A process for the preparation of buspirone hydrochloride

Abstract

The application relates to a preparation method of buspirone hydrochloride: (1) 1-(2-pyrimidyl)-piperazine is reacted with hydrogen chloride ethanol solution to prepare 1-(2-pyrimidyl)-piperazine dihydrochloride; (2) 1-(2-pyrimidyl)-piperazine dihydrochloride is reacted with alkali and 1,4-dibromobutane to prepare 1-(4-bromobutyl)-4-(2-pyrimidyl)-piperazine; (3) 1-(4-bromobutyl)-4-(2-pyrimidyl)-piperazine is reacted with alkali and 3,3-tetramethylene glutarimide to prepare 8-[4-[4-(2-pyrimidyl)-1-piperazine]butyl-8-azaspiro[4,5]decane-7,9-diketone; (4) 8-[4-[4-(2-pyrimidyl)-1-piperazine]butyl-8-azaspiro[4,5]decane-7,9-diketone is added into isopropyl alcohol to react to obtain the product. The application improves product purity and reaction yield, does not use a catalyst, reduces cost, and shortens a production cycle.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, in particular to a preparation method of buspirone hydrochloride. BACKGROUND

[0002] Buspirone hydrochloride (CAS: 33386-08-2), chemical name 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, which is the first non-benzodiazepine anxiolytic drug developed by Mead Johnson Company in the United States. Compared with traditional drugs, the drug has high selectivity, does not affect alertness, has less tendency to form addiction, and has definite efficacy, and has been marketed in many countries.

[0005] Patent US4351939A discloses a preparation method of buspirone hydrochloride. Its main synthetic route is as follows:

[0006]

[0007] The synthetic route is to react 1-(2-pyrimidinyl)piperazine with 1,5-dibromo-n-pentane or 1,5-dichloro-n-pentane to obtain the quaternary ammonium salt spiro tetramine piperazine derivative intermediate I, and then condense intermediate I with 3,3-tetramethylene glutarimide in n-butanol or DMF as solvent, and then treat the condensation reaction liquid to obtain buspirone. However, this process also has serious shortcomings, such as low total reaction yield, long reaction time, synthetic route including multiple steps, and difficult product purification, which is not suitable for industrial production.

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

[0009]

[0010] The synthetic route directly obtains buspirone free base from II by hydrogenation, and finally obtains buspirone hydrochloride by salification. In this preparation process, palladium or Raney nickel is used as catalyst for hydrogenation, high-pressure equipment is used, the cost is high, and the operation is difficult, which is not suitable for industrial production.

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

[0012] The application aims to provide a preparation method of buspirone hydrochloride as shown in formula I, comprising the following steps:

[0013] (1) reacting 2-chloropyrimidine and piperazine in water at 20-30°C in the presence of a base; reacting the prepared 1-(2-pyrimidyl)-piperazine with hydrogen chloride ethanol solution, adjusting pH to 1-4 to prepare 1-(2-pyrimidyl)-piperazine dihydrochloride;

[0014] (2) reacting the 1-(2-pyrimidyl)-piperazine dihydrochloride prepared in step (1) with a base, 1,4-dibromobutane in an organic solvent at 60-90°C, hot filtering, concentrating the filtrate under reduced pressure to 1 / 5-1 / 2 of the concentrated solution, adding tert-butyl methyl ether, stirring at 0-25°C to precipitate crystals, filtering, washing, and drying to prepare 1-(4-bromobutyl)-4-(2-pyrimidyl)-piperazine;

[0015] (3) reacting the 1-(4-bromobutyl)-4-(2-pyrimidyl)-piperazine prepared in step (2) with a base, 3,3-tetramethylene glutarimide in an organic solvent at 120-130°C, after the reaction is completed, lowering to 15-35°C, adding water, stirring to precipitate crystals, filtering, washing, collecting the filter cake, recrystallizing by adding isopropyl alcohol, suction filtering, washing, and drying to prepare 8-[4-[4-(2-pyrimidyl)-1-piperazine]butyl-8-azaspiro[4,5]decane-7,9-dione;

[0016] (4) adding the 8-[4-[4-(2-pyrimidyl)-1-piperazine]butyl-8-azaspiro[4,5]decane-7,9-dione prepared in step (3) into isopropyl alcohol, warming to 55-65°C to dissolve, then adding 20%-40% hydrogen chloride ethanol solution dropwise, keeping the reaction; lowering to 15-30°C to keep the reaction, filtering, washing, and drying to obtain,

[0017]

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

[0019] In the preferred technical scheme of the application, in step (1), the base is selected from any one or combination of sodium carbonate, potassium carbonate, and sodium bicarbonate.

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

[0021] In the preferred technical scheme of the application, in step (1), the 2-chloropyrimidine is added in batches, preferably in 2-5 batches, more preferably in 3-4 batches.

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

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

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

[0025] In the preferred technical scheme of the present application, 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.

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

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

[0028] In the preferred technical scheme of the present application, in step (2), the reaction temperature is 70-80℃.

[0029] In the preferred technical scheme of the present application, in 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 scheme of the present application, in step (2), the stirring crystallization temperature is 10-20℃.

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

[0032] In the preferred technical scheme of the present application, in step (3), the molar ratio of 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine to 3,3-tetramethylene glutarimide is 1:1-3, and the preferred molar ratio is 1:1.1-1.5.

[0033] In the preferred technical scheme of the present application, in step (3), the molar ratio of 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine to 3,3-tetramethylene glutarimide is 1:1-3, and the preferred molar ratio is 1:1.1-1.5.

[0034] In the preferred technical scheme of the present application, in step (3), the molar ratio of 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine to 3,3-tetramethylene glutarimide is 1:1-3, and the preferred molar ratio is 1:1.1-1.5.

[0035] In the preferred technical scheme of the present application, in step (3), the molar ratio of 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine to 3,3-tetramethylene glutarimide is 1:1-3, and the preferred molar ratio is 1:1.1-1.5.

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

[0037] In the preferred technical scheme of the present application, in the step (3), the ratio of 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine to isopropyl alcohol is 1:2-6 (m:v), preferably 1:3-5 (m:v).

[0038] In the preferred technical scheme of the present application, in the step (3), the recrystallization heating temperature of isopropyl alcohol is 50-60℃.

[0039] In the preferred technical scheme of the present application, in the step (4), the dissolving temperature is 55-65℃.

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

[0041] In the preferred technical scheme of the present application, in the step (4), the weight / volume ratio of 8-[4-[4-(2-pyrimidinyl)-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.

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

[0043] Compared with the prior art, the present application has the beneficial effects that:

[0044] 1. The present application provides a new method for preparing buspirone hydrochloride, which has mild reaction conditions, is simple and easy to operate, can avoid using microwave reaction in the preparation process of buspirone, improves the product purity (the purity of intermediates and final products can both reach more than 99%), improves the reaction yield, and at the same time, does not use catalyst, greatly reduces the production cost and shortens the production cycle.

[0045] 2. The intermediate 1-(2-pyrimidinyl)-piperazine hydrochloride prepared by the present application is a good solid and is easy to store, solving the defects that 1-(2-pyrimidinyl)-piperazine is easy to be oxidized and not easy to store.

[0046] 3. In the production process of the present application, there is no special requirement for the reaction equipment, and no dangerous operation such as hydrogenation is involved, the reaction is safe, and is suitable for industrial production. Attached Figure Description

[0047] Figure 1 The proton NMR spectrum of buspirone hydrochloride of this invention.

[0048] Figure 2 The mass spectrum of buspirone hydrochloride of this invention. Detailed Implementation

[0049] Example 1

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

[0051] Add 60 ml of purified water, anhydrous sodium carbonate (11.56 g, 0.109 mol), and anhydrous piperazine (11.28 g, 0.131 mol) to a three-necked flask. Stir at room temperature, then add 2-chloropyrimidine (5.00 g, 0.044 mol) in four portions over half an hour. After addition, maintain the reaction temperature at 25°C for 2 hours. Filter the solution, extract the filtrate three times with 40 ml of dichloromethane each time, combine the organic phases, and concentrate to approximately 40 ml of solution. Adjust the pH to 2-3 by adding 25% hydrogen chloride ethanol solution dropwise to the reaction solution while maintaining the temperature below 30°C. After addition, maintain the temperature at 25°C with stirring for 2 hours. Filter, wash, and dry the filter cake at 45°C-55°C to obtain the target compound (white solid, 8.80 g). Yield: 85.02%.

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

[0053] Compound II (5.00 g, 0.021 mol), 40 mL of acetonitrile, 1.26 g of sodium hydroxide (0.032 mol), and 13.66 g of 1,4-dibromobutane (0.063 mol) were added to a three-necked flask. After the addition was complete, the mixture was heated to 75 °C and stirred for 4 h. The mixture was then hot-filtered, and the filtrate was concentrated to remove approximately half of the solvent. 30 mL of tert-butyl methyl ether was added, and the mixture was stirred at 15 °C for 3 h. The mixture was then filtered, washed, and the filter cake was dried at 45 °C-55 °C to obtain the target compound (pale 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] Compound III (5 g, 0.0167 mol), 40 mL of N,N-dimethylformamide, 4.62 g of potassium carbonate (0.033 mol), and 3.35 g of tetramethyleneglutimide (0.020 mol) were added to a three-necked flask. The mixture was stirred and heated to 130 °C, and the reaction was maintained at this temperature for 20 h. The reaction solution was cooled to room temperature, purified water was added, and crystals were precipitated. The crystals were filtered, washed, and 20 mL of isopropanol was added to the resulting solid. The mixture was heated to 50-60 °C to dissolve the crystals, then cooled to allow crystals to precipitate. The crystals were filtered, washed, and dried to obtain compound IV, buspirone (pale yellow solid, 5.18 g). Yield: 80.43%.

[0056] 4.53 g of compound IV was added to 45 ml of isopropanol, and the mixture was heated to 55-65 °C until dissolved. Then, 6.9 ml of 25% hydrogen chloride ethanol solution was added dropwise with stirring. After the addition was complete, the mixture was kept at this temperature for 1 h, then cooled to 20 °C and stirred for 3 h. The solution was filtered, washed, and dried to obtain buspirone hydrochloride (white solid, 4.58 g). Yield: 92.34%. Purity: 99.8%.

[0057] Example 2

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

[0059] Add 60 ml of purified water, anhydrous sodium carbonate (11.56 g, 0.109 mol), and anhydrous piperazine (7.52 g, 0.087 mol) to a three-necked flask. Stir at room temperature, then add 2-chloropyrimidine (5.00 g, 0.044 mol) in four portions over half an hour. After addition, maintain the reaction temperature at 20°C for 2 hours. Filter the solution, extract the filtrate three times with 40 ml of dichloromethane each time, combine the organic phases, and concentrate to approximately 40 ml of solution. Adjust the pH to 2-3 by adding 25% hydrogen chloride ethanol solution dropwise to the reaction solution while maintaining the temperature below 30°C. After addition, maintain the temperature at 20°C with stirring for 2 hours. Filter, wash, and dry the filter cake at 45°C-55°C to obtain the target compound (white solid, 8.90 g). Yield: 85.99%.

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

[0061] Compound II (5.00 g, 0.021 mol), 40 mL of acetonitrile, 4.73 g of potassium hydroxide (0.084 mol), and 13.66 g of 1,4-dibromobutane (0.063 mol) were added to a three-necked flask. After the addition was complete, the mixture was heated to 70 °C and stirred for 4 h. The mixture was then hot-filtered, and the filtrate was concentrated to remove approximately half of the solvent. 30 mL of tert-butyl methyl ether was added, and the mixture was stirred at 10 °C for 3 h. The mixture was then filtered, washed, and the filter cake was dried at 45 °C–55 °C to obtain the target compound (pale yellow solid, 5.50 g). Yield: 87.16%.

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

[0063] Into a three-necked flask, compound III (5 g, 0.0167 mol), N,N- dimethylformamide 40 ml, potassium carbonate (4.62 g, 0.033 mol), tetramethylene glutarimide (3.35 g, 0.020 mol) were added and stirred to 120°C, and kept for 20 h. The reaction solution was cooled to room temperature, purified water was added and stirred to crystallize, filtered, washed, and the obtained solid was added with isopropyl alcohol 20 ml, and heated to 50-60°C to dissolve, and then cooled to crystallize, filtered, and dried to obtain compound IV, buspirone (yellowish solid, 5.30 g). Yield: 82.30%.

[0064] Further, 4.62 g of compound IV was added to 46 ml of acetone, heated to 55-65°C to dissolve, and then 7.0 ml of 25% hydrogen chloride ethanol solution was added dropwise with stirring, and after completion of the addition, the reaction was kept for 1 h, and then cooled to 15°C, and stirred for 3 h, filtered, washed, and dried to obtain buspirone hydrochloride (white solid, 4.60 g). Yield: 90.91%. Purity: 99.8%.

[0065] Example 3

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

[0067] Into a three-necked flask, purified water 60 ml, anhydrous sodium carbonate (11.56 g, 0.109 mol), and anhydrous piperazine (11.28 g, 0.131 mol) were added, and stirred at room temperature, and then 2-chloropyrimidine (5.00 g, 0.044 mol) was added in four portions, and after completion of the addition, the reaction was kept for 2 h at 30°C. The reaction solution was filtered, and the filtrate was extracted with dichloromethane three times, each time 40 ml, and the combined organic phase was concentrated to about 40 ml of solution, and then 25% hydrogen chloride ethanol solution was added dropwise to the reaction solution at 30°C or less, and the pH was adjusted to 2-3, and after completion of the addition, the reaction was stirred for 2 h at 30°C, filtered, washed, and the filter cake was dried at 45-55°C to obtain the target compound (white solid, 9.05 g). Yield: 87.44%.

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

[0069] To a three-necked flask was added compound II (5.00 g, 0.021 mol), acetonitrile 40 ml, sodium hydroxide (2.53 g, 0.063 mol), 1,4-dibromobutane (13.66 g, 0.063 mol), after addition, the temperature was raised to 80 °C and the reaction was stirred for 4 h. The hot filtrate was concentrated to remove about half of the solvent, t-butyl methyl ether 30 ml was added, stirred at 20 °C for 3 h, filtered, washed, and the filter cake was dried at 45-55 °C to obtain the target compound (pale yellow solid, 5.50 g). Yield: 87.16%.

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

[0071] To a three-necked flask was added compound III (5 g, 0.0167 mol), N,N- dimethylformamide 40 ml, potassium carbonate (4.62 g, 0.033 mol), tetramethylene glutarimide (3.35 g, 0.020 mol), stirred and the temperature was raised to 125 °C, and the reaction was maintained for 20 h. The reaction solution was cooled to room temperature, purified water was added, stirred, and the crystals were separated, suction filtered, isopropyl alcohol 20 ml was added to the obtained solid, the temperature was raised to 50-60 °C, the solution was clarified, and then cooled to separate the crystals, suction filtered, washed, and dried to obtain the compound IV, butalbucarb (pale yellow solid, 5.38 g). Yield: 83.54%.

[0072] Further, 4.63 g of compound IV was added to 46 ml of isopropyl alcohol, the temperature was raised to 55-65 °C, the solution was clarified, 7 ml of 25% hydrogen chloride ethanol solution was added dropwise with stirring, after addition, the reaction was maintained for 1 h, the temperature was further lowered to 15 °C, and the stirring was maintained for 3 h, suction filtered, washed, and dried to obtain butalbucarb hydrochloride (white solid, 4.65 g). Yield: 91.72%. Purity: 99.9%.

[0073] H-NMR (500 MHz, DMSO-d6): δ 1.54 (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] Into a three-necked flask was placed purified water 60 ml, anhydrous sodium carbonate (11.56 g, 0.109 mol), anhydrous piperazine (11.28 g, 0.131 mol), stirred at room temperature, 2-chloropyrimidine (5.00 g, 0.044 mol) was added in four batches, and the addition was completed in half an hour. After completion of the addition, the reaction was incubated at 25 °C for 2 h. Filtration was performed, and the filtrate was extracted with dichloromethane three times, 40 ml each time. The combined organic phase was concentrated to about 40 ml of solution. The temperature was controlled below 30 °C, and 25% hydrogen chloride ethanol solution was added dropwise to the reaction liquid. The pH was adjusted to 2-3, and after the dropwise addition was completed, the reaction was incubated at 25 °C for 2 h with stirring. Filtration was performed, and the filter cake was washed and dried at 45-55 °C to obtain the target compound (white solid, 7.83 g). Yield: 80.19%.

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

[0079] Into a three-necked flask was placed compound II (5.00 g, 0.021 mol), acetonitrile 40 ml, potassium carbonate (11.66 g, 0.084 mol), 1,4-dibromobutane (13.66 g, 0.063 mol), and the addition was completed. The reaction was incubated at 75 °C for 4 h with stirring. Hot filtration was performed, and the filtrate was concentrated to remove about half of the solvent. Tert-butyl methyl ether 30 ml was added, and the mixture was stirred at 15 °C for 3 h. Filtration was performed, and the filter cake was washed and dried at 45-55 °C to obtain the target compound (pale yellow solid, 4.30 g). Yield: 68.15%.

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

[0081] Into a three-necked flask was placed compound III (5 g, 0.0167 mol), N,N-dimethylformamide 40 ml, potassium carbonate (4.62 g, 0.033 mol), and tetramethylene glutarimide (3.35 g, 0.020 mol) was stirred and incubated at 130 °C for 20 h. The reaction liquid was cooled to room temperature, and purified water was added to induce crystallization. Filtration was performed, and the filter cake was washed. Isopropyl alcohol 20 ml was added to the obtained solid, and the mixture was incubated at 50-60 °C until it became clear. Crystallization was induced by cooling, and filtration was performed. The filter cake was washed and dried to obtain butalbucarb (pale yellow solid, 5.17 g). Yield: 80.38%.

[0082] To a three-necked flask was added 4.53 g of compound IV and 45 ml of isopropyl alcohol, and the mixture was heated to 55-65°C until it became clear. Then 6.9 ml of 25% hydrogen chloride ethanol solution was added dropwise with stirring, and the mixture was kept at 55-65°C for 1 hour. The mixture was then cooled to 20°C and stirred for 3 hours. The product was filtered, washed and dried to obtain 4.57 g of butyrospiroketone hydrochloride (white solid). Yield: 92.15%.

[0083] Comparative Example 2

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

[0085] To a three-necked flask was added 60 ml of purified water, 11.56 g of anhydrous sodium carbonate (0.109 mol), 11.28 g of anhydrous piperazine (0.131 mol), and the mixture was stirred at room temperature. Then 5.00 g of 2-chloropyrimidine (0.044 mol) was added in four portions within half an hour. After the addition was completed, the mixture was kept at 25°C for 2 hours. The mixture was filtered, and the filtrate was extracted three times with 40 ml of dichloromethane each time. The combined organic phase was concentrated to about 40 ml of solution, and 25% hydrogen chloride ethanol solution was added dropwise to the mixture while the temperature was kept below 30°C. The pH of the mixture was adjusted to 2-3, and the mixture was stirred at 25°C for 2 hours. The mixture was filtered, washed and dried at 45-55°C to obtain 7.83 g of the target compound (white solid). Yield: 83.28%.

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

[0087] To a three-necked flask was added 5.00 g of compound II, 40 ml of acetonitrile, 1.26 g of sodium hydroxide (0.032 mol), and 13.66 g of 1,4-dibromobutane (0.063 mol). The mixture was heated to 75°C and stirred for 4 hours. The mixture was filtered while hot, and about half of the solvent was removed by concentration. Then 30 ml of t-butyl methyl ether was added, and the mixture was stirred at 15°C for 3 hours. The mixture was filtered, washed and dried at 45-55°C to obtain 5.50 g of the target compound (pale yellow solid). Yield: 83.99%.

[0088] (3) Preparation of 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl-8-azaspiro[4,5] decane-7,9-dione hydrochloride (compound I)

[0089] To a three-necked flask, compound III (5 g, 0.0167 mol), N,N-dimethylformamide 40 ml, potassium carbonate (4.62 g, 0.033 mol), tetramethylene glutarimide (3.35 g, 0.020 mol) were added and stirred to 110°C, and kept for 20 h. The reaction solution was cooled to room temperature, and purified water was added to stir and crystallize. The obtained solid was filtered, washed, and dried. Then, isopropyl alcohol 20 ml was added to the solid, and the mixture was heated to 50-60°C to dissolve, and then cooled to crystallize. The obtained solid was filtered, washed, and dried to obtain compound IV, butyrospiroketone (pale yellow solid, 3.87 g). Yield: 60.08%.

[0090] Then, 4.53 g of compound IV was added to 45 ml of isopropyl alcohol, and the mixture was heated to 55-65°C to dissolve. Then, 25% hydrogen chloride ethanol solution 6.9 ml was added dropwise with stirring, and the mixture was kept for 1 h. Then, the mixture was cooled to 20°C, and kept for 3 h with stirring. The obtained solid was filtered, washed, and dried to obtain butyrospiroketone hydrochloride (white solid, 4.56 g). Yield: 92.05%.

[0091] The above description of the specific embodiments of the present application does not limit the present application, and various changes or modifications can be made to the present application by those skilled in the art without departing from the spirit of the present application, and all such changes or modifications shall fall within the scope of the present application.

Claims

1. A method for preparing buspirone hydrochloride, comprising the following steps: (1) reacting 2-chloropyrimidine and piperazine in water at 20-30 °C in the presence of a base to obtain 1-(2-pyrimidinyl)-piperazine, and then reacting the obtained 1-(2-pyrimidinyl)-piperazine with hydrogen chloride ethanol solution, and adjusting the pH to 1-4 to obtain 1-(2-pyrimidinyl)-piperazine dihydrochloride; (2) The 1-(2-pyrimidinyl)-piperazine dihydrochloride prepared in the above step (1) is dissolved in an organic solvent, and the solution is heated to 60-90°C. The solution is filtered, and the filtrate is concentrated under reduced pressure to 1 / 5-1 / 2 of the original volume. Tert-butyl methyl ether is added, and the mixture is stirred at 0°C-25°C to precipitate crystals. The crystals are filtered, washed, and dried to obtain 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine, wherein, the base is selected from any one or combination of sodium hydroxide and potassium hydroxide; (3) after the reaction of the obtained 1-(4-bromobutyl)-4-(2-pyrimidinyl)-piperazine with a base, 3,3-tetramethylene glutarimide in an organic solvent at 120-130 °C is completed, cooling to 15-35 °C, adding water, stirring, crystallizing, filtering, washing, collecting the filter cake, recrystallizing by adding isopropyl alcohol, filtering, washing, and drying to obtain 8-[4-[4-(2-pyrimidinyl)-1-piperazine]butyl-8-azaspiro[4,5]decane-7,9-dione, wherein the organic solvent is selected from any one or combination of N,N-dimethylformamide and N,N-dimethylacetamide; (4) adding the obtained 8-[4-[4-(2-pyrimidinyl)-1-piperazine]butyl-8-azaspiro[4,5]decane-7,9-dione into isopropyl alcohol, heating to 55-65 °C until dissolved, then adding dropwise 20%-40% hydrogen chloride ethanol solution, and keeping the reaction; cooling to 15-30 °C, standing, filtering, washing, and drying to obtain the product.

2. The method of claim 1, wherein the molar ratio of 2-chloropyrimidine to piperazine in step (1) is 1:1-4.

3. The method of claim 2, wherein the molar ratio of 2-chloropyrimidine to piperazine is 1:2-3.

4. The method of claim 1, wherein the base in step (1) is selected from any one or combination of sodium carbonate, potassium carbonate, and sodium bicarbonate.

5. The method of claim 1, wherein the concentration of the base in step (1) is 1.5-2.5 mol / L.

6. The method of claim 5, wherein the concentration of the base is 1.8-2.0 mol / L.

7. The method of claim 1, wherein the 2-chloropyrimidine in step (1) is added in batches.

8. The method of claim 7, wherein the 2-chloropyrimidine is added in 2-5 batches.

9. The method of claim 8, wherein the 2-chloropyrimidine is added in 3-4 batches.

10. The method of claim 1, wherein the 2-chloropyrimidine in step (1) is added for 20 min-60 min.

11. The method of claim 10, wherein the 2-chloropyrimidine is added for 30 min-50 min.

12. The method of claim 1, wherein the mass fraction of the hydrogen chloride ethanol solution in step (1) is 20%-40%.

13. The method of claim 12, wherein the mass fraction of the hydrogen chloride ethanol solution is 25%-30%.

14. The method of claim 1, wherein the pH in step (1) is adjusted to 2-3.

15. The preparation method of claim 1, wherein the molar ratio of 1-(2-pyrimidinyl)- piperazine dihydrochloride to 1,4-dibromobutane in step (2) is 1:1-4.

16. The preparation method of claim 15, wherein the molar ratio of 1-(2-pyrimidinyl)- piperazine dihydrochloride to 1,4-dibromobutane is 1:2-3.

17. The preparation method of claim 1, wherein the organic solvent in step (2) is acetonitrile.

18. The preparation method of claim 1, wherein the reaction temperature in step (2) is 70-80 °C.

19. The preparation method of claim 1, wherein the volume ratio of the concentrated solution: t-butyl methyl ether in step (2) is 1:1-8.

20. The preparation method of claim 19, wherein the volume ratio of the concentrated solution: t-butyl methyl ether is 1:1.5-6.

21. The preparation method of claim 1, wherein the stirring and crystallization temperature in step (2) is 10-20 °C.

22. The preparation method of claim 1, wherein the molar ratio of 1-(4-bromobutyl)-4-(2- pyrimidinyl)-piperazine to 3,3-tetramethylene glutarimide in step (3) is 1:1-3.

23. The preparation method of claim 22, wherein the molar ratio of 1-(4-bromobutyl)-4-(2- pyrimidinyl)-piperazine to 3,3-tetramethylene glutarimide is 1:1.1-1.

5.

24. The preparation method of claim 1, wherein the molar ratio of 1-(4-bromobutyl)-4-(2- pyrimidinyl)-piperazine to base in step (3) is 1:1-3.

25. The preparation method of claim 24, wherein the molar ratio of 1-(4-bromobutyl)-4-(2- pyrimidinyl)-piperazine to base is 1:1.5-2.

26. The preparation method of claim 1, wherein the ratio of 1-(4-bromobutyl)-4-(2- pyrimidinyl)-piperazine: isopropyl alcohol in step (3) is 1:2-6 (m:v).

27. The preparation method of claim 26, wherein the ratio of 1-(4-bromobutyl)-4-(2- pyrimidinyl)-piperazine: isopropyl alcohol is 1:3-5 (m:v).

28. The preparation method of claim 1, wherein the recrystallization heating temperature of isopropyl alcohol in step (3) is 50-60 °C.

29. The preparation method of claim 1, wherein the solution clearing temperature in step (4) is 55-65 °C.

30. The preparation method of claim 1, wherein the mass fraction of hydrogen chloride ethanol solution in step (4) is 25%-30%.

31. The preparation method of claim 1, wherein the weight to volume ratio of 8-[4-[4-(2- pyrimidinyl)-1-piperazinyl]butyl-8-azaspiro[4,5]decan-7,9-dione: hydrogen chloride ethanol solution in step (4) is 1:1-5 (m:v).

32. The preparation method of claim 31, wherein the weight to volume ratio of 8-[4-[4-(2- pyrimidinyl)-1-piperazinyl]butyl-8-azaspiro[4,5]decan-7,9-dione: hydrogen chloride ethanol solution is 1:1.5-3.

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