Preparation method of brexpiprazole

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of brexpiprazole. 4-halogenated benzo [b] thiophene is used as a starting material and reacts with piperazine-2-ketone to obtain a product, the product is reduced to obtain 1-(benzo [b] thiophene-4-yl) piperazine hydrochloride, then the 1-(benzo [b] thiophene-4-yl) piperazine hydrochloride reacts with 7-(4-chlorobutoxy)-1H-quinoline-2-ketone to obtain brexpiprazole, the reaction conditions are milder, only sodium borohydride is needed to participate in the lactam reduction step in the process, the yield is high, and the yield is high. No other activators are needed, and the operation is simpler and more convenient.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing birepiperazole. Background Technology

[0002] The global incidence of adult schizophrenia and major depressive disorder (MDD) is increasing year by year. According to the World Health Organization (WHO), approximately one million people die from these conditions each year, and about 1% of the population is affected. In recent years, psychopharmacology has gradually become one of the fastest-growing disciplines in clinical medicine, with a large number of new antipsychotic drugs with diverse structures emerging.

[0003] On July 10, 2015, the U.S. Food and Drug Administration (FDA) approved brexpiprazole, jointly developed by Lundbeck Pharmaceuticals (licensed) of Denmark and Otsuka Pharmaceutical Co., Ltd. of Japan (original developer), for marketing. This drug is available as oral tablets in six strengths: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg. Brand name: Biriperazole is an experimental serotonin-dopamine activity modulator (SDAM), a novel multi-target mechanism of action drug for the treatment of mental disorders. In addition to its primary dopamine D2 receptor partial agonist activity, it also exhibits D3 receptor partial agonist activity and 5-HT activity. 1A Partial receptor agonism and 5-HT 2A Partial receptor antagonism; this is a novel drug developed targeting multiple sites of monoamine neurotransmitters, possessing both antipsychotic and antidepressant effects. Eripiprazole is considered another blockbuster drug following the company's best-selling aripiprazole, offering better efficacy and tolerability, and reducing adverse reactions such as akathisia, restlessness, and / or insomnia. Clinically, it is primarily used as adjunctive therapy for schizophrenia and major depressive disorder.

[0004] The chemical name of bromepiperazole is 7-{4-[4-(benzo[b]thiophene)-4-yl-piperazin-1-yl]butoxy}-1H-quinoline-2-one, and its CAS number is 913611-97-9. Its chemical structural formula is as follows:

[0005]

[0006] Currently, there are many synthetic methods for bripiprazole. Among them, Hiroshi Yamashita et al., in their original patent WO2006112464A1 (family CN101155804A), used 4-bromobenzo[b]thiophene as the starting material, reacting it with piperazine under palladium catalysis via a Buchwald-Hartwig coupling reaction to obtain the key intermediate 1-(benzo[b]thiophene-4-yl)piperazine. 7-hydroxy-2(1H)-quinolinone reacted with 1-bromo-4-chlorobutane under alkaline conditions with potassium hydroxide to give another intermediate, 7-(4-chlorobutoxy)-1H-quinolin-2-one. Finally, the two intermediates underwent a substitution reaction to obtain the final product, bripiprazole. The route reported in this patent requires column chromatography separation at each step, resulting in high cost and a low overall yield of 36%. This route uses a palladium-catalyzed reaction system in the synthesis of 1-(benzo[b]thiophene-4-yl)piperazine, which is costly. Furthermore, due to the high reactivity of palladium, piperazine disubstitution and thiophene coupling byproducts easily occur, leading to reduced reaction yield and difficulties in post-processing, making it unsuitable for industrial production. The synthetic route and impurity structures are shown below:

[0007]

[0008] As can be seen from the above, 1-(benzo[b]thiophene-4-yl)piperazine can serve as a key intermediate in the preparation of bripiprazole, thereby directly affecting the production, market supply, and quality of this drug. Currently, the commercially available product is mainly its hydrochloride salt, namely 1-(benzo[b]thiophene-4-yl)piperazine hydrochloride, the specific structural formula of which is as follows:

[0009]

[0010] To avoid the formation of the two aforementioned "dimer" impurities, Chinese invention patent application CN104829602A uses anhydrous piperazine as a starting material. It first reacts with Boc anhydride to obtain N-Boc-piperazine, which, without separation, is coupled with 4-bromobenzo[b]thiophene in the presence of the catalyst palladium acetate and the ligand BINAP to yield 1-(benzo[b]thiophene-4-yl)piperazine hydrochloride (I). However, this process still makes it difficult to avoid the formation of N,N′-bisBoc-piperazine in the preparation of N-Boc-piperazine. The synthetic route is shown below:

[0011]

[0012] Chinese invention patent application CN105461704A uses 2-chloro-6-fluorobenzaldehyde as a starting material, reacts with N-Boc-piperazine, and then with mercaptoacetic acid to construct a benzo[b]thiophene ring. Finally, high-temperature deprotection and decarboxylation are performed to obtain 1-(benzo[b]thiophene-4-yl)piperazine hydrochloride. The synthetic route is shown below:

[0013]

[0014] Chinese invention patents CN103717587B and CN107428718B use m-chlorofluorobenzene as a starting material. Under alkaline conditions with LDA, 2-chloro-6-fluorobenzaldehyde is obtained by DMF formylation, followed by reaction with N-monoprotected piperazine (protecting group is Boc or Ac group), condensation with rhodanine, and finally cyclization and decarboxylation under alkaline conditions to obtain 1-(benzo[b]thiophene-4-yl)piperazine. The synthetic route is shown below:

[0015]

[0016] The above-mentioned scheme requires a high temperature and long reaction time in the final decarboxylation preparation of 1-(benzo[b]thiophene-4-yl)piperazine, and the reaction conditions are harsh, making it difficult to scale up for industrial production.

[0017] Given the numerous technical problems encountered in the preparation of bripiprazole intermediate 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride, researching and finding a safe, simple, and high-yield, high-purity process route for the production of bripiprazole intermediate 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride to ensure the production, market supply, and quality of related products remains one of the issues that need to be addressed. Summary of the Invention

[0018] To address the numerous problems existing in the current technology for preparing bripiprazole intermediate 1-(benzo[b]thiophene-4-yl)piperazine hydrochloride, this invention provides a novel method for preparing bripiprazole intermediate 1-(benzo[b]thiophene-4-yl)piperazine hydrochloride. This method features mild reaction conditions, a safe and simple operation, and yields a target product with high purity and yield.

[0019] The specific technical solution of the present invention is as follows:

[0020]

[0021] A method for preparing 1-(benzo[b]thiophene-4-yl)piperazine hydrochloride, an intermediate of bripiprazole, includes the following steps:

[0022] Step 1: Preparation of compound I-1

[0023] Under inert gas protection, compounds SM-1 and SM-2, a base, a palladium catalyst, and a ligand were added to a reaction solvent, and the reaction was carried out at a controlled temperature (T1). Post-treatment yielded intermediate compound I-1. The synthetic route is shown below:

[0024]

[0025] In the SM-1 compound, X = Cl, Br, I or TfO, with Br being particularly preferred.

[0026] In a preferred embodiment, the alkali is one or a combination of potassium phosphate, cesium carbonate, potassium tert-butoxide, and sodium tert-butoxide, with sodium tert-butoxide being particularly preferred.

[0027] In a preferred embodiment, the catalyst is one or a combination of palladium dichloride (PdCl2), palladium acetate [Pd(OAc)2], tris(dibenzylacetone)dipalladium [Pd2(dba)3], with Pd(OAc)2 being particularly preferred.

[0028] In a preferred embodiment, the ligand is one or a combination of triphenylphosphine (PPh3), tri-tert-butylphosphine [P(t-Bu)3], tricyclohexylphosphine (PCy3), tri-o-tolylphosphine [P(o-tol)3], tri(2-furanyl)phosphine (TFP), S-(-)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (BINAP), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (Xantphos), with BINAP being particularly preferred.

[0029] In a preferred embodiment, the reaction solvent is one or a combination of toluene, xylene, and 1,4-dioxane, with toluene being particularly preferred.

[0030] In a preferred embodiment, the molar ratio of compound SM-1 and compound SM-2, base, catalyst, and ligand is 1:1.1-1.8:1.5-3.5:0.03-0.08:0.1-0.2, with a particularly preferred ratio of 1:1.3:2.5:0.05:0.15.

[0031] In a preferred embodiment, the reaction temperature T1 is 80–110°C, with a particularly preferred temperature of 90–95°C.

[0032] In a preferred embodiment, the post-processing step is as follows: adding purified water to the reaction system, separating the organic phase, washing the organic phase with purified water, washing with saturated brine, concentrating under reduced pressure to dryness, and recrystallizing with ethanol to obtain intermediate I-1.

[0033] In a preferred embodiment, the inert gas is one or a combination of argon and nitrogen, with argon being particularly preferred.

[0034] Step 2: Preparation of compound I-2

[0035] Compound I-1 and a metal hydride were added to tert-butanol at room temperature, and methanol was added under controlled reflux. After the reaction was completed, post-treatment was performed to obtain the target product I-2. The synthetic route is shown below:

[0036]

[0037] In a preferred embodiment, the metal hydride is one or a combination of NaBH4 or KBH4, with NaBH4 being particularly preferred.

[0038] In a preferred embodiment, the molar ratio of I-1 to the metal hydride is 1:1.5 to 4.0, with a particularly preferred ratio of 1:2.0.

[0039] In a preferred embodiment, the mass-to-volume ratio of I-1 to methanol and tert-butanol is 1:2 to 8:6 to 20, g / mL, with a particularly preferred ratio of 1:4:10, g / mL.

[0040] In a preferred embodiment, the methanol is added via a flow-through or drop-through method; the drop-through method is preferred, and the time is controlled between 1 and 6 hours.

[0041] In a preferred embodiment, the reaction temperature T2 is 40–80°C, with a particularly preferred temperature of 50–55°C.

[0042] In the preferred embodiment, the post-processing steps are as follows: the reaction solution is cooled to room temperature, purified water is added to quench the reaction solution, dichloromethane is used for extraction, the organic phases are combined, saturated brine is used for washing, the organic phase is concentrated under reduced pressure to dryness, then salted by HCl-MeOH, filtered, and the resulting solid is dried under reduced pressure to obtain the target product I.

[0043] The intermediate compound I-2 prepared using the above method can be used to prepare bripiprazole, which can be prepared as follows: Compound SM-3, compound I-2, potassium carbonate, and sodium iodide are added to dimethylformamide and reacted to obtain the final product bripiprazole; the synthetic route is as follows:

[0044]

[0045] The molar ratio of compound SM-3, compound I-2, potassium carbonate, and sodium iodide is 1:1.30:3.30:1.30.

[0046] The beneficial effects of this invention are:

[0047] 1. This invention provides a novel method for preparing 1-(benzo[b]thiophene-4-yl)piperazine hydrochloride, an intermediate of bripiprazole. The target product is obtained by reacting SM-1 and SM-2 as starting materials and then reducing them with amide. This method can effectively avoid the generation of impurities such as dimers.

[0048] 2. In this process, only sodium borohydride is required for the lactam reduction step, without the need for other activators, making the operation simpler.

[0049] 3. The products obtained through this process have high yield and purity, making them suitable for industrial production. Detailed Implementation

[0050] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.

[0051] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0052] Example 1

[0053] Under argon protection, compounds SM-1-1 (X=Br, 10.65g, 0.05mol), SM-2 (6.51g, 0.065mol), sodium tert-butoxide (12.01g, 0.125mol), palladium acetate (0.56g, 2.5mmol), and S-(-)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (4.67g, 7.5mmol) were added to toluene (200ml). The reaction was carried out at 90-95℃. After the reaction was detected to be complete, the reaction solution was filtered through diatomaceous earth while hot. The filtrate was cooled to room temperature and added to purified water (1500ml). The toluene phase was separated, and the aqueous phase was extracted with dichloromethane (500ml×3). The organic phases were combined and washed with saturated brine (500ml×2). The organic phase was concentrated to dryness under reduced pressure and recrystallized from ethanol to obtain intermediate I-1, with a yield of 98.6% and a purity of 99.92%.

[0054] Example 2

[0055] Under argon protection, compounds SM-1-1 (X=Br, 10.65g, 0.05mol), SM-2 (7.51g, 0.075mol), potassium phosphate (26.53g, 0.125mol), palladium acetate (0.56g, 2.5mmol), and S-(-)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (4.67g, 7.5mmol) were added to xylene (200ml). The reaction was carried out at 80-85℃. After the reaction was detected to be complete, the reaction solution was filtered through diatomaceous earth while hot. The filtrate was cooled to room temperature and added to purified water (1500ml). The toluene phase was separated, and the aqueous phase was extracted with dichloromethane (500ml×3). The organic phases were combined and washed with saturated brine (500ml×2). The organic phase was concentrated to dryness under reduced pressure and recrystallized from ethanol to obtain intermediate I-1, with a yield of 94.3% and a purity of 99.70%.

[0056] Example 3

[0057] Under argon protection, compounds SM-1-1 (X=Br, 10.65g, 0.05mol), SM-2 (9.01g, 0.09mol), cesium carbonate (40.73g, 0.125mol), palladium acetate (0.56g, 2.5mmol), and S-(-)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (4.67g, 7.5mmol) were added to xylene (200ml). The reaction was carried out at a controlled temperature of 105–110℃. After the reaction was detected to be complete, the reaction solution was filtered through diatomaceous earth while hot. The filtrate was cooled to room temperature and added to purified water (1500ml). The toluene phase was separated, and the aqueous phase was extracted with dichloromethane (500ml×3). The organic phases were combined and washed with saturated brine (500ml×2). The organic phase was concentrated to dryness under reduced pressure and recrystallized from ethanol to obtain intermediate I-1, with a yield of 95.0% and a purity of 99.59%.

[0058] Example 4

[0059] Under argon protection, compounds SM-1-1 (X = Br, 10.65 g, 0.05 mol), SM-2 (6.51 g, 0.065 mol), sodium tert-butoxide (7.21 g, 0.075 mol), palladium dichloride (0.44 g, 2.5 mmol), and triphenylphosphine (1.97 g, 7.5 mmol) were added to toluene (200 ml) and reacted at a controlled temperature of 90–95 °C. After the reaction was completed, the reaction solution was filtered through diatomaceous earth while still hot. The filtrate was cooled to room temperature and added to purified water (1500 ml). The toluene phase was separated, and the aqueous phase was extracted with dichloromethane (500 ml × 3). The organic phases were combined and washed with saturated brine (500 ml × 2). The organic phase was concentrated to dryness under reduced pressure and recrystallized from ethanol to obtain intermediate I-1, with a yield of 94.3% and a purity of 99.68%.

[0060] Example 5

[0061] Under argon protection, compounds SM-1-1 (X = Br, 10.65 g, 0.05 mol), SM-2 (6.51 g, 0.065 mol), sodium tert-butoxide (16.80 g, 0.175 mol), tris(dibenzylacetone)palladium (2.29 g, 2.5 mmol), and tricyclohexylphosphine (2.10 g, 7.5 mmol) were added to toluene (200 ml). The reaction was carried out at 90–95 °C. After the reaction was detected to be complete, the reaction solution was filtered through diatomaceous earth while hot. The filtrate was cooled to room temperature and added to purified water (1500 ml). The toluene phase was separated, and the aqueous phase was extracted with dichloromethane (500 ml × 3). The organic phases were combined and washed with saturated brine (500 ml × 2). The organic phase was concentrated to dryness under reduced pressure and recrystallized from ethanol to obtain intermediate I-1, with a yield of 95.3% and a purity of 99.61%.

[0062] Example 6

[0063] Under argon protection, compounds SM-1-1 (X = Br, 10.65 g, 0.05 mol), SM-2 (6.51 g, 0.065 mol), sodium tert-butoxide (12.01 g, 0.125 mol), palladium acetate (0.34 g, 1.5 mmol), and tri-o-tolylphosphine (1.52 g, 5.0 mmol) were added to toluene (200 ml). The reaction was carried out at 90–95 °C. After the reaction was detected to be complete, the reaction solution was filtered through diatomaceous earth while hot. The filtrate was cooled to room temperature and added to purified water (1500 ml). The toluene phase was separated, and the aqueous phase was extracted with dichloromethane (500 ml × 3). The organic phases were combined and washed with saturated brine (500 ml × 2). The organic phase was concentrated to dryness under reduced pressure and recrystallized from ethanol to obtain intermediate I-1, with a yield of 95.5% and a purity of 99.81%.

[0064] Example 7

[0065] Under argon protection, compounds SM-1-1 (X = Br, 10.65 g, 0.05 mol), SM-2 (6.51 g, 0.065 mol), sodium tert-butoxide (12.01 g, 0.125 mol), palladium acetate (0.91 g, 4.0 mmol), and tris(2-furanyl)phosphine (2.32 g, 10.0 mmol) were added to toluene (200 ml). The reaction was carried out at 90–95 °C. After the reaction was detected to be complete, the reaction solution was filtered through diatomaceous earth while still hot. The filtrate was cooled to room temperature and added to purified water (1500 ml). The toluene phase was separated, and the aqueous phase was extracted with dichloromethane (500 ml × 3). The organic phases were combined and washed with saturated brine (500 ml × 2). The organic phase was concentrated to dryness under reduced pressure and recrystallized from ethanol to obtain intermediate I-1, with a yield of 96.3% and a purity of 99.65%.

[0066] Example 8

[0067] Under argon protection, compounds SM-1-1 (X = Cl, 8.43 g, 0.05 mol), SM-2 (5.01 g, 0.05 mol), sodium tert-butoxide (4.81 g, 0.05 mol), palladium acetate (0.23 g, 1.0 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (2.60 g, 4.5 mmol) were added to 1,4-dioxane (200 ml). The reaction was carried out at 75–80 °C. After the reaction was detected to be complete, the reaction solution was filtered through diatomaceous earth while still hot. The filtrate was cooled to room temperature and added to purified water (1500 ml). The toluene phase was separated, and the aqueous phase was extracted with dichloromethane (500 ml × 3). The organic phases were combined and washed with saturated brine (500 ml × 2). The organic phase was concentrated to dryness under reduced pressure and recrystallized from ethanol to obtain intermediate I-1, with a yield of 88.6% and a purity of 98.92%.

[0068] Example 9

[0069] Under argon protection, compounds SM-1-1 (X = TfO, 14.11 g, 0.05 mol), SM-2 (10.02 g, 0.10 mol), sodium tert-butoxide (17.78 g, 0.185 mol), palladium acetate (1.12 g, 5.0 mmol), and tri-tert-butylphosphine (4.05 g, 20.0 mmol) were added to xylene (200 ml) and reacted at a controlled temperature of 110–115 °C. After the reaction was completed, the reaction solution was filtered through diatomaceous earth while still hot. The filtrate was cooled to room temperature and added to purified water (1500 ml). The toluene phase was separated, and the aqueous phase was extracted with dichloromethane (500 ml × 3). The organic phases were combined and washed with saturated brine (500 ml × 2). The organic phase was concentrated to dryness under reduced pressure and recrystallized from ethanol to obtain intermediate I-1, with a yield of 90.1% and a purity of 95.63%.

[0070] Preparation of compound I-2

[0071] Example 10

[0072] At room temperature, compound I-1 (11.62 g, 0.05 mol) and sodium borohydride (3.78 g, 0.10 mol) were added to tert-butanol (110 ml). Methanol (46 ml) was slowly added while maintaining the temperature at 50–55 °C. After the reaction was detected to be complete, the reaction solution was cooled to room temperature. The reaction solution was quenched and diluted with purified water (500 ml). It was extracted with dichloromethane (200 ml × 3), and the organic phases were combined. The organic phases were washed with saturated brine (220 ml × 2). The organic phases were concentrated to dryness under reduced pressure and then added to HCl-MeOH. The mixture was stirred at room temperature to form a salt. After filtration, the resulting solid was dried under reduced pressure to obtain the target product compound I-2, with a yield of 98.1% and a purity of 99.98%.

[0073] Example 11

[0074] At room temperature, compound I-1 (11.62 g, 0.05 mol) and sodium borohydride (2.84 g, 0.075 mol) were added to tert-butanol (67 ml). Methanol (23 ml) was slowly added while maintaining the temperature at 40–45 °C. After the reaction was detected to be complete, the reaction solution was cooled to room temperature. The reaction solution was quenched and diluted with purified water (500 ml). It was extracted with dichloromethane (200 ml × 3), and the organic phases were combined. The organic phases were washed with saturated brine (220 ml × 2). The organic phases were concentrated to dryness under reduced pressure and then added to HCl-MeOH. The mixture was stirred at room temperature to form a salt. After filtration, the resulting solid was dried under reduced pressure to obtain the target product compound I-2, with a yield of 96.3% and a purity of 99.70%.

[0075] Example 12

[0076] At room temperature, compound I-1 (11.62 g, 0.05 mol) and sodium borohydride (7.57 g, 0.20 mol) were added to tert-butanol (230 ml). Methanol (90 ml) was slowly added while maintaining the temperature at 75–80 °C. After the reaction was detected to be complete, the reaction solution was cooled to room temperature. The reaction solution was quenched and diluted with purified water (500 ml). It was extracted with dichloromethane (200 ml × 3), and the organic phases were combined. The organic phases were washed with saturated brine (220 ml × 2). The organic phases were concentrated to dryness under reduced pressure and then added to HCl-MeOH. The mixture was stirred at room temperature to form a salt. After filtration, the resulting solid was dried under reduced pressure to obtain the target product compound I-2, with a yield of 97.1% and a purity of 99.56%.

[0077] Example 13

[0078] At room temperature, compound I-1 (11.62 g, 0.05 mol) and sodium borohydride (1.89 g, 0.05 mol) were added to tert-butanol (56 ml). Methanol (18 ml) was slowly added while maintaining the temperature at 35–40 °C. After the reaction was detected to be complete, the reaction solution was cooled to room temperature. The reaction solution was quenched and diluted with purified water (500 ml). It was extracted with dichloromethane (200 ml × 3), and the organic phases were combined. The organic phases were washed with saturated brine (220 ml × 2). The organic phases were concentrated to dryness under reduced pressure and then added to HCl-MeOH. The mixture was stirred at room temperature to form a salt. The mixture was filtered, and the resulting solid was dried under reduced pressure to obtain the target product compound I-2, with a yield of 85.3% and a purity of 98.85%.

[0079] Example 14

[0080] At room temperature, compound I-1 (11.62 g, 0.05 mol) and potassium borohydride (13.49 g, 0.25 mol) were added to tert-butanol (240 ml). Methanol (100 ml) was slowly added while maintaining the temperature at 80–85 °C. After the reaction was detected as complete, the reaction solution was cooled to room temperature. The reaction solution was quenched and diluted with purified water (500 ml), extracted with dichloromethane (200 ml × 3), and the organic phases were combined. The mixture was washed with saturated brine (220 ml × 2), concentrated to dryness under reduced pressure, added to HCl-MeOH, stirred at room temperature to form a salt, filtered, and the resulting solid was dried under reduced pressure to obtain the target product compound I-2, with a yield of 89.3% and a purity of 98.12%.

[0081] Preparation of irinotecan

[0082] A mixture of compound SM-3 (7.55 g, 0.03 mol), compound I-2 (8.73 g, 0.04 mol), potassium carbonate (13.82 g, 0.1 mol), sodium iodide (6.00 g, 0.04 mol), and N,N-dimethylformamide (80 ml) was reacted at 80 °C for 2 h. Water was added to the reaction solution, and the precipitated crystals were separated by filtration. The crystals were dissolved in a mixed solvent of dichloromethane and methanol, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give bripiprazole, with a yield of 98.6% and a purity of 99.92%.

Claims

1. A method for preparing an iripepiperazole intermediate, characterized in that, The preparation method includes the following steps: Step 1: Under inert gas protection, compound SM-1, compound SM-2, base, palladium catalyst, and ligand are added to the reaction solvent and reacted at temperature T1. After post-treatment, intermediate compound I-1 is obtained. Step 2: At room temperature, compound I-1 and the metal hydride were added to tert-butanol, and methanol was added under controlled reflux. After the reaction was detected to be complete, the intermediate compound I-2 was obtained through post-processing. The reaction route is as follows:

2. The preparation method according to claim 1, characterized in that, The alkali mentioned in step 1 is one or a combination of potassium phosphate, cesium carbonate, potassium tert-butoxide, and sodium tert-butoxide.

3. The preparation method according to claim 1, characterized in that, The catalyst mentioned in step 1 is one or a combination of palladium dichloride, palladium acetate, tris(dibenzylacetone)palladium.

4. The preparation method according to claim 1, characterized in that, The ligand mentioned in step 1 is one or a combination of triphenylphosphine, tritert-butylphosphine, S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine, and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene.

5. The preparation method according to claim 1, characterized in that, The reaction solvent mentioned in step 1 is one or a combination of benzene, toluene, xylene, and 1,4-dioxane.

6. The preparation method according to claim 1, characterized in that, The molar ratio of compounds SM-1 and SM-2, base, catalyst, and ligand in step 1 is 1:1.1-1.8:1.5-3.5:0.03-0.08:0.1-0.

2.

7. The preparation method according to claim 1, characterized in that, The reaction temperature T1 mentioned in step 1 is 80-110℃.

8. The preparation method according to claim 1, characterized in that, The metal hydride mentioned in step 2 is one or a combination of sodium borohydride or potassium borohydride; the molar ratio of compound I-1 to the metal hydride is 1:1.5 to 4.0; the mass-volume ratio of compound I-1 to methanol and tert-butanol is 1:2 to 8:6 to 20, in g / mL.

9. The preparation method according to claim 1, characterized in that, The reaction temperature T2 mentioned in step 2 is 40-80℃.

10. The use of a bripiprazole intermediate obtained by the preparation method according to claim 1 for the preparation of bripiprazole, characterized in that, The preparation method includes the following steps: compound SM-3, compound I-2, potassium carbonate, and sodium iodide are added to N,N-dimethylformamide and reacted to obtain the final product bripiprazole; the synthetic route is as follows:

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