A preparation method of lumiperone intermediate compound

Abstract

The present invention discloses a lumiperone intermediate compound and a preparation method thereof, and relates to the technical field of pharmaceutical intermediate synthesis. A preparation method of a lumiperone intermediate compound comprises: adding a bromide as shown in Formula 2 to a solvent, adding a copper salt, a base and a ligand, and reacting to obtain (6bR, 10aS)-3-methyl-2-oxo-2,3,6b, 9,10,10a-hexahydro-1H, 7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8-carboxylic acid ethyl ester as shown in Formula 1. The preparation method of the present invention is simple, has reasonable process conditions, is less polluting, and the method operating conditions are easy to control, has a short cycle, is low in cost, does not involve hazardous substances such as hydrogen in the preparation process, has high production safety, is suitable for industrial production, has a yield of more than 92%, and has greater implementation value and economic benefits.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a method for preparing a lumiperone intermediate compound. Background Art

[0002] The structural formula of ethyl (6bR, 10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8-carboxylate is as follows:

[0003]

[0004] It has a wide range of applications in medicinal chemistry and organic synthesis, and serves as an important intermediate for lumepirone p-toluenesulfonate.

[0005] Lumateperone p-toluenesulfonate, English name: lumateperone (Tosylate), chemical name: 1-(4-fluorophenyl)-4-[(6BR,10AS)-2,3,6B,9,10,10A-hexahydro-3-methyl-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl]-1-butanone p-toluenesulfonate, English name: 1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)butan-1-one 4-methylbenzenesulfonate.

[0006] Lumateperone (ITI-007), a novel drug developed by Intra-Cellular Therapies, combines a potent 5-HT2A receptor antagonist, a dopamine receptor phosphorylation modulator (DPPM), a glutamate modulator, and a serotonin reuptake inhibitor. It is indicated for the treatment of acute and residual schizophrenia, while also improving sleep quality and reducing negative symptoms of schizophrenia. It also has some efficacy against depression, anxiety, and other symptoms associated with impaired social functioning. It is expected to be a major breakthrough in the field of multi-target antipsychotic drugs, bringing new hope to patients with schizophrenia. As a novel antipsychotic with a unique mechanism of action, lumateperone acts synergistically across the serotonin, dopamine, and glutamatergic systems, improving not only the positive symptoms of schizophrenia but also negative and depressive symptoms.

[0007] In December 2019, the FDA approved lumepirone for the treatment of schizophrenia in adults.

[0008] Currently, the following methods are known for preparing the compound of formula 1:

[0009] 1) Patent WO2008112280A discloses the main synthesis method currently on the market. This method uses cuprous iodide as a metal catalyst to react with the key raw material (Formula 2) at a reaction temperature of 100°C. Industrially, this requires the use of high-temperature equipment and the use of glacial ethanol for cooling. Furthermore, this method has a low yield and places high demands on enterprises for industrialization.

[0010] 2) Patent CN114105980A discloses a preparation method using palladium-carbon hydrogenation and dehalogenation.

[0011] While this method avoids high-temperature reactions, it uses expensive palladium catalysts, making it very costly. Furthermore, it is a pressure reaction, requiring the use of an autoclave, making it unsuitable for industrial-scale production. Furthermore, the use of hydrogen poses significant safety risks. Summary of the Invention

[0012] The technical problem to be solved by the present invention is that the existing methods for preparing lumiperone intermediate compounds have problems such as low yield, high industrialization requirements, and potential safety hazards. The purpose is to provide a lumiperone intermediate compound and a preparation method thereof, which solves the problems of low yield, high industrialization requirements, and potential safety hazards in the existing methods for preparing lumiperone intermediate compounds.

[0013] The present invention is achieved through the following technical solutions:

[0014] A method for preparing a lumiperone intermediate compound comprises:

[0015] The bromide shown in Formula 2 is added to a solvent, and a copper salt, a base and a ligand are added. After reaction, (6bR, 10aS)-3-methyl-2-oxo-2,3,6b, 9,10,10a-hexahydro-1H, 7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8-carboxylic acid ethyl ester shown in Formula 1 is obtained.

[0016]

[0017] As a possible design, the ligand is L-proline and / or L-3-hydroxyproline.

[0018] As a possible design, the copper salt is CuCl, CuI and / or CuBr.

[0019] As a possible design, the base is K3PO4.

[0020] As a possible design, the solvent is dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and / or 1,4-dioxane.

[0021] As a possible design, the reaction temperature is 90-110°C.

[0022] As a possible design, the solid-liquid ratio of the above-mentioned brominated compound to the solvent is 0.1 to 0.3 kg / L.

[0023] As a possible design, the molar ratio of the bromide to the copper salt, the base and the ligand is 1:0.05-0.5:1.5-2.5:0.1-0.5.

[0024] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0025] The preparation method of the present invention is simple, with clear steps and easy operation. It does not require complex equipment or technology and is easy to understand and execute. The process conditions are reasonable, ensuring the stability of the production process and the consistency of the product. Compared with traditional methods, the waste and pollutants generated in the preparation process of the present invention are significantly reduced, meeting environmental protection requirements. The key parameters in the production process are easy to monitor and adjust, ensuring product quality and production efficiency. Compared with traditional preparation methods, the present invention greatly shortens the production cycle and improves production efficiency. Due to the simplified process flow and reduced raw material consumption, the preparation cost of the present invention is far lower than the industry average. The preparation process does not involve flammable and explosive dangerous goods such as hydrogen, reducing production risks and improving safety. Therefore, the present method is suitable for industrial production, with a yield of more than 92%, and has great implementation value and economic benefits.

[0026] Specifically, the present invention adds the bromide represented by Formula 2 to a solvent, controls the reaction temperature, adds a copper salt, a base, and a ligand, and performs a CN Ullmann coupling reaction at a specific temperature. The resulting product is post-treated to obtain (6bR, 10aS)-3-methyl-2-oxo-2,3,6b, 9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8-carboxylic acid ethyl ester (Formula 1). The present invention does not use highly toxic or expensive reagents, does not require low temperature or high pressure reactions, has mild reaction conditions, has low equipment requirements, and is suitable for large-scale industrial production. It is particularly suitable for the synthesis of intermediates for lumiperone drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the following briefly introduces the drawings required for use in the examples. It should be understood that the following drawings only illustrate certain embodiments of the present invention and should not be considered as limiting the scope. A person of ordinary skill in the art can also derive other relevant drawings based on these drawings without inventive effort. In the drawings:

[0028] Figure 1 For Example 1 1 H NMR spectrum and 1 H attribution analysis. DETAILED DESCRIPTION

[0029] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with Examples and accompanying drawings. The illustrative embodiments of the present invention and their description are only used to explain the present invention and are not intended to limit the present invention. In the examples, if specific conditions are not specified, the conditions according to conventional conditions or manufacturer's recommendations are used. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially.

[0030] The following detailed description of the embodiments of the present invention is specifically disclosed with appropriate reference to the accompanying drawings. However, unnecessary detailed descriptions may be omitted. For example, detailed descriptions of well-known matters and repeated descriptions of substantially identical structures may be omitted. This is to avoid unnecessary lengthiness in the following description and to facilitate understanding by those skilled in the art. In addition, the drawings and the following description are provided to enable those skilled in the art to fully understand the present invention and are not intended to limit the subject matter described in the claims.

[0031] The "ranges" disclosed herein are defined in terms of lower and upper limits, where a given range is defined by selecting a lower limit and an upper limit, and the selected lower and upper limits define the boundaries of the particular range. Ranges defined in this manner may be inclusive or exclusive of the end values ​​and may be combined arbitrarily, i.e., any lower limit may be combined with any upper limit to form a range. For example, if ranges of 60 to 120 and 80 to 110 are listed for a particular parameter, it is understood that ranges of 60 to 110 and 80 to 120 are also contemplated. Furthermore, if minimum range values ​​of 1 and 2 are listed, and if maximum range values ​​of 3, 4, and 5 are listed, the following ranges are all contemplated: 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, and 2 to 5. In the present invention, unless otherwise indicated, the numerical range "a to b" is a shorthand representation of any combination of real numbers between a and b, where a and b are both real numbers. For example, a numerical range of "0-5" indicates that all real numbers between "0-5" are listed herein, and "0-5" is simply an abbreviation for these numerical combinations. Furthermore, when a parameter is expressed as an integer ≥ 2, this is equivalent to disclosing that the parameter is, for example, an integer of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0032] Unless otherwise specified, all embodiments and optional embodiments of the present invention can be combined with each other to form a new technical solution. Unless otherwise specified, all technical features and optional technical features of the present invention can be combined with each other to form a new technical solution. Unless otherwise specified, all steps of the present invention can be performed sequentially or randomly, preferably sequentially. For example, the method includes steps (a) and (b), which means that the method may include steps (a) and (b) performed sequentially, or may include steps (b) and (a) performed sequentially. For example, it is mentioned that the method may also include step (c), which means that step (c) can be added to the method in any order, for example, the method may include steps (a), (b) and (c), or may include steps (a), (c) and (b), or may include steps (c), (a) and (b), etc.

[0033] Unless otherwise specified, the terms "include" and "comprising" used in the present invention may be open-ended or closed-ended. For example, "include" and "comprising" may mean that other components not listed may also be included or that only the listed components are included.

[0034] Unless otherwise specified, the term "or" is inclusive in this disclosure. For example, the phrase "A or B" means "A, B, or both A and B." More specifically, the condition "A or B" is satisfied by any of the following conditions: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist).

[0035] Existing methods for preparing lumiperone intermediate compounds have problems such as low yield, high industrialization requirements, and potential safety hazards. The present invention involves adding a brominated compound represented by Formula 2 to a solvent, controlling the reaction temperature, adding a copper salt, a base, and a ligand, and conducting a CN Ullmann coupling reaction at a specific temperature. The resulting product is post-treated to obtain (6bR, 10aS)-3-methyl-2-oxo-2,3,6b, 9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8-carboxylic acid ethyl ester represented by Formula 1. The entire reaction has low equipment requirements, is suitable for large-scale industrial production, does not use hazardous materials as raw materials, is highly safe, and has a yield of over 92%.

[0036] In a first aspect, the present invention provides a method for preparing a lumiperone intermediate compound, comprising:

[0037] The bromide shown in Formula 2 is added to a solvent, and a copper salt, a base and a ligand are added. After reaction, (6bR, 10aS)-3-methyl-2-oxo-2,3,6b, 9,10,10a-hexahydro-1H, 7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8-carboxylic acid ethyl ester shown in Formula 1 is obtained.

[0038] The above reaction refers to the following formula:

[0039]

[0040] In some embodiments of the present invention, the ligand is L-proline. Using L-proline as a ligand effectively improves yield. L-proline is a five-membered amino acid. The cyclic portion of its structure gives it a unique spatial configuration and chemical properties, enabling it to form stable complexes with substances such as cuprous ions, thereby participating in the catalytic cycle.

[0041] In some embodiments of the present invention, the copper salt is CuCl, CuI and / or CuBr.

[0042] In some embodiments of the present invention, the base is K3PO4.

[0043] In some embodiments of the present invention, the solvent is dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and / or 1,4-dioxane.

[0044] In some embodiments of the present invention, the preparation method comprises:

[0045] After stirring the solvent, the bromide shown in Formula 2 is added, stirring is continued, and a ligand, a base, and a copper salt are added. After heating for reaction, the reaction is carried out by heat preservation. After cooling, the filtrate 1 is filtered out, and the filtrate 1 is rinsed with a solvent. The filtrate and the rinsing liquid are collected and water is added to precipitate the filtrate 2, and the filtrate 2 is dried to obtain a lumiperone intermediate compound.

[0046] In some embodiments of the present invention, the molar ratio of the bromide to the copper salt, base and ligand is 1:0.05-0.5:1.5-2:0.1-0.5. The molar ratio of the bromide to the copper salt, base and ligand is preferably 1:0.1:2:0.3.

[0047] In some embodiments of the present invention, the reaction temperature is 90-110° C. The reaction temperature can be any value within the range of 90-110° C., and can be 95° C., 98° C., 105° C., 108° C., or other values. The reaction temperature can be any value within the range of 90-110° C., and can be 92° C., 93° C., 95° C., 98° C., 101° C., 105° C., 108° C., or other values.

[0048] Preferably, the reaction temperature is 100°C.

[0049] In some embodiments of the present invention, the solid-liquid ratio of the brominated compound to the solvent is 0.1-0.3 kg / L. The solid-liquid ratio of the brominated compound to the solvent can be any value within the range of 0.1-0.3 kg / L, such as 0.15 kg / L, 0.22 kg / L, 0.28 kg / L, or other values.

[0050] The material-liquid ratio of the bromide to water is 0.4-0.6 Kg / L. The material-liquid ratio of the bromide to water can be any value within the range of 0.4-0.6 Kg / L, such as 0.45 Kg / L, 0.55 Kg / L, 0.58 Kg / L or other values.

[0051] Example 1

[0052] Add 2.5L of DMF (KF≤0.05%) to a dry and clean 5L four-necked flask, start stirring, then add 500g (1.26mol) of bromide compound 2, stir for 5min, control the temperature at 15-25℃, add 43.5g (0.378mol) of L-Proline, 535g (2.52mol) of K3PO4, and 12.5g (0.126mol) of CuCl to the system, heat the system to an internal temperature of 100℃, keep warm for 4h, take a sample by HPLC to track the raw material, and then cool the reaction system to 15℃, filter the system directly, and use 1L The filter cake was washed with DMF and discarded if no product was present. The filtrate was cooled to 15°C in a 20L jacketed kettle. 14L of water was added dropwise to the system, and the temperature was maintained below 30°C. An off-white solid precipitated. The mixture was kept at 15-25°C for 1 hour and filtered to obtain the product. The product was then dried under vacuum at 60-65°C to obtain 367g of a white solid. The yield was 92%.

[0053] Combine Figure 1 ,'H-NMR(600MHz,CDCl3)l.28(t,J=6.9Hz,3H,-CH3),l.86-l.96(m,2H,-CH2),2.72(br,1H,-CH),3.11-3.22(m,1H ,-CH),3.35(s,3H,-CH3),3.33-3.34(m,1H,-CH),6.78(t,J=7.8Hz,1H,Ar-H),6.92(dd,J=1.2,7.2Hz,1H,Ar-H).

[0054] This spectrum and the spectrum reported in the literature (WO2019 / 241278) can confirm the structure of the compound.

[0055] Example 2

[0056] Add 2.5L of DMF (KF≤0.05%) to a dry and clean 5L four-necked flask, start stirring, then add 250g (0.63mol) of bromide compound 2, stir for 10min, control the temperature at 15-25°C, add L-Proline 21.78g (0.189mol), K3PO4 240g (1.134mol), and CuCl3.12g (0.0315mol) to the system, heat the system to an internal temperature of 90°C, keep warm for 2h, take a sample by HPLC tracking, and there is no residual raw material. Then cool the reaction system to 20°C, filter the system directly, and use 1.0L The filter cake was washed with DMF and discarded if no product was present. The filtrate was cooled to 20°C in a 20L jacketed kettle. 14L of water was added dropwise to the system, and the temperature was maintained below 30°C. An off-white solid precipitated. The product was obtained by filtration after maintaining the temperature at 15-25°C for 1.5 hours. The white solid (175g) was dried under vacuum at 60-65°C. The yield was 88%.

[0057] Example 3

[0058] Add 2.5L of DMF (KF≤0.05%) to a dry and clean 5L four-necked flask, start stirring, then add 750g (1.89mol) of bromide compound 2, stir for 5min, control the temperature at 15-25°C, add L-Proline 87g (0.756mol), K3PO4 858.6g (4.05mol), CuCl2 8.12g (0.284mol) to the system, heat the system to an internal temperature of 110°C, keep warm for 6h, take a sample by HPLC tracking, and there is no residual raw material. Then cool the reaction system to 25°C, filter the system directly, and use 1L The filter cake was washed with DMF and discarded if no product was present. The filtrate was cooled to 25°C in a 20L jacketed kettle. 14L of water was added dropwise to the system, and the temperature was maintained below 30°C. An off-white solid precipitated. The product was obtained by filtration after maintaining the temperature at 15-25°C for 1.5 hours. 543g of the white solid was dried under vacuum at 60-65°C. Yield: 91%.

[0059] Comparative Example 1

[0060] This comparative example is basically the same as Example 1, except that the L-proline ligand is changed.

[0061] To a dry and clean 250mL four-necked flask, 100mL of DMF (KF≤0.05%) was added, stirred, and then 20g (50mmol) of bromide compound 2 was added. After stirring for 5min, the temperature was controlled at 15-25°C. DMEDA1.33g (15mmol), K3PO421.4g (100mmol), and CuCl495mg (5mmol) were added to the system. The system was heated to an internal temperature of 105°C and kept warm for 5h. Samples were taken for HPLC tracking to show that there was no residual raw material. The reaction system was then cooled to 25°C, the system was directly filtered, the filter cake was rinsed with 40mL of DMF, and the filter cake was discarded without product. The filtrate was cooled to 25°C in a 1L reaction flask. 550mL of water was added dropwise to the system, the temperature was controlled below 30°C, and an off-white solid was precipitated. The product was filtered at 15-25°C for 1.5h and dried in vacuo at 60-65°C to obtain 9.6g of a light purple solid. Yield 60%.

[0062] Comparative Example 2

[0063] This comparative example is basically the same as Example 1, except that the post-processing process is changed.

[0064] Add 100 mL of DMF (KF ≤ 0.05%) to a clean, dry 250 mL four-necked flask, stir, then add 20 g (50 mmol) of the bromide compound of formula 2. Stir for 5 minutes, then control the temperature at 15-25°C. Add 1.75 g (15 mmol) of L-proline, 21.4 g (100 mmol) of K3PO4, and 495 mg (5 mmol) of CuCl. Raise the system temperature to 100°C, keep it warm for 3 hours, and sample it for HPLC tracking to see if there is any residual raw material. Then cool the reaction system to 25°C, control the temperature below 30°C, and add 550 mL of water dropwise to the system. A white solid precipitates. Keep it warm at 15-25°C for 1.5 hours, filter, and dry it in a vacuum at 60-65°C to obtain 13.5 g of a light gray solid. Yield: 85%

[0065] Comparative Example 3

[0066] This comparative example is basically the same as Example 1, except that the reaction temperature is 88°C / 112°C.

[0067] To a dry and clean 1L four-necked flask, add 100mL of DMF (KF required ≤ 0.05%) and start stirring. Then add 20g (50mmol) of the bromide compound of formula 2. After stirring for 5min, control the temperature at 15-25°C and add L-proline 1.75g ​​(15mmol), K3PO421.4g (100mmol), and CuCl 495mg (5mmol). The system is heated to an internal temperature of 70°C and kept warm for 6h. Samples are taken for HPLC tracking. The remaining raw material is ∼30% and no further treatment is done.

[0068] Comparative Example 4

[0069] This comparative example is basically the same as comparative example 1, except that L-proline ligand is used.

[0070] To a dry and clean 250mL four-necked flask, 100mL of DMF (KF≤0.05%) was added, stirred, and then 20g (50mmol) of bromide compound 2 was added. After stirring for 5min, the temperature was controlled at 15-25°C. L-proline 1.76g (15mmol), K3PO421.4g (100mmol), and CuCl 497mg (5mmol) were added to the system. The system was heated to an internal temperature of 103°C and kept warm for 5h. Samples were taken for HPLC tracking to show that there was no residual raw material. The reaction system was then cooled to 25°C, the system was directly filtered, the filter cake was rinsed with 40mL of DMF, and the filter cake was discarded without product. The filtrate was cooled to 25°C in a 1L reaction flask. 550mL of water was added dropwise to the system, the temperature was controlled below 30°C, and an off-white solid was precipitated. The product was filtered at 15-25°C for 1.5h and dried in vacuo at 60-65°C to obtain 14.4g of a light purple solid. Yield 90%.

[0071] From the two cases of Comparative Example 1 and Comparative Example 4 and Example 1, it can be seen that the yield is improved by using L-proline as a ligand.

[0072] The preparation method of the present invention is simple, with clear steps and easy operation. It does not require complex equipment or technology and is easy to understand and execute. The process conditions are reasonable, ensuring the stability of the production process and the consistency of the product. Compared with traditional methods, the waste and pollutants generated in the preparation process of the present invention are significantly reduced, meeting environmental protection requirements. The key parameters in the production process are easy to monitor and adjust, ensuring product quality and production efficiency. Compared with traditional preparation methods, the present invention greatly shortens the production cycle and improves production efficiency. Due to the simplified process flow and reduced raw material consumption, the preparation cost of the present invention is far lower than the industry average. The preparation process does not involve flammable and explosive dangerous goods such as hydrogen, reducing production risks and improving safety. Therefore, the present method is suitable for industrial production, with a yield of more than 92%, and has great implementation value and economic benefits.

[0073] Specifically, the present invention adds the bromide represented by Formula 2 to a solvent, controls the reaction temperature, adds a copper salt, a base, and a ligand, and performs a CN Ullmann coupling reaction at a specific temperature. The resulting product is post-treated to obtain (6bR, 10aS)-3-methyl-2-oxo-2,3,6b, 9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8-carboxylic acid ethyl ester (Formula 1). The present invention does not use highly toxic or expensive reagents, does not require low temperature or high pressure reactions, has mild reaction conditions, has low equipment requirements, and is suitable for large-scale industrial production. It is particularly suitable for the synthesis of intermediates for lumiperone drugs.

[0074] The specific implementation methods described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation method of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing a lumiperone intermediate compound, characterized in that: include: The bromide shown in Formula 2 is added to a solvent, and a copper salt, a base and a ligand are added. After reaction, (6bR, 10aS)-3-methyl-2-oxo-2,3,6b, 9,10,10a-hexahydro-1H, 7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8-carboxylic acid ethyl ester shown in Formula 1 is obtained. ； The ligand is L-proline and / or L-3-hydroxyproline.

2. The method for preparing a lumiperone intermediate compound according to claim 1, wherein The copper salt is CuCl, CuI and / or CuBr.

3. The method for preparing a lumiperone intermediate compound according to claim 1, wherein: The base is K3PO4.

4. The method for preparing a lumiperone intermediate compound according to claim 1, wherein The solvent is dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and / or 1,4-dioxane.

5. The method for preparing a lumiperone intermediate compound according to claim 1, wherein: The reaction temperature is 90-110°C.

6. The method for preparing a lumiperone intermediate compound according to claim 1, wherein: The material-liquid ratio of the brominated compound to the solvent is 0.1-0.3 kg / L.

7. The method for preparing a lumiperone intermediate compound according to claim 1 or 6, wherein: The molar ratio of the bromide to the copper salt, the base and the ligand is 1:0.05-0.5:1.5-2.5:0.1-0.5.

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