained target product, simplifies operation, shorten the production cycle, dropped using the technique of " cooking all things in one pot "
Low production cost；
2nd, in the preparation method of 2- hydroxyl -4- carboxyl quinolines of the invention, the glacial acetic acid that step (3) is steamed out can be applied mechanically, molten
Agent consumption is less, while also avoids the generation of a large amount of waste water；
3rd, product purity height, high income are obtained, it is safe and environment-friendly to be suitable for large-scale production.
Specific embodiment
The present invention is further described with reference to specific embodiment, so that those skilled in the art knows more about
The present invention, but be not intended to limit the present invention.
Embodiment 1
400kg glacial acetic acid is inserted in 1000L reaction kettles, is added with stirring 100kg isatin, 160kg malonic acid, 15kg acetic acid
Sodium.Reflux is heated to, when back flow reaction 6 is small.It has reacted and has been down to room temperature, carried out removing glacial acetic acid under reduced pressure, added in 300kg and go
Ionized water stirring and crystallizing, solid is first eluted with cold 40kg glacial acetic acid, eluted again with cold 40kg methanol after filtering, obtains 2- hydroxyls
Base -4- carboxyl quinoline wet products when 45-70 DEG C of baking material 24 is small after rejection filter, obtain 2- hydroxyl -4- carboxyl quinoline 124.7kg, yield
97%, liquid phase purity 99.6%.
Embodiment 2
400kg recycling glacial acetic acid is inserted in 1000L reaction kettles, is added with stirring 100kg isatin, 160kg malonic acid, 15kg vinegar
Sour sodium.Reflux is heated to, when back flow reaction 6 is small.It has reacted and has been down to room temperature, carried out removing glacial acetic acid under reduced pressure, add in 300kg
Deionized water stirring and crystallizing, solid is first eluted with cold 30kg glacial acetic acid, eluted again with cold 30kg methanol after filtering, obtains 2-
Hydroxyl -4- carboxyl quinoline wet products when 45-70 DEG C of baking material 24 is small after rejection filter, obtain 2- hydroxyl -4- carboxyl quinoline 125kg, yield
97.3%, liquid phase purity 99.6%.
Embodiment 3
300kg glacial acetic acid is inserted in 1000L reaction kettles, is added with stirring 50kg isatin, 100kg malonic acid, 15kg sodium carbonate.
Reflux is heated to, when back flow reaction 4 is small.Reacted and be down to room temperature, remove under reduced pressure glacial acetic acid, add in 300kg go from
Sub- water stirring and crystallizing, solid is first eluted with cold 20kg glacial acetic acid, eluted again with cold 10kg methanol after filtering, obtains 2- hydroxyls
Base -4- carboxyl quinoline wet products when 45-70 DEG C of baking material 24 is small after rejection filter, obtain 2- hydroxyl -4- carboxyl quinoline 61.7kg, yield
96%, liquid phase purity 99.5%.
Claims (10)
1. a kind of preparation method of 2- hydroxyls -4- carboxyl quinolines, which is characterized in that comprise the following steps:
(1) glacial acetic acid is inserted in reaction kettle, is added with stirring isatin, malonic acid, sodium acetate；
(2) solution in step (1) is heated to reflux, has flowed back and be down to room temperature；
(3) material carries out removing glacial acetic acid under reduced pressure in step (2)；
(4) it is evaporated off adding in deionized water stirring and crystallizing in the material after glacial acetic acid in step (3), rejection filter after crystallization, first
It is eluted with glacial acetic acid, again with methanol elution, wet product baking material obtains 2- hydroxyl -4- carboxyl quinolines.
2. the preparation method of 2- hydroxyls -4- carboxyl quinolines according to claim 1, which is characterized in that the step (1）In
Sodium acetate can use sodium carbonate, sodium acid carbonate to substitute.
3. the preparation method of 2- hydroxyls -4- carboxyl quinolines according to claim 1, which is characterized in that the step (1)
In, the weight ratio to isatin, malonic acid, sodium acetate, glacial acetic acid is:1:1.3-2:0.1-0.3:3-8.
4. the preparation method of 2- hydroxyls -4- carboxyl quinolines according to claim 3, which is characterized in that the step (1)
In, the weight ratio to isatin, malonic acid, sodium acetate, glacial acetic acid is:1:1.6:0.15:4.
5. the preparation method of 2- hydroxyls -4- carboxyl quinolines according to claim 1, which is characterized in that in the step (2)
When reflux time is 3-9 small.
6. the preparation method of 2- hydroxyls -4- carboxyl quinolines according to claim 1, which is characterized in that in the step (4)
Deionized water and the weight ratio of isatin in step (1) are 2-7:1.
7. the preparation method of 2- hydroxyls -4- carboxyl quinolines according to claim 6, which is characterized in that in the step (4)
The optimum weight ratio of deionized water and isatin in step (1) is 3:1.
8. the preparation method of 2- hydroxyls -4- carboxyl quinolines according to claim 1, which is characterized in that the step (4)
In, the weight ratio of glacial acetic acid and isatin is 0.25-0.5:1, the weight ratio of methanol and isatin is 0.25-0.5:1.
9. the preparation method of 2- hydroxyls -4- carboxyl quinolines according to claim 8, which is characterized in that the step (4)
In, the optimum weight ratio of glacial acetic acid and isatin is 0.4:1, the optimum weight ratio of methanol and isatin is 0.4:1.
10. the preparation method of 2- hydroxyls -4- carboxyl quinolines according to claim 1, which is characterized in that including walking as follows
Suddenly:
(1) 300-800kg glacial acetic acid is inserted in 1000L reaction kettles, is added with stirring 100kg isatin, 130-200kg the third two
Acid, 10-30kg sodium acetates or sodium carbonate or sodium acid carbonate, obtain mixed liquor；
(2) solution in step (1) is heated to reflux, when back flow reaction 3-9 is small, has reacted and be down to room temperature；
(3) material carries out removing glacial acetic acid under reduced pressure in step (2)；
(4) it is evaporated off adding in 200-700kg deionized water stirring and crystallizings in the material after glacial acetic acid in step (3), it is solid after filtering
Body is first eluted with cold 25-50kg glacial acetic acid, eluted again with cold 25-50kg methanol, and it is wet to obtain 2- hydroxyl -4- carboxyl quinolines
Product dry after rejection filter, obtain 2- hydroxyl -4- carboxyl quinolines.
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| CN201711469792.7A CN108101842B (en) | 2017-12-29 | 2017-12-29 | Preparation method of 2-hydroxy-4-carboxyquinoline |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20140075082A (en) * | 2012-12-10 | 2014-06-19 | 주식회사 이큐스앤자루 | Dihydroquinoline derivatives, preparation method thereof and pharmaceutically composition containing the same as an active ingredient for preventing or treatment of disease by influenza A virus |
| CN104302624A (en) * | 2012-04-10 | 2015-01-21 | 邓迪大学 | Anti-malarial agents |
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- 2017-12-29 CN CN201711469792.7A patent/CN108101842B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104302624A (en) * | 2012-04-10 | 2015-01-21 | 邓迪大学 | Anti-malarial agents |
| KR20140075082A (en) * | 2012-12-10 | 2014-06-19 | 주식회사 이큐스앤자루 | Dihydroquinoline derivatives, preparation method thereof and pharmaceutically composition containing the same as an active ingredient for preventing or treatment of disease by influenza A virus |
Non-Patent Citations (1)
| Title |
|---|
| KEN S. FELDMAN ET AL.: "Synthesis of the pentacyclic core of lihouidine", 《TETRAHEDRON LETTERS》 * |
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Denomination of invention: A preparation method of 2-hydroxy-4-carboxyquinoline Effective date of registration: 20220616 Granted publication date: 20210430 Pledgee: Shandong Pingyuan Rural Commercial Bank Co.,Ltd. Pledgor: SHANDONG CHENGHUI SHUANGDA PHARMACEUTICAL CO.,LTD. Registration number: Y2022980007784 |
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Date of cancellation: 20230726 Granted publication date: 20210430 Pledgee: Shandong Pingyuan Rural Commercial Bank Co.,Ltd. Pledgor: SHANDONG CHENGHUI SHUANGDA PHARMACEUTICAL CO.,LTD. Registration number: Y2022980007784 |