CN111440118A - New synthesis process of 4-hydroxy-7-methoxyquinoline - Google Patents
New synthesis process of 4-hydroxy-7-methoxyquinoline Download PDFInfo
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- CN111440118A CN111440118A CN202010341644.2A CN202010341644A CN111440118A CN 111440118 A CN111440118 A CN 111440118A CN 202010341644 A CN202010341644 A CN 202010341644A CN 111440118 A CN111440118 A CN 111440118A
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- methoxyquinoline
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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
- C07D215/22—Oxygen atoms attached in position 2 or 4
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- Organic Chemistry (AREA)
- Quinoline Compounds (AREA)
Abstract
The invention discloses a new synthesis process of 4-hydroxy-7-methoxyquinoline, which comprises the following steps: s1, uniformly mixing trimethyl orthoformate and isopropylidene malonate; s2, carrying out reflux reaction; s3, adding 3, 4-dimethoxyaniline, and continuing reflux reaction; s4, centrifuging and collecting a BA-1 product crude product; s5, pulping the BA-1 crude product with methanol, and centrifugally collecting a refined solid; s6, drying the refined solid in an oven at 45-50 ℃ for 22-25 h; s7, adding diphenyl ether into a second reaction kettle, adding 200kg of BA-1 refined solid, and heating to react for 2-3 h; s8, sampling, detecting and centrifuging to obtain a BA-2 crude product; s9, adding dichloromethane and a BA-2 crude product into a third reaction kettle, stirring for 1h at normal temperature, and centrifuging to obtain 4-hydroxy-7-methoxyquinoline; s10, drying to obtain a finished product of 4-hydroxy-7-methoxyquinoline. The invention changes the feeding sequence on the basis of the existing cyclization process, strictly controls the reaction temperature and time and improves the yield.
Description
Technical Field
The invention relates to the technical field of biochemical engineering, in particular to a novel synthesis process of 4-hydroxy-7-methoxyquinoline.
Background
With the development of biotechnology, a great number of compounds with new functions are developed, and new compounds with resistance to various difficult and complicated diseases are searched all over the world, so that a great number of new structures and new structural compounds are generated in the process of developing the new compounds, and further, useful and therapeutic molecules are searched for in the great number of new compounds.
In the existing overweight synthesis of quinoline derivatives, the cyclization process must be carried out at a higher temperature, and the energy consumption is relatively high. Therefore, a new process for synthesizing the quinoline derivatives with low energy consumption needs to be developed.
Disclosure of Invention
In order to solve the existing problems, the invention provides a new synthesis process of 4-hydroxy-7-methoxyquinoline. The invention is realized by the following technical scheme.
The new synthesis process of 4-hydroxy-7-methoxyquinoline includes the following steps:
s1, cleaning a first reaction kettle, drying, cooling to room temperature, closing a bottom valve of the reaction kettle, pumping in 1000kg of trimethyl orthoformate, stirring, adding 250kg of 220-membered isopropylidene malonate, stirring for 20-30min, and uniformly mixing;
s2, slowly heating to 60-65 ℃, timing when reflux occurs, and refluxing for 1.5-2 h;
s3, closing a steam valve, slightly vacuumizing, putting 250kg of 3, 4-dimethoxyaniline 220-; detecting that the 3, 4-dimethoxyaniline is less than or equal to 1.5 percent after the reaction is qualified, and cooling to room temperature;
s4, centrifuging and collecting a BA-1 product crude product;
s5, pulping the crude product BA-1 with methanol, and centrifugally collecting a solid fine BA-1 product;
s6, drying the refined solid in an oven at 45-50 ℃ for 22-25h, detecting that the water content is less than or equal to 1%, and packaging;
s7, adding 650kg of diphenyl ether 550-containing organic silicon, adding 200kg of BA-1 refined product, heating to 190 ℃ of 170-containing organic silicon, and carrying out heat preservation reaction for 2-3 h;
s8, sampling and detecting, wherein the content of qualified BA-1 is less than or equal to 1%, cooling to room temperature, and centrifuging to obtain a BA-2 crude product;
s9, adding dichloromethane and a BA-2 crude product into a third reaction kettle, wherein the mass ratio of the dichloromethane to the BA-2 crude product is 1:1, stirring at normal temperature for 1h, and centrifuging to obtain 4-hydroxy-7-methoxyquinoline;
s10, drying to obtain a finished product of 4-hydroxy-7-methoxyquinoline.
Preferably, the first reaction kettle is a 2000L reaction kettle, and the second reaction kettle is a 1000L reaction kettle.
Preferably, in the step S7, the aminolysis intermediate is added at 170-180 ℃.
Preferably, the mass ratio of the dichloromethane in the step S9 to the crude BA-2 is 1: 1.
Preferably, the reaction is stopped immediately 1h after the end of the addition of the material in step S9.
The invention has the beneficial effects that:
the new synthesis process of 4-hydroxy-7-methoxyquinoline adopts a method of recycling trimethyl orthoformate, so that unit consumption is reduced; the feeding temperature of the aminolysis process is controlled to be 60-65 ℃; the cyclization process comprises the steps of heating diphenyl ether, strictly controlling the temperature interval, adding an aminolysis intermediate, strictly controlling the time and the temperature according to the completion of material addition after the reaction is finished, and improving the yield.
Compared with the prior art: the invention reduces unit consumption by optimizing the process; the method changes the feeding sequence on the basis of the prior cyclization process, strictly controls the reaction temperature and time and improves the yield.
The chemical reaction conditions of the invention are mild, the yield of each step of reaction is as high as about 90%, the total yield of the product is 75.3-79.3%, and the raw materials used in the invention are cheap and easily available, safe, low-toxic, environment-friendly, simple in preparation process and suitable for industrial production.
Drawings
FIG. 1 shows the results of detection of 4-hydroxy-7-methoxyquinoline in example 1.
Detailed Description
The technical scheme of the invention is more fully described in detail and in detail by combining the drawings and the specific embodiments.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The new synthesis process of 4-hydroxy-7-methoxyquinoline includes the following steps:
s1, cleaning a 2000L reaction kettle, drying and cooling to room temperature, closing a bottom valve of the reaction kettle, pumping 900kg of trimethyl orthoformate, adding 240kg of cyclic isopropylidene malonate in a stirring manner, stirring for 20min, and uniformly mixing;
s2, slowly heating to about 64 ℃, timing when reflux occurs, and refluxing for about 2 hours;
s3, closing a steam valve, slightly vacuumizing, putting 232kg of 3, 4-dimethoxyaniline under the vacuum degree of less than or equal to-0.05 Mpa, and continuously slightly refluxing and carrying out heat preservation reaction for 2-3 hours; after the detection reaction is qualified, the 3, 4-dimethoxyaniline is less than or equal to 1.5 percent and is cooled to the room temperature;
s4, centrifuging, and collecting 415.5kg of crude product BA-1;
s5, pulping the BA-1 crude product with methanol, and centrifugally collecting 394.7kg of BA-1 fine solid;
s6, drying the refined solid in an oven at 45-50 ℃ for about 24 hours, detecting that the moisture is less than or equal to 1%, and packaging;
S7.1000L reaction kettle, diphenyl ether 600kg, adding 200kg of BA-1 refined product, heating to 180 ℃, and keeping the temperature for reaction for 2 hours;
s8, sampling and detecting, wherein the content of qualified BA-1 is less than or equal to 1%, cooling to room temperature, and centrifuging 126kg of BA-2 crude product;
s9, adding dichloromethane into another clean reaction kettle: stirring the crude BA-2 product at normal temperature for 1h, and centrifuging to obtain 120kg of 4-hydroxy-7-methoxyquinoline;
s10, drying in an oven to obtain a finished product of the 4-hydroxy-7-methoxyquinoline.
The detection result of the finally obtained 4-hydroxy-7-methoxyquinoline by gas chromatography is shown in figure 1, wherein the peak number 1 represents 4-hydroxy-7-methoxyquinoline, and the content of the 4-hydroxy-7-methoxyquinoline reaches 99.4%.
It is to be understood that the described embodiments are merely individual embodiments of the invention, rather than all embodiments. All other implementations made by those skilled in the art without any inventive step based on the embodiments of the present invention belong to the protection scope of the present invention.
Claims (5)
- A new synthesis process of 4-hydroxy-7-methoxyquinoline is characterized in that: the method comprises the following steps:s1, cleaning a first reaction kettle, drying, cooling to room temperature, closing a bottom valve of the reaction kettle, pumping in 1000kg of trimethyl orthoformate, stirring, adding 250kg of 220-membered isopropylidene malonate, stirring for 20-30min, and uniformly mixing;s2, slowly heating to 60-65 ℃, timing when reflux occurs, and refluxing for 1.5-2 h;s3, closing a steam valve, slightly vacuumizing, putting 250kg of 3, 4-dimethoxyaniline 220-; detecting that the 3, 4-dimethoxyaniline is less than or equal to 1.5 percent after the reaction is qualified, and cooling to room temperature;s4, centrifuging and collecting a BA-1 product crude product;s5, pulping the crude product BA-1 with methanol, and centrifugally collecting a solid fine BA-1 product;s6, drying the refined solid in an oven at 45-50 ℃ for 22-25h, detecting that the water content is less than or equal to 1%, and packaging;s7, adding 650kg of diphenyl ether 550-containing organic silicon, adding 200kg of BA-1 refined product, heating to 190 ℃ of 170-containing organic silicon, and carrying out heat preservation reaction for 2-3 h;s8, sampling and detecting, wherein the content of qualified BA-1 is less than or equal to 1%, cooling to room temperature, and centrifuging to obtain a BA-2 crude product;s9, adding dichloromethane and a BA-2 crude product into a third reaction kettle, wherein the mass ratio of the dichloromethane to the BA-2 crude product is 1:1, stirring at normal temperature for 1h, and centrifuging to obtain 4-hydroxy-7-methoxyquinoline;s10, drying to obtain a finished product of 4-hydroxy-7-methoxyquinoline.
- 2. The new process for synthesizing 4-hydroxy-7-methoxyquinoline as claimed in claim 1, wherein the first reaction vessel is 2000L reaction vessel, and the second reaction vessel is 1000L reaction vessel.
- 3. The novel process for synthesizing 4-hydroxy-7-methoxyquinoline as claimed in claim 1, wherein: in the step S7, the ammonolysis of the intermediate is started at 170-180 ℃.
- 4. The novel process for synthesizing 4-hydroxy-7-methoxyquinoline as claimed in claim 1, wherein: and the mass ratio of the dichloromethane to the crude BA-2 in the step S9 is 1: 1.
- 5. The novel process for synthesizing 4-hydroxy-7-methoxyquinoline as claimed in claim 1, wherein: and stopping the reaction immediately after 1h when the material addition in the step S9 is finished.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010341644.2A CN111440118A (en) | 2020-04-27 | 2020-04-27 | New synthesis process of 4-hydroxy-7-methoxyquinoline |
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| CN202010341644.2A CN111440118A (en) | 2020-04-27 | 2020-04-27 | New synthesis process of 4-hydroxy-7-methoxyquinoline |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115368301A (en) * | 2022-07-18 | 2022-11-22 | 常州琦诺生物科技有限公司 | Preparation method of 4-hydroxy-7-methoxyquinoline |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115368301A (en) * | 2022-07-18 | 2022-11-22 | 常州琦诺生物科技有限公司 | Preparation method of 4-hydroxy-7-methoxyquinoline |
| CN115368301B (en) * | 2022-07-18 | 2023-10-20 | 常州琦诺生物科技有限公司 | Preparation method of 4-hydroxy-7-methoxyquinoline |
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Application publication date: 20200724 |