Preparation method of 7-(4-chlorobutoxy)-1H-quinoline-2-ketone

Abstract

The invention relates to a preparation method of 7-(4-chlorobutoxy)-1H-quinoline-2-ketone, which comprises the following steps: carrying out reaction on 7-hydroxy-1, 2, 3, 4-tetrahydroquinoline-2-ketone and 1-chloro-4-bromobutane under the action of potassium carbonate to generate 7-(4-chlorobutoxy)-1, 2, 3, 4-tetrahydroquinoline-2-ketone, and carrying out reaction on 7-(4-chlorobutoxy)-1, 2, 3, 4-tetrahydroquinoline-2-ketone and 1-chloro-4-bromobutane under the action of potassium carbonate to generate 7-(4-chlorobutoxy)-1H-quinoline-2-ketone. The method comprises the following steps: reacting 7-(4-chlorobutoxy)-1, 2, 3, 4-tetrahydroquinoline-2-ketone with copper bromide under the action of a catalyst 1 to obtain 3-bromo-7-(4-chlorobutoxy)-1, 2, 3, 4-tetrahydroquinoline-2-ketone; the preparation method comprises the following steps: carrying out debromination on 3-bromo-7-(4-chlorobutoxy)-1, 2, 3, 4-tetrahydroquinoline-2-ketone under the action of a catalyst 2 to obtain 7-(4-chlorobutoxy)-1H-quinoline-2-ketone; the purification difficulty is reduced, the yield and the purity are improved, and the cost is reduced.

Description

[0001] The invention belongs to the technical field of pharmaceutical preparation, and specifically relates to a preparation method of 7-(4-chlorobutoxy)-1H-quinoline-2-one. Background Art

[0002] Brexprazole, chemical name 7-[4-(4-benzo[B]-thiophen-4-yl-1-piperazine)butoxy]-1 H -Quinoline-2-one, CAS number 913611-97-9. It was jointly developed by Lundbeck Pharma of Denmark and Otsuka Co., Ltd. of Japan. On July 10, 2015, it was approved for marketing by the U.S. Food and Drug Administration (FDA). Brepiraazole is an experimental serotonin-dopamine activity modulator (SDAM), which is effective in the adjuvant treatment of schizophrenia and depressive disorders and has good safety and tolerability. Brepiraazole is considered to be one of the most promising drugs in the market after the best-selling antipsychotic drug aripiprazole.

[0003] 7-(4-chlorobutoxy)-1H-quinolin-2-one is an important intermediate in the synthesis of brepirazole. Some of the reported synthesis methods of brepirazole are to obtain brepirazole through nucleophilic substitution of 7-(4-chlorobutoxy)-1H-quinolin-2-one and 4-piperazinebenzothiophene hydrochloride.

[0004] The patent report of Otsuka Co., Ltd. (WO2006112464A1, CN103717587A) discloses a method for preparing breprazol, which uses 7-hydroxy-1H-quinolin-2-one (compound 5) and 4-bromobenzothiophene (compound 2) as raw materials to prepare key intermediates 7-(4-chlorobutoxy)-1H-quinolin-2-one (compound 7) and 1-(benzo[b]thiophene-4-yl)-piperazine (compound 4), and then prepares breprazol through condensation reaction. The reaction formula is as follows:

[0005] Each step of this route requires column chromatography purification, and the reaction time for preparing compound 4 is long (about 40 hours), there are many side reactions, and the yield is low (about 60.0%); even after column chromatography, high-purity compound 4 cannot be obtained, which affects the quality of the final product, brepazole, and is not suitable for industrial production.

[0006] WO2013015456 and the Chinese patent CN 103717587 A of the same family disclose the following synthetic routes:

[0007] This method uses 4-chlorobenzothiophene-2-carboxylic acid (compound 8) as a raw material, which is converted into 4-chlorobenzothiophene (compound 2) after decarboxylation. The rest is similar to WO2006112464A1, so it is also not suitable for industrial production.

[0008] The following preparation routes are reported in patent WO2017115287 and its family patents IN2015CH06994 and US20190010145:

[0009] This synthetic route reports a method for preparing 7-hydroxy-2 (1H) -quinolinone, in which the target product is generated by N- (3-methoxyphenyl) cinnamamide under the catalysis of aluminum chloride. The starting material is expensive and requires column separation to obtain 7-hydroxy-2 (1H) -quinolinone with high purity, so this route is not suitable for industrial production.

[0010] Chinese patent CN104447723A discloses the following synthesis route:

[0011] Chinese patent CN104844585A discloses the following synthesis route:

[0012] Chinese patent CN104829602 reports the following synthesis route:

[0013] These processes have one thing in common, that is, they all use highly toxic DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) for oxidative dehydrogenation, which has a certain impact on the quality of the target product, and DDQ is difficult to remove completely, thus determining the limitations of the industrialization of this method. Summary of the invention

[0014] The technical problem to be solved by the present invention is to provide a preparation method of 7-(4-chlorobutoxy)-1H-quinoline-2-one, which can reduce the difficulty of purification, improve the yield and purity, and thus reduce the production cost.

[0015] The present invention includes a method for preparing 7-(4-chlorobutoxy)-1H-quinolin-2-one, which comprises the following steps: reacting 7-hydroxy-1,2,3,4-tetrahydroquinolin-2-one with 1-chloro-4-bromobutane under the action of potassium carbonate to generate 7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one; reacting 7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one with copper bromide under the action of catalyst 1 to obtain 3-bromo-7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one; and debrominating 3-bromo-7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one under the action of catalyst 2 to obtain 7-(4-chlorobutoxy)-1H-quinolin-2-one.

[0016] The preparation method of the catalyst 1 is to mix the carrier particles and the metal salt solution, then adjust the pH to alkaline (preferably 8-10), wash, dry, immerse in a sulfuric acid solution, filter, and then roast to obtain the catalyst; the carrier particles are aluminum oxide or silicon dioxide, and the metal salt solution is a salt solution of Zr, Ti or Sn.

[0017] Preferably, the carrier particles are alumina, and the metal salt solution is ZrCl4.

[0018] Preferably, the acid strength of the catalyst is -16.02 to -14.52.

[0019] Preferably, when 7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one reacts with copper bromide, the solvent is chloroform / ethyl acetate, ethyl acetate or alcohols; more preferably, the solvent is ethanol.

[0020] Preferably, the heteropoly acid is phosphotungstic acid, phosphomolybdic acid, vanadium phosphotungstic acid, vanadium phosphomolybdic acid, silicotungstic acid, silicomolybdic acid, vanadium silicotungstic acid or vanadium silicomolybdic acid.

[0021] Preferably, the heteropolyacid is a supported heteropolyacid catalyst, and the preparation method is as follows: immersing the carrier in an acid solution, washing to neutrality, drying, and calcining to activate, to obtain an activated carrier; then immersing the activated carrier in an aqueous solution of the heteropolyacid and refluxing for a period of time, and finally drying and calcining to obtain a supported heteropolyacid catalyst.

[0022] Preferably, in the method for preparing the catalyst, the weight concentration of the metal salt solution is 3-5%, and the calcination temperature is 500-600°C.

[0023] Preferably, in the preparation step of 7-(4-chlorobutoxy)-1H-quinolin-2-one, the solvent is acetone.

[0024] The invention skillfully applies the above-mentioned bromine-debromination idea to the preparation method and achieves satisfactory results.

[0025] The present invention does not require complicated purification and can obtain a high-purity 7-(4-chlorobutoxy)-1H-quinoline-2-one intermediate, which meets the requirements for preparing qualified brexpiprazole.

[0026] In the present invention, 7-hydroxy-1,2,3,4-tetrahydroquinolin-2-one and 1-chloro-4-bromobutane react under the action of potassium carbonate to generate 7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one, and 7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one reacts with copper bromide under the action of catalyst 1 to obtain 3-bromo-7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one, and then refluxes and removes hydrogen bromide in an organic solvent under the catalysis of a heteropolyacid catalyst to obtain 7-(4-chlorobutoxy)-1H-quinolin-2-one. The total yield can reach more than 77%, and the HPLC is more than 99.5%, and green and environmentally friendly industrial production can be achieved. DETAILED DESCRIPTION

[0027] The following examples are only intended to illustrate the present invention in detail, but not to limit the present invention. Example 1

[0028] Preparation of supported heteropolyacid catalyst by impregnation method Add a certain amount of 5A molecular sieve into 2mol / L sulfuric acid solution, filter after soaking for 12h, then wash with distilled water until neutral, drain and put into oven, dry at 100℃ for 2h, then heat to 360℃ and activate by roasting for 5h. After activation, cool to room temperature in a dryer for use to obtain a molecular sieve that meets the requirements.

[0029] A certain amount of phosphomolybdic acid is dissolved in distilled water, and the activated molecular sieve is immersed in the solution and heated under reflux for 24 hours, then dried at 120°C for 2 hours, and then calcined at 400°C for 4 hours for activation to obtain a supported heteropoly acid catalyst. Example 2

[0030] Preparation of (4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one Add 70kg acetone and 47.3kg 1-bromo-4-chlorobutane to a 200L reactor, add 10kg 7-hydroxy-1,2,3,4-tetrahydroquinoline-2-one and 0.5kg TBAB under stirring, and stir for 5min. Heat to reflux. At the same time, add 30kg process water and 12kg potassium carbonate to a 60L dropping kettle, stir to dissolve, and set aside. Under reflux, add potassium carbonate solution dropwise. After dropping, stir and react under reflux for 14 to 18h; detect the end point of the reaction by HPLC. The reaction is considered complete when the starting material 7-hydroxy-1,2,3,4-tetrahydroquinoline-2-one is ≤2%. After the reaction was completed, the reaction liquid was concentrated to an internal temperature of 95°C under normal pressure, cooled, and 100 kg of process water was added. The temperature was controlled below 35°C and stirred for crystallization for 1.5 hours. The mixture was filtered, washed, drained, and dried at 70-80°C to obtain about 14.89 kg of the intermediate 7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinoline-2-one crude product with a yield of 95.78%. Recrystallization with 95% ethanol gave 13.7 kg of white crystalline powder with a yield of 88.12% and a purity of 99.47% (HPLC). Example 3 Synthesis of 3-bromo-7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one In a 1000ml three-necked reaction flask equipped with a stirrer, a constant pressure funnel, a reflux condenser with a calcium chloride drying tube and a hydrogen bromide gas absorption device, add 7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one (white crystals) (38g, 0.15mol), 150ml of anhydrous ethanol, and catalyst 1 (5.25g), stir, heat to reflux, and dropwise add copper bromide ethanol solution under reflux [67g (0.3mol) copper bromide dissolved in 200ml ethanol], add dropwise in about 1h, and continue reflux reaction for 2h (HPLC monitoring reaction end point). After the reaction, filter while hot, wash the filter cake with hot ethanol, and recover the catalyst and cuprous bromide. The filtrate is concentrated to an appropriate amount, cooled for crystallization, filtered, and dried to obtain 47.4g of off-white solid. The yield is 95%, and the purity is 99.38% (HPLC).

[0031] Preparation of Catalyst 1: The Al2O3 particle base carrier was immersed in a 4% Zr salt solution (i.e., ZrCl4), ammonia water was added and the pH value was adjusted to 9, washed, dried to remove the ammonia water, immersed in a dilute sulfuric acid solution (concentration of 8 mol / L), filtered, and calcined at 550°C. The acid strength is determined by the color change reaction of Hammentt indicator 2,4-dinitrotoluene (H0=-13.75), 2,4-dinitrofluorobenzene (H0=-14.52), and 1,3,5-trinitrobenzene (H0=-16.02). The test results show that the catalyst can cause 2,4-dinitrotoluene to change color dramatically, 2,4-dinitrofluorobenzene to change color, and 1,3,5-trinitrobenzene to change color slightly. Therefore, the acid strength of the catalyst is -16.02<HO<-14.52, and the dosage is 5% of the total mass of the reactants (total mass of 7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one and copper bromide). Example 4

[0032] Synthesis of 7-(4-chlorobutoxy)-1H-quinolin-2-one In a clean, dry 1000ml four-necked bottle, add 3-bromo-7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one (47g, 0.14mol), 500ml acetone, quickly add 20g of the supported heteropolyacid catalyst of Example 1, and reflux for 8h. After the reaction, cool the tap water to below 50°C, filter, wash, and concentrate to dryness. Recrystallize from ethanol. Obtain 32.77g of off-white powder, with a yield of 93% and a purity of 99.52% (HPLC).

[0033] The structural information of each intermediate is as follows: 7-(4-Chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one ESI-MS(m / z): 255(M+H). 1H NMR(CDCl3)δ: 1.91~2.15(m, 4H), 2.24(t, J=9Hz, 2H), 2.77(t, J=9Hz, 2H), 3.57(t, J=9.0Hz, 2H), 3.98(t, J=9Hz, 2H), 5.53(s, 1H), 6.91(s, 1H), 7.24 (d, J=8.4Hz, 1H), 7.51 (s, 1H).

[0034] 3-Bromo-7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one ESI-MS(m / z): 333.622(M+H). 1H NMR(CDCl3)1.91~2.15(m, 4H), 3.12(t, J=9Hz, 2H), 3.57(t, J=9.0Hz, 2H), 3.98(t, J=9Hz, 2H), 4.43(s, 1H), 5.53(s, 1H), 6.91(s,1H), 7.24 (d, J=8.4Hz, 1H), 7.51 (s, 1H).

[0035] 7-(4-Chlorobutoxy)-1H-quinolin-2-one ESI-MS (m / z): 252 (M+H). 1 HNMR (CDCl 3， 400MH Z )δ: 1.95~2.15(m, 4H), 3.60~3.70(m, 2H), 4.10(t, J=5.6Hz, 2H), 6.56 (dd, J=9.0Hz, 3.8Hz, 1H), 6.81 (dd, J=8.7Hz, 2.4Hz, 1H), 6.85 (d, J=2.3Hz, 1H), 7.45 (d, J=8.7Hz, 1H), 7.75 (d, J=9.4Hz, 1H), 12.54 (br, 1H).

[0036] The reaction route is as follows:

[0037] Comparative Example 1 Synthesis of 3-bromo-7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one In a 1000ml three-necked reaction flask equipped with a stirrer, a constant pressure funnel, a reflux condenser with a calcium chloride drying tube and a hydrogen bromide gas absorption device, add 7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one (white crystals) (38g, 0.15mol), 150ml of anhydrous ethanol, stir, heat to reflux, add copper bromide ethanol solution dropwise under reflux [67g (0.3mol) copper bromide dissolved in 200ml ethanol], add dropwise in about 1h, and continue reflux reaction for 2h (HPLC monitoring reaction end point). After the reaction, filter while hot, wash the filter cake with hot ethanol, and recover cuprous bromide. The filtrate is concentrated to an appropriate amount, cooled for crystallization, filtered, and dried to obtain 37.4g of off-white solid. The yield is 75%, and the purity is 99.18% (HPLC).

[0038] Synthesis of 7-(4-chlorobutoxy)-1H-quinolin-2-one In a clean, dry 1000ml four-necked bottle, add 3-bromo-7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one (37g, 0.11mol), 500ml acetone, quickly add 20g of the supported heteropolyacid catalyst of Example 1, and reflux for 8h. After the reaction, cool the tap water to below 50°C, filter, wash, and concentrate to dryness. Recrystallize from ethanol. Obtain 24.92g of off-white powder, with a yield of 90% and a purity of 99.47% (HPLC).

[0039] Synthesis of 7-(4-chlorobutoxy)-1H-quinolin-2-one DDQ (25 g, 0.11 mol) was put into dry dichloromethane (200 ml), and a dichloromethane solution (100 ml) of 7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one (25.3 g, 0.1 mol) was added dropwise at 20°C. After the addition was completed, the temperature was controlled at 30-40°C and stirred for 4 h (the reaction endpoint was monitored by HPLC, and the reaction was considered complete when 7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one ≤ 2%). After the reaction, the temperature was lowered and the mixture was filtered. The filtrate was washed with saturated sodium bicarbonate solution (100 ml×3), water (100 ml) and saturated brine (100 ml) in sequence, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated from the filtrate. The residue was recrystallized with ethanol-water (5:3) and dried to obtain 17.24 g of off-white powder with a purity of 99.15% (HPLC) and a yield of 68.5%.

[0040] Preparation of supported Ti / silica gel catalyst Titanium tetrachloride, 15% (w / w) hydrochloric acid solution and silica gel are mixed and aged at 30°C for 6 hours, then the pH value of the mixture is adjusted to about 1 with ammonia water, and then the mixture is heated to 90°C to evaporate and remove water. After the mixture is dried, it is placed in a muffle furnace and calcined at 500°C for 2 hours to obtain a supported Ti / silica gel catalyst. Among them, silica gel, titanium tetrachloride (in terms of titanium dioxide) and hydrochloric acid solution (in terms of H + The weight ratio of (in terms of weight) is 1:0.06:2.

[0041] Synthesis of 3-bromo-7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one In a 1000ml three-necked reaction flask equipped with a stirrer, a constant pressure funnel, a reflux condenser with a calcium chloride drying tube and a hydrogen bromide gas absorption device, add 7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one (white crystals) (38g, 0.15mol), 150ml of anhydrous ethanol, and a supported Ti / silica gel catalyst (5.25g), stir, heat to reflux, and dropwise add a copper bromide ethanol solution under reflux [67g (0.3mol) copper bromide dissolved in 200ml ethanol], add dropwise in about 1h, and continue to reflux for 2h (HPLC monitors the reaction end point). After the reaction, filter while hot, wash the filter cake with hot ethanol, and recover the catalyst and cuprous bromide. The filtrate is concentrated to an appropriate amount, cooled for crystallization, filtered, and dried to obtain 42.4g of off-white solid. The yield is 85%, and the purity is 99.28% (HPLC).

[0042] A person skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of protection of the present application is limited to these examples. In line with the concept of the present application, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of different aspects of one or more embodiments of the present application as described above, which are not provided in detail for the sake of simplicity.

[0043] One or more embodiments of the present application are intended to cover all such substitutions, modifications and variations that fall within the broad scope of the present application. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of one or more embodiments of the present application should be included in the protection scope of the present application.

Claims

1. A method for preparing 7-methoxynaphthaleneacetonitrile, characterized in that: The steps are: 7-hydroxy-1,2,3,4-tetrahydroquinolin-2-one reacts with 1-chloro-4-bromobutane under the action of potassium carbonate to generate 7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one; 7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one reacts with copper bromide under the action of catalyst 1 to obtain 3-bromo-7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one; 3-bromo-7-(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one is debrominated under the action of catalyst 2 to obtain 7-(4-chlorobutoxy)-1H-quinolin-2-one; The preparation method of the catalyst comprises the following steps: mixing carrier particles and a metal salt solution, adjusting the pH to alkaline, washing, drying, immersing in a sulfuric acid solution, filtering, and then roasting to obtain the catalyst; the carrier particles are aluminum oxide or silicon dioxide, and the metal salt solution is a salt solution of Zr, Ti or Sn.

2. The preparation method according to claim 1, characterized in that: The carrier particles are aluminum oxide, and the metal salt solution is ZrCl4.

3. The preparation method according to claim 1, characterized in that: The acid strength of the catalyst is -16.02 to -14.

52.

4. The preparation method according to claim 1, characterized in that: When -(4-chlorobutoxy)-1,2,3,4-tetrahydroquinolin-2-one reacts with copper bromide, the solvent is ethanol.

5. The preparation method according to claim 1, characterized in that: The heteropoly acid is phosphotungstic acid, phosphomolybdic acid, vanadophosphotungstic acid, vanadophosphomolybdic acid, silicotungstic acid, silicomolybdic acid, vanadosilicotungstic acid or vanadosilicomolybdic acid.

6. The preparation method according to claim 1 or 5, characterized in that: The heteropoly acid is a supported heteropoly acid catalyst, and the preparation method is as follows: immersing the carrier in an acid solution, washing to neutrality, drying, calcining and activating to obtain an activated carrier; then immersing the activated carrier in a heteropoly acid aqueous solution and refluxing for a period of time, and finally drying and calcining to obtain a supported heteropoly acid catalyst.

7. The preparation method according to any one of claims 1 to 5, characterized in that: In the preparation method of the catalyst, the weight concentration of the metal salt solution is 3-5%, and the calcination temperature is 500-600°C.

8. The preparation method according to any one of claims 1 to 5, characterized in that: In the preparation step of 7-(4-chlorobutoxy)-1H-quinolin-2-one, the solvent is acetone.

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