CN117186000A - A kind of preparation method of quinoline compound - Google Patents
A kind of preparation method of quinoline compound Download PDFInfo
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- CN117186000A CN117186000A CN202311030040.6A CN202311030040A CN117186000A CN 117186000 A CN117186000 A CN 117186000A CN 202311030040 A CN202311030040 A CN 202311030040A CN 117186000 A CN117186000 A CN 117186000A
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Abstract
The application discloses a preparation method of quinoline compounds, and belongs to the field of organic synthesis. In the method, in an organic solvent, a compound of the formula I and an acylating reagent are subjected to an acylation reaction under the action of Lewis acid to obtain a reaction solution; then adding hydrochloric acid solution into the reaction solution to quench the reaction to obtain quenching solution; and adding specific inorganic salt into the quenching liquid, uniformly mixing, filtering, taking solid, dissolving in a second solvent, regulating the pH value of the second solvent to 5-6, separating liquid, taking an organic phase, and concentrating to obtain the compound shown in the formula II. The method reduces the loss of the acylated product, and the yield reaches more than 77 percent, and the purity is not lower than 93 percent.
Description
Technical Field
The application relates to the field of organic synthesis, in particular to a preparation method of quinoline compounds.
Background
Quinoline compounds have important value in the field of biological medicine. For example, patent WO2008156102A1 discloses pyrazolone core structure compounds having a fused heterocyclic system attached thereto, 1- (8-hydroxyquinolin-5-yl) acetone as PDE3/4 dual inhibitors, as important intermediates for the synthesis of such compounds. In addition, chinese patent CN103298790a discloses a novel multifunctional neuroprotective compound, which can be used for preparing a medicament with cytoprotective effect, for preventing or treating diseases related to neurodegeneration, including parkinson, cerebral apoplexy, etc., and 1- (8-hydroxyquinolin-5-yl) ethanone is an important intermediate for synthesizing the compound.
In the prior art, a method for preparing 1- (8-hydroxyquinolin-5-yl) ethanone by using 8-hydroxyquinoline as a starting material and performing Friedel-crafts acylation is a common method for preparing the compounds.
For example, the Friedel and Crafts reaction with-hydroxyquinoline (Journal of the American Chemical Society,1930, vol.52, p. 4433-4435) A process for the preparation of 1- (8-hydroxyquinolin-5-yl) ethanone is reported herein, using acetyl chloride as the acylating agent, aluminum trichloride as the Lewis acid, nitrobenzene as the solvent to prepare the above compound, quenching with hydrochloric acid, removing nitrobenzene, recrystallising in hot water, yield 45%.
Patent WO2008104781A1 also discloses a process for the preparation of 1- (8-hydroxyquinolin-5-yl) ethanone using acetyl chloride as the reactant, aluminium trichloride as the lewis acid, dichloroethane as the solvent to give the above-mentioned compounds, quenching with hydrochloric acid, basifying the mixture with aqueous ammonia in the post-treatment, extracting with dichloromethane, stirring with activated carbon and silica gel, filtering, washing, distilling, adding diisopropyl ether, stirring, filtering, drying in vacuo to give the product in 39% yield.
For the reported preparation methods of the above two documents, the applicant believes that since the hydroxyl group of the product 1- (8-hydroxyquinolin-5-yl) ethanone is a hydrophilic group, a considerable part of the product dissolves in the aqueous phase during the work-up, which results in difficult collection and further results in a reaction with a high conversion, the isolation yield remains low.
Disclosure of Invention
The present application has been made to solve the above problems, and an object of the present application is to provide a method for producing a quinoline compound with a simple post-treatment and a high yield.
The application provides a preparation method of quinoline compounds, which has the characteristics of being used for converting a compound of a formula I into a compound of a formula II,
in the above, R 1 Is a C1-C10 alkyl group,
the method comprises the following steps:
in an organic solvent, carrying out acylation reaction on a compound of the formula I and an acylating reagent under the action of Lewis acid to obtain a reaction solution;
adding aqueous hydrochloric acid solution into the reaction solution for quenching reaction to obtain a quenching solution;
adding inorganic salt into the quenching liquid, uniformly mixing, filtering, taking solid, dissolving in a second solvent, regulating the pH value of the second solvent to 5-6, separating liquid, taking an organic phase, concentrating to obtain a compound of the formula II,
wherein the inorganic salt is any one or more of hydrogen phosphate, dihydrogen phosphate or sulfate.
The preparation method of the quinolinone compound provided by the application can also have the following characteristics: wherein the inorganic salt is selected from any one or more of potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, lithium sulfate, sodium sulfate, cesium sulfate, ammonium sulfate, cobalt sulfate or nickel sulfate.
The preparation method of the quinoline compound provided by the application can also have the following characteristics: wherein the mass ratio of the inorganic salt to the reaction liquid is 0.05-0.1:1.
The preparation method of the quinoline compound provided by the application can also have the following characteristics: wherein the concentration of the hydrochloric acid aqueous solution is 0.01-12mol/L; specifically, 1mol/L is selected.
The preparation method of the quinoline compound provided by the application can also have the following characteristics: wherein, the volume ratio of the hydrochloric acid aqueous solution to the reaction solution is 1: (1.5-3); specifically, 1:2.
the preparation method of the quinoline compound provided by the application can also have the following characteristics: wherein the reagent for adjusting the pH value is selected from any one of sodium hydroxide and potassium hydroxide.
The preparation method of the quinoline compound provided by the application can also have the following characteristics: wherein the molar ratio of the compound of formula I to the Lewis acid is 1:2-3.
The preparation method of the quinoline compound provided by the application can also have the following characteristics: wherein the concentration of the compound of the formula I relative to the organic solvent is 0.5-1.0mol/L.
The preparation method of the quinoline compound provided by the application can also have the following characteristics: wherein the organic solvent is any one or more of dichloroethane, carbon disulfide, nitrobenzene, petroleum ether, tetrachloroethane and chloroform.
The preparation method of the quinoline compound provided by the application can also have the following characteristics: wherein the Lewis acid is any one of aluminum trichloride, ferric chloride, stannic chloride and titanium tetrachloride.
The preparation method of the quinoline compound provided by the application can also have the following characteristics: wherein the molar ratio of the compound 1 to the acylating agent is 1: (1-1.5).
The preparation method of the quinoline compound provided by the application can also have the following characteristics: wherein the second solvent is any one or more of DCM, tetrahydrofuran and ethyl acetate.
The preparation method of the quinoline compound provided by the application can also have the following characteristics: wherein the dosage of the second solvent relative to the compound of the formula I is 5-15mL/g; specifically, 8mL/g is selected.
Effects and effects of the application
According to the preparation method of the quinoline compound, in the post-treatment process, the specific inorganic salt is firstly added into the reaction solution quenched by the hydrochloric acid aqueous solution to separate out more hydrochloride of the product from the system, and then the hydrochloride of the product obtained by separation is dissolved and regulated to a proper pH value to enable the product to be free, so that the product is further purified.
Detailed Description
The present application will be described in detail with reference to the following examples, so that the technical means, the creation characteristics, the achievement of the purpose and the effect achieved by the present application are easily understood.
In the examples described below, each of the reaction materials was a commercially available product unless otherwise specified.
Example 1 ]
Preparation of Compound 3a
This example provides a process for the preparation of compound 3a, having the following formula:
the method comprises the following steps:
100g of compound 1a (0.69 mol,1.0 eq), 65.16g of acetyl chloride (0.83 mol,1.2 eq), 230.68g of aluminum trichloride (1.73 mol,2.5 eq) and 1000mL of dichloroethane are added to a reaction vessel, the temperature is raised to 70 ℃, the reaction is carried out for 16 hours, 2000mL of 1mol/L hydrochloric acid is used for quenching, 82.79g of sodium sulfate (5% of the mass sum of compound 1a, acetyl chloride, aluminum trichloride and dichloroethane) is added, after uniform mixing, solids are separated out, filtration is carried out, the solids are added to 800mL of DCM for dissolution, the pH is adjusted to 5-6 with sodium hydroxide, the liquid is separated, and the organic phase is concentrated to obtain compound 3a, the yield is 82.8%, and the content of compound 3a in the product is 95.3% (HPLC purity).
Example 2 ]
Screening of pH values during post-treatment
In this example, the following method was used to screen the pH during post-treatment, and the reaction formula was as follows:
the method comprises the following steps:
100g of Compound 1a (0.69 mol,1.0 eq), 65.16g of acetyl chloride (0.83 mol,1.2 eq), 230.68g of aluminum trichloride (1.73 mol,2.5 eq) and 1000mL of dichloroethane were added to a reaction vessel, the temperature was raised to 70 ℃, the reaction was allowed to proceed for 16 hours, quenched with hydrochloric acid (2000 mL,1 mol/L), 82.79g of sodium sulfate was added, a large amount of solids was precipitated after uniform mixing, filtration was performed, the solids were added to 800mL of DCM, the pH of the solution was adjusted with sodium hydroxide solids, the solution was separated to obtain an aqueous phase and an organic phase, the organic phase was concentrated under reduced pressure to obtain Compound 3a, the yield of Compound 3a was calculated, and the content of Compound 3a in the aqueous phase and the purity of the product separated from the organic phase were measured using HPLC. The specific results are shown in Table 1.
TABLE 1 screening of pH values during post-treatment
| Sequence number | pH value of | Product content in aqueous phase | Product yield | Purity of |
| 1 | 2-3 | 15.55％ | 64.4％ | 94.3％ |
| 2 | 5-6 | 0.06％ | 82.8％ | 95.3％ |
| 3 | 8-9 | 7.11％ | 74.7％ | 95.5％ |
As shown in the table above, in the post-treatment process, the pH value of the system is adjusted to 5-6, so that the free product is beneficial to entering the organic phase, and the product yield is improved.
Example 3 ]
Screening of the salt species added during the post-treatment
In this example, the types of salts added during the post-treatment were selected as follows:
100g of Compound 1a (0.69 mol,1.0 eq), 65.16g of acetyl chloride (0.83 mol,1.2 eq), 230.68g of aluminum trichloride (1.73 mol,2.5 eq) and 1000mL of dichloroethane were added to a reaction vessel, the temperature was raised to 70 ℃, the reaction was allowed to proceed for 16 hours, quenched with hydrochloric acid (2000 mL,1 mol/L), 82.79g of an inorganic salt was added, a large amount of solids was precipitated after uniform mixing, filtration was performed, the solids were added to 800mL of DCM, the pH of the solution was adjusted to 5-6 with sodium hydroxide solids, the aqueous phase and the organic phase were separated, the organic phase was concentrated under reduced pressure to give Compound 3a, the yield of Compound 3a was calculated, and the content of Compound 3a in the aqueous phase and the purity of the resulting product isolated from the organic phase were measured using HPLC. The specific results are shown in Table 2.
TABLE 2 preparation of different salts
| Sequence number | Inorganic salt | Product yield | Purity of |
| 1 | Disodium hydrogen phosphate | 81.7％ | 95.3％ |
| 2 | Ammonia sulfate | 81.2％ | 95.1％ |
| 3 | Cesium sulfate | 80.3％ | 94.6％ |
| 4 | Zinc sulfate | 77.6％ | 93.5％ |
| 5 | Sodium chloride | 67.0％ | 92.9％ |
| 6 | Ammonium chloride | 39.9％ | Undetected |
| 7 | Sodium nitrate | 31.2％ | Undetected |
As shown in the above table, the inorganic salts such as disodium hydrogen phosphate, ammonium sulfate, cesium sulfate, zinc sulfate and the like can promote the precipitation of the product, so that the product yield is improved, sodium chloride has no remarkable influence on promoting the precipitation of the product, and ammonium chloride and sodium nitrate have no promoting function, but rather inhibit the precipitation of the product, so that the reaction yield is reduced.
Comparative example
Without adding sodium sulfate
This example uses the following procedure to prepare the 3a compound, having the following formula:
the method comprises the following steps:
100g of Compound 1a (0.69 mol,1.0 eq), 65.16g of acetyl chloride (0.83 mol,1.2 eq), 230.68g of aluminum trichloride (1.73 mol,2.5 eq) and 1000mL of dichloroethane were added to a reaction vessel, the temperature was raised to 70 ℃, the reaction was allowed to proceed for 16 hours, quenched with hydrochloric acid (2000 mL,1 mol/L), stirred at room temperature, solids precipitated, filtered, the solids added to DCM, the pH of the solution was adjusted with sodium hydroxide solids, the solution was separated to give an aqueous phase and an organic phase, the organic phase was concentrated under reduced pressure to give Compound 3a, the yield of Compound 3a was calculated, and the content of Compound 3a in the aqueous phase and the purity of the resulting product isolated from the organic phase were measured using HPLC.
The results are shown in Table 3.
Table 3 results of preparation without sodium sulfate
| Sequence number | pH value of | Product content in aqueous phase | Product yield | Purity of |
| 1 | 2-3 | 3.97％ | 65.2％ | 94.0％ |
| 2 | 5-6 | 1.11％ | 68.6％ | 94.6％ |
| 3 | 8-9 | 25.69％ | 42.5％ | Undetected |
As can be seen from the above table in combination with the table 1, the absence of sodium sulfate during the post-treatment resulted in a large slip in the product yield, probably due to insufficient sodium sulfate resulting in insufficient precipitation of the hydrochloride salt of the quinoline derivative from the liquid phase.
Effects and effects of the examples
According to the preparation method of the quinoline compound, which is related to the embodiment, because a proper amount of sodium sulfate is added in the reaction for salting out, the application promotes the precipitation of the product, thereby obtaining better product yield.
According to the preparation method of quinoline compounds in the above examples, since the pH of the solution is adjusted to 5-6 by sodium hydroxide during the post-treatment, the product of the present application is more concentrated in the organic phase to facilitate collection.
The above examples are not intended to limit the scope of the application nor the order of execution of the steps described. The present application is obviously modified by a person skilled in the art in combination with the prior common general knowledge, and falls within the scope of protection defined by the claims of the present application.
Claims (10)
1. A preparation method of quinoline compounds is characterized by being used for converting a compound of a formula I into a compound of a formula II,
wherein R1 is a C1-C10 alkyl group,
the method comprises the following steps:
treating a compound of the formula I with an acylating agent in an organic solvent in the presence of a Lewis acid to obtain a reaction solution;
adding aqueous hydrochloric acid solution into the reaction solution for quenching reaction to obtain a quenching solution;
adding inorganic salt into the quenching liquid, filtering, taking solid, dissolving in a second solvent, regulating the pH value of the second solvent to 5-6, separating liquid, taking an organic phase, concentrating to obtain a compound of a formula II,
wherein the inorganic salt is any one or more of hydrogen phosphate, dihydrogen phosphate or sulfate.
2. The method for producing a quinoline compound according to claim 1, wherein:
wherein the inorganic salt is selected from any one or more of potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, lithium sulfate, sodium sulfate, cesium sulfate, ammonium sulfate, cobalt sulfate or nickel sulfate.
3. The method for producing a quinoline compound according to claim 1, wherein:
wherein the mass ratio of the inorganic salt to the reaction liquid is 0.05-0.1:1.
4. The method for producing a quinoline compound according to claim 1, wherein:
wherein the concentration of the hydrochloric acid aqueous solution is 0.01-12mol/L,
the reagent for regulating the pH value is selected from any one of sodium hydroxide and potassium hydroxide.
5. The method for producing a quinoline compound according to claim 1, wherein:
wherein the molar ratio of the compound of formula I to the lewis acid is 1:2-3.
6. The method for producing a quinoline compound according to claim 1, wherein:
wherein the organic solvent is any one or more of dichloroethane, carbon disulfide, nitrobenzene, petroleum ether, tetrachloroethane and chloroform.
7. The method for producing a quinoline compound according to claim 1, wherein:
wherein the Lewis acid is any one of aluminum trichloride, ferric chloride, stannic chloride and titanium tetrachloride.
8. The method for producing a quinoline compound according to claim 1, wherein:
wherein the molar ratio of the compound 1 to the acylating agent is 1: (1-1.5).
9. The method for producing a quinoline compound according to claim 1, wherein:
the concentration of the compound of the formula I relative to the organic solvent is 0.5-1.0mol/L.
10. The process for the preparation of quinolines according to any one of claims 1-9, characterized in that:
the second solvent is any one or a combination of a plurality of DCM, tetrahydrofuran and ethyl acetate; the amount of the second solvent relative to the compound of formula I is 5-15mL/g.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080200503A1 (en) * | 2005-07-29 | 2008-08-21 | Kenneth Alan Simmen | Macrocylic Inhibitors Of Hepatitis C Virus |
| CN107629000A (en) * | 2017-09-19 | 2018-01-26 | 南京法恩化学有限公司 | The preparation method of 5 chloracetyl of QAB-149 intermediate 8 benzyloxy 2 (1H) quinolinone |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080200503A1 (en) * | 2005-07-29 | 2008-08-21 | Kenneth Alan Simmen | Macrocylic Inhibitors Of Hepatitis C Virus |
| CN107629000A (en) * | 2017-09-19 | 2018-01-26 | 南京法恩化学有限公司 | The preparation method of 5 chloracetyl of QAB-149 intermediate 8 benzyloxy 2 (1H) quinolinone |
Non-Patent Citations (2)
| Title |
|---|
| C.B. VAGISH ET AL.: "Synthesis, Characterization, Crystallographic Studies of 5-Acetyl-8-hydroxyquinoline and Their Chalcone Derivatives", 《ASSIIANJJOURNAL OFCHEMIISSTRY》, vol. 32, no. 7, 27 June 2020 (2020-06-27), pages 1609 - 1613 * |
| 伊策等: "8 -羟基喹啉酮类β2 受体激动剂的设计合成 及生物活性评价", 《中国药物化学杂志》, vol. 32, no. 8, 31 August 2022 (2022-08-31), pages 581 * |
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