Preparation method of buspirone hydrochloride

Abstract

The invention belongs to the technical field of medicine synthesis processes, and particularly relates to a preparation method of high-yield and high-purity buspirone hydrochloride. According to the method, 8-(2-pyrimidinyl)-8-aza-5-5-azonium spiro [4.5] decane hydrobromide (pyrimidino piperazine quaternary ammonium salt for short) and 3, 3-tetramethylene glutarimide are taken as raw materials, a mixed solvent of methylbenzene and n-amyl alcohol and / or n-hexanol is taken as a solvent, buspirone can be generated in the presence of sodium carbonate without adding a phase transfer catalyst, and buspirone can be obtained through acid adjustment and extraction. After toluene reverse phase impurity removal, a water phase is adjusted to be alkaline, an ethanol solution of hydrogen chloride is added after toluene extraction, and buspirone hydrochloride solid is directly separated out. The preparation process has a very good cleaning effect on impurities, and the obtained buspirone hydrochloride is high in purity, high in process yield, good in atom economy and low in output of three wastes.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical chemistry, and in particular to a method for preparing buspirone hydrochloride with high purity and high yield. Background Art

[0002] Buspirone hydrochloride, chemically known as N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dione hydrochloride, is a non-diazepine antianxiety drug developed by Mead Johnson in the United States and launched in Germany and France in 1985. The drug is a 5-HT1A receptor partial agonist with the characteristics of rapid oral absorption, short peak time and high plasma protein binding rate. It has significant efficacy and good tolerability, no addiction and withdrawal reaction, and is recommended as a first-line drug by many clinical guidelines. In addition to being used for antianxiety, it can also relieve anxiety symptoms with or without depression, with few side effects.

[0003] The structure of buspirone hydrochloride is as follows:

[0004]

[0005] U.S. Patent No. 4351939 discloses a method for preparing buspirone hydrochloride: 3,3-tetramethyleneglutarimide and quaternary ammonium salt of pyrimidopiperazine react in n-butanol to generate buspirone, which is filtered and distilled under reduced pressure to obtain crude buspirone. The crude buspirone is acidified to form a salt, and the base is adjusted to precipitate to obtain a buspirone free base solid. The buspirone free base solid is dissolved in isopropanol and then salted with concentrated hydrochloric acid to obtain a crude buspirone hydrochloride. The crude buspirone hydrochloride is recrystallized from isopropanol to obtain buspirone hydrochloride.

[0006]

[0007] The preparation method uses n-butanol as a reaction solvent, has a high reflux temperature (117.6°C), a long reaction time (21 hours), and poor process safety. The yield of buspirone preparation is only 66.5%, which is very low and has no cost advantage. The obtained crude buspirone hydrochloride has low purity and must be refined again to obtain a qualified product.

[0008] U.S. Patent No. 4351939 discloses another method for preparing buspirone: 3,3-tetramethyleneglutarimide and quaternary ammonium salt of pyrimidopiperazine are reacted in DMF to generate buspirone, which is filtered and distilled under reduced pressure to obtain crude buspirone. The crude buspirone is subjected to acid adjustment to form a salt, and alkali adjustment to precipitate to obtain a solid buspirone free base.

[0009]

[0010] The above method uses DMF as a reaction solvent, and the reaction temperature is 150-155° C. If the temperature is too high, more impurities will be generated in the reaction system, and the process safety is poor, which is not suitable for large-scale industrial production.

[0011] U.S. Patent No. 238551 discloses a method for preparing buspirone hydrochloride: 3,3-tetramethyleneglutarimide is first reacted with potassium tert-butoxide to form 3,3-tetramethyleneglutarimide potassium salt, which is then reacted with intermediate II in butyl acetate to form buspirone, and then the buspirone free base solid is obtained by adjusting the acid to form a salt and adjusting the base to precipitate.

[0012]

[0013] This method requires nitrogen protection during the preparation of 3,3-tetramethyleneglutarimide potassium salt, and the reaction conditions are relatively harsh. The preparation process of buspirone free base requires stirring for 6 to 8 hours under butyl acetate reflux (125-126°C), which is too high in temperature and too long in time, and the process safety is poor, making it unsuitable for large-scale industrial production.

[0014] The document "An Efficient Synthesis of Buspirone and its Analogues" (Archivder Pharmazie, 1992, 325 (5): 313-315) discloses a method for preparing buspirone hydrochloride: 3,3-tetramethyleneglutarimide and quaternary ammonium salt of pyrimidopiperazine are added to xylene with a phase transfer catalyst 18-crown ether-6 and refluxed (137-140°C) for 6 hours to generate buspirone, which is filtered and distilled under reduced pressure to obtain a crude buspirone. The crude buspirone is recrystallized from ethyl acetate to obtain buspirone. Buspirone is salted with an ethanol solution of hydrogen chloride in ethanol to obtain buspirone hydrochloride.

[0015]

[0016] This method requires the additional addition of a phase transfer catalyst to increase the reaction rate, resulting in a high production cost. In addition, xylene is used as a reaction solvent, and the reaction temperature is 150 to 155°C, which is too high and has poor process safety, making it unsuitable for large-scale industrial production. The obtained crude buspirone has a poor purity and needs to be refined to obtain a qualified product.

[0017] Under the prior art, although there are many methods for preparing buspirone hydrochloride, most of them have the problems of high reaction temperature, long reaction time and low conversion rate for preparing buspirone. In order to speed up the reaction speed, the reaction temperature is often increased by using a high boiling point reaction solvent and / or adding a phase transfer catalyst, resulting in poor process safety and low product purity. In addition, due to the large number of production processes, most of them have the problems of low yield and large output of three wastes. Buspirone and buspirone hydrochloride are carried out step by step, and the production cycle is long. The atomic economy of the buspirone hydrochloride preparation process is poor, and the production energy consumption and labor cost are high. These problems have always been the key technical problems restricting the amplification of buspirone hydrochloride production. Summary of the invention

[0018] In order to solve the problems of the prior art, the present invention provides a one-pot method for synthesizing buspirone hydrochloride, which has a short production cycle, low three waste output, is green and environmentally friendly, has a high yield, and has good process safety. The purity of the prepared buspirone hydrochloride product can reach more than 99.95%. The method of the present invention has low production cost, simple operation, high yield, mild reaction conditions, high purity, and is suitable for industrial production.

[0019] In order to achieve the above object, the present invention adopts the following technical scheme:

[0020] (1) 8-(2-pyrimidinyl)-8-aza-5-5-azoniaspiro[4.5]decane hydrobromide (abbreviated as pyrimidopiperazine quaternary ammonium salt) and 3,3-tetramethyleneglutarimide are reacted with a mixed solvent as solvent in the presence of a base 1 to prepare buspirone.

[0021] (2) Add an acidic aqueous solution to the reaction solution of step (1), adjust to acidity, stir and separate the liquids, and use toluene to perform reverse phase extraction to remove impurities from the aqueous phase.

[0022] (3) adding an organic solvent and an aqueous solution of alkali 2 to the acidic aqueous solution of buspirone in step (2), stirring to separate the liquids, and washing the buspirone organic phase with water.

[0023] (4) adding a hydrogen chloride ethanol solution to the buspirone organic phase of step (3), stirring, cooling and crystallizing to obtain buspirone hydrochloride.

[0024] The specific synthetic route is as follows:

[0025]

[0026] The mixed solvent in step (1) is toluene / n-pentanol or toluene / n-hexanol, preferably toluene / n-pentanol.

[0027] The ratio of the mixed solvent in step (1) is 5 to 20:1, preferably 10 to 15:1.

[0028] The reaction temperature in step (1) is 90°C to 110°C, preferably 100°C to 105°C.

[0029] In the step (1), the molar ratio of pyrimidopiperazine quaternary ammonium salt to 3,3-tetramethyleneglutarimide is 1:1.0-1.3, preferably 1:1.1.

[0030] In the step (1), the base 1 is sodium carbonate.

[0031] In the step (1), the molar ratio of the pyrimidopiperazine quaternary ammonium salt to the base 1 is 1:1.0-2.5, preferably 1:1.5.

[0032] The acidic aqueous solution in step (2) is an acidic aqueous solution such as hydrochloric acid aqueous solution, hydrobromic acid aqueous solution, sulfuric acid aqueous solution, phosphoric acid aqueous solution, nitric acid aqueous solution, etc., preferably hydrobromic acid aqueous solution.

[0033] The base 2 used for pH modulation in step (3) is sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, triethylamine, etc., preferably sodium carbonate.

[0034] The salt formation temperature in step (4) is 40°C to 70°C, preferably 50°C to 60°C.

[0035] The crystallization temperature in step (4) is -10°C to 10°C, preferably -5°C to 5°C.

[0036] Through the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0037] (1) The present invention adopts a "one-pot method" process to directly prepare buspirone hydrochloride, which has a short production cycle and low production cost.

[0038] (2) Using a specific mixed solvent as the reaction solvent greatly reduces the reaction temperature, shortens the reaction time, and improves process safety.

[0039] (3) The “one-pot” process effectively reduces the output of “three wastes” and is green and environmentally friendly.

[0040] (4) The entire process has mild reaction conditions and is easy to operate.

[0041] (5) Through the "one-pot" reaction post-treatment extraction and impurity removal design, the product purity is improved, the number of refining times is reduced, the production cost is reduced, and it is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 The present invention discloses the hydrogen nuclear magnetic spectrum (H-NMR) of buspirone hydrochloride prepared by the method of the present invention.

[0043] Figure 2 The figure is the mass spectrum (HRMS) of buspirone hydrochloride prepared by the method of the present invention.

[0044] Figure 3 The HPLC diagram of buspirone hydrochloride prepared by the method of the present invention (Figure A is the HPLC diagram of buspirone hydrochloride at 210 nm, and Figure B is the HPLC diagram of buspirone hydrochloride at 240 nm). DETAILED DESCRIPTION

[0045] The following is a further detailed description of the above content of the present invention through specific implementation methods in the form of examples, but the examples cannot be understood as any limitation of the present invention. The scope of protection of the present invention is subject to the claims. Unless otherwise specified, the following examples are all completed using conventional existing technologies. Specific examples are described as follows:

[0046] Example 1 Effect of different reaction solvents on the yield and purity of buspirone hydrochloride

[0047] (1) Add 210 g of different reaction solvents to a 500 mL three-necked flask, start stirring, add 20.0 g of pyrimidopiperazine quaternary ammonium salt, 12.3 g of 3,3-tetramethyleneglutarimide and 10.6 g of sodium carbonate, heat to 100° C. to 105° C. and keep warm for 5 h.

[0048] (2) After the reaction was completed, 150 g of water was added, stirred for 10 min, separated, and a 10% aqueous solution of hydrobromic acid was added to the organic phase to adjust the pH of the system to 1-2. The liquid was separated, and the aqueous phase was extracted with 50 g of toluene 3 times.

[0049] (3) Separate the liquids, add 200 g of toluene to the aqueous phase, start stirring, cool to 0°C to 10°C, add 10% sodium carbonate aqueous solution to adjust the system pH to 9 to 10. Separate the liquids, wash the organic phase with 100 g of purified water to obtain a buspirone toluene solution.

[0050] (4) Add 8.1 g of 30% hydrogen chloride ethanol solution to the buspirone toluene solution, raise the temperature to 50°C to 60°C, and continue stirring for 1 hour. Lower the temperature to -5°C to 5°C, continue stirring for 2 hours, filter, and dry to obtain buspirone hydrochloride, calculate the yield, and test the purity.

[0051] Detection method: high performance liquid chromatography.

[0052] Method source: EP11.0 related substance detection method.

[0053] The effects of different reaction solvents in step (1) on the yield and purity of buspirone hydrochloride are shown in Table 1.

[0054] Table 1

[0055]

[0056] The experimental results show that the target product can be obtained by using single solvents such as n-butanol, n-pentanol, n-hexanol, toluene as solvents and mixed solvents such as toluene / methanol, toluene / ethanol, toluene / isopropanol, toluene / n-butanol, toluene / n-heptanol, but the product yield and purity are low; the target product can be obtained by using mixed solvents such as toluene / n-pentanol and toluene / n-hexanol as solvents, with a yield of more than 90% and a purity higher than 99%. Considering the comprehensive yield, quality and other factors, toluene / n-pentanol is the best reaction solvent, followed by toluene / n-hexanol.

[0057] Example 2 Effect of different ratios of toluene / n-pentanol or toluene / n-hexanol mixed solutions on the yield and purity of buspirone hydrochloride

[0058] (1) Add 210 g of a mixed solution of toluene / n-pentanol or toluene / n-hexanol in different proportions into a 500 mL three-necked flask, start stirring, add 20.0 g of pyrimidopiperazine quaternary ammonium salt, 12.3 g of 3,3-tetramethyleneglutarimide and 10.6 g of sodium carbonate, heat to 100°C to 105°C and keep warm for 5 h.

[0059] (2) After the reaction was completed, 150 g of water was added, stirred for 10 min, separated, and a 10% aqueous solution of hydrobromic acid was added to the organic phase to adjust the pH of the system to 1-2. The liquid was separated, and the aqueous phase was extracted with 50 g of toluene 3 times.

[0060] (3) Separate the liquids, add 200 g of toluene to the aqueous phase, start stirring, cool to 0°C to 10°C, add 10% sodium carbonate aqueous solution to adjust the system pH to 9 to 10. Separate the liquids, wash the organic phase with 100 g of purified water to obtain a buspirone toluene solution.

[0061] (4) Add 8.1 g of 30% hydrogen chloride ethanol solution to the buspirone toluene solution, raise the temperature to 50°C to 60°C, and continue stirring for 1 hour. Lower the temperature to -5°C to 5°C, continue stirring for 2 hours, filter, and dry to obtain buspirone hydrochloride, calculate the yield, and test the purity.

[0062] Detection method: high performance liquid chromatography.

[0063] Method source: EP11.0 related substance detection method.

[0064] The effects of different ratios of toluene / n-pentanol and toluene / n-hexanol mixed solutions in step (1) on the yield and purity of buspirone hydrochloride are shown in Table 2.

[0065] Table 2

[0066]

[0067] The experimental results show that the yield and purity of the target product obtained by using mixed solvents of toluene / n-pentanol and toluene / n-hexanol in different proportions vary greatly. The yield and purity of the product obtained are better when the volume ratio of methanol / n-pentanol and toluene / n-hexanol is 10-15:1.

[0068] Example 3 Effect of reaction time on yield and purity of buspirone hydrochloride

[0069] (1) Add 210 g of a toluene / n-pentanol mixed solution (V / V=10:1) into a 500 mL three-necked flask, start stirring, add 20.0 g of pyrimidopiperazine quaternary ammonium salt, 12.3 g of 3,3-tetramethyleneglutarimide and 10.6 g of sodium carbonate, and heat to 100° C. to 105° C. for reaction.

[0070] (2) After the reaction was completed, 150 g of water was added, stirred for 10 min, separated, and a 10% aqueous solution of hydrobromic acid was added to the organic phase to adjust the pH of the system to 1-2. The liquid was separated, and the aqueous phase was extracted with 50 g of toluene 3 times.

[0071] (3) Separate the liquids, add 200 g of toluene to the aqueous phase, start stirring, cool to 0°C to 10°C, add 10% sodium carbonate aqueous solution to adjust the system pH to 9 to 10. Separate the liquids, wash the organic phase with 100 g of purified water to obtain a buspirone toluene solution.

[0072] (4) Add 8.1 g of 30% hydrogen chloride ethanol solution to the buspirone toluene solution, raise the temperature to 50°C to 60°C, and continue stirring for 1 hour. Lower the temperature to -5°C to 5°C, continue stirring for 2 hours, filter, and dry to obtain buspirone hydrochloride, calculate the yield, and test the purity.

[0073] Detection method: high performance liquid chromatography.

[0074] Method source: EP11.0 related substance detection method.

[0075] The effect of the reaction time in step (1) on the yield and purity of buspirone hydrochloride is shown in Table 3.

[0076] Table 3

[0077]

[0078] The experimental results show that the product yield and purity are good and the difference is not large when the reaction time is 5h to 8h; if the reaction time is further extended, the product purity and yield tend to decrease.

[0079] Example 4 Effect of reaction temperature on yield and purity of buspirone hydrochloride

[0080] (1) Add 210 g of a toluene / n-pentanol mixed solution (V / V=10:1) into a 500 mL three-necked flask, start stirring, add 20.0 g of pyrimidopiperazine quaternary ammonium salt, 12.3 g of 3,3-tetramethyleneglutarimide and 10.6 g of sodium carbonate, heat to different temperatures and keep the reaction for 5 h.

[0081] (2) After the reaction was completed, 150 g of water was added, stirred for 10 min, separated, and a 10% aqueous solution of hydrobromic acid was added to the organic phase to adjust the pH of the system to 1-2. The liquid was separated, and the aqueous phase was extracted with 50 g of toluene 3 times.

[0082] (3) Separate the liquids, add 200 g of toluene to the aqueous phase, start stirring, cool to 0°C to 10°C, add 10% sodium carbonate aqueous solution to adjust the system pH to 9 to 10. Separate the liquids, wash the organic phase with 100 g of purified water to obtain a buspirone toluene solution.

[0083] (4) Add 8.1 g of 30% hydrogen chloride ethanol solution to the buspirone toluene solution, raise the temperature to 50°C to 60°C, and continue stirring for 1 hour. Lower the temperature to -5°C to 5°C, continue stirring for 2 hours, filter, and dry to obtain buspirone hydrochloride, calculate the yield, and test the purity.

[0084] Detection method: High performance liquid chromatography

[0085] Method source: EP11.0 related substance detection method

[0086] The effects of different reaction temperatures on the yield and purity of buspirone hydrochloride in step (1) are shown in Table 4.

[0087] Table 4

[0088]

[0089] The experimental results show that the yield and purity of the product obtained at 100℃~105℃ are good, the yield and quality of the product obtained by lowering the reaction temperature are poor, and the yield and purity of the product obtained by increasing the reaction temperature are also significantly reduced.

[0090] Example 5 Step (1) Effect of different bases 1 on the yield and purity of buspirone hydrochloride

[0091] (1) Add 210 g of a toluene / n-pentanol mixed solution (V / V=10:1) to a 500 mL three-necked flask, start stirring, add 20.0 g of pyrimidopiperazine quaternary ammonium salt, 12.3 g of 3,3-tetramethyleneglutarimide and 1 different base. Heat to 100°C to 105°C and keep the temperature for 5 h.

[0092] (2) After the reaction was completed, 150 g of water was added, stirred for 10 min, separated, and a 10% aqueous solution of hydrobromic acid was added to the organic phase to adjust the pH of the system to 1-2. The liquid was separated, and the aqueous phase was extracted with 50 g of toluene 3 times.

[0093] (3) Separate the liquids, add 200 g of toluene to the aqueous phase, start stirring, cool to 0°C to 10°C, add 10% sodium carbonate aqueous solution to adjust the system pH to 9 to 10. Separate the liquids, wash the organic phase with 100 g of purified water to obtain a buspirone toluene solution.

[0094] (4) Add 8.1 g of 30% hydrogen chloride ethanol solution to the buspirone toluene solution, raise the temperature to 50°C to 60°C, and continue stirring for 1 hour. Lower the temperature to -5°C to 5°C, continue stirring for 2 hours, filter, and dry to obtain buspirone hydrochloride, calculate the yield, and test the purity.

[0095] Detection method: High performance liquid chromatography

[0096] Method source: EP11.0 related substance detection method

[0097] Step (1) The effects of different bases 1 on the yield and purity of buspirone hydrochloride are shown in Table 5

[0098] Table 5

[0099]

[0100] The experimental results show that no target product is generated when potassium carbonate, sodium tert-butoxide, triethylamine and DIEA are used as bases; although the target product can be obtained when sodium methoxide, sodium ethoxide and sodium hydroxide are used as bases, the product yield and purity are poor. Sodium carbonate is used as a base, and the reaction effect is the best.

[0101] Example 6 Step (1) Effect of different sodium carbonate dosages on the yield and purity of buspirone hydrochloride

[0102] (1) Add 210 g of toluene / n-pentanol mixed solution (V / V=10:1) to a 500 mL three-necked flask, start stirring, add 20.0 g of pyrimidopiperazine quaternary ammonium salt, 12.3 g of 3,3-tetramethyleneglutarimide and different amounts of sodium carbonate, heat to 100°C to 105°C and keep the temperature for 5 h.

[0103] (2) After the reaction was completed, 150 g of water was added, stirred for 10 min, separated, and a 10% aqueous solution of hydrobromic acid was added to the organic phase to adjust the pH of the system to 1-2. The liquid was separated, and the aqueous phase was extracted with 50 g of toluene 3 times.

[0104] (3) Separate the liquids, add 200 g of toluene to the aqueous phase, start stirring, cool to 0°C to 10°C, add 10% sodium carbonate aqueous solution to adjust the system pH to 9 to 10. Separate the liquids, wash the organic phase with 100 g of purified water to obtain a buspirone toluene solution.

[0105] (4) Add 8.1 g of 30% hydrogen chloride ethanol solution to the buspirone toluene solution, raise the temperature to 50°C to 60°C, and continue stirring for 1 hour. Lower the temperature to -5°C to 5°C, continue stirring for 2 hours, filter, and dry to obtain buspirone hydrochloride, calculate the yield, and test the purity.

[0106] Detection method: high performance liquid chromatography.

[0107] Method source: EP11.0 related substance detection method.

[0108] The effects of different amounts of sodium carbonate in step (1) on the yield and purity of buspirone hydrochloride are shown in Table 6.

[0109] Table 6

[0110]

[0111]

[0112] The experimental results show that the amount of sodium carbonate also has a certain influence on the yield and purity of the product. When the amount of sodium carbonate is 1.2-1.5eq, the yield and purity of the product are better.

[0113] Example 7 Step (1) Effect of Different Amounts of 3,3-Tetramethyleneglutarimide on the Yield and Purity of Buspirone Hydrochloride

[0114] (1) Add 210 g of toluene / n-pentanol mixed solution (V / V=10:1) to a 500 mL three-necked flask, start stirring, add 20.0 g of pyrimidopiperazine quaternary ammonium salt, different amounts of 3,3-tetramethyleneglutarimide and 10.6 g of sodium carbonate, heat to 100°C to 105°C and keep the reaction for 5 h.

[0115] (2) After the reaction was completed, 150 g of water was added, stirred for 10 min, separated, and a 10% aqueous solution of hydrobromic acid was added to the organic phase to adjust the pH of the system to 1-2. The liquid was separated, and the aqueous phase was extracted with 50 g of toluene 3 times.

[0116] (3) Separate the liquids, add 200 g of toluene to the aqueous phase, start stirring, cool to 0°C to 10°C, add 10% sodium carbonate aqueous solution to adjust the system pH to 9 to 10. Separate the liquids, wash the organic phase with 100 g of purified water to obtain a buspirone toluene solution.

[0117] (4) Add 8.1 g of 30% hydrogen chloride ethanol solution to the buspirone toluene solution, raise the temperature to 50°C to 60°C, and continue stirring for 1 hour. Lower the temperature to -5°C to 5°C, continue stirring for 2 hours, filter, and dry to obtain buspirone hydrochloride, calculate the yield, and test the purity.

[0118] Detection method: high performance liquid chromatography.

[0119] Method source: EP11.0 related substance detection method.

[0120] The effects of different amounts of 3,3-tetramethyleneglutarimide in step (1) on the yield and purity of buspirone hydrochloride are shown in Table 7.

[0121] Table 7

[0122]

[0123] The experimental results show that the yield and purity of the product obtained by using different amounts of 3,3-tetramethyleneglutarimide vary greatly. When the molar ratio of pyrimidopiperazine quaternary ammonium salt to 3,3-tetramethyleneglutarimide is 1:1.1, the yield and purity of the product are better.

[0124] Example 8 Step (2) Effect of Acidic Aqueous Solution and Water Layer pH on Yield and Purity of Buspirone Hydrochloride

[0125] (1) Add 210 g of toluene / n-pentanol mixed solution (V / V=10:1) to a 500 mL three-necked flask, start stirring, add 20.0 g of pyrimidopiperazine quaternary ammonium salt, 12.3 g of 3,3-tetramethyleneglutarimide and 10.6 g of sodium carbonate, heat to 100°C to 105°C and keep the temperature for 5 h.

[0126] (2) After the reaction is complete, add 150 g of water, stir for 10 min, separate the liquids, add different acidic aqueous solutions to the organic phase to adjust the system to different pH values, separate the liquids, and extract the aqueous phase with 50 g of toluene 3 times.

[0127] (3) Separate the liquids, add 200 g of toluene to the aqueous phase, start stirring, cool to 0°C to 10°C, add 10% sodium carbonate aqueous solution to adjust the system pH to 9 to 10. Separate the liquids, wash the organic phase with 100 g of purified water to obtain a buspirone toluene solution.

[0128] (4) Add 8.1 g of 30% hydrogen chloride ethanol solution to the buspirone toluene solution, raise the temperature to 50°C to 60°C, and continue stirring for 1 hour. Lower the temperature to -5°C to 5°C, continue stirring for 2 hours, filter, and dry to obtain buspirone hydrochloride, calculate the yield, and test the purity.

[0129] Detection method: high performance liquid chromatography.

[0130] Method source: EP11.0 related substance detection method.

[0131] The effects of different acidic aqueous solutions and water layer pH values ​​on the yield and purity of buspirone hydrochloride in step (2) are shown in Table 8.

[0132] Table 8

[0133]

[0134] The experimental results show that the product obtained by using hydrobromic acid aqueous solution has high yield and high purity; the yield of the product when the pH value of the water layer is 1-2 is higher than that when the pH value is 3-4 and the pH value is 5-6.

[0135] Example 9 Step (2) Effect of the Type of Acidic Aqueous Layer Extraction Solvent on the Yield and Purity of Buspirone Hydrochloride

[0136] (1) Add 210 g of toluene / n-pentanol mixed solution (V / V=10:1) to a 500 mL three-necked flask, start stirring, add 20.0 g of pyrimidopiperazine quaternary ammonium salt, 12.3 g of 3,3-tetramethyleneglutarimide and 10.6 g of sodium carbonate, heat to 100°C to 105°C and keep the temperature for 5 h.

[0137] (2) After the reaction was completed, 150 g of water was added, stirred for 10 min, separated, and a 10% aqueous solution of hydrobromic acid was added to the organic phase to adjust the pH of the system to 1-2. The aqueous phase was separated and extracted with 50 g of different solvents for 3 times.

[0138] (3) Separate the liquids, add 200 g of toluene to the aqueous phase, start stirring, cool to 0°C to 10°C, add 10% sodium carbonate aqueous solution to adjust the system pH to 9 to 10. Separate the liquids, wash the organic phase with 100 g of purified water to obtain a buspirone toluene solution.

[0139] (4) Add 8.1 g of 30% hydrogen chloride ethanol solution to the buspirone toluene solution, raise the temperature to 50°C to 60°C, and continue stirring for 1 hour. Lower the temperature to -5°C to 5°C, continue stirring for 2 hours, filter, and dry to obtain buspirone hydrochloride, calculate the yield, and test the purity.

[0140] Detection method: high performance liquid chromatography.

[0141] Method source: EP11.0 related substance detection method.

[0142] The effects of different impurity removal extraction solvents in step (2) on the yield and purity of buspirone hydrochloride are shown in Table 9.

[0143] Table 9

[0144]

[0145] The experimental results show that the yield and purity of the product obtained by using toluene as the extraction solvent are better.

[0146] Effect of the extraction solvent on the yield and purity of buspirone hydrochloride in step (3) of Example 10

[0147] (1) Add 210 g of toluene / n-pentanol mixed solution (V / V=10:1) to a 500 mL three-necked flask, start stirring, add 20.0 g of pyrimidopiperazine quaternary ammonium salt, 12.3 g of 3,3-tetramethyleneglutarimide and 10.6 g of sodium carbonate, heat to 100°C to 105°C and keep the temperature for 5 h.

[0148] (2) After the reaction was completed, 150 g of water was added, stirred for 10 min, separated, and a 10% aqueous solution of hydrobromic acid was added to the organic phase to adjust the pH of the system to 1-2. The liquid was separated, and the aqueous phase was extracted with 50 g of toluene 3 times.

[0149] (3) Separate the liquids, add 200 g of different extraction solvents to the aqueous phase, start stirring, cool to 0°C to 10°C, add 10% sodium carbonate aqueous solution to adjust the system pH to 9 to 10. Separate the liquids, wash the organic phase with 100 g of purified water to obtain a buspirone toluene solution.

[0150] (4) Add 8.1 g of 30% hydrogen chloride ethanol solution to the buspirone toluene solution, raise the temperature to 50°C to 60°C, and continue stirring for 1 hour. Lower the temperature to -5°C to 5°C, continue stirring for 2 hours, filter, and dry to obtain buspirone hydrochloride, calculate the yield, and test the purity.

[0151] Detection method: high performance liquid chromatography.

[0152] Method source: EP11.0 related substance detection method.

[0153] The effects of different extraction solvents in step (3) on the yield and purity of buspirone hydrochloride are shown in Table 10.

[0154] Table 10

[0155]

[0156] The experimental results show that when toluene is used as the extraction solvent, the product yield is high and the purity is high.

[0157] Example 11 Step (3) Effect of the Type of Base 2 and pH Value of the Aqueous Layer on the Yield and Purity of Buspirone Hydrochloride

[0158] (1) Add 210 g of toluene / n-pentanol mixed solution (V / V=10:1) to a 500 mL three-necked flask, start stirring, add 20.0 g of pyrimidopiperazine quaternary ammonium salt, 12.3 g of 3,3-tetramethyleneglutarimide and 10.6 g of sodium carbonate, heat to 100°C to 105°C and keep the temperature for 5 h.

[0159] (2) After the reaction was completed, 150 g of water was added, stirred for 10 min, separated, and a 10% aqueous solution of hydrobromic acid was added to the organic phase to adjust the pH of the system to 1-2. The liquid was separated, and the aqueous phase was extracted with 50 g of toluene 3 times.

[0160] (3) Separate the liquids, add 200 g of toluene to the aqueous phase, start stirring, cool to 0°C to 10°C, add different bases 2 to adjust the system to different pH values. Separate the liquids, wash the organic phase with 100 g of purified water, and obtain a buspirone toluene solution.

[0161] (4) Add 8.1 g of 30% hydrogen chloride ethanol solution to the buspirone toluene solution, raise the temperature to 50°C to 60°C, and continue stirring for 1 hour. Lower the temperature to -5°C to 5°C, continue stirring for 2 hours, filter, and dry to obtain buspirone hydrochloride, calculate the yield, and test the purity.

[0162] Detection method: high performance liquid chromatography.

[0163] Method source: EP11.0 related substance detection method.

[0164] The effects of different base types and water layer pH values ​​on the yield and purity of buspirone hydrochloride in step (3) are shown in Table 11.

[0165] Table 11

[0166]

[0167]

[0168] The experimental results show that when sodium carbonate is used as the base and the pH value of the water layer is 9-10, the product yield and purity are better.

[0169] Example 12 Step (4) Effect of Salt Formation Temperature on Yield and Purity of Buspirone Hydrochloride

[0170] (1) Add 210 g of toluene / n-pentanol mixed solution (V / V=10:1) to a 500 mL three-necked flask, start stirring, add 20.0 g of pyrimidopiperazine quaternary ammonium salt, 12.3 g of 3,3-tetramethyleneglutarimide and 10.6 g of sodium carbonate, heat to 100°C to 105°C and keep the temperature for 5 h.

[0171] (2) After the reaction was completed, 150 g of water was added, stirred for 10 min, separated, and a 10% aqueous solution of hydrobromic acid was added to the organic phase to adjust the pH of the system to 1-2. The liquid was separated, and the aqueous phase was extracted with 50 g of toluene 3 times.

[0172] (3) Separate the liquids, add 200 g of toluene to the aqueous phase, start stirring, cool to 0°C to 10°C, add 10% sodium carbonate aqueous solution to adjust the pH to 9 to 10. Separate the liquids, wash the organic phase with 100 g of purified water to obtain a buspirone toluene solution.

[0173] (4) Add 8.1 g of 30% hydrogen chloride ethanol solution to the buspirone toluene solution, raise the temperature to different temperatures, and continue stirring for 1 hour. Cool down to -5°C to 5°C, continue stirring for 2 hours, filter, and dry to obtain buspirone hydrochloride, calculate the yield, and test the purity.

[0174] Detection method: high performance liquid chromatography.

[0175] Method source: EP11.0 related substance detection method.

[0176] The effects of different salt-forming temperatures in step (4) on the yield and purity of buspirone hydrochloride are shown in Table 12.

[0177] Table 12

[0178]

[0179] The experimental results show that the yield and purity of the product are better when the salt-forming temperature is 50℃~60℃.

[0180] Example 13 Step (4) Effect of Crystallization Temperature on Yield and Purity of Buspirone Hydrochloride

[0181] (1) Add 210 g of toluene / n-pentanol mixed solution (V / V=10:1) to a 500 mL three-necked flask, start stirring, add 20.0 g of pyrimidopiperazine quaternary ammonium salt, 12.3 g of 3,3-tetramethyleneglutarimide and 10.6 g of sodium carbonate, heat to 100°C to 105°C and keep the temperature for 5 h.

[0182] (2) After the reaction was completed, 150 g of water was added, stirred for 10 min, separated, and a 10% aqueous solution of hydrobromic acid was added to the organic phase to adjust the pH of the system to 1-2. The liquid was separated, and the aqueous phase was extracted with 50 g of toluene 3 times.

[0183] (3) Separate the liquids, add 200 g of toluene to the aqueous phase, start stirring, cool to 0°C to 10°C, add 10% sodium carbonate aqueous solution to adjust the pH to 9 to 10. Separate the liquids, wash the organic phase with 100 g of purified water to obtain a buspirone toluene solution.

[0184] (4) Add 8.1 g of 30% hydrogen chloride ethanol solution to the buspirone toluene solution, raise the temperature to 50°C to 60°C, and continue stirring for 1 hour. Cool down to different temperatures, continue stirring for 2 hours, filter, and dry to obtain buspirone hydrochloride, calculate the yield, and test the purity.

[0185] Detection method: high performance liquid chromatography.

[0186] Method source: EP11.0 related substance detection method.

[0187] The effects of different crystallization temperatures in step (4) on the yield and purity of buspirone hydrochloride are shown in Table 13.

[0188] Table 13

[0189]

[0190] The experimental results show that different crystallization temperatures have different effects on the yield and purity of the product. The yield and purity are better when the crystallization temperature is -5℃~-5℃. The H-NMR spectrum of buspirone hydrochloride obtained corresponding to No. 2 is as follows: Figure 1 As shown, the mass spectrum (HRMS) is as Figure 2 As shown, the HPLC liquid phase diagram is as follows Figure 3 As shown (Figure A is the liquid phase diagram of buspirone hydrochloride at 210nm, and Figure B is the liquid phase diagram of buspirone hydrochloride at 240nm).

Claims

1. A method for preparing buspirone hydrochloride, characterized in that The steps include: (1) 8-(2-pyrimidinyl)-8-aza-5-5-azoniaspiro[4.5]decane hydrobromide and 3,3-tetramethyleneglutarimide are reacted in the presence of sodium carbonate at 95°C to 110°C, using a mixed solvent of toluene and a lower alcohol as a solvent, wherein the volume ratio of toluene to the lower alcohol is 5 to 20:1, and the lower alcohol is n-pentanol and / or n-hexanol, to obtain buspirone; (2) adding an acidic aqueous solution to the reaction solution of step (1), adjusting the pH to 1 to 5, stirring and separating the liquids, and extracting the aqueous phase with toluene to remove impurities; (3) adding an organic solvent and an aqueous sodium carbonate solution to the acidic aqueous solution of buspirone in step (2), adjusting the pH to 9-12, stirring and separating the liquids, wherein the organic solvent is selected from one or more of toluene, ethyl acetate, and isopropyl acetate, and washing the buspirone organic phase with water; (4) adding a hydrogen chloride ethanol solution to the buspirone organic phase of step (3), stirring, cooling and crystallizing to obtain buspirone hydrochloride.

2. The preparation method according to claim 1, characterized in that: Step (1); the molar ratio of 8-(2-pyrimidinyl)-8-aza-5-5-azoniaspiro[4.5]decane hydrobromide to 3,3-tetramethyleneglutarimide is 1:1.0-1.

3.

3. The preparation method according to claim 1, characterized in that: Step (1) The molar ratio of 8-(2-pyrimidinyl)-8-aza-5-(5-nitrogen)spiro[4.5]decane hydrobromide to sodium carbonate is 1:1.2-1.

5.

4. The preparation method according to claim 3, characterized in that: The reaction temperature of step (1) is 100° C. to 105° C., the molar ratio of 8-(2-pyrimidinyl)-8-aza-5-5-azoniaspiro[4.5]decane hydrobromide to 3,3-tetramethyleneglutarimide is 1:1.1; and the volume ratio of toluene to lower alcohol is 10 to 15:

1.

5. The preparation method according to claim 1, characterized in that: The acidic aqueous solution described in step (2) is an aqueous hydrochloric acid solution and / or an aqueous hydrobromic acid solution.

6. The preparation method according to claim 5, characterized in that: The acidic aqueous solution described in step (2) is a hydrobromic acid aqueous solution, which is adjusted to a pH of 1-2.

7. The preparation method according to claim 1, characterized in that: The organic solvent described in step (3) is toluene; and the pH is adjusted to 9-10.

8. The preparation method according to claim 1, characterized in that: The salt formation temperature in step (4) is 40°C to 70°C; the crystallization temperature is -10°C to 10°C.

9. The preparation method according to claim 8, characterized in that: The salt formation temperature in step (4) is 50°C to 60°C; the crystallization temperature is -5°C to 5°C.

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