Preparation method of lumepirone intermediate compound

Abstract

The invention discloses a lumepirone intermediate compound and a preparation method thereof, and relates to the technical field of drug intermediate synthesis. The invention relates to a lumepirone intermediate compound preparation method, which comprises: adding a bromide represented by a formula 2 into a solvent, adding a copper salt, an alkali and a ligand, and carrying out a reaction to obtain (6bR, 10aS)-3-methyl-2-oxo-2, 3, 6b, 9, 10, 10a-hexahydro-1H, 7H-pyridino [3 ', 4': 4, 5] pyrrolo [1, 2, 3-de] quinoxaline-8-carboxylic acid ethyl ester represented by a formula 1. The preparation method disclosed by the invention is simple, reasonable in process condition, less in pollution, easy to control in operation condition, short in period, low in cost, high in production safety and suitable for industrial production, does not involve hazardous articles such as hydrogen and the like in the preparation process, has the yield of 92% or above, and has relatively high implementation value and economic benefit.

Description

Technical Field

[0001] The 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 (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 is as follows:

[0003]

[0004] It has a wide range of applications in the fields of medicinal chemistry and organic synthesis as an important intermediate of 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) is a new drug developed by Intra-Cellular Therapies Biopharmaceuticals that combines a potent 5-HT2A receptor antagonist, a dopamine receptor phosphorylation modulator (DPPM), a glutamate modulator, and a serotonin reuptake inhibitor. It can be used to treat acute and residual schizophrenia, improve sleep quality, and reduce negative symptoms of schizophrenia. It also has a certain effect on depression, anxiety, and other symptoms related to impaired social function. It is expected to become a major breakthrough in the field of multi-target antipsychotic drugs and bring new hope to the majority of schizophrenia patients. As a new antipsychotic drug with a unique mechanism of action, Lumateperone can synergistically act on the serotonin, dopamine, and glutamatergic systems. It can not only improve the positive symptoms of schizophrenia patients, but also be effective for negative symptoms and depressive symptoms.

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

[0008] At present, the known methods for preparing the compound of formula 1 are mainly as follows:

[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. The reaction temperature is 100°C. The industry requires the use of high-temperature equipment and the cooling system needs to use ice ethanol for cooling. In addition, the yield of this method is not high, and the industrialization requirements of enterprises are relatively high.

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

[0011] Although this method avoids high-temperature reactions, it uses expensive palladium catalysts, which is very costly. It is also a pressure reaction, requiring the use of an autoclave, which is not suitable for industrial-scale production. It also uses hydrogen, which poses a major safety hazard. Summary of the invention

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

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

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

[0015] The bromide compound shown in Formula 2 is added to a solvent, and 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 0.1-0.3 Kg / L.

[0023] As a possible design, the molar ratio of the above-mentioned 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, easy operation, no need for 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 the traditional method, 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 the traditional preparation method, the present invention greatly shortens the production cycle and improves production efficiency; due to the simplification of the process flow and the reduction of raw material consumption, the preparation cost of the present invention is much lower than the industry average; the preparation process does not involve inflammable 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 shown in 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 obtained 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, is not a low-temperature or high-pressure reaction, has mild reaction conditions, has low equipment requirements, is suitable for large-scale industrial production, and 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 embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and should not be regarded as limiting the scope. For those of ordinary skill in the art, other relevant drawings can be obtained based on these drawings without creative work. 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 scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with examples and 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. If specific conditions are not specified in the examples, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0030] Hereinafter, the embodiments of the present invention will be specifically disclosed in detail with appropriate reference to the accompanying drawings. However, there may be cases where unnecessary detailed descriptions are omitted. For example, there may be cases where detailed descriptions of well-known matters and repeated descriptions of actually the same structures are omitted. This is to avoid the following description from becoming unnecessarily lengthy and to facilitate understanding by those skilled in the art. In addition, the accompanying drawings and the following description are provided for 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 "range" disclosed in the present invention is defined in the form of a lower limit and an upper limit, and a given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundaries of the particular range. The range defined in this way can be inclusive or exclusive of the end values, and can be arbitrarily combined, that is, any lower limit can be combined with any upper limit to form a range. For example, if a range of 60 to 120 and 80 to 110 is listed for a particular parameter, it is understood that a range of 60 to 110 and 80 to 120 is also expected. In addition, if the minimum range values ​​1 and 2 are listed, and if the maximum range values ​​3, 4 and 5 are listed, the following ranges can all be expected: 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 specified, the numerical range "a to b" represents an abbreviation of any real number combination between a and b, wherein a and b are both real numbers. For example, the numerical range "0-5" means that all real numbers between "0-5" are listed in this document, and "0-5" is just an abbreviation of these numerical combinations. In addition, when a parameter is expressed as an integer ≥ 2, it 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] If not otherwise specified, all embodiments and optional embodiments of the present invention can be combined with each other to form a new technical solution. If not 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. If not 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] If there is no special explanation, the "include" and "comprising" mentioned in the present invention represent open-ended or closed-ended expressions. For example, the "include" and "comprising" may represent that other components not listed may also be included or only the listed components may be included or only the listed components may be included.

[0034] If not specifically stated, in the present invention, the term "or" is inclusive. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, any of the following conditions satisfies the condition "A or B": 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] The existing preparation method of lumiperone intermediate compound has the problems of low yield, high industrialization requirements, potential safety hazards, etc. The present invention adds the bromide shown in formula 2 to a solvent, controls the reaction temperature, adds copper salt, base, and ligand, and performs CN Ullmann coupling reaction at a specific temperature. The obtained 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 shown in formula 1. It can be seen that the whole reaction has low equipment requirements, is suitable for large-scale industrial production, does not use dangerous goods as raw materials, has high safety, and has a yield of more than 92%.

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

[0037] The bromide compound shown in Formula 2 is added to a solvent, and 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 the yield. L-proline is a five-membered ring amino acid. The cyclic part in its structure gives it a unique spatial configuration and chemical properties, so that it can form a stable complex with substances such as cuprous ions, and then participate 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 above preparation method comprises:

[0045] After stirring the solvent, add the bromide shown in formula 2, continue stirring, add the ligand, base and copper salt, heat up to react, keep warm, cool down, filter out the filtrate 1, add solvent to rinse the filtrate 1, collect the filtrate and the rinse liquid, add water, precipitate the filtrate 2, dry the filtrate 2, and obtain the lumepirone intermediate compound.

[0046] In some embodiments of the present invention, the molar ratio of the bromide to the copper salt, the base and the ligand is 1:0.05-0.5:1.5-2:0.1-0.5. The molar ratio of the bromide to the copper salt, the base and the 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, and can be 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 bottle, 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, and track the raw material without residue by HPLC, then cool the reaction system to 15℃, filter the system directly, and use 1L The filter cake was washed with DMF and discarded if there was no product. 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 controlled below 30°C. An off-white solid precipitated, and the product was filtered at 15-25°C for 1h and dried in vacuum at 60-65°C to obtain 367g of a white solid. The yield was 92%.

[0053] Combination 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 bottle, 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), CuCl 3.12g (0.0315mol) to the system, heat the system to an internal temperature of 90°C, keep warm for 2h, take a sample, and track the raw material for HPLC without residue, then cool the reaction system to 20°C, filter the system directly, and use 1.0L The filter cake was washed with DMF, and no product was discarded. The filtrate was cooled to 20°C in a 20L jacketed kettle, and 14L of water was added dropwise to the system. The temperature was controlled below 30°C, and an off-white solid precipitated. The product was filtered at 15-25°C for 1.5h, and 175g of white solid was dried in 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 bottle, start stirring, then add 750g (1.89mol) of bromide compound 2, stir for 5min, control the temperature at 15-25°C, add 87g (0.756mol) of L-Proline, 858.6g (4.05mol) of K3PO4, and 8.12g (0.284mol) of CuCl2 to the system, heat the system to an internal temperature of 110°C, keep warm for 6h, take a sample, and track the raw material for HPLC without residue, 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 there was no product. 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 controlled below 30°C. An off-white solid precipitated, and the product was obtained by filtration at 15-25°C for 1.5h. The white solid was dried in vacuum at 60-65°C for 543g. The yield was 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] Add 100 mL of DMF (KF≤0.05%) to a dry and clean 250 mL four-necked bottle, start stirring, then add 20 g (50 mmol) of bromide compound 2, stir for 5 min, control the temperature at 15-25 ° C, add 1.33 g (15 mmol) of DMEDA, 21.4 g (100 mmol) of K3PO4, and 495 mg (5 mmol) of CuCl to the system, heat the system to an internal temperature of 105 ° C, keep warm for 5 h, take a sample for HPLC tracking, and there is no residual raw material. Then cool the reaction system to 25 ° C, filter the system directly, rinse the filter cake with 40 mL of DMF, discard the filter cake without product, cool the filtrate to 25 ° C in a kettle in a 1 L reaction bottle, add 550 mL of water dropwise to the system, control the temperature below 30 ° C, and a white solid precipitates. Keep warm at 15-25 ° C for 1.5 h to obtain the product by filtration, and dry in vacuo at 60-65 ° C to obtain 9.6 g of light purple solid. Yield: 60%.

[0062] Comparative Example 2

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

[0064] Add 100mL of DMF (KF≤0.05%) to a clean, dry 250mL four-necked bottle, start stirring, then add 20g (50mmol) of bromide compound 2, stir for 5min, control the temperature at 15-25°C, add 1.75g ​​(15mmol) of L-proline, 21.4g (100mmol) of K3PO4, and 495mg (5mmol) of CuCl to the system, heat the system to an internal temperature of 100°C, keep it warm for 3h, take a sample and track the raw material by HPLC, then cool the reaction system to 25°C, control the temperature below 30°C, add 550mL of water to the system, and a white solid precipitates. Keep it warm at 15-25°C for 1.5h, filter to obtain the product, and dry it in a vacuum at 60-65°C to obtain 13.5g of a light grey 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] Add 100 mL of DMF (KF ≤ 0.05%) to a dry and clean 1L four-necked bottle, start stirring, then add 20 g (50 mmol) of bromide compound 2, stir for 5 min, control the temperature at 15-25 ° C, add L-proline 1.75 g (15 mmol), K3PO4 21.4 g (100 mmol), CuCl 495 mg (5 mmol) to the system, heat the system to an internal temperature of 70 ° C, keep warm for 6 h, take samples for HPLC tracking, and the remaining raw material is ~30%, without further treatment.

[0068] Comparative Example 4

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

[0070] Add 100 mL of DMF (KF≤0.05%) to a dry and clean 250 mL four-necked bottle, start stirring, then add 20 g (50 mmol) of bromide compound 2, stir for 5 min, control the temperature at 15-25 ° C, add 1.76 g (15 mmol) of L-proline, 21.4 g (100 mmol) of K3PO4, and 497 mg (5 mmol) of CuCl to the system, heat the system to an internal temperature of 103 ° C, keep warm for 5 h, take a sample for HPLC tracking, and there is no residual raw material, then cool the reaction system to 25 ° C, filter the system directly, rinse the filter cake with 40 mL of DMF, discard the filter cake without product, cool the filtrate to 25 ° C in a kettle in a 1 L reaction bottle, add 550 mL of water dropwise to the system, control the temperature below 30 ° C, a white solid precipitates, keep warm at 15-25 ° C for 1.5 h, filter to obtain the product, and vacuum dry at 60-65 ° C to obtain 14.4 g of light purple solid. Yield 90%.

[0071] Based on the comparative examples 1 and 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, easy operation, no need for 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 the traditional method, 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 the traditional preparation method, the present invention greatly shortens the production cycle and improves production efficiency; due to the simplification of the process flow and the reduction of raw material consumption, the preparation cost of the present invention is much lower than the industry average; the preparation process does not involve inflammable 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 shown in 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 obtained 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, is not a low-temperature or high-pressure reaction, has mild reaction conditions, has low equipment requirements, is suitable for large-scale industrial production, and 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 compound shown in Formula 2 is added to a solvent, and 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.

2. The method for preparing a lumiperone intermediate compound according to claim 1, characterized in that: The ligand is L-proline and / or L-3-hydroxyproline.

3. The method for preparing a lumiperone intermediate compound according to claim 1, characterized in that: The copper salt is CuCl, CuI and / or CuBr.

4. The method for preparing a lumiperone intermediate compound according to claim 1, characterized in that: The base is K3PO4.

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

6. The method for preparing a lumiperone intermediate compound according to claim 1, characterized in that: The reaction temperature is 90-110°C.

7. The method for preparing a lumiperone intermediate compound according to claim 1, characterized in that: The solid-liquid ratio of the brominated compound to the solvent is 0.1-0.3 Kg / L.

8. The method for preparing a lumiperone intermediate compound according to claim 1 or 7, characterized in that: 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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