Preparation method of buspirone hydrochloride

Abstract

The invention relates to a preparation method of buspirone hydrochloride. The preparation method comprises the following steps: (1) reacting 1-(2-pyrimidinyl)-piperazine with a hydrogen chloride ethanol solution to prepare 1-(2-pyrimidinyl)-piperazine dihydrochloride; (2) enabling the 1-(2-pyrimidinyl)-piperazine dihydrochloride to react with alkali and 1, 4-dibromobutane, so as to obtain 1-(4-bromobutane)-4-(2-pyrimidinyl)-piperazine; (3) enabling the 1-(4-bromobutanyl)-4-(2-pyrimidinyl)-piperazine to react with alkali and 3, 3-tetramethylene glutarimide, so as to obtain 8-[4-[4-(2-pyrimidinyl)-1-piperazine] butyl-8-azaspiro [4, 5] decane-7, 9-diketone, and enabling the 8-[4-[4-(2-pyrimidinyl)-1-piperazine] butyl-8-azaspiro [4, 5] decane-7, 9-diketone to react with the alkali And (4) adding 8-[4-[4-(2-pyrimidine)-1-piperazine] butyl-8-azaspiro [4, 5] decane-7, 9-diketone into isopropanol, and carrying out a reaction, thereby obtaining the product. According to the method, the product purity and the reaction yield are improved, no catalyst is used, the cost is reduced, and the production period is shortened.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for preparing buspirone hydrochloride. Background Art

[0002] Buspirone hydrochloride (CAS: 33386-08-2), chemical name is 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dione-hydrochloride, its structural formula is:

[0003]

[0004] Buspirone hydrochloride is a new type of azaspirodecanedione compound and the first non-benzodiazepine antianxiety drug developed by Mead Johnson in the United States. Compared with traditional drugs, this drug has high selectivity, does not affect alertness, has a low tendency to be addictive, has a definite therapeutic effect, and has been marketed in many countries.

[0005] Patent US4351939A discloses a method for preparing buspirone hydrochloride compounds. The main synthesis route is as follows:

[0006]

[0007] The synthetic route is that 1-(2-pyrimidinyl) piperazine reacts with 1,5-dibromopentane or 1,5-dichloropentane to obtain a quaternary ammonium salt spirotetramine piperazine derivative of intermediate I, intermediate I and 3,3-tetramethylene glutarimide are subjected to condensation reaction in n-butanol or DMF as solvent, and the condensation reaction liquid is treated to obtain buspirone. However, this process is also accompanied by serious shortcomings, such as low overall reaction yield, long reaction time, multiple steps in the synthetic route, difficulty in product purification, and unsuitable for industrial-scale production.

[0008] Patent US5473072A discloses a preparation process of high-purity buspirone and its hydrochloride. The main synthesis route is as follows:

[0009]

[0010] This synthetic route directly obtains buspirone free base from II through hydrogenation, and finally obtains buspirone hydrochloride through salt formation. In this preparation process, palladium or Raney nickel is used as a catalyst for hydrogenation, and high-pressure equipment is used, which is costly and difficult to operate, and is not suitable for industrial production.

[0011] Therefore, there is an urgent need for a method for preparing buspirone hydrochloride with high reaction yield, mild reaction conditions and suitable for industrial production. Summary of the invention

[0012] The object of the present invention is to provide a method for preparing buspirone hydrochloride as shown in formula I, comprising the following steps:

[0013] (1) piperazine and 2-chloropyrimidine react in water at 20-30° C. in the presence of a base; the obtained 1-(2-pyrimidinyl)-piperazine reacts with a hydrogen chloride ethanol solution, and the pH is adjusted to 1-4 to prepare 1-(2-pyrimidinyl)-piperazine dihydrochloride;

[0014] (2) The 1-(2-pyrimidinyl)-piperazine dihydrochloride prepared in step (1) is reacted with a base and 1,4-dibromobutane in an organic solvent at 60-90° C., filtered hot, and the filtrate is concentrated under reduced pressure to 1 / 5-1 / 2 of the concentrated solution, and tert-butyl methyl ether is added, and crystallization is carried out by stirring at 0° C.-25° C., filtering, washing, and drying to prepare 1-(4-bromobutanyl)-4-(2-pyrimidinyl)-piperazine;

[0015] (3) The 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine prepared in step (2) is reacted with a base and 3,3-tetramethyleneglutarimide in an organic solvent at 120-130° C. After the reaction is completed, the temperature is lowered to 15-35° C., water is added, stirred for crystallization, filtered, washed, the filter cake is collected, isopropanol is added for recrystallization, suction filtered, washed, and dried to prepare 8-[4-[4-(2-pyrimidinyl)-1-piperazine]butyl-8-azaspiro[4,5]decane-7,9-dione;

[0016] (4) adding 8-[4-[4-(2-pyrimidine)-1-piperazine]butyl-8-azaspiro[4,5]decane-7,9-dione obtained in step (3) to isopropanol, heating to 55-65° C. to dissolve, adding dropwise 20%-40% hydrogen chloride ethanol solution, and keeping the temperature for reaction; cooling to 15-30° C. to keep the temperature for reaction, filtering, washing, and drying to obtain:

[0017]

[0018] In the preferred technical solution of the present invention, in the step (1), the molar ratio of 2-chloropyrimidine to piperazine is 1:1-4, preferably 1:2-3.

[0019] In a preferred technical solution of the present invention, in step (1), the base is selected from any one of sodium carbonate, potassium carbonate, sodium bicarbonate or a combination thereof.

[0020] In a preferred technical solution of the present invention, in step (1), the concentration of the base is 1.5-2.5 mol / L, preferably 1.8-2.0 mol / L.

[0021] In a preferred technical solution of the present invention, in step (1), the 2-chloropyrimidine is added in batches, preferably in 2-5 batches, and more preferably in 3-4 batches.

[0022] In the preferred technical solution of the present invention, in the step (1), the 2-chloropyrimidine addition time is 20 min-60 min, preferably 30 min-50 min.

[0023] In the preferred technical solution of the present invention, in the step (1), the mass fraction of the hydrogen chloride ethanol solution is 20%-40%, preferably 25%-30%.

[0024] In a preferred technical solution of the present invention, in step (1), the pH is adjusted to 2-3.

[0025] In the preferred technical solution of the present invention, in the step (2), the molar ratio of 1-(2-pyrimidinyl)-piperazine dihydrochloride to 1,4-dibromobutane is 1:1-4, and the preferred molar ratio is 1:2-3.

[0026] In a preferred technical solution of the present invention, in the step (2), the organic solvent is selected from acetonitrile.

[0027] In a preferred technical solution of the present invention, in step (2), the base is selected from any one of sodium hydroxide and potassium hydroxide or a combination thereof.

[0028] In the preferred technical solution of the present invention, in the step (2), the reaction temperature is 70-80°C.

[0029] In the preferred technical solution of the present invention, in the step (2), the volume ratio of the concentrated solution to tert-butyl methyl ether is 1:1-8, preferably 1:1.5-6.

[0030] In the preferred technical solution of the present invention, in the step (2), the stirring crystallization temperature is 10°C-20°C.

[0031] In a preferred technical solution of the present invention, in step (3), the base is any one or a combination of sodium hydroxide, potassium hydroxide and potassium carbonate.

[0032] In the preferred technical solution of the present invention, in step (3), 1-(4-bromobutyl)-4-

[0033] The molar ratio of (2-pyrimidinyl)-piperazine to 3,3-tetramethyleneglutarimide is 1:1-3, preferably 1:1.1-1.5.

[0034] In the preferred technical solution of the present invention, in step (3), 1-(4-bromobutyl)-4-

[0035] The molar ratio of (2-pyrimidinyl)-piperazine to the base is 1:1-3, preferably 1:1.5-2.

[0036] In a preferred technical solution of the present invention, in step (3), the organic solvent is selected from any one of N,N-dimethylformamide and N,N-dimethylacetamide or a combination thereof.

[0037] In the preferred technical solution of the present invention, in the step (3), the ratio of 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine:isopropanol is 1:2-6 (m:v), preferably 1:3-5 (m:v).

[0038] In the preferred technical solution of the present invention, in the step (3), the isopropanol recrystallization heating temperature is 50-60°C.

[0039] In the preferred technical solution of the present invention, in the step (4), the dissolving temperature is 55-65°C.

[0040] In the preferred technical solution of the present invention, in the step (4), the mass fraction of the hydrogen chloride ethanol solution is 25%-30%.

[0041] In the preferred technical scheme of the present invention, in the step (4), the weight volume ratio of 8-[4-[4-(2-pyrimidine)-1-piperazine]butyl-8-azaspiro[4,5]decane-7,9-dione:hydrogen chloride ethanol solution is 1:1-5 (m:v), preferably 1:1.5-3.

[0042] Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between liquids and solids, the percentage is volume / weight percentage; when the present invention relates to the percentage between solids and liquids, the percentage is weight / volume percentage; the rest are weight / weight percentages.

[0043] Compared with the prior art, the preparation method of the present invention has the following beneficial effects:

[0044] 1. The present invention provides a new method for preparing buspirone hydrochloride, which has mild reaction conditions and is simple and easy to operate. Microwave reaction can be avoided in the preparation process of buspirone, thereby improving product purity (the purity of both intermediates and final products can reach more than 99%) and reaction yield. At the same time, no catalyst is used, which greatly reduces production costs and shortens production cycles.

[0045] 2. The intermediate 1-(2-pyrimidinyl)-piperazine hydrochloride prepared by the present invention is a good solid and easy to store, which solves the defects of 1-(2-pyrimidinyl)-piperazine that it is easy to be oxidized and difficult to store.

[0046] 3. In the production process of the present invention, there is no special requirement for reaction equipment, no dangerous operations such as hydrogenation are involved, the reaction is safe, and it is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The hydrogen nuclear magnetic resonance spectrum of buspirone hydrochloride of the present invention.

[0048] Figure 2 The mass spectrum of buspirone hydrochloride of the present invention. DETAILED DESCRIPTION

[0049] Example 1

[0050] (1) Preparation of 1-(2-pyrimidinyl)-piperazine dihydrochloride (Compound II)

[0051] Add 60ml of purified water, anhydrous sodium carbonate (11.56g, 0.109mol), anhydrous piperazine (11.28g, 0.131mol) to a three-necked flask, stir at room temperature, add 2-chloropyrimidine (5.00g, 0.044mol) in four batches, add in half an hour, and keep warm at 25℃ for 2h. Filter by suction, extract the filtrate with dichloromethane three times, 40ml each time, combine the organic phases, and concentrate to about 40ml of solution. Control the temperature below 30℃ and add 25% hydrogen chloride ethanol solution to the reaction solution, adjust the pH to 2-3, and keep warm at 25℃ for 2h after the addition. Filter, wash, and dry the filter cake at 45℃-55℃ to obtain the target compound (white solid, 8.80g). Yield: 85.02%.

[0052] (2) Preparation of 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine (Compound III)

[0053] Add compound II (5.00 g, 0.021 mol), 40 ml of acetonitrile, sodium hydroxide (1.26 g, 0.032 mol), and 1,4-dibromobutane (13.66 g, 0.063 mol) to a three-necked flask. After the addition, heat to 75°C and stir for 4 hours. Filter hot, concentrate the filtrate to remove about half of the solvent, add 30 ml of tert-butyl methyl ether, stir at 15°C for 3 hours, filter, wash, and dry the filter cake at 45°C-55°C to obtain the target compound (light yellow solid, 5.67 g). Yield: 89.85%.

[0054] (3) Preparation of 8-[4-[4-(2-pyrimidine)-1-piperazine]butyl-8-azaspiro[4,5]decane-7,9-dione hydrochloride (Compound Ⅰ)

[0055] Add compound III (5g, 0.0167mol), N,N-dimethylformamide 40ml, potassium carbonate (4.62g, 0.033mol), tetramethylene glutarimide (3.35g, 0.020mol) to a three-necked flask, stir and heat to 130℃, keep warm and react for 20h. Cool the reaction solution to room temperature, add purified water, stir and crystallize, filter and wash, add 20ml of isopropanol to the obtained solid, heat to 50-60℃ to dissolve, cool and crystallize, filter, wash and dry to obtain compound IV buspirone (light yellow solid, 5.18g). Yield: 80.43%.

[0056] Then add 4.53g of compound IV to 45ml of isopropanol, heat to 55-65℃ to dissolve, then add 6.9ml of 25% hydrogen chloride ethanol solution dropwise under stirring, after addition, keep warm for 1h, then cool to 20℃ and keep warm for 3h, filter, wash and dry to obtain buspirone hydrochloride (white solid, 4.58g). Yield: 92.34%. Purity: 99.8%.

[0057] Example 2

[0058] (1) Preparation of 1-(2-pyrimidinyl)-piperazine dihydrochloride (Compound II)

[0059] Add 60ml of purified water, anhydrous sodium carbonate (11.56g, 0.109mol), anhydrous piperazine (7.52g, 0.087mol) to a three-necked flask, stir at room temperature, add 2-chloropyrimidine (5.00g, 0.044mol) in four batches, add in half an hour, and keep warm at 20℃ for 2h. Filter by suction, extract the filtrate with dichloromethane three times, 40ml each time, combine the organic phases, and concentrate until about 40ml of solution remains. Control the temperature below 30℃ and add 25% hydrogen chloride ethanol solution to the reaction solution, adjust the pH to 2-3, and keep warm at 20℃ for 2h after the addition. Filter, wash, and dry the filter cake at 45℃-55℃ to obtain the target compound (white solid, 8.90g). Yield: 85.99%.

[0060] (2) Preparation of 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine (Compound III)

[0061] Add compound II (5.00 g, 0.021 mol), 40 ml of acetonitrile, potassium hydroxide (4.73 g, 0.084 mol), and 1,4-dibromobutane (13.66 g, 0.063 mol) to a three-necked flask. After the addition, heat to 70°C and stir for 4 hours. Filter hot, concentrate the filtrate to remove about half of the solvent, add 30 ml of tert-butyl methyl ether, stir at 10°C for 3 hours, filter, wash, and dry the filter cake at 45°C-55°C to obtain the target compound (light yellow solid, 5.50 g). Yield: 87.16%.

[0062] (3) Preparation of 8-[4-[4-(2-pyrimidine)-1-piperazine]butyl-8-azaspiro[4,5]decane-7,9-dione hydrochloride (Compound Ⅰ)

[0063] Add compound III (5g, 0.0167mol), N,N-dimethylformamide 40ml, potassium carbonate (4.62g, 0.033mol), tetramethylene glutarimide (3.35g, 0.020mol) to a three-necked flask, stir and heat to 120℃, keep warm and react for 20h. Cool the reaction solution to room temperature, add purified water, stir and crystallize, filter and wash, add 20ml of isopropanol to the obtained solid, heat to 50-60℃ to dissolve, cool and crystallize, filter and dry to obtain compound IV buspirone (light yellow solid, 5.30g). Yield: 82.30%.

[0064] Then add 4.62g of compound IV to 46ml of acetone, heat to 55-65℃ to dissolve, then add 7.0ml of 25% hydrogen chloride ethanol solution dropwise with stirring, and keep warm for 1h after addition, then cool to 15℃ and keep warm for 3h, filter, wash and dry to obtain buspirone hydrochloride (white solid, 4.60g). Yield: 90.91%. Purity: 99.8%.

[0065] Example 3

[0066] (1) Preparation of 1-(2-pyrimidinyl)-piperazine dihydrochloride (Compound II)

[0067] Add 60ml of purified water, anhydrous sodium carbonate (11.56g, 0.109mol), anhydrous piperazine (11.28g, 0.131mol) to a three-necked flask, stir at room temperature, add 2-chloropyrimidine (5.00g, 0.044mol) in four batches, add in one hour, and keep warm at 30℃ for 2h. Filter by suction, extract the filtrate with dichloromethane three times, 40ml each time, combine the organic phases, and concentrate until about 40ml of solution remains. Control the temperature below 30℃ and add 25% hydrogen chloride ethanol solution to the reaction solution, adjust the pH to 2-3, and keep warm at 30℃ for 2h after the addition. Filter, wash, and dry the filter cake at 45℃-55℃ to obtain the target compound (white solid, 9.05g). Yield: 87.44%.

[0068] (2) Preparation of 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine (Compound III)

[0069] Add compound II (5.00 g, 0.021 mol), 40 ml of acetonitrile, sodium hydroxide (2.53 g, 0.063 mol), and 1,4-dibromobutane (13.66 g, 0.063 mol) to a three-necked flask. After the addition, heat to 80°C and stir for 4 hours. Filter hot, concentrate the filtrate to remove about half of the solvent, add 30 ml of tert-butyl methyl ether, stir at 20°C for 3 hours, filter, wash, and dry the filter cake at 45°C-55°C to obtain the target compound (light yellow solid, 5.50 g). Yield: 87.16%.

[0070] (3) Preparation of 8-[4-[4-(2-pyrimidine)-1-piperazine]butyl-8-azaspiro[4,5]decane-7,9-dione hydrochloride (Compound Ⅰ)

[0071] Add compound III (5g, 0.0167mol), N,N-dimethylformamide 40ml, potassium carbonate (4.62g, 0.033mol), tetramethylene glutarimide (3.35g, 0.020mol) to a three-necked flask, stir and heat to 125℃, keep warm and react for 20h. Cool the reaction solution to room temperature, add purified water, stir and crystallize, filter by suction, add 20ml of isopropanol to the obtained solid, heat to 50-60℃ to dissolve, cool and crystallize, filter by suction, wash and dry to obtain compound IV buspirone (light yellow solid, 5.38g). Yield: 83.54%.

[0072] Then add 4.63g of compound IV to 46ml of isopropanol, heat to 55-65℃ to dissolve, then add 7ml of 25% hydrogen chloride ethanol solution dropwise with stirring, after addition, keep warm for 1h, then cool to 15℃ and keep warm for 3h, filter, wash and dry to obtain buspirone hydrochloride (white solid, 4.65g). Yield: 91.72%. Purity: 99.9%.

[0073] H-NMR (500MHz, DMSO-d6): δ1.54 (m, 4H, 2CH2), 1.60 (m, 2H, CH2), 1.65 (m, 4H, 2CH2), 1.76 (m, 2H, 2CH2), 2.70 (s, 4H, 2CH2), 3.21 (m, 4H, 2CH2), 3.25 (t, 2H, CH2), 3.49 (m, 4H, 2CH2), 4.69 (t, 2H, CH2), 6.95 (m, 1H, CH), 8.49 (m, 2H, 2CH).

[0074] ESI-MS (m / z) 386.25.

[0075] Comparative Example 1

[0076] (1) Preparation of 1-(2-pyrimidinyl)-piperazine dihydrochloride (Compound II)

[0077] Add 60ml of purified water, anhydrous sodium carbonate (11.56g, 0.109mol), anhydrous piperazine (11.28g, 0.131mol) to a three-necked flask, stir at room temperature, add 2-chloropyrimidine (5.00g, 0.044mol) in four batches, add in half an hour, and keep warm at 25℃ for 2h. Filter by suction, extract the filtrate with dichloromethane three times, 40ml each time, combine the organic phases, and concentrate until about 40ml of solution remains. Control the temperature below 30℃ and add 25% hydrogen chloride ethanol solution to the reaction solution, adjust the pH to 2-3, and keep warm at 25℃ for 2h after the addition. Filter, wash, and dry the filter cake at 45℃-55℃ to obtain the target compound (white solid, 7.83g). Yield: 80.19%.

[0078] (2) Preparation of 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine (Compound III)

[0079] Add compound II (5.00 g, 0.021 mol), 40 ml of acetonitrile, potassium carbonate (11.66 g, 0.084 mol), and 1,4-dibromobutane (13.66 g, 0.063 mol) to a three-necked flask. After the addition, heat to 75°C and stir for 4 hours. Filter hot, concentrate the filtrate to remove about half of the solvent, add 30 ml of tert-butyl methyl ether, stir at 15°C for 3 hours, filter, wash, and dry the filter cake at 45°C-55°C to obtain the target compound (light yellow solid, 4.30 g). Yield: 68.15%.

[0080] (3) Preparation of 8-[4-[4-(2-pyrimidine)-1-piperazine]butyl-8-azaspiro[4,5]decane-7,9-dione hydrochloride (Compound Ⅰ)

[0081] Add compound III (5g, 0.0167mol), N,N-dimethylformamide 40ml, potassium carbonate (4.62g, 0.033mol), tetramethylene glutarimide (3.35g, 0.020mol) to a three-necked flask, stir and heat to 130℃, keep warm and react for 20h. Cool the reaction solution to room temperature, add purified water, stir and crystallize, filter and wash, add 20ml of isopropanol to the obtained solid, heat to 50-60℃ to dissolve, cool and crystallize, filter, wash and dry to obtain compound IV buspirone (light yellow solid, 5.17g). Yield: 80.38%.

[0082] Then add 4.53g of compound IV to 45ml of isopropanol, heat to 55-65℃ to dissolve, add 6.9ml of 25% hydrogen chloride ethanol solution dropwise with stirring, keep warm for 1h, cool to 20℃ and keep warm for 3h, filter, wash and dry to obtain buspirone hydrochloride (white solid, 4.57g), yield: 92.15%.

[0083] Comparative Example 2

[0084] (1) Preparation of 1-(2-pyrimidinyl)-piperazine dihydrochloride (Compound II)

[0085] Add 60ml of purified water, anhydrous sodium carbonate (11.56g, 0.109mol), anhydrous piperazine (11.28g, 0.131mol) to a three-necked flask, stir at room temperature, add 2-chloropyrimidine (5.00g, 0.044mol) in four batches, add in half an hour, and keep warm at 25℃ for 2h. Filter by suction, extract the filtrate with dichloromethane three times, 40ml each time, combine the organic phases, and concentrate until about 40ml of solution remains. Control the temperature below 30℃ and add 25% hydrogen chloride ethanol solution to the reaction solution, adjust the pH to 2-3, and keep warm at 25℃ for 2h after the addition. Filter, wash, and dry the filter cake at 45℃-55℃ to obtain the target compound (white solid, 7.83g). Yield: 83.28%.

[0086] (2) Preparation of 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine (Compound III)

[0087] Add compound II (5.00 g, 0.021 mol), 40 ml of acetonitrile, sodium hydroxide (1.26 g, 0.032 mol), and 1,4-dibromobutane (13.66 g, 0.063 mol) to a three-necked flask. After the addition, heat to 75°C and stir for 4 hours. Filter hot, concentrate the filtrate to remove about half of the solvent, add 30 ml of tert-butyl methyl ether, stir at 15°C for 3 hours, filter, wash, and dry the filter cake at 45°C-55°C to obtain the target compound (light yellow solid, 5.50 g). Yield: 83.99%.

[0088] (3) Preparation of 8-[4-[4-(2-pyrimidine)-1-piperazine]butyl-8-azaspiro[4,5]decane-7,9-dione hydrochloride (Compound Ⅰ)

[0089] Add compound III (5g, 0.0167mol), N,N-dimethylformamide 40ml, potassium carbonate (4.62g, 0.033mol), tetramethylene glutarimide (3.35g, 0.020mol) to a three-necked flask, stir and heat to 110℃, keep warm and react for 20h. Cool the reaction solution to room temperature, add purified water, stir and crystallize, filter and wash, add 20ml of isopropanol to the obtained solid, heat to 50-60℃ to dissolve, cool and crystallize, filter, wash and dry to obtain compound IV buspirone (light yellow solid, 3.87g). Yield: 60.08%.

[0090] Then add 4.53g of compound IV to 45ml of isopropanol, heat to 55-65℃ to dissolve, add 6.9ml of 25% hydrogen chloride ethanol solution dropwise with stirring, keep warm for 1h, cool to 20℃ and keep warm for 3h, filter, wash and dry to obtain buspirone hydrochloride (white solid, 4.56g), yield: 92.05%.

[0091] The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art may make various changes or modifications based on the present invention. As long as they do not depart from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing buspirone hydrochloride as shown in formula I, comprising the following steps: (1) piperazine and 2-chloropyrimidine react in water at 20-30° C. in the presence of a base; the obtained 1-(2-pyrimidinyl)-piperazine reacts with a hydrogen chloride ethanol solution, and the pH is adjusted to 1-4 to prepare 1-(2-pyrimidinyl)-piperazine dihydrochloride; (2) The 1-(2-pyrimidinyl)-piperazine dihydrochloride prepared in step (1) is reacted with a base and 1,4-dibromobutane in an organic solvent at 60-90° C., filtered hot, and the filtrate is concentrated under reduced pressure to 1 / 5-1 / 2 of the concentrated solution, and tert-butyl methyl ether is added, and crystallization is carried out by stirring at 0° C.-25° C., filtering, washing, and drying to prepare 1-(4-bromobutanyl)-4-(2-pyrimidinyl)-piperazine; (3) The 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine prepared in step (2) is reacted with a base and 3,3-tetramethyleneglutarimide in an organic solvent at 120-130° C. After the reaction is completed, the temperature is lowered to 15-35° C., water is added, stirred for crystallization, filtered, washed, the filter cake is collected, isopropanol is added for recrystallization, suction filtered, washed, and dried to prepare 8-[4-[4-(2-pyrimidinyl)-1-piperazine]butyl-8-azaspiro[4,5]decane-7,9-dione; (4) adding 8-[4-[4-(2-pyrimidine)-1-piperazine]butyl-8-azaspiro[4,5]decane-7,9-dione obtained in step (3) to isopropanol, heating to 55-65° C. to dissolve, adding dropwise 20%-40% hydrogen chloride ethanol solution, and keeping the temperature for reaction; cooling to 15-30° C. to keep the temperature for reaction, filtering, washing, and drying to obtain: Preferably, in step (1), the molar ratio of 2-chloropyrimidine to piperazine is 1:1-4, preferably 1:2-3. Preferably, in step (1), the base is selected from any one of sodium carbonate, potassium carbonate, sodium bicarbonate or a combination thereof. Preferably, in step (1), the concentration of the base is 1.5-2.5 mol / L, preferably 1.8-2.0 mol / L. Preferably, in step (1), the mass fraction of the hydrogen chloride ethanol solution is 20%-40%, preferably 25%-30%. Preferably, in step (2), the molar ratio of 1-(2-pyrimidinyl)-piperazine dihydrochloride to 1,4-dibromobutane is 1:1-4, and the preferred molar ratio is 1:2-3.

2. The method according to claim 1, wherein in step (2), the organic solvent is selected from acetonitrile.

3. The method according to any one of claims 1 to 2, wherein in step (2), the alkali is selected from any one of sodium hydroxide and potassium hydroxide or a combination thereof.

4. The method according to any one of claims 1 to 3, wherein in step (2), the volume ratio of the concentrated solution to tert-butyl methyl ether is 1:1-8, preferably 1:1.5-6.

5. The method according to any one of claims 1 to 4, wherein in step (3), the alkali is any one or a combination of sodium hydroxide, potassium hydroxide, and potassium carbonate.

6. The method according to any one of claims 1 to 5, wherein in step (3), the molar ratio of 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine to 3,3-tetramethyleneglutarimide is 1:1-3, preferably 1:1.1-1.

5.

7. The method according to any one of claims 1 to 6, wherein in step (3), the molar ratio of 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine to the base is 1:1-3, preferably 1:1.5-2.

8. The method according to any one of claims 1 to 7, wherein in step (3), the organic solvent is selected from any one of N,N-dimethylformamide and N,N-dimethylacetamide or a combination thereof.

9. The method according to any one of claims 1 to 8, wherein in step (3), the ratio of 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine to isopropanol is 1:2-6 (m:v), preferably 1:3-5 (m:v).

10. The method according to any one of claims 1 to 9, wherein in step (4), the weight volume ratio of 8-[4-[4-(2-pyrimidine)-1-piperazine]butyl-8-azaspiro[4,5]decane-7,9-dione to hydrogen chloride ethanol solution is 1:1-5 (m:v), preferably 1:1.5-3.

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