Amplified preparation method of 6-bromo-4-hydroxyquinoline
Through the addition reaction of bromoaniline and acrylate, combined with the ring-closing reaction of mixed acid catalysts and the aromatization reaction of metal catalysts, 6-bromo-4-hydroxyquinoline was successfully prepared, solving the problems of low yields of existing processes and complex operations, and achieving an efficient and environmentally friendly production process.
Patent Information
- Application Number
- CN202480004069.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-06
- Publication Date
- 2025-05-23
AI Technical Summary
The existing 6-bromo-4-hydroxyquinoline production process has low yield, complex operation, long process steps, difficult reactions, and poor economic benefits and environmental impact.
The addition reaction of p-bromoaniline and acrylate in the presence of a base is obtained intermediate 1; then in an organic solvent, intermediate 1 undergoes a ring-closing reaction in the presence of a mixed acid catalyst to obtain intermediate 2; finally, intermediate 2 undergoes an aromatization reaction in the presence of a metal catalyst to obtain 6-bromo-4-hydroxyquinoline.
The reaction process and post-treatment process are simplified, the operation is simple, the yield is high, the production cost is reduced, and it is suitable for industrial scale production, and the process is environmentally friendly.
Smart Images
Figure CN120035581A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of pharmaceutical chemistry, and specifically relates to an enlarged preparation method of 6-bromo-4-hydroxyquinoline. Background Art
[0002] Omipalisib (GSK2126458, GSK458) is a highly selective and potent p110α / β / γ / δ and mTORC1 / 2 inhibitor, and is a therapeutic drug primarily used to treat solid tumors, lymphomas, idiopathic pulmonary fibrosis and idiopathic pulmonary interstitial fibrosis.
[0003] 6-Bromo-4-hydroxyquinoline is an important intermediate of Omipalisib. The original production synthesis process has a yield of only 34.3%, which is complicated to operate, has long process steps, is difficult to react, has low yield, and has poor economic benefits and environmental impact. Since the drug is currently in the clinical research stage, there are few reports on the synthesis of the drug at home and abroad. Summary of the invention
[0004] In order to overcome the above technical defects, the present invention provides a method for preparing 6-bromo-4-hydroxyquinoline. With p-bromoaniline and acrylate as raw materials, an addition reaction is carried out in the presence of a base, and then hydrolyzed to obtain an intermediate 1; then in an organic solvent, in the presence of a mixed acid catalyst, the intermediate 1 is heated to undergo a ring-closing reaction to obtain an intermediate 2; finally, in the presence of a metal catalyst, the intermediate 2 undergoes an aromatization reaction to obtain 6-bromo-4-hydroxyquinoline. The present invention has the advantages of simple operation, high yield, environmental friendliness, low production cost, etc., and is suitable for industrial-scale production.
[0005] The enlarged preparation method of 6-bromo-4-hydroxyquinoline of the present invention comprises the following steps:
[0006] Step 1, addition reaction: p-bromoaniline reacts with acrylate in the presence of a base, and then hydrolyzes to obtain intermediate 1;
[0007]
[0008] Further, in the above technical solution, the base is selected from NaH or DBU;
[0009] Furthermore, in the above technical solution, the acrylate is selected from methyl acrylate, ethyl acrylate or isopropyl acrylate.
[0010] Furthermore, in the above technical solution, the molar ratio of p-bromoaniline, acrylate and base is 1:1-1.2:0.2-1.5.
[0011] Furthermore, in the above technical solution, the hydrolysis adopts sodium hydroxide or potassium hydroxide aqueous solution.
[0012] Step 2: Ring-closing reaction: Intermediate 1 undergoes ring-closing reaction in an organic solvent in the presence of a mixed acid catalyst by heating to obtain intermediate 2;
[0013] Furthermore, in the above technical solution, the mixed acid catalyst is selected from MsOH and B(C 6 F 5 ) 3 combination.
[0014] Furthermore, in the above technical solution, the intermediate 1, MsOH and B(C 6 F 5 ) 3 The molar ratio is 1:0.4-0.6:0.1-0.2.
[0015] Furthermore, in the above technical solution, the organic solvent is selected from a mixed solvent of sulfolane and dioxane, toluene, xylene or chlorobenzene.
[0016] Furthermore, in the above technical solution, the temperature of the heating reaction is 60-110°C.
[0017] Step 3, aromatization reaction: Intermediate 2 is heated in an organic solvent in the presence of a metal catalyst to obtain 6-bromo-4-hydroxyquinoline;
[0018] Furthermore, in the above technical solution, the metal catalyst is selected from palladium carbon or manganese dioxide.
[0019] Furthermore, in the above technical solution, the organic solvent is selected from isopropanol, ethylene glycol dimethyl ether, and dioxane. Beneficial effects of the present invention
[0020] The present invention optimizes the reaction conditions of the preparation process, especially the second step reaction ring closure, which is smooth under the catalysis of a protonic acid and a Lewis acid mixed acid. At the same time, the selection of reaction solvents and reactants in the process of the present invention is reasonable, and the reaction process and post-treatment process are greatly simplified, the operation is simple, and the production cost is greatly reduced. BRIEF DESCRIPTION OF THE DRAWINGS
[0021] Figure 1 The HNMR spectrum of the product 6-bromo-4-hydroxyquinoline in Example 1 is shown in FIG. DETAILED DESCRIPTION
[0022] Example 1
[0023] The first step of addition reaction:
[0024] p-Bromoaniline (10 g, 58.13 mmol), methyl acrylate (6.01 g, 69.76 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (9.73 g, 63.94 mmol) and tetrahydrofuran (50 ml) were added to a reaction kettle, and the reaction mixture was heated to 65-70°C for 16 hours. The solvent was removed, and a 1M aqueous sodium hydroxide solution was added for hydrolysis. Then, hydrochloric acid was added to adjust the pH to 4-5, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and spin-dried to obtain intermediate 1, which was directly used in the next reaction.
[0025] The second step cyclization reaction:
[0026] In the reactor, add B(C 6 F 5 ) 3 (2.80g, 11.55mmol) and methanesulfonic acid (3.35g, 34.88mmol) were added to the intermediate 1 (theoretical molar number 58.13mmol) obtained in the previous step in toluene (100ml) solvent, and the temperature was raised to reflux for water separation reaction for 2-3 hours. After the reaction, the reaction solution was poured into water and neutralized with solid sodium carbonate to pH = 5. After extraction with ethyl acetate, it was washed with saturated sodium carbonate aqueous solution, dilute hydrochloric acid and saturated brine in sequence, and dried over anhydrous sodium sulfate and then spin-dried to obtain the intermediate 2 (10.77g, yield: 82%).
[0027] Step 3 Oxidative aromatization
[0028] Intermediate 2 (10 g, 44.23 mmol), 2-propanol (50 ml), sodium hydroxide (0.9 g, 29% aqueous solution) and 1 g of 10% palladium on carbon were added to a reaction kettle and stirred at 70-85° C. for 8 hours. After HPLC showed that the raw materials had reacted, aqueous hydrochloric acid was added to pH = 7. After filtration, extraction was performed and dried to obtain the product 6-bromo-4-hydroxyquinoline (8.97 g, yield: 90.55%).
[0029] Example 2
[0030] The first step of addition reaction:
[0031] p-Bromoaniline (2kg, 11.63mol), methyl acrylate (1.1kg, 12.79mol), 60% sodium hydrogen sulfide (139.6g, 3.49mol) and tetrahydrofuran (10L) were added to a reaction kettle, and the reaction mixture was heated to 65-70°C for 16 hours. The solvent was removed, and a 1M sodium hydroxide aqueous solution was added for hydrolysis. Then, hydrochloric acid was added to adjust the pH to 4-5, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and spin-dried to obtain intermediate 1, which was directly used in the next step.
[0032] The second step cyclization reaction:
[0033] In the reactor, add B(C 6 F 5 ) 3 (280.86g, 1.16mol) and methanesulfonic acid (0.45kg, 4.65mol) were added to the intermediate 1 (theoretical molar number 11.63mol) obtained in the previous step in a dioxane (15L) solvent, and the temperature was raised to reflux to separate the water and react for 2-3 hours. After the reaction, the reaction solution was poured into water and neutralized with solid sodium carbonate to pH = 5. After extraction with ethyl acetate, it was washed with saturated sodium carbonate aqueous solution, dilute hydrochloric acid and saturated brine in sequence, and dried over anhydrous sodium sulfate and then spin-dried to obtain the intermediate 2 (2.21kg, yield: 84%).
[0034] Step 3 Oxidative aromatization
[0035] Intermediate 2 (2.21 kg, 9.78 mol), dioxane (11 L), sodium hydroxide (0.20 kg, 29% aqueous solution) and 0.22 kg of 10% palladium on carbon were added to a reaction kettle and stirred at 70-85° C. for 8 hours. After HPLC showed that the raw materials had reacted, aqueous hydrochloric acid was added to pH = 7, and the mixture was filtered and extracted with dichloromethane. The product 6-bromo-4-hydroxyquinoline (2.02 kg, yield: 92.1%) was obtained by spin drying.
[0036] Example 3
[0037] The first step of addition reaction:
[0038] p-Bromoaniline (25 kg, 145.33 mol), methyl acrylate (13.76 kg, 159.86 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (4.43 kg, 29.07 mol) and tetrahydrofuran (125 L) were added to a reaction kettle, and the reaction mixture was heated to 65-70 ° C for 16 hours. The solvent was removed, and a 1M potassium hydroxide aqueous solution was added for hydrolysis. Then, hydrochloric acid was added to adjust the pH to 4-5, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and spin-dried to obtain intermediate 1, which was directly used in the next reaction.
[0039] The second step cyclization reaction:
[0040] In the reactor, add B(C 6 F 5 ) 3(7.04kg, 29.06mol) and methanesulfonic acid (6.98kg, 72.66mol) were added to the intermediate 1 (theoretical molar number 145.33mol) obtained in the previous step in a xylene (175L) solvent, and the temperature was raised to reflux to separate the water and react for 2-3 hours. After the reaction, the reaction solution was poured into water and neutralized with solid sodium carbonate to pH = 5. After extraction with ethyl acetate, it was washed with saturated sodium carbonate aqueous solution, dilute hydrochloric acid and saturated brine in sequence, and dried over anhydrous sodium sulfate and then spin-dried to obtain the intermediate 2 (27.27kg, yield: 83%).
[0041] Step 3 Oxidative aromatization
[0042] Intermediate 2 (27 kg, 44.23 mmol), isopropanol (135 L), sodium hydroxide (2.4 kg, 29% aqueous solution) and 2.7 kg of 10% palladium on carbon were added to a reaction kettle and stirred at 70-85° C. for 8 hours. After HPLC showed that the raw materials had reacted, aqueous hydrochloric acid was added to pH = 7, and the product 6-bromo-4-hydroxyquinoline (24.48 kg, yield: 91.5%) was obtained after filtration and extraction.
[0043] In short, the embodiments of the present invention disclose preferred implementation methods, but are not limited thereto. A person skilled in the art can easily understand the spirit of the present invention based on the above embodiments and make different extensions and changes, but as long as they do not deviate from the spirit of the present invention, they are all within the protection scope of the present invention.
Claims
1. A method for enlarging the preparation of 6-bromo-4-hydroxyquinoline, characterized in that: The steps include: Step 1, addition reaction: p-bromoaniline reacts with acrylate in the presence of a base, and then hydrolyzes to obtain intermediate 1; Step 2: Ring-closing reaction: Intermediate 1 undergoes ring-closing reaction in an organic solvent in the presence of a mixed acid catalyst by heating to obtain intermediate 2; Step 3: Aromatization reaction: Intermediate 2 is heated in an organic solvent in the presence of a metal catalyst to obtain 6-bromo-4-hydroxyquinoline.
2. The method for preparing 6-bromo-4-hydroxyquinoline according to claim 1, characterized in that: In the first step, the base is selected from NaH or DBU; the acrylate is selected from methyl acrylate, ethyl acrylate or isopropyl acrylate.
3. The enlarged preparation method of 6-bromo-4-hydroxyquinoline according to claim 1, characterized in that: In the first step, the molar ratio of p-bromoaniline, acrylate and base is 1:1-1.2:0.2-1.
5.
4. The enlarged preparation method of 6-bromo-4-hydroxyquinoline according to claim 1, characterized in that: In the first step, the hydrolysis is carried out using an aqueous solution of sodium hydroxide or potassium hydroxide.
5. The enlarged preparation method of 6-bromo-4-hydroxyquinoline according to claim 1, characterized in that: In the second step, the mixed acid catalyst is selected from a combination of MsOH and B(C6F5)3.
6. The method for enlarging the preparation of 6-bromo-4-hydroxyquinoline according to claim 5, characterized in that: In the second step, the molar ratio of the intermediate 1, MsOH and B(C6F5)3 is 1:0.4-0.6:0.1-0.
2.
7. The method for enlarging the preparation of 6-bromo-4-hydroxyquinoline according to claim 1, characterized in that: In the second step, the organic solvent is selected from a mixed solvent of sulfolane and dioxane, toluene, xylene or chlorobenzene.
8. The method for enlarging the preparation of 6-bromo-4-hydroxyquinoline according to claim 1, characterized in that: In the second step, the reaction temperature is raised to 60-110°C.
9. The method for enlarging the preparation of 6-bromo-4-hydroxyquinoline according to claim 1, characterized in that: In the third step, the metal catalyst is selected from palladium carbon or manganese dioxide.
10. The method for enlarging the preparation of 6-bromo-4-hydroxyquinoline according to claim 1, characterized in that: In the third step, the organic solvent is selected from isopropyl alcohol, ethylene glycol dimethyl ether, and dioxane.