Preparation method of brexpiprazole

Abstract

The invention provides a preparation method of brexpiprazole, which comprises the following steps: by taking 7-hydroxy-2 (1H)-quinolinone as a starting material, carrying out nucleophilic substitution type etherification reaction on the 7-hydroxy-2 (1H)-quinolinone and 4-chloro-1-butanol in an alkaline medium to generate a 7-(4-hydroxybutoxy)-2 (1H)-quinolinone intermediate; then, a ruthenium catalyst is used as a catalytic system, the intermediate and 4-(1-piperazinyl) benzothiophene hydrochloride are subjected to an N-alkylation reaction, and synthesis of the target compound brexpiprazole is completed. The synthesis route of the brexpiprazole has the advantages of being short in technological process, high in atom utilization rate, high in yield, low in cost, environmentally friendly and the like.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a method for preparing birepiperazole, a drug for schizophrenia and major depressive disorder. Background Technology

[0002] Brepiprazole is a quinolinone derivative, belonging to the atypical antipsychotic class, primarily used to treat schizophrenia and major depressive disorder. Its chemical name is 7-[4-(4-benzo[b]thiophene-4-yl-1-piperazine)butoxy]-2( 1H )-Quinolinone, with the molecular formula C 26 H 27 N3O2S, CAS registration number 129722-12-9, trade name Rexulti, has the following structural formula:

[0003] In 2006, Hiroshi Yamashita et al. filed patent CN200680011923 with 7-hydroxy-2 ( 1H Starting with quinolinone, it reacts with 1-bromo-4-chlorobutane under alkaline conditions to produce the intermediate 7-(4-chlorobutoxy)-2( 1H The intermediate is reacted with 1-bromo-4-chlorobutane to produce bripiprazole, with an overall yield of approximately 55%. This route suffers from poor selectivity in the reaction with 1-bromo-4-chlorobutane, easily generating multi-substituted impurities, some of which are genotoxic, making post-processing and purification difficult. Furthermore, in the presence of a base, the intermediate may undergo nitrogen alkylation with bripiprazole, reducing the yield.

[0004]

[0005] In 2016, Xu Kui et al. synthesized bripiprazole using 4-halo-1-butanol (with chlorine or bromine as the halogen) as the etherifying agent in patent CN201610006862. The reaction involved three steps (generating an alcohol-containing hydroxyl intermediate, preparing a sulfonate ester, and reacting with 4-(1-piperazinyl)benzothiophene), with an overall yield of 65%. This route improves selectivity due to the difference in the activity of the reagent groups, and the sulfonate ester enhances the reaction activity. However, it suffers from problems such as multiple steps, high reagent cost, and easy generation of quaternary ammonium salt byproducts (increasing purification difficulty, reducing atom utilization and yield).

[0006]

[0007] Therefore, developing a simple, efficient, and environmentally friendly method for preparing birepiperazole is an urgent problem to be solved. Summary of the Invention

[0008] This invention develops a method using 7-hydroxy-2( 1H A novel route for obtaining buripiperazole was developed using quinolinone as the starting material and 4-chloro-1-butanol as the etherifying agent, through a two-step reaction involving etherification and transition metal-catalyzed N-alkylation.

[0009] This invention employs a "hydrogen transfer" strategy to catalyze the N-alkylation reaction of alcohols and amines to synthesize bripiprazole. The method includes the following steps:

[0010] (1) Dissolve 7-hydroxy-2(1H)-quinolinone (as shown in formula (I) and basic substance A in organic solvent A, stir at 20-40°C for 0-30 min (preferably at 40°C for 30 min), then add 4-chloro-1-butanol (as shown in formula (II)) and catalyst A, heat to 70-100°C (preferably 80°C) and react for 8-12 h (preferably 12 h). The resulting reaction mixture A is post-treated A to obtain 7-(4-hydroxybutoxy)- (as shown in formula (III)). 2(1H)-quinolinone; the catalyst A is one or more of NaI, KI, CuI, NH4I, KI, CsI or LiI (preferably KI); the molar ratio of 7-hydroxy-2(1H)-quinolinone of formula (I), 4-chloro-1-butanol of formula (II), basic substance A and catalyst substance A is 1:0.5-2.0:1.0-3.0:1.0-5.0 (preferably 1:0.5-1.5:1.25-2.0:2.5-3.5, most preferably 1:1.2:2.0:3.0); (2) Under an inert gas atmosphere (preferably a nitrogen atmosphere), the 7-(4-hydroxybutoxy)-2(1H)-quinolinone described in step (1), the 4-(1-piperazinyl)benzothiophene hydrochloride shown in formula (IV), the basic substance B and the catalyst B are dissolved in organic solvent B and reacted at 120℃-160℃ for 9-12h (preferably 150℃ for 12h). The resulting reaction mixture B is post-treated by B to obtain bripiprazole shown in formula (V); the catalyst B is Pd(OAc)2, RuCl2(PPh3)3, RuCl2(CO)(PPh3)2(H2O), RuCl2(CO)(PPh3)2(CH3CN), [Cp IrCl]2, RuCl2 (PPh3)4, Fe2(SO4)3· xOne or more of H2O / SiO2, Ni(cod)2 or Co2Rh2 / C (preferably RuCl2(CO)(PPh3)2(CH3CN)); the molar ratio of the 7-(4-hydroxybutoxy)-2(1H)-quinolinone, 4-(1-piperazinyl)benzothiophene hydrochloride as shown in formula (IV), basic substance B and catalyst B is 1:0.5-2.0:1.0-3.0:0.01-0.08 (preferably 1:0.5-1.1:1.25-1.75:0.035-0.045, most preferably 1:1.0:1.50:0.04).

[0011] Furthermore, the organic solvent A is one or more of ethyl acetate, ethanol, isopropanol, acetonitrile, 1,4-dioxane, tetrahydrofuran, toluene, xylene, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, or N-methylpyrrolidone (preferably N,N-dimethylacetamide).

[0012] Furthermore, the alkaline substance A is one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, DBU, DIEA, potassium phosphate, potassium tert-butoxide, sodium methoxide, or sodium ethoxide (preferably potassium carbonate).

[0013] Furthermore, the organic solvent B is one or more of toluene, xylene, trifluorotoluene, DMF, chlorobenzene, dimethyl sulfoxide, propylene glycol methyl ether, 2-methyl-1-phenyl-propanol, 2-methylcyclohexanol or tert-amyl alcohol (preferably 2-methyl-1-phenyl-propanol). Furthermore, the alkaline substance B is Na₂CO₃, K₂CO₃, Cs₂CO₃, NaHCO₃, K₃PO₄, NaOH, t BuONa or t One or more of the following (preferably K2CO3): BuOK.

[0014] Further, the post-treatment A is as follows: the reaction mixture A is concentrated, quenched with water, extracted with an organic solvent, and purified by column chromatography to obtain 7-(4-hydroxybutoxy)-2(1H)-quinolinone as shown in formula (III). The organic solvent is one or more of ethyl acetate, toluene, diethyl ether, petroleum ether, dichloromethane, or chloroform, with dichloromethane being recommended.

[0015] Further, the post-treatment B is as follows: the reaction mixture B is cooled to room temperature, filtered, and the resulting solid is purified by column chromatography to obtain buriperazole as shown in formula (V).

[0016] Furthermore, the volume of the organic solvent A is 20-40 mL / g (preferably 20-37 mL / g) based on the mass of the 7-hydroxy-2(1H)-quinolinone shown in (I).

[0017] Furthermore, the volume of the organic solvent B is 8-20 mL / g (preferably 8-12 mL / g) based on the mass of 7-(4-hydroxybutoxy)-2(1H)-quinolinone as shown in formula (III).

[0018] Furthermore, the preparation method is as follows: (1) Dissolve 7-hydroxy-2(1H)-quinolinone as shown in formula (I) and basic substance A in organic solvent A, stir at 40°C for 30 min, then add 4-chloro-1-butanol as shown in formula (II) and catalyst A, heat to 80°C and react for 12 h, and the resulting reaction mixture A is post-treated A to obtain 7-(4-hydroxybutoxy)-2(1H)-quinolinone as shown in formula (III); the catalyst A is KI; the molar ratio of 7-hydroxy-2(1H)-quinolinone as shown in formula (I), 4-chloro-1-butanol as shown in formula (II), basic substance A and catalyst A is 1:1.2:2.0:3.0.

[0019] (2) Under a nitrogen atmosphere, the 7-(4-hydroxybutoxy)-2(1H)-quinolinone, the 4-(1-piperazinyl)benzothiophene hydrochloride shown in formula (IV), the basic substance B and the catalyst B are dissolved in an organic solvent and reacted at 150°C for 12 h. The resulting reaction mixture B is post-treated by B to obtain bripiprazole shown in formula (V). The catalyst B is RuCl2(CO)(PPh3)2(CH3CN). The molar ratio of the 7-(4-hydroxybutoxy)-2(1H)-quinolinone, the 4-(1-piperazinyl)benzothiophene hydrochloride shown in formula (IV), the basic substance B and the catalyst B is 1:1.0:1.50:0.04.

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention, through analysis of existing literature and patents, comparison of the advantages and disadvantages of synthetic methods, and combining the N-alkylation reaction of alcohols and amines catalyzed by transition metals, proposes a method using 7-hydroxy-2-( 1H A route for synthesizing bripiprazole from quinolinone via a two-step reaction involving etherification with 4-chloro-1-butanol and N-alkylation catalyzed by ruthenium is proposed. This route is characterized by its short process flow, simple operation, high yield and atom utilization, and is economical and environmentally friendly, thus playing a positive role in related synthetic research. Attached Figure Description

[0021] Figure 1The nuclear magnetic resonance hydrogen spectrum of the final product 7-(4-hydroxybutoxy)-2(1H)-quinolinone in Example 1; Figure 2 This is the 1H NMR spectrum of the final product birepiperazole in Example 6; Detailed Implementation

[0022] Example 1: Add 7-hydroxy-2-( 1H 3.220 g (20 mmol) of quinolinone, potassium carbonate (4.140 g, 30 mmol), and 120 mL of ethanol were added to the mixture. The mixture was stirred at 40 °C for 30 min, and then 4-chloro-1-butanol (2.171 g, 20 mmol) and sodium iodide (8.993 g, 60 mmol) were added dropwise to the reaction solution. After the addition was complete, the temperature was raised to 80 °C and the reaction was carried out for 12 h. After the reaction was completed, the solvent was evaporated under reduced pressure, and 120 mL of water was added. The mixture was extracted with dichloromethane (160 mL × 3). The organic phases were combined and separated by column chromatography (EA:MeOH = 30:1) to obtain a white solid 7-(4-hydroxybutoxy)-2-( 1H 1.678 g of quinolinone (III) (yield 32%, purity 98%).

[0023] 1 HNMR (400 MHz, (CD3)2SO) δ = 11.58 (s, 1H), 7.79 (d, J =9.60 Hz, 1H), 7.54 (d, J =8.40 Hz, 1H), 6.77 (d, J =7.20 Hz, 2H), 6.29 (d, J =9.60 Hz, 1H),4.49 (s, 1H), 4.00 (t, J =6.50 Hz, 2H), 3.45 (t, J =6.40 Hz, 2H), 1.81-1.72 (m,3H), 1.62-1.53 ​​(m, 3H).

[0024] Example 2: Add 7-hydroxy-2-( 1H3.260 g (20 mmol) of quinolinone, potassium carbonate (4.140 g, 30 mmol) and 120 mL of N,N-dimethylformamide were added to the mixture and stirred at 40 °C for 30 min. Then, 4-chloro-1-butanol (2.171 g, 20 mmol) and sodium iodide (8.993 g, 60 mmol) were added dropwise to the reaction solution. After the addition was complete, the temperature was raised to 80 °C and the reaction was carried out for 12 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 120 mL of water was added, and the mixture was extracted with dichloromethane (160 mL × 3). The organic phases were combined and separated by column chromatography (EA:MeOH = 30:1) to obtain a white solid 7-(4-hydroxybutoxy)-2-( 1H 1.724 g of quinolinone (III) (yield 37%, purity 96%).

[0025] Example 3: Add 7-hydroxy-2-( 1H 3.260 g (20 mmol) of quinolinone, potassium carbonate (4.140 g, 30 mmol) and 120 mL of N,N-dimethylacetamide were added to the mixture and stirred at 40 °C for 30 min. Then, 4-chloro-1-butanol (2.171 g, 20 mmol) and sodium iodide (8.993 g, 60 mmol) were added dropwise to the reaction solution. After the addition was complete, the temperature was raised to 80 °C and the reaction was carried out for 12 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 120 mL of water was added, and the mixture was extracted with dichloromethane (160 mL × 3). The organic phases were combined and separated by column chromatography (EA:MeOH = 30:1) to obtain a white solid 7-(4-hydroxybutoxy)-2-( 1H )-Quinolinone (III) 2.144 g (yield 46%, purity 98%).

[0026] Example 4: Add 7-hydroxy-2-( 1H 3.260 g (20 mmol) of 7-(4-hydroxybutoxy)-2(1H)-quinolinone (Ⅲ) was added to 120 mL of N,N-dimethylacetamide and stirred at 40 °C for 30 min. Then, 2.606 g (24 mmol) of 4-chloro-1-butanol and 9.960 g (60 mmol) of potassium iodide were added dropwise to the reaction solution. After the addition was complete, the temperature was raised to 80 °C and the reaction was carried out for 12 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 120 mL of water was added, and the mixture was extracted with dichloromethane (160 mL × 3). The organic phases were combined and separated by column chromatography (EA:MeOH = 30:1) to obtain 3.262 g of white solid 7-(4-hydroxybutoxy)-2(1H)-quinolinone (Ⅲ) (yield 70%, purity 97%).

[0027] Example 5: Add 7-hydroxy-2-( 1H 3.260 g (20 mmol) of 7-(4-hydroxybutoxy)-2(1H)-quinolinone (Ⅲ) was added to 120 mL of N,N-dimethylacetamide and stirred at 40 °C for 30 min. Then, 2.606 g (24 mmol) of 4-chloro-1-butanol and 9.960 g (60 mmol) of potassium iodide were added dropwise to the reaction solution. After the addition was complete, the temperature was raised to 80 °C and the reaction was carried out for 48 h. After the reaction was completed, the solvent was evaporated under reduced pressure, 120 mL of water was added, and the mixture was extracted with dichloromethane (160 mL × 3). The organic phases were combined and separated by column chromatography (EA:MeOH = 30:1) to obtain 4.227 g of white solid 7-(4-hydroxybutoxy)-2(1H)-quinolinone (Ⅲ) (yield 90.7%, purity 97%).

[0028] Example 6: Add 7-(4-hydroxybutoxy)-2-( 1H 4-(1-piperazinyl)benzothiophene hydrochloride (Ⅳ) (2.540 g, 10 mmol), potassium carbonate (2.070 g, 15 mmol), RuCl2(CO)(PPh3)2(MeCN) (0.297 g, 4 mol%), and 20 mL of toluene were reacted at 150 °C for 12 hours under nitrogen protection. After the reaction was completed and cooled to room temperature, the mixture was filtered and separated by solid column chromatography (EA:MeOH = 15:1) to give 2.816 g of pale yellow solid birepiperazole (yield 80.4%, purity 98%).

[0029] 1 HNMR (400 MHz, CDCl3) δ = 12.82 (s, 1H), 7.74 (d, J =9.60 Hz, 1H), 7.56 (d, J =8.00 Hz, 1H), 7.43 (m, 3H), 7.28 (dd, J =8.00 Hz, 6.80, 1H), 6.92(m, 2H), 6.83 (dd, J =8.40 Hz, 2.40, 1H), 6.58 (d, J =9.20 Hz, 1H), 4.12 (t, J=6.00 Hz, 2H), 3.22 (m, 4H), 2.75 (s, 4H), 2.58 (m, 3H), 1.98-1.72 (m, 4H).

[0030] Example 7: Add 7-(4-hydroxybutoxy)-2-( 1H )-Quinolinone (III) (2.330 g, 10 mmol), 4-(1-piperazinyl)benzothiophene hydrochloride (IV) (2.540 g, 10 mmol), potassium carbonate (2.070 g, 15 mmol), [Cp IrCl]2 (0.3184 g, 4 mol%) and 20 mL of toluene were reacted at 150 °C for 12 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, filtered, and separated by solid column chromatography (EA:MeOH = 15:1) to give 1.906 g of pale yellow solid birepiperazole (yield 44.0%, purity 99%).

[0031] Example 8: Add 7-(4-hydroxybutoxy)-2-( 1H 4-(1-piperazinyl)benzothiophene hydrochloride (Ⅳ) (2.540 g, 10 mmol), potassium carbonate (2.070 g, 15 mmol), RuCl2(PPh3)3 (0.3835 mg, 4 mol%), and 20 mL of toluene were reacted at 150 °C for 12 hours under nitrogen protection. After the reaction was completed and cooled to room temperature, the mixture was filtered and separated by solid column chromatography (EA:MeOH = 15:1) to give 2.467 g of pale yellow solid birepiperazole (yield 57%, purity 98%).

[0032] Example 9: Add 7-(4-hydroxybutoxy)-2-( 1H 1,350 g (10 mmol) of quinolinone (III), 4-(1-piperazinyl)benzothiophene hydrochloride (IV) (2.540 g, 10 mmol), potassium carbonate (2.070 g, 15 mmol), RuCl2 (PPh3)4 (0.4884 mg, 4 mol%), and 20 mL of toluene were added. The mixture was heated to 150 °C and reacted for 12 hours under nitrogen protection. After the reaction was completed and cooled to room temperature, the mixture was filtered and separated by solid column chromatography (EA:MeOH = 15:1) to give 1.732 g of pale yellow solid birepiperazole (yield 45.0%, purity 99%).

Claims

1. A method for preparing birepiperazole as shown in formula (V), Its features are, The preparation method is as follows: (1) Dissolve 7-hydroxy-2(1H)-quinolinone as shown in formula (I) and basic substance A in organic solvent A, stir at 20-40℃ for 0-30 min, then add 4-chloro-1-butanol as shown in formula (II) and catalyst A, heat to 70-100℃ and react for 8-12 h, and the resulting reaction mixture A is post-treated A to obtain 7-(4-hydroxybutoxy)-2(1H)-quinolinone as shown in formula (III); the catalyst A is one or more of NaI, KI, CuI, NH4I, KI, CsI or LiI; the molar ratio of 7-hydroxy-2(1H)-quinolinone as shown in formula (I), 4-chloro-1-butanol as shown in formula (II), basic substance A and catalyst A is 1:0.5-2.0:1.0-3.0:1.0-5.0; (2) Under an inert gas atmosphere, the 7-(4-hydroxybutoxy)-2(1H)-quinolinone, the 4-(1-piperazinyl)benzothiophene hydrochloride shown in step (IV), basic substance B and catalyst B are dissolved in organic solvent B and reacted at 120℃-160℃ for 9-12h. The resulting reaction mixture B is post-treated by B to obtain bripiprazole shown in formula (V); the catalyst B is Pd(OAc)2, RuCl2(PPh3)3, RuCl2(CO)(PPh3)2(H2O), RuCl2(CO)(PPh3)2(CH3CN), [Cp IrCl]2, RuCl2 (PPh3)4, Fe2(SO4)3· x One or more of H2O / SiO2, Ni(cod)2 or Co2Rh2 / C; the molar ratio of the 7-(4-hydroxybutoxy)-2(1H)-quinolinone, 4-(1-piperazinyl)benzothiophene hydrochloride as shown in formula (IV), basic substance B and catalyst B is 1:0.5-2.0:1.0-3.0:0.01-0.

08.

2. The method for preparing birepiperazole according to claim 1, characterized in that, The organic solvent A is one or more of ethyl acetate, ethanol, isopropanol, acetonitrile, 1,4-dioxane, tetrahydrofuran, toluene, xylene, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, or N-methylpyrrolidone.

3. The method for preparing biriperazole as described in claim 1, characterized in that, The alkaline substance A is one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, DBU, DIEA, potassium phosphate, potassium tert-butoxide, sodium methoxide, or sodium ethoxide.

4. The method for preparing birepiperazole according to claim 1, characterized in that, The organic solvent B is one or more of toluene, xylene, trifluorotoluene, DMF, chlorobenzene, dimethyl sulfoxide, propylene glycol methyl ether, 2-methyl-1-phenyl-propanol, 2-methylcyclohexanol, or tert-amyl alcohol.

5. The method for preparing birepiperazole according to claim 1, characterized in that, The alkaline substance B is Na₂CO₃, K₂CO₃, Cs₂CO₃, NaHCO₃, K₃PO₄, or NaOH. t BuONa or t One or more of the following: BuOK.

6. The method for preparing birepiperazole according to claim 1, characterized in that, The post-treatment A is as follows: the reaction mixture A is concentrated and quenched with water, extracted with an organic solvent, and purified by column chromatography to obtain 7-(4-hydroxybutoxy)-2(1H)-quinolinone as shown in formula (III).

7. The method for preparing birepiperazole according to claim 1, characterized in that, The post-treatment B is as follows: the reaction mixture B is cooled to room temperature, filtered, and the resulting solid is purified by column chromatography to obtain buriperazole as shown in formula (V).

8. The method for preparing birepiperazole according to claim 1, characterized in that, The volume of the organic solvent A is 20-40 mL / g based on the mass of the 7-hydroxy-2(1H)-quinolinone shown in (I).

9. The method for preparing birepiperazole according to claim 1, characterized in that, The volume of the organic solvent B is 8-20 mL / g based on the mass of 7-(4-hydroxybutoxy)-2(1H)-quinolinone as shown in formula (III).

10. The method for preparing birepiperazole according to claim 1, characterized in that, The preparation method is as follows: (1) Dissolve 7-hydroxy-2(1H)-quinolinone as shown in formula (I) and basic substance A in organic solvent A, stir at 40°C for 30 min, then add 4-chloro-1-butanol as shown in formula (II) and catalyst A, heat to 80°C and react for 12 h, and the resulting reaction mixture A is post-treated A to obtain 7-(4-hydroxybutoxy)-2(1H)-quinolinone as shown in formula (III); the catalyst A is KI; the molar ratio of 7-hydroxy-2(1H)-quinolinone as shown in formula (I), 4-chloro-1-butanol as shown in formula (II), basic substance A and catalyst A is 1:1.2:2.0:3.0; (2) Under a nitrogen atmosphere, the 7-(4-hydroxybutoxy)-2(1H)-quinolinone, the 4-(1-piperazinyl)benzothiophene hydrochloride shown in formula (IV), the basic substance B and the catalyst B are dissolved in organic solvent B and reacted at 150°C for 12 h. The resulting reaction mixture B is post-treated by B to obtain bripiprazole shown in formula (V). The catalyst B is RuCl2 (CO)(PPh3)2 (CH3CN). The molar ratio of the 7-(4-hydroxybutoxy)-2(1H)-quinolinone, the 4-(1-piperazinyl)benzothiophene hydrochloride shown in formula (IV), the basic substance B and the catalyst B is 1:1.0:1.50:0.04.

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