A method for preparing a quinoline compound
By adding inorganic salts and adjusting the pH value during the preparation of quinoline compounds, the problem of large product loss during post-processing was solved, and high-yield and high-purity quinoline compounds were prepared.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANGHAI LINKCHEM TECHNOLOGY CO LTD
- Filing Date
- 2023-08-16
- Publication Date
- 2026-06-02
AI Technical Summary
In the post-processing of quinoline compounds in the prior art, the hydroxyl group of the product 1-(8-hydroxyquinoline-5-yl)acetone is a hydrophilic group, which leads to a large loss during the separation process and a low yield.
After the acylation reaction, hydrochloric acid aqueous solution is added to quench the reaction solution, and inorganic salts such as hydrogen phosphate or sulfate are added to adjust the pH value to 5-6. The product hydrochloride is precipitated from the system by salting out, and then the pH value is adjusted with hydroxide to release the product and improve the separation efficiency.
The yield of quinoline compounds was increased to over 77%, with a purity of no less than 93%, significantly improving separation efficiency.
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Figure CN117186000B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis, and more specifically to a method for preparing quinoline compounds. Background Technology
[0002] Quinoline compounds have significant value in the biopharmaceutical field. For example, patent WO2008156102A1 discloses a pyrazolone core structure compound with a fused heterocyclic system linked to a dual PDE3 / 4 inhibitor, with 1-(8-hydroxyquinoline-5-yl)acetone being an important intermediate in its synthesis. Furthermore, Chinese patent CN103298790A discloses a novel multifunctional neuroprotective compound that can be used to prepare drugs with cell-protective effects for the prevention or treatment of neurodegenerative diseases, including Parkinson's disease and stroke; 1-(8-hydroxyquinoline-5-yl)acetone is an important intermediate in its synthesis.
[0003] In the existing technology, the method of preparing 1-(8-hydroxyquinoline-5-yl)ethyl ketone by Friedel-Crafts acylation using 8-hydroxyquinoline as the starting material is a relatively common method for preparing this type of compound.
[0004] For example, the article "The Friedel and Crafts reaction with 8-hydroxyquinoline" (Journal of the American Chemical Society, 1930, vol. 52, pp. 4433-4435) reports a method for preparing 1-(8-hydroxyquinoline-5-yl)ethyl ketone. The compound was prepared by using acetyl chloride as the acylation reagent, aluminum trichloride as the Lewis acid, and nitrobenzene as the solvent. The nitrobenzene was removed by quenching with hydrochloric acid, and the compound was recrystallized in hot water with a yield of 45%.
[0005] Patent WO2008104781A1 also discloses a method for preparing 1-(8-hydroxyquinoline-5-yl)ethyl ketone. The above compound is prepared by using acetyl chloride as a reactant, aluminum trichloride as a Lewis acid, and dichloroethane as a solvent. The mixture is quenched with hydrochloric acid, alkalized with ammonia in the post-treatment, extracted with dichloromethane, stirred with activated carbon and silica gel, filtered, washed, distilled, stirred with diisopropyl ether, filtered, and dried under vacuum to obtain the product with a yield of 39%.
[0006] Regarding the preparation methods reported in the two aforementioned documents, the applicant believes that because the hydroxyl group of the product 1-(8-hydroxyquinoline-5-yl)acetone is a hydrophilic group, a considerable portion of the product will dissolve in the aqueous phase during the post-processing, making it difficult to collect. This further leads to a situation where, despite achieving a high conversion rate, the separation yield remains low. Summary of the Invention
[0007] This invention is made to solve the above-mentioned problems, and aims to provide a method for preparing quinoline compounds that has simple post-processing and high yield.
[0008] This invention provides a method for preparing quinoline compounds, characterized by its ability to convert a compound of formula I into a compound of formula II.
[0009]
[0010] In the above formula, R1 is a C1-C10 alkyl group.
[0011] Includes the following steps:
[0012] In an organic solvent, the compound of formula I and the acylation reagent undergo an acylation reaction under the action of a Lewis acid to obtain a reaction solution;
[0013] The reaction was quenched by adding hydrochloric acid aqueous solution to the reaction solution to obtain a quenching solution;
[0014] Inorganic salts were added to the quenching solution, mixed thoroughly, filtered, and the solid was collected and dissolved in a second solvent. The pH of the second solvent was adjusted to 5-6, the mixture was separated, the organic phase was collected, and concentrated to obtain compound II.
[0015] The inorganic salt is any one or more of hydrogen phosphate, dihydrogen phosphate, or sulfate.
[0016] The method for preparing quinolinone compounds provided by the present invention may also have the following feature: 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.
[0017] The method for preparing quinoline compounds provided by the present invention may also have the following feature: wherein the mass ratio of the inorganic salt to the reaction solution is 0.05-0.1:1.
[0018] The method for preparing quinoline compounds provided by this invention may also have the following feature: the concentration of the hydrochloric acid aqueous solution is 0.01-12 mol / L; specifically, 1 mol / L may be selected.
[0019] The method for preparing quinoline compounds provided by this invention may also have the following feature: the volume ratio of the hydrochloric acid aqueous solution to the reaction solution is 1:(1.5-3); specifically, 1:2 may be selected.
[0020] The method for preparing quinoline compounds provided by this invention may also have the following feature: the reagent used to adjust the pH value is selected from either sodium hydroxide or potassium hydroxide.
[0021] The method for preparing quinoline compounds provided by the present invention may also have the following feature: wherein the molar ratio of the compound of formula I to the Lewis acid is 1:2-3.
[0022] The method for preparing quinoline compounds provided by the present invention may also have the following feature: wherein the concentration of the compound of formula I relative to the organic solvent is 0.5-1.0 mol / L.
[0023] The method for preparing quinoline compounds provided by this invention may also have the following feature: wherein the organic solvent is any one or more combinations of dichloroethane, carbon disulfide, nitrobenzene, petroleum ether, tetrachloroethane, and chloroform.
[0024] The method for preparing quinoline compounds provided by this invention may also have the following feature: wherein the Lewis acid is any one of aluminum trichloride, ferric chloride, tin tetrachloride, and titanium tetrachloride.
[0025] The method for preparing quinoline compounds provided by the present invention may also have the following feature: wherein the molar ratio of compound 1 to the acylation reagent is 1:(1-1.5).
[0026] The method for preparing quinoline compounds provided by the present invention may also have the following feature: wherein the second solvent is any one or more combinations of DCM, tetrahydrofuran, and ethyl acetate.
[0027] The method for preparing quinoline compounds provided by the present invention may also have the following feature: the amount of the second solvent relative to the compound of formula I is 5-15 mL / g; specifically, 8 mL / g may be selected.
[0028] The role and effect of invention
[0029] According to the preparation method of quinoline compounds involved in this application, in the post-processing, a specific inorganic salt is first added to the reaction solution quenched by hydrochloric acid aqueous solution to precipitate more of the product hydrochloride from the system. Then, the hydrochloride of the separated product is dissolved and adjusted to an appropriate pH value to release the product, thereby further purifying the product. Through the above technical solution, this application can reduce product loss and obtain quinoline compounds with a high yield, wherein the yield is above 77% and the purity is not less than 93%. Detailed Implementation
[0030] To make the technical means, creative features, objectives and effects of this invention easy to understand, the invention will be specifically described below in conjunction with embodiments.
[0031] In the following examples, unless otherwise stated, all reactants are commercially available products.
[0032] <Example 1>
[0033] Preparation of compound 3a
[0034] This embodiment provides a method for preparing compound 3a, and the reaction formula is as follows:
[0035]
[0036] Includes the following steps:
[0037] 100 g of compound 1a (0.69 mol, 1.0 eq), 65.16 g of acetyl chloride (0.83 mol, 1.2 eq), 230.68 g of aluminum trichloride (1.73 mol, 2.5 eq), and 1000 mL of dichloroethane were added to a reaction vessel. The mixture was heated to 70 °C and reacted for 16 h. The reaction was quenched with 2000 mL of 1 mol / L hydrochloric acid. 82.79 g of sodium sulfate (5% of the total mass of compound 1a, acetyl chloride, aluminum trichloride, and dichloroethane) was added and mixed thoroughly. A solid precipitated out. The mixture was filtered, and the solid was dissolved in 800 mL of DCM. The pH was adjusted to 5-6 with sodium hydroxide. The mixture was separated, and the organic phase was concentrated to obtain compound 3a with a yield of 82.8%. The content of compound 3a in the product was 95.3% (HPLC purity).
[0038] <Example 2>
[0039] pH screening during post-processing
[0040] This embodiment used the following method to screen the pH value in the post-treatment process, and the reaction formula is as follows:
[0041]
[0042] Includes the following steps:
[0043] 100 g of compound 1a (0.69 mol, 1.0 eq), 65.16 g of acetyl chloride (0.83 mol, 1.2 eq), 230.68 g of aluminum trichloride (1.73 mol, 2.5 eq), and 1000 mL of dichloroethane were added to a reaction vessel. The mixture was heated to 70 °C and reacted for 16 h. The reaction was quenched with hydrochloric acid (2000 mL, 1 mol / L), and 82.79 g of sodium sulfate was added. After thorough mixing, a large amount of solid precipitated. The mixture was filtered, and the solid was added to 800 mL of DCM. The pH of the solution was adjusted with sodium hydroxide. The mixture was separated into aqueous and organic phases. 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 determined by HPLC. The specific results are shown in Table 1.
[0044] Table 1. Screening of pH values during post-treatment.
[0045] Serial Number pH value Product content in aqueous phase Product yield purity 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％
[0046] As shown in the table above, adjusting the pH of the system to 5-6 during the post-processing process facilitates the entry of free products into the organic phase, thereby improving the product yield.
[0047] <Example 3>
[0048] Screening of the types of salts added during post-processing
[0049] This embodiment screened the types of salts added during the post-processing. The screening method is as follows:
[0050]
[0051] 100 g of compound 1a (0.69 mol, 1.0 eq), 65.16 g of acetyl chloride (0.83 mol, 1.2 eq), 230.68 g of aluminum trichloride (1.73 mol, 2.5 eq), and 1000 mL of dichloroethane were added to a reaction vessel. The mixture was heated to 70 °C and reacted for 16 h. The reaction was quenched with hydrochloric acid (2000 mL, 1 mol / L). 82.79 g of inorganic salt was added, and after thorough mixing, a large amount of solid precipitated. The mixture was filtered, and the solid was added to 800 mL of DCM. The pH of the solution was adjusted to 5-6 with sodium hydroxide. The mixture was separated into aqueous and organic phases. 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 determined by HPLC. The specific results are shown in Table 2.
[0052] Table 2. Preparation results of different types of salts
[0053] Serial Number Inorganic salts Product yield purity 1 Sodium hydrogen phosphate 81.7％ 95.3％ 2 Ammonium 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％ Not detected 7 Sodium nitrate 31.2％ Not detected
[0054] As shown in the table above, inorganic salts such as disodium hydrogen phosphate, ammonium sulfate, cesium sulfate, and zinc sulfate can promote product precipitation, thereby increasing product yield. Sodium chloride, on the other hand, has no significant effect on promoting product precipitation. Ammonium chloride and sodium nitrate not only do not have a promoting function, but on the contrary, they inhibit product precipitation, thus leading to a decrease in reaction yield.
[0055] <Comparative Example>
[0056] No sodium sulfate added
[0057] In this embodiment, compound 3a was prepared using the following method, with the reaction formula as follows:
[0058]
[0059] Includes the following steps:
[0060] 100 g of compound 1a (0.69 mol, 1.0 eq), 65.16 g of acetyl chloride (0.83 mol, 1.2 eq), 230.68 g of aluminum trichloride (1.73 mol, 2.5 eq), and 1000 mL of dichloroethane were added to a reaction vessel. The mixture was heated to 70 °C and reacted for 16 h. The reaction was quenched with hydrochloric acid (2000 mL, 1 mol / L) and stirred at room temperature. A solid precipitated out. The solid was filtered and added to DCM. The pH of the solution was adjusted with sodium hydroxide. The mixture was separated into 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. The content of compound 3a in the aqueous phase and the purity of the product separated from the organic phase were determined by HPLC.
[0061] The results are shown in Table 3.
[0062] Table 3. Preparation results without sodium sulfate
[0063] Serial Number pH value Product content in aqueous phase Product yield purity 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％ Not detected
[0064] As can be seen from the table above and Table 1, the absence of sodium sulfate in the post-processing leads to a significant drop in product yield. This may be because insufficient sodium sulfate prevents the hydrochloride of quinoline derivatives from being fully extracted from the liquid phase.
[0065] The role and effect of the embodiments
[0066] According to the preparation method of quinoline compounds involved in the above embodiments, because an appropriate amount of sodium sulfate is added during the reaction for salting out, this application promotes product precipitation, thereby achieving a better product yield.
[0067] According to the preparation method of quinoline compounds involved in the above embodiments, because the pH of the solution is adjusted to 5-6 with sodium hydroxide during the post-processing, the product of this application will be more concentrated in the organic phase, thus facilitating collection.
[0068] The embodiments provided above are not intended to limit the scope of the invention, nor are the described steps intended to limit the order of execution. Any obvious modifications made to the invention by those skilled in the art based on existing common knowledge also fall within the scope of protection defined by the claims.
Claims
1. A method for preparing a quinoline compound, characterized in that, Used to convert compounds of formula I into compounds of formula II. In the above formula, R1 is a methyl group. Includes the following steps: In an organic solvent, in the presence of a Lewis acid, the compound of formula I is treated with an acylation reagent to obtain a reaction solution; The reaction was quenched by adding hydrochloric acid aqueous solution to the reaction solution to obtain a quenching solution; Inorganic salts were added to the quenching solution, filtered, and the solid was collected and dissolved in a second solvent. The pH of the second solvent was adjusted to 5-6, the mixture was separated, the organic phase was collected, and concentrated to obtain compound II. The inorganic salt is any one or more of hydrogen phosphate, dihydrogen phosphate, or sulfate. Lewis acid is aluminum trichloride.
2. The method for preparing quinoline compounds according to claim 1, characterized in that: in, 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 preparing quinoline compounds according to claim 1, characterized in that: in, The mass ratio of the inorganic salt to the reaction solution is 0.05-0.1:
1.
4. The method for preparing quinoline compounds according to claim 1, characterized in that: in, The concentration of the hydrochloric acid aqueous solution is 0.01-12 mol / L. The reagent used to adjust the pH value is selected from either sodium hydroxide or potassium hydroxide.
5. The method for preparing quinoline compounds according to claim 1, characterized in that: in, The molar ratio of the compound of formula I to the Lewis acid is 1:2-3.
6. The method for preparing quinoline compounds according to claim 1, characterized in that: in, The organic solvent is any one or a combination of dichloroethane, carbon disulfide, nitrobenzene, petroleum ether, tetrachloroethane, and chloroform.
7. The method for preparing quinoline compounds according to claim 1, characterized in that: in, The molar ratio of the compound of Formula I to the acylation reagent is 1:(1-1.5).
8. The method for preparing quinoline compounds according to claim 1, characterized in that: The concentration of the compound of Formula I relative to the organic solvent is 0.5-1.0 mol / L.
9. The method for preparing quinoline compounds according to any one of claims 1-8, characterized in that: The second solvent is any one or a combination of DCM, tetrahydrofuran, and ethyl acetate; the amount of the second solvent relative to the compound of formula I is 5-15 mL / g.