Scale-up preparation method for 6-bromo-4-hydroxyquinoline

Abstract

The present invention belongs to the field of pharmaceutical chemistry. Disclosed in the present invention is a scale-up preparation method for 6-bromo-4-hydroxyquinoline. The method comprises: subjecting p-bromoaniline and acrylate, which serve as raw materials, to an addition reaction in the presence of a base, followed by hydrolysis to obtain intermediate 1; subsequently, subjecting intermediate 1 to a cyclization reaction in an organic solvent under heating in the presence of a mixed acid catalyst to obtain intermediate 2; and finally, subjecting intermediate 2 to an aromatization reaction in the presence of a metal catalyst so as to obtain 6-bromo-4-hydroxyquinoline. The present invention has the advantages of simple operation, high yield, being environmentally friendly, low production cost, etc., and is thus suitable for industrial-scale production.

Description

An amplification preparation method of 6-bromo-4-hydroxyquinoline TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to an amplification preparation method of 6-bromo-4-hydroxyquinoline. BACKGROUND

[0002] Omipalisib (GSK2126458, GSK458) is a highly selective and effective p110 alpha / beta / gamma / delta and mTORC1 / 2 inhibitor, and is a therapeutic drug mainly used for treating solid tumors, lymphoma, idiopathic pulmonary fibrosis and idiopathic interstitial pulmonary fibrosis.

[0003] 6-bromo-4-hydroxyquinoline is an important intermediate of Omipalisib drug, and the original production and synthesis process has a yield of only 34.3%, is complex in operation, long in process steps, difficult in reaction, and low in yield, economic benefit 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

[0004] In order to overcome the above technical defects, the present application provides a preparation method of 6-bromo-4-hydroxyquinoline. With p-bromoaniline and acrylic ester as raw materials, addition reaction is carried out in the presence of a base, and then the intermediate 1 is obtained by hydrolysis; then the intermediate 1 is subjected to ring closure reaction in the presence of a mixed acid catalyst in an organic solvent to obtain the intermediate 2; and finally, the intermediate 2 is subjected to aromatization reaction in the presence of a metal catalyst to obtain 6-bromo-4-hydroxyquinoline. The present application has the advantages of simple operation, high yield, environmental friendliness, low production cost and the like, and is suitable for industrialized scale production.

[0005] The amplification preparation method of 6-bromo-4-hydroxyquinoline provided by the present application comprises the following steps:

[0006] In the first step, p-bromoaniline and acrylic ester are subjected to addition reaction in the presence of a base, and then the intermediate 1 is obtained by hydrolysis;

[0007]

[0008] Further, in the above technical solution, the base is selected from NaH or DBU.

[0009] Further, in the above technical solution, the acrylic ester is selected from methyl acrylate, ethyl acrylate or isopropyl acrylate.

[0010] Further, in the above technical solution, the molar ratio of p-bromoaniline, acrylic ester and base is 1:1-1.2:0.2-1.5.

[0011] Further, in the above technical solution, the hydrolysis uses sodium hydroxide or potassium hydroxide aqueous solution.

[0012] The second step, the ring-closing reaction: the intermediate 1 is mixed with an acid catalyst in an organic solvent, and the ring-closing reaction is carried out by heating to obtain the intermediate 2;

[0013] Further, in the above technical solution, the mixed acid catalyst is selected from MsOH and B(C6F5)3.

[0014] Further, in the above technical solution, the molar ratio of the intermediate 1, MsOH and B(C6F5)3 is 1: 0.4-0.6: 0.1-0.2.

[0015] Further, in the above technical solution, the organic solvent is selected from a mixed solvent of sulfolane and dioxane, toluene, xylene or chlorobenzene.

[0016] Further, in the above technical solution, the reaction temperature is 60-110℃.

[0017] The third step, the aromatization reaction: the intermediate 2 is heated in an organic solvent in the presence of a metal catalyst to obtain 6-bromo-4-hydroxyquinoline;

[0018] Further, in the above technical solution, the metal catalyst is selected from palladium on carbon or manganese dioxide.

[0019] Further, in the above technical solution, the organic solvent is selected from isopropyl alcohol, ethylene glycol dimethyl ether and dioxane. Advantages of the present application

[0020] The present application optimizes the reaction conditions of the preparation process, especially the ring-closing reaction in the second step, which is carried out smoothly under the catalysis of a mixed acid of a protonic acid and a Lewis acid. In addition, the selection of the reaction solvent and the reactant in the process of the present application is reasonable, and the reaction process and the post-processing process are greatly simplified, the operation is simple, and the production cost is greatly reduced. BRIEF DESCRIPTION OF DRAWINGS

[0021] Fig. 1 is the HNMR spectrum of the product 6-bromo-4-hydroxyquinoline in Example 1; DETAILED DESCRIPTION

[0022] Example 1

[0023] The first step, the addition reaction:

[0024] In a reaction vessel, 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 and the reaction mixture was heated to 65-70°C for 16 hours. The solvent was removed, 1M aqueous sodium hydroxide solution was added for hydrolysis, hydrochloric acid was added to adjust pH = 4-5, ethyl acetate was added for extraction, anhydrous magnesium sulfate was added for drying, and the product was obtained by rotary evaporation. The crude product was used directly in the next step.

[0025] Second step: cyclization reaction

[0026] In a reaction vessel, B(C6F5)3 (2.80 g, 11.55 mmol) and methanesulfonic acid (3.35 g, 34.88 mmol) were added to the toluene (100 ml) solution of the intermediate 1 (theoretical molar number 58.13 mmol) obtained in the previous step, and the temperature was raised to reflux for 2-3 hours. After the reaction was completed, the reaction solution was poured into water, neutralized to pH = 5 with solid sodium carbonate, extracted with ethyl acetate, washed with saturated sodium carbonate aqueous solution, dilute hydrochloric acid and saturated brine in sequence, dried with anhydrous sodium sulfate, and the product was obtained by rotary evaporation. The yield of intermediate 2 was 10.77 g (yield: 82%).

[0027] Third step: oxidative aromatization

[0028] In a reaction vessel, 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, and stirred at 70-85°C for 8 hours. After the HPLC showed that the raw material was completely reacted, hydrochloric acid aqueous solution was added to adjust pH = 7, filtered, extracted and rotary evaporated to obtain the product 6-bromo-4-hydroxyquinoline (8.97 g, yield: 90.55%).

[0029] Example 2

[0030] First step: addition reaction

[0031] In a reaction vessel, p-bromoaniline (2 kg, 11.63 mol), methyl acrylate (1.1 kg, 12.79 mol), sodium hydride 60% (139.6 g, 3.49 mol) and tetrahydrofuran (10 L) were added, and the reaction mixture was heated to 65-70°C for 16 hours. The solvent was removed, 1M aqueous sodium hydroxide solution was added for hydrolysis, hydrochloric acid was added to adjust pH = 4-5, ethyl acetate was added for extraction, anhydrous magnesium sulfate was added for drying, and the product was obtained by rotary evaporation. The crude product was used directly in the next step.

[0032] Second step: cyclization reaction

[0033] In a reaction kettle, B(C6F5)3(280.86 g, 1.16 mol) and methanesulfonic acid (0.45 kg, 4.65 mol) were added to the intermediate 1 (theoretical molar number 11.63 mol) obtained in the previous step in a dioxane (15 L) solvent, and the temperature was raised to reflux for 2-3 hours of water removal reaction. After the reaction was completed, the reaction solution was poured into water, neutralized to pH = 5 with solid sodium carbonate, and then extracted with ethyl acetate. After washing with saturated sodium carbonate aqueous solution, dilute hydrochloric acid, and saturated brine, respectively, the product was dried over anhydrous sodium sulfate and then rotary evaporated to obtain intermediate 2 (2.21 kg, yield: 84%).

[0034] Third step: oxidative aromatization

[0035] In a reaction kettle, intermediate 2 (2.21 kg, 9.78 mol), dioxane (11 L), sodium hydroxide (0.20 kg, 29% aqueous solution), and 10% palladium on carbon (0.22 kg) were added, and stirred at 70-85°C for 8 hours. After the HPLC showed that the raw material was completely reacted, hydrochloric acid aqueous solution was added to pH = 7, filtered, extracted with dichloromethane, and rotary evaporated to obtain the product 6-bromo-4-hydroxyquinoline (2.02 kg, yield: 92.1%).

[0036] Example 3

[0037] First step: addition reaction

[0038] In a reaction kettle, 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, and the reaction mixture was heated to 65-70°C for 16 hours. After removing the solvent, 1M potassium hydroxide aqueous solution was added for hydrolysis, then hydrochloric acid was added to adjust pH = 4-5, and then extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and rotary evaporation, the crude product was directly used in the next step.

[0039] Second step: cyclization reaction

[0040] In a reaction kettle, B(C6F5)3(7.04 kg, 29.06 mol) and methanesulfonic acid (6.98 kg, 72.66 mol) were added to the intermediate 1 (theoretical molar number 145.33 mol) obtained in the previous step in a dioxane (175 L) solvent, and the temperature was raised to reflux for 2-3 hours of water removal reaction. After the reaction was completed, the reaction solution was poured into water, neutralized to pH = 5 with solid sodium carbonate, and then extracted with ethyl acetate. After washing with saturated sodium carbonate aqueous solution, dilute hydrochloric acid, and saturated brine, respectively, the product was dried over anhydrous sodium sulfate and then rotary evaporated to obtain intermediate 2 (27.27 kg, yield: 83%).

[0041] Third step Oxidative aromatization

[0042] Intermediate 2 (27 kg, 44.23 mmol), isopropyl alcohol (135 L), sodium hydroxide (2.4 kg, 29% aqueous solution) and 10% palladium on carbon 2.7 kg were added into the reaction kettle, stirred at 70-85 °C for 8 hours, HPLC showed that the raw material reacted completely, then hydrochloric acid aqueous solution was added to pH = 7, filtered and extracted to dryness to obtain the product 6-bromo-4-hydroxyquinoline (24.48 kg, yield: 91.5%).

[0043] In summary, the embodiments of the present application disclose the preferred embodiments, but are not limited thereto. Those skilled in the art can easily understand the spirit of the present application according to the above embodiments, and make different inferences and changes, as long as they do not deviate from the spirit of the present application, which are within the protection scope of the present application.

Claims

1. A process for the scale-up production of 6-bromo-4-hydroxyquinoline, characterized in that, The method comprises the following steps: ; The first step, addition reaction: addition reaction of p-bromoaniline and acrylic ester in the presence of base, and then hydrolysis to obtain intermediate 1; The second step, ring closure reaction: ring closure reaction of intermediate 1 in the presence of mixed acid catalyst in organic solvent, and heating to obtain intermediate 2; The third step, aromatization reaction: heating reaction of intermediate 2 in the presence of metal catalyst in organic solvent to obtain 6-bromo-4-hydroxyquinoline.

2. The process according to claim 1 for the scale-up production of 6-bromo-4- hydroxyquinoline, characterized by: In the first step, the base is selected from NaH or DBU; the acrylic ester is selected from methyl acrylate, ethyl acrylate or isopropyl acrylate.

3. The process according to claim 1 for the scale-up production of 6-bromo-4- hydroxyquinoline, characterized by: In the first step, the molar ratio of p-bromoaniline, acrylic ester and base is 1: 1-1.2: 0.2-1.

5.

4. The process according to claim 1 for the scale-up production of 6-bromo-4- hydroxyquinoline, characterized by: In the first step, the hydrolysis adopts sodium hydroxide or potassium hydroxide aqueous solution.

5. The process according to claim 1 for the scale-up production of 6-bromo-4- hydroxyquinoline, characterized by: In the second step, the mixed acid catalyst is selected from MsOH and B(C6F5)3 combination.

6. The process according to claim 5 for the scale-up production of 6-bromo-4- hydroxyquinoline, characterized by: In the second step, the molar ratio of intermediate 1, MsOH and B(C6F5)3 is 1: 0.4-0.6: 0.1-0.

2.

7. The process according to claim 1 for the scale-up production of 6-bromo-4- hydroxyquinoline, characterized by: In the second step, the organic solvent is selected from mixed solvents of sulfolane and dioxane, toluene, xylene or chlorobenzene.

8. The process according to claim 1 for the scale-up production of 6-bromo-4- hydroxyquinoline, characterized by: In the second step, the reaction temperature is 60-110 DEG C.

9. The process according to claim 1 for the scale-up production of 6-bromo-4- hydroxyquinoline, characterized by: In the third step, the metal catalyst is selected from palladium on carbon or manganese dioxide.

10. The process according to claim 1 for the scale-up production of 6-bromo-4- hydroxyquinoline, characterized by: In the third step, the organic solvent is selected from isopropyl alcohol, ethylene glycol dimethyl ether, dioxane.

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