Efficient synthesis method of brexpiprazole
By optimizing the synthesis method of buripiperazole, using supported catalysts and multi-stage crystallization purification processes, the problems of high cost and pollution in existing technologies have been solved, achieving efficient and low-cost buripiperazole production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SUZHOU JINGYE MEDICINE & CHEM
- Filing Date
- 2025-12-24
- Publication Date
- 2026-05-19
AI Technical Summary
Existing methods for synthesizing bripiprazole use expensive and hazardous potassium iodide, and Pd catalysts are costly, polluting, and difficult to adapt to large-scale production. Furthermore, the purification process is complex, resulting in high production costs and severe environmental pollution.
Using 4-bromo-benzothiophene and N-Boc-piperazine as starting materials, a supported catalyst was used with hierarchical porous nitrogen-doped carbon nanomaterials as the support and palladium as the active component. Combined with BINAP or RuPhos ligands, the reaction conditions and purification process were optimized, and high-purity birepiperazole was obtained through multi-stage crystallization purification.
It reduces the amount of palladium used, decreases side reactions, improves the selectivity and purity of the target product, is suitable for industrial production, reduces production costs, and reduces environmental pollution.
Smart Images
Figure CN122059942A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis technology, specifically relating to an efficient method for synthesizing buripiperazole. Background Technology
[0002] Biriperazole is an atypical antipsychotic drug primarily used to treat schizophrenia and as an adjunct therapy for major depressive disorder. It exerts its unique pharmacological activity by acting on multiple neurotransmitter receptors, exhibiting definite efficacy and relatively low side effects, and shows promising potential in clinical applications. With the continuous growth of market demand, developing efficient, economical, and environmentally friendly synthetic processes for biriperazole has become a research hotspot in the pharmaceutical field.
[0003] Currently, the synthetic routes for bripiprazole mainly revolve around the construction and connection of its core structure—a benzothiophene piperazine derivative and a quinolinone butoxy side chain. Traditional synthetic methods typically involve multiple steps, such as the introduction of the piperazine derivative, alkylation of the quinolinone core, oxidation, and final nucleophilic substitution coupling. Patent WO2017216661A1 discloses a preparation method, the specific reaction process of which is shown in formula (I). , (I); In the above reaction, potassium iodide is used when the final BRX-2 and BRX-6 fragments are joined. This reagent is relatively expensive, increasing production costs; it also causes significant environmental pollution, is flammable and explosive, and is quite dangerous. This is not conducive to production. Literature (DOI: 101039 / C9QO00726A) discloses a method for preparing bripiprazole. The reaction process of this method is shown in formula (II), specifically including: reacting 4-piperazine-benzothiophene hydrochloride and 7-(3-chloropropoxy)quinoline-2(1H)-one, potassium tert-butoxide, and Pd-PEPPSI complex in 1,4-dioxane solution at 100°C for 2 hours. After cooling to room temperature, the mixture is washed with water, diluted with dichloromethane, separated to obtain an organic phase, washed with dichloromethane, combined with anhydrous magnesium sulfate, dried with the organic solvent to obtain crude bripiprazole, and then subjected to column chromatography with petroleum ether and dichloromethane to obtain the product bripiprazole. , (II); The above process requires the use of Pd catalyst, and purification requires column chromatography. The raw material cost is high, the pollution is significant, and the need for column chromatography is not conducive to large-scale production applications.
[0004] In summary, in order to solve the above-mentioned technical problems, it is necessary to provide a new synthetic method for producing buripiperazole. Summary of the Invention
[0005] Therefore, the technical problem to be solved by the present invention is to provide an efficient method for synthesizing burepiperazole. The present invention uses 4-bromo-benzothiophene and N-Boc-piperazine as starting materials, optimizes the selection of catalysts and the conditions of each step, and obtains high-purity burepiperazole through excellent purification process.
[0006] To solve the above-mentioned technical problems, the present invention provides the following technical solution: An efficient method for synthesizing birepiperazole includes the following steps: (1) Under nitrogen protection, 4-bromo-benzothiophene, N-Boc-piperazine, sodium tert-butoxide, supported catalyst, and ligand were added to a solvent for reaction. The resulting reaction solution was filtered, and the mother liquor was crystallized with an inert solvent to obtain 4-Boc-piperazine-benzothiophene. The supported catalyst used hierarchical porous nitrogen-doped carbon nanomaterials as a support and tetrakis(triphenylphosphine)palladium as the active component. (2) Add acid dropwise to a methanol solution of 4-Boc piperazine-benzothiophene and stir to react, to obtain 4-piperazine benzothiophene hydrochloride; (3) Mix 3,4-dihydro-7-hydroxy-2(1H)quinolinone, 1-bromo-4-chloro-butane, base and solvent and react. After the reaction is complete, add water to the reaction system to precipitate and obtain 3,4-dihydro-7-(4-chlorobutoxy)-2(1H)-quinolinone; (4) Mix 3,4-dihydro-7-(4-chlorobutoxy)-2(1H)-quinolinone, catalyst and solvent and react. After the reaction is completed, pour the reaction solution into the reducing agent aqueous solution to precipitate and obtain 7-(4-chlorobutoxy)-2(1H)-quinolinone. (5) Mix 7-(4-chlorobutoxy)-2(1H)-quinolinone, 4-piperazine benzothiophene hydrochloride, base and solvent, heat to reflux reaction, monitor the complete reaction of the raw materials, cool down and filter to obtain crude bripiprazole; (6) The crude buripiperazole was purified by multiple crystallizations to obtain buripiperazole.
[0007] Preferably, in step (1), the solvent is selected from at least one of toluene, xylene, N,N-dimethylformamide, dimethyl sulfoxide, and tetrahydrofuran; And / or the ligand is selected from at least one of BINAP and RuPhos; And / or the molar ratio of the 4-bromobenzothiophene, N-Boc-piperazine, sodium tert-butoxide, and ligand is 1:(1.3-1.5):3.0:(0.001-0.002); And / or the amount of the catalyst used, calculated as palladium acetate, is 0.08-0.2% of the molar amount of 4-bromobenzothiophene; And / or the temperature during the reaction in the solvent is 100℃-140℃; And / or the crystallization temperature is 0-10℃.
[0008] Preferably, the method for preparing the supported catalyst includes the following steps: S1. Sodium lignosulfonate, chitosan, potassium ferrate and deionized water are mixed and placed in a reaction vessel for hydrothermal reaction to obtain the carrier precursor, which is then pyrolyzed to obtain the carrier. S2. Under a nitrogen atmosphere, the above-mentioned support was dispersed in anhydrous 1,4-dioxane. Triethylamine and diphenyl chlorophosphate were slowly added under an ice-water bath and stirring. After the addition was completed, the ice-water bath was removed, the temperature was raised and the mixture was refluxed and stirred to obtain the functionalized support. S3. Under a nitrogen atmosphere, functionalized support, palladium acetate, triphenylphosphine and 2-methyltetrahydrofuran were ultrasonically dispersed, heated and stirred for adsorption, and then L-ascorbic acid solution was added and stirred to react, thus obtaining a supported catalyst.
[0009] Preferably, in step S1, the mass ratio of sodium lignosulfonate, chitosan, potassium ferrate, and deionized water is (1.5-2.5):1:(0.4-0.5):50; And / or the hydrothermal reaction is carried out at a temperature of 180°C for a time of 10-15 hours; And / or the pyrolysis conditions are: nitrogen atmosphere, heating to 350-380℃ at a heating rate of 3-5℃ / min, and holding at that temperature for 2-3 hours.
[0010] Preferably, in step S2, the ratio of the carrier to triethylamine and diphenyl chlorophosphate is 1g:(1.0-1.5)ml:(2-3)ml; The temperature and / or the temperature for reflux stirring is 80℃, and the time is 10-15h.
[0011] Preferably, in step S3, the ratio of the functionalized carrier, palladium acetate, triphenylphosphine, and ascorbic acid is (0.7-0.8):(0.05-0.06):(0.3-0.4):(0.25-0.3). And / or the L-ascorbic acid solution comprises 0.5-0.3 g ascorbic acid and 5 ml 2-methyltetrahydrofuran; And / or the stirring and dispersion temperature is 40-50℃, and the time is 0.5-1.5h; The temperature of the stirring reaction is 40-50℃ and the time is 5-6h.
[0012] Preferably, in step (2), the acid is selected from at least one of concentrated hydrochloric acid, dilute hydrochloric acid, hydrochloric acid ethanol, hydrochloric acid ethyl acetate, and dioxane hydrochloride; the amount of acid added is 7-8 times the molar amount of 4-Boc piperazine-benzothiophene; the solvent is selected from at least one of water, ethanol, methanol, and ethyl acetate; and the temperature of the stirring reaction is 0-100℃. In step (3), the base is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, triethylamine, and sodium hydride; the solvent is selected from at least one of water, N,N-dimethylformamide, and dimethyl sulfoxide; the temperature of the mixed reaction is 25℃-100℃; the amount of water added is 2-5 times the total volume of the reaction solution; and the molar ratio of 3,4-dihydro-7-hydroxy-2(1H)-quinolinone, 1-bromo-4-chlorobutane, and the base is 1:(2-3):(1.5-2).
[0013] Preferably, in step (4), the catalyst is DDQ; And / or the solvent is selected from at least one of tetrahydrofuran, dichloromethane, dichloroethane, and ethyl acetate; The molar ratio of the 3,4-dihydro-7-(4-chlorobutoxy)-2(1H)-quinolinone to the catalyst is 1:(0.2-0.3). And / or the temperature of the mixture reaction is 25℃-80℃; And / or the reducing agent aqueous solution is selected from one of sodium bisulfite aqueous solution and sodium sulfite aqueous solution; And / or the concentration of the reducing agent solution is 2.0-2.5 wt%.
[0014] Preferably, in step (5), the alkali is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, triethylamine, and sodium hydride; And / or the solvent is selected from at least one of tetrahydrofuran, water, methanol, ethanol, N,N-dimethylformamide, and dimethyl sulfoxide; The molar ratio of the 7-(4-chlorobutoxy)-2(1H)-quinolinone, 4-piperazine benzothiophene hydrochloride, and base is 1:(1.0-1.3):(1.1-1.5). The temperature for the reaction, including / or reflux and stirring, is 90-100℃.
[0015] Preferably, in step (6), the process of purifying the crude biriperazole by multiple crystallizations includes: mixing the crude biriperazole with a solvent and an acid, heating until the solution is clear, cooling and crystallizing, filtering to obtain crude product two; mixing crude product two with an ethanol solution, adding activated carbon and refluxing, filtering while hot, cooling the mother liquor and crystallizing, filtering to obtain crude product three; mixing crude product three with an ethanol solution, heating and refluxing until the solution is clear, adding sodium hydroxide solution dropwise and continuing to reflux, cooling and crystallizing, filtering, and drying the filter cake to obtain biriperazole.
[0016] Preferably, the solvent is selected from at least one of tetrahydrofuran, water, methanol, ethanol, N,N-dimethylformamide, and dimethyl sulfoxide; the acid is selected from at least one of acetic acid, concentrated hydrochloric acid, dilute hydrochloric acid, ethyl acetate hydrochloride, and dioxane hydrochloride.
[0017] Preferably, the preparation of crude product II includes at least one of the following characteristics: The ratio of crude bripiprazole to solvent is 1g:(8-20)ml. Add acid to adjust the pH of the system to 2.0-3.0; The temperature at which the solution is heated until it becomes clear is 60-65℃; The cooling crystallization conditions are as follows: first, cool down to 20±5℃ at a rate of 10℃ / min, then cool down to 2-5℃ at a rate of 4-5℃ / min, and crystallize for 2-4 hours.
[0018] Preferably, the preparation of crude product 3 includes at least one of the following characteristics: The concentration of the ethanol solution is 60-65% v / v; The mass ratio of the ethanol solution to crude product II is 1:(10-20). The amount of activated carbon added is 8-12 wt% of the crude product; the reflux temperature after adding activated carbon is 70-80℃ and the time is 1-1.5h. The cooling and crystallization conditions are as follows: first, cool naturally to room temperature, then cool to 2-5°C under ice-water bath conditions, and crystallize for 4-6 hours.
[0019] Preferably, the process of mixing the crude product with an ethanol solution, heating under reflux until the solution becomes clear, adding sodium hydroxide solution dropwise and continuing reflux, and then cooling to crystallize includes at least one of the following characteristics: The concentration of the ethanol solution is 55-60% v / v; The mass ratio of the ethanol solution to the crude product is 1:(15-30). The temperature of the heating reflux is 75-80℃; The concentration of the sodium hydroxide solution is 3-4 wt%. The pH of the system is adjusted to 10.0 ± 0.5 by adding sodium hydroxide solution, and the reflux time is continued for 0.5-1 h. The cooling and crystallization conditions are as follows: cooling to 20±5℃ at a rate of 0.3-0.5℃ / min, then cooling to 2-5℃ in an ice-water bath, and crystallizing for 2-3 hours.
[0020] The chemical reaction formulas involved in the synthesis method of this invention are as follows: .
[0021] The technical solution provided by this invention has the following advantages: This invention discloses an efficient synthesis method for bripiprazole. First, 4-bromobenzothiophene and N-Boc piperazine are used as starting materials. A self-made supported catalyst is used to prepare 4-Boc piperazine benzothiophene. This supported catalyst uses hierarchical porous nitrogen-doped carbon nanomaterials as a support. Through functionalization modification, the supported palladium-phosphine active centers are immobilized. The support structure and active components synergistically enhance the catalyst's high catalytic activity and selectivity during the reaction, effectively reducing the amount of palladium used and lowering the preparation cost. Furthermore, the catalyst is easily recyclable. This invention uses BINAP or RuPhos as ligands to effectively stabilize the palladium active centers, suppress side reactions, further improve the selectivity of the target product 4-Boc piperazine benzothiophene, and reduce impurity formation.
[0022] This invention utilizes reactions such as catalytic coupling, acid deprotection, etherification, oxidation, and intermolecular cyclization. By optimizing the conditions of each reaction stage, it minimizes side reactions, facilitates the separation and purification of intermediates, and is suitable for industrial production.
[0023] In purifying crude biriperazole, this invention employs a multi-stage purification and crystallization process. First, most impurities are initially removed through pH adjustment and specific crystallization conditions. Then, activated carbon is used for decolorization combined with cooling crystallization to further remove colored impurities and trace organic impurities. Finally, under alkaline conditions, the product is slowly cooled and recrystallized for further purification, resulting in high-purity biriperazole. Attached Figure Description
[0024] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.
[0025] Figure 1 The 4-Boc piperazine benzothiophene HNMR spectrum is shown in Application Example 1; Figure 2 The HNMR spectrum of 4-piperazine benzothiophene hydrochloride in Application Example 3; Figure 3The HNMR spectrum of 3,4-dihydro-7-(4-chlorobutoxy)-2(1H)-quinolinone in Application Example 4; Figure 4 The 1H NMR spectrum of 7-(4-chlorobutoxy)-2(1H)-quinolinone in Application Example 5; Figure 5 The image shows the HNMR spectrum of birepiperazole in Application Example 8. Detailed Implementation
[0026] The technical solution of the present invention will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. The present invention will be described in detail below with reference to the accompanying drawings and embodiments. It should be noted that, unless otherwise specified, the embodiments and features in the embodiments of the present invention can be combined with each other.
[0027] Example 1 The preparation method of the supported catalyst includes the following steps: S1. Preparation of the carrier: Weigh 1.5g sodium lignosulfonate, 1g chitosan, 0.4g potassium ferrate, and 50g deionized water. Mix the above reaction materials evenly and place them in a 100ml stainless steel reactor lined with polytetrafluoroethylene. Seal the reactor and place it in an oven. React at 180℃ for 12h. After the reaction is completed, allow it to cool naturally to room temperature. Filter the reaction solution, wash the precipitate, and dry it to obtain the carrier precursor. Place the above carrier precursor in a tube furnace and heat it to 370℃ at a heating rate of 5℃ / min under nitrogen atmosphere protection. Hold the temperature at this temperature for pyrolysis for 2.5h. After the pyrolysis is completed, allow it to cool naturally to room temperature to obtain the carrier. S2. Functionalization of the carrier: Under a nitrogen atmosphere, 1.0 g of the support prepared in step S1 and 50 ml of anhydrous 1,4-dioxane were placed in a three-necked flask. The three-necked flask was placed in an ice-water bath at 0 °C. While stirring continuously, 1.2 ml of triethylamine and 2.5 ml of diphenyl chlorophosphate were added dropwise to the three-necked flask. After the addition was completed, the ice-water bath was removed, and the reaction system was heated to 80 °C and stirred under reflux at this temperature for 12 h. After the reaction was completed, the reaction system was cooled to room temperature, and the solid product was separated by filtration. The product was then thoroughly washed with anhydrous dioxane, anhydrous ethanol, and deionized water in sequence. Finally, the obtained solid was vacuum dried at 80 °C for 6 h to obtain the functionalized support. S3, Loading of active components Under a nitrogen atmosphere, 0.75 g of the functionalized support obtained in step S2, 0.055 g of palladium acetate, 0.35 g of triphenylphosphine, and 50 ml of 2-methyltetrahydrofuran were added sequentially to a dry round-bottom flask. The mixture was ultrasonically dispersed for 30 min to ensure homogeneity. Subsequently, the reaction solution was heated to 45 °C under magnetic stirring and stirred at a constant temperature for 1 h for adsorption. Then, 0.28 g of L-ascorbic acid solution (prepared by dissolving 0.28 g of L-ascorbic acid in 5 ml of 2-methyltetrahydrofuran) was slowly added to the above reaction system. After the addition was completed, the reaction was stirred at 45 °C for 5.5 h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the solid product was washed three times alternately with 2-methyltetrahydrofuran and ethanol. The obtained solid was vacuum dried at 60 °C for 8 h to obtain the supported palladium catalyst.
[0028] Comparative Example 1 The difference between this example and Example 1 is that step S2 is not included; the other operations are the same as in Example 1.
[0029] Comparative Example 2 The catalyst is palladium acetate, which is not supported.
[0030] In the following application examples, the product yield is calculated as follows: Yield (%) = (Actual product output / Theoretical product output) × 100%.
[0031] Application Example 1 Preparation of 4-Boc piperazine benzothiophene (BRX-1): In a 1000 ml three-necked flask, add 4-bromobenzothiophene BRX-SM-1 (42.6 g, 200 mmol), N-Boc piperazine BRX-SM-3 (52.1 g, 280 mmol), sodium tert-butoxide (57.6 g, 600 mmol), the supported catalyst prepared in Example 1 (the amount of palladium acetate in the supported catalyst is 0.2% of the molar amount of 4-bromobenzothiophene), BINAP (253 mg), 400 ml of xylene, and nitrogen. The system was purged three times to remove air, then heated to 125°C under nitrogen protection. TLC monitoring showed the 4-Br benzothiophene reaction was complete. The reaction solution was cooled to room temperature, washed once with water, and then washed twice with saturated brine. The organic phase was evaporated to dryness, and the concentrated solution was mixed with 300g of n-hexane. The mixture was then cooled to 0°C to allow crystallization until no new precipitate formed. After crystallization, the mixture was filtered, and the filter cake was washed three times with n-hexane and then dried at 40°C to obtain 58.6g of product. Figure 1 It can be seen that the product is 4-Boc piperazine benzothiophene (Y=92.0%; purity 99.6%).
[0032] Application Example 2 Preparation of 4-Boc piperazine benzothiophene: In a 1000 ml three-necked flask, 4-bromobenzothiophene (41.3 g, 200 mmol), N-Boc piperazine (52.1 g), sodium tert-butoxide (57.6 g), the supported catalyst prepared in Example 1 (the amount of palladium acetate in the supported catalyst was 0.15% of the molar amount of 4-bromobenzothiophene), BINAP (253 mg), and 400 ml of xylene were added. The mixture was purged with nitrogen three times to remove air from the system. Then, under nitrogen protection, the temperature was raised to 125 °C for reaction. TLC monitoring showed that the 4-Br benzothiophene reaction was complete. The reaction solution was cooled to room temperature, washed once with water, and then washed twice with saturated brine. The organic phase was evaporated to dryness, and the resulting concentrate was mixed with 300 g of n-hexane. The mixture was then cooled to 0 °C to crystallize until no new precipitate formed. After crystallization, the mixture was filtered, and the filter cake was washed three times with n-hexane and then dried at 40 °C to obtain 57.1 g of the solution. 4-Boc piperazine benzothiophene (Y=89.7%; purity 99.7%).
[0033] Application Comparative Example 1 The difference between this example and Application Example 1 is that the catalyst of Comparative Example 1 was used instead of the catalyst of Example 1, and the other operations were the same as in Application Example 1; 54.9 g of 4-Boc piperazine benzothiophene was obtained (Y=86.2%; purity 98.2%).
[0034] Application Comparative Example 2 The difference between this example and Application Example 1 is that the catalyst of Comparative Example 2 was used instead of the catalyst of Example 1, and the other operations were the same as in Application Example 1; 51.9 g of 4-Boc piperazine benzothiophene was obtained (Y=81.5%; purity 96.5%).
[0035] Application Example 3 Preparation of 4-piperazine benzothiophene hydrochloride (BRX-2): 80 g of 4-Boc piperazine benzothiophene prepared in Example 1 was added to a 1000 ml four-necked flask, followed by 250 ml of methanol. Concentrated hydrochloric acid (12 mol / L) was added dropwise under an ice-water bath (to adjust the pH of the system to <1). The mixture was then stirred at room temperature for 1.5 h. TLC monitoring showed that the reaction of the 4-Boc piperazine benzothiophene was complete. The mixture was filtered, and the filter cake was dried to obtain 61.47 g of product. Figure 2 As can be seen, the product is 4-piperazine benzothiophene hydrochloride (Y=96.5%; purity 99.7%).
[0036] Application Example 4 Preparation of 3,4-dihydro-7-(4-chlorobutoxy)-2(1H)-quinolinone (BRX-5): In a 1000 ml four-necked flask, 3,4-dihydro-7-hydroxy-2(1H)-quinolinone BRX-SM-4 (98 g, 600 mmol), 1-bromo-4-chlorobutane BRX-SM-5 (308 g, 1800 mmol), potassium carbonate (124 g, 900 mmol), and 400 ml DMF were added. The mixture was stirred at room temperature for 20 h. TLC monitoring showed that the reaction of 3,4-dihydro-7-hydroxy-2(1H)-quinolinone in the system was complete. Then, 1000 ml of water was added, and the mixture was stirred at room temperature for 30 min to precipitate. The reaction solution was filtered, and the filter cake was washed with water (200 ml × 3), and finally dried to obtain 146.6 g of product. Figure 3 It can be seen that the product is 3,4-dihydro-7-(4-chlorobutoxy)-2(1H)-quinolinone (Y=96.3%; purity 98.6%).
[0037] Application Example 5 Preparation of 7-(4-chlorobutoxy)-2(1H)-quinolinone (BRX-6): 101.2 g of 3,4-dihydro-7-(4-chlorobutoxy)-2(1H)-quinolinone (prepared in Example 4), 109 g of DDQ, and 700 ml of THF were added to a 1000 ml three-necked flask. The mixture was heated to 35 °C and stirred for 2.5 h. TLC monitoring showed that the reaction of 3,4-dihydro-7-(4-chlorobutoxy)-2(1H)-quinolinone was complete. The reaction solution was then added to an aqueous solution of sodium sulfite (prepared by dissolving 50 g of sodium sulfite in 2300 ml of water), and stirred at room temperature for 30 min. The product precipitated, was then filtered, and the filter cake was washed and dried to obtain 93.7 g of product. Figure 4 It can be seen that the product is 7-(4-chlorobutoxy)-2(1H)-quinolinone (Y=93%; purity 99.2%).
[0038] Application Example 6 The difference between this example and Application Example 5 is that the molar ratio of 3,4-dihydro-7-(4-chlorobutoxy)-2(1H)-quinolinone to DDQ is 1:0.3, and the other operations are the same as in Application Example 5; 94.2g of 7-(4-chlorobutoxy)-2(1H)-quinolinone was obtained (Y=93.5%; purity 99.0%).
[0039] Application Example 7 The difference between this example and Application Example 5 is that the concentration of the sodium sulfite aqueous solution is 3.0 wt%, and the other operations are the same as in Application Example 5; 92.5 g of 7-(4-chlorobutoxy)-2(1H)-quinolinone was obtained (Y=91.8%; purity 99.1%).
[0040] Application Example 8 Preparation of crude biriperazole: 100 g of 7-(4-chlorobutoxy)-2(1H)-quinolinone prepared in Example 5, 112 g of 4-piperazine benzothiophene hydrochloride prepared in Example 3, 66.3 g of potassium carbonate, and solvent (EtOH:H2O volume ratio of 1:2.5, 1000 ml) were added to a 2000 ml three-necked flask. The mixture was refluxed at 95 °C. TLC was used to monitor the reaction of the 7-(4-chlorobutoxy)-2(1H)-quinolinone until it was completely reacted. The reaction was stopped, and the mixture was cooled to 10 °C until crystallization occurred and no new precipitate was formed. The mixture was filtered, and the filter cake was collected to obtain crude bripiprazole. Preparation of high-purity birepiperazole: Crude bripiprazole and an ethanol solution (ethanol to deionized water volume ratio 3:1) were mixed (the ratio of crude bripiprazole to ethanol solution was 1g:15ml). The mixture was heated to 58℃ and stirred until the solid dissolved. The temperature was then lowered to 40℃, and a 0.4M acetic acid aqueous solution was added dropwise at a rate of 1.0ml / min to adjust the pH to 6.5. Then, a saturated sodium bicarbonate aqueous solution and deionized water were added simultaneously to further adjust the pH to 8.5 (the dropwise rate of the saturated sodium bicarbonate aqueous solution was 0.4ml / min, and the dropwise rate of the deionized water was twice that of the saturated sodium bicarbonate solution). After the addition was complete, the temperature was lowered to 10℃ at a rate of 0.1℃ / min, and crystallization was carried out for 6 hours. After crystallization, the crystallization solution was filtered, the precipitate was washed, and dried to obtain 148.4g of product. Figure 5 As can be seen, the product is biriperazole (BRX) (Y=85.6%; purity 99.89%).
[0041] Application Example 9 The difference between this example and Application Example 8 is that the acetic acid aqueous solution was added at a rate of 1.5 ml / min, and the pH of the system was adjusted to 7.0 by adding the acetic acid aqueous solution; other operations were the same as in Application Example 8; 146.0 g of buripiperazole was obtained (Y=84.2%; purity 99.8%).
[0042] Application Example 10 The difference between this example and Application Example 8 is that the dropping rate of the saturated sodium bicarbonate aqueous solution is 0.8 ml / min, and the pH of the system is adjusted to 9.0 by adding the saturated sodium bicarbonate aqueous solution; other operations are the same as in Application Example 8; 146.8 g of bripiprazole (Y=84.6%; purity 99.8%) is obtained.
[0043] Application Comparative Example 3 The difference between this example and Application Example 8 is that in step (6), the acetic acid aqueous solution is added at a rate of 3.0 ml / min, while other operations are the same as in Application Example 8; 143.7 g of bripiprazole is obtained (Y=82.9%; purity 99.6%). Excessive dropping speed of the acetic acid aqueous solution can lead to localized pH changes within the system, causing uneven crystallization or impurity encapsulation, thereby affecting the purity and yield of the product.
[0044] Application Comparative Example 4 The difference between this example and Application Example 8 is that in step (6), an aqueous acetic acid solution is added to adjust the pH of the system to 5.5, while other operations are the same as in Application Example 8; 144.6 g of bripiprazole is obtained (Y=83.4%; purity 99.5%). Bripiprazole is highly alkaline and will be completely protonated at pH<6, dissolving in a high concentration as a salt. This leads to instantaneous supersaturation of the product during subsequent alkalization, resulting in explosive nucleation and the formation of fine or amorphous particles. These particles easily encapsulate solvents, impurities, and intermediates, causing a certain degree of decrease in purity and yield.
[0045] Application Comparative Example 5 The difference between this example and Application Example 8 is that in step (6), an aqueous acetic acid solution was added to adjust the pH of the system to 7.5, while other operations were the same as in Application Example 8; 145.2 g of bripiprazole was obtained (Y=83.7%; purity 99.7%). When adjusting the pH with an aqueous acetic acid solution, when pH>7, the free base of bripiprazole has begun to precipitate, and some acidic or neutral impurities have poor solubility under alkaline conditions and may co-precipitate with the product, resulting in a decrease in product purity.
[0046] Application Comparative Example 6 The difference between this example and application example 8 is that in step (6), the dropping rate of the saturated sodium bicarbonate aqueous solution is 1.0 ml / min, and the other operations are the same as in application example 8; 144.2 g of bripiprazole (Y=83.1%; purity 99.6%) is obtained.
[0047] Application Comparative Example 7 The difference between this example and Application Example 8 is that in step (6), a saturated sodium bicarbonate aqueous solution is added to adjust the pH of the system to 9.5, and the other operations are the same as in Application Example 8; 143.1g of buriperazole is obtained (Y=82.5%; purity 99.6%).
[0048] Application Comparative Example 8 The difference between this example and application example 8 is that in step (6), deionized water is not added while saturated sodium bicarbonate aqueous solution is added, and other operations are the same as in application example 8; 142.1g of buriperazole is obtained (Y=81.9%; purity 99.5%).
[0049] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.
Claims
1. A highly efficient method for synthesizing birepiperazole, characterized in that, Includes the following steps: (1) Under nitrogen protection, 4-bromo-benzothiophene, N-Boc-piperazine, sodium tert-butoxide, supported catalyst, and ligand were added to a solvent for reaction. The resulting reaction solution was filtered, and the mother liquor was crystallized with an inert solvent to obtain 4-Boc-piperazine-benzothiophene. The supported catalyst used hierarchical porous nitrogen-doped carbon nanomaterials as a support and tetrakis(triphenylphosphine)palladium as the active component. (2) Add acid dropwise to a methanol solution of 4-Boc piperazine-benzothiophene and stir to react, to obtain 4-piperazine benzothiophene hydrochloride; (3) Mix 3,4-dihydro-7-hydroxy-2(1H)quinolinone, 1-bromo-4-chloro-butane, base and solvent and react. After the reaction is complete, add water to the reaction system to precipitate and obtain 3,4-dihydro-7-(4-chlorobutoxy)-2(1H)-quinolinone; (4) Mix 3,4-dihydro-7-(4-chlorobutoxy)-2(1H)-quinolinone, catalyst and solvent and react. After the reaction is completed, pour the reaction solution into the reducing agent aqueous solution to precipitate and obtain 7-(4-chlorobutoxy)-2(1H)-quinolinone. (5) Mix 7-(4-chlorobutoxy)-2(1H)-quinolinone, 4-piperazine benzothiophene hydrochloride, base and solvent, heat to reflux reaction, monitor the complete reaction of the raw materials, cool down and filter to obtain crude bripiprazole; (6) The crude buripiperazole was purified by multiple crystallizations to obtain buripiperazole.
2. The efficient synthesis method of birepiperazole according to claim 1, characterized in that, In step (1), the solvent is selected from at least one of toluene, xylene, N,N-dimethylformamide, dimethyl sulfoxide, and tetrahydrofuran; And / or the ligand is selected from at least one of BINAP and RuPhos; And / or the molar ratio of the 4-bromobenzothiophene, N-Boc-piperazine, sodium tert-butoxide, and ligand is 1:(1.3-1.5):3.0:(0.001-0.002); And / or the amount of the catalyst used, calculated as palladium acetate, is 0.08-0.2% of the molar amount of 4-bromobenzothiophene; And / or the temperature during the reaction in the solvent is 100℃-140℃; And / or the crystallization temperature is 0-10℃.
3. The efficient synthesis method of buriperazole according to claim 1, characterized in that, The preparation method of the supported catalyst includes the following steps: S1. Sodium lignosulfonate, chitosan, potassium ferrate and deionized water are mixed and placed in a reaction vessel for hydrothermal reaction to obtain the carrier precursor, which is then pyrolyzed to obtain the carrier. S2. Under a nitrogen atmosphere, the above-mentioned support was dispersed in anhydrous 1,4-dioxane. Triethylamine and diphenyl chlorophosphate were slowly added under an ice-water bath and stirring. After the addition was completed, the ice-water bath was removed, the temperature was raised and the mixture was refluxed and stirred to obtain the functionalized support. S3. Under a nitrogen atmosphere, functionalized support, palladium acetate, triphenylphosphine and 2-methyltetrahydrofuran were ultrasonically dispersed, heated and stirred for adsorption, and then L-ascorbic acid solution was added and stirred to react, thus obtaining a supported catalyst.
4. The efficient synthesis method of birepiperazole according to claim 3, characterized in that, In step S1, the mass ratio of sodium lignosulfonate, chitosan, potassium ferrate, and deionized water is (1.5-2.5):1:(0.4-0.5):
50. And / or the hydrothermal reaction is carried out at a temperature of 180°C for a time of 10-15 hours; And / or the pyrolysis conditions are: nitrogen atmosphere, heating to 350-380℃ at a heating rate of 3-5℃ / min, and holding at that temperature for 2-3 hours.
5. The efficient synthesis method of birepiperazole according to claim 3, characterized in that, In step S2, the ratio of the carrier to triethylamine and diphenyl chlorophosphate is 1g:(1.0-1.5)ml:(2-3)ml; The temperature for reflux stirring is 80℃, and the time is 10-15h. And / or in step S3, the ratio of the functionalized carrier, palladium acetate, triphenylphosphine, and ascorbic acid is (0.7-0.8):(0.05-0.06):(0.3-0.4):(0.25-0.3). And / or the L-ascorbic acid solution comprises 0.5-0.3 g ascorbic acid and 5 ml 2-methyltetrahydrofuran; And / or the stirring and dispersion temperature is 40-50℃, and the time is 0.5-1.5h; The temperature of the stirring reaction is 40-50℃ and the time is 5-6h.
6. The efficient synthesis method of buriperazole according to claim 1, characterized in that, In step (2), the acid is selected from at least one of concentrated hydrochloric acid, dilute hydrochloric acid, hydrochloric acid ethanol, hydrochloric acid ethyl acetate, and dioxane hydrochloride; the amount of acid added is 7-8 times the molar amount of 4-Boc piperazine-benzothiophene; the solvent is selected from at least one of water, ethanol, methanol, and ethyl acetate; and the temperature of the stirring reaction is 0-100℃. In step (3), the base is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, triethylamine, and sodium hydride; the solvent is selected from at least one of water, N,N-dimethylformamide, and dimethyl sulfoxide; the temperature of the mixed reaction is 25℃-100℃; the amount of water added is 2-5 times the total volume of the reaction solution; the molar ratio of 3,4-dihydro-7-hydroxy-2(1H)-quinolinone, 1-bromo-4-chlorobutane, and the base is 1:(2-3):(1.5-2); And / or in step (4), the catalyst is DDQ; And / or the solvent is selected from at least one of tetrahydrofuran, dichloromethane, dichloroethane, and ethyl acetate; The molar ratio of the 3,4-dihydro-7-(4-chlorobutoxy)-2(1H)-quinolinone to the catalyst is 1:(0.2-0.3). And / or the temperature of the mixture reaction is 25℃-80℃; And / or the reducing agent aqueous solution is selected from one of sodium bisulfite aqueous solution and sodium sulfite aqueous solution; And / or the concentration of the reducing agent solution is 2.0-2.5 wt%; And / or in step (5), the base is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, triethylamine, and sodium hydride; And / or the solvent is selected from at least one of tetrahydrofuran, water, methanol, ethanol, N,N-dimethylformamide, and dimethyl sulfoxide; The molar ratio of the 7-(4-chlorobutoxy)-2(1H)-quinolinone, 4-piperazine benzothiophene hydrochloride, and base is 1:(1.0-1.3):(1.1-1.5). The temperature for the reaction, including / or reflux and stirring, is 90-100℃.
7. The efficient synthesis method of buripiperazole according to claim 1, characterized in that, In step (6), the process of purifying the crude bripiprazole by multiple crystallizations includes: mixing the crude bripiprazole with a solvent and an acid, heating until the solution is clear, cooling and crystallizing, filtering to obtain crude product two; mixing crude product two with an ethanol solution, adding activated carbon and refluxing, filtering while hot, cooling the mother liquor and crystallizing, filtering to obtain crude product three; mixing crude product three with an ethanol solution, heating and refluxing until the solution is clear, adding sodium hydroxide solution dropwise and continuing to reflux, cooling and crystallizing, filtering, and drying the filter cake to obtain bripiprazole; the solvent is selected from at least one of tetrahydrofuran, water, methanol, ethanol, N,N-dimethylformamide, and dimethyl sulfoxide; the acid is selected from at least one of acetic acid, concentrated hydrochloric acid, dilute hydrochloric acid, ethyl acetate hydrochloride, and dioxane hydrochloride.
8. The efficient synthesis method of birepiperazole according to claim 1, characterized in that, The preparation of crude product II shall include at least one of the following characteristics: The ratio of crude bripiprazole to solvent is 1g:(8-20)ml. Add acid to adjust the pH of the system to 2.0-3.0; The temperature at which the solution is heated until it becomes clear is 60-65℃; The cooling crystallization conditions are as follows: first, cool down to 20±5℃ at a rate of 10℃ / min, then cool down to 2-5℃ at a rate of 4-5℃ / min, and crystallize for 2-4 hours.
9. The efficient synthesis method of birepiperazole according to claim 1, characterized in that, The preparation of crude product 3 must include at least one of the following characteristics: The concentration of the ethanol solution is 60-65% v / v; The mass ratio of the ethanol solution to crude product II is 1:(10-20). The amount of activated carbon added is 8-12 wt% of the crude product; the reflux temperature after adding activated carbon is 70-80℃ and the time is 1-1.5h. The cooling and crystallization conditions are as follows: first, cool naturally to room temperature, then cool to 2-5°C under ice-water bath conditions, and crystallize for 4-6 hours.
10. The efficient synthesis method of birepiperazole according to claim 1, characterized in that, The crude product is mixed with an ethanol solution and heated under reflux until the solution becomes clear. Sodium hydroxide solution is then added dropwise, and reflux is continued until cooling and crystallization occurs. This process includes at least one of the following characteristics: The concentration of the ethanol solution is 55-60% v / v; The mass ratio of the ethanol solution to the crude product is 1:(15-30). The temperature of the heating reflux is 75-80℃; The concentration of the sodium hydroxide solution is 3-4 wt%. The pH of the system is adjusted to 10.0 ± 0.5 by adding sodium hydroxide solution, and the reflux time is continued for 0.5-1 h. The cooling and crystallization conditions are as follows: cooling to 20±5℃ at a rate of 0.3-0.5℃ / min, then cooling to 2-5℃ in an ice-water bath, and crystallizing for 2-3 hours.