A process for the preparation of buspirone hydrochloride

Abstract

The application belongs to the technical field of medicine synthesis process, and particularly relates to a preparation method of high-yield and high-purity buspirone hydrochloride. The application takes 8-(2-pyrimidyl)-8-azido-5-5-azospiro[4.5]decane hydrobromide (referred to as pyrimidine piperazine quaternary ammonium salt) and 3,3-tetramethylene glutarimide as raw materials, takes a mixed solvent of toluene, normal pentanol and / or normal hexanol as a solvent, does not need to add a phase transfer catalyst, and can generate buspirone in the presence of sodium carbonate. After acid adjustment and extraction, toluene is removed in the reverse phase, the water phase is adjusted to be alkaline, toluene is extracted, hydrogen chloride ethanol solution is added, and buspirone hydrochloride solid is directly precipitated. The preparation process has a good removal effect on impurities, the obtained buspirone hydrochloride has high purity, high process yield, good atomic economy and small three-waste output.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemistry, in particular to a preparation method of high-purity and high-yield buspirone hydrochloride. BACKGROUND

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

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

[0004]

[0005] US4351939 discloses a preparation method of buspirone hydrochloride: 3,3-tetramethylene glutarimide reacts with pyrimidinyl piperazine quaternary ammonium salt in n-butanol to generate buspirone, which is filtered and distilled under reduced pressure to obtain buspirone crude product. The buspirone crude product is salted by adjusting the acid, and the free base solid of buspirone is obtained by adjusting the alkali. The free base solid of buspirone is dissolved in isopropyl alcohol, and then salted with concentrated hydrochloric acid to obtain buspirone hydrochloride crude product. The buspirone hydrochloride crude product is recrystallized with isopropyl alcohol to obtain buspirone hydrochloride.

[0006]

[0007] The preparation method uses n-butanol as the reaction solvent, the reflux temperature is high (117.6℃), and the reaction time is long (21 hours). Not only is the process safety poor, but the yield of buspirone is only 66.5%, which is very low and has no cost advantage. The purity of the prepared buspirone hydrochloride crude product is not high, and it is necessary to refine it again to obtain qualified products.

[0008] US4351939 discloses another preparation method of buspirone: 3,3-tetramethylene glutarimide reacts with pyrimidinyl piperazine quaternary ammonium salt in DMF to generate buspirone, which is filtered and distilled under reduced pressure to obtain buspirone crude product. The buspirone crude product is salted by adjusting the acid, and the free base solid of buspirone is obtained by adjusting the alkali.

[0009]

[0010] The above method uses DMF as the reaction solvent, and the reaction temperature is 150-155°C. The high temperature leads to the generation of more impurities in the reaction system, and the process safety is poor, which is not suitable for industrial mass production.

[0011] US238551 discloses a method for preparing buspirone hydrochloride: 3,3-tetramethylene glutarimide is first reacted with potassium tert-butoxide to form 3,3-tetramethylene glutarimide potassium salt, which is then reacted with intermediate II in butyl acetate to form buspirone, and then buspirone free base solid is prepared by adjusting the acid to form a salt and adjusting the base to precipitate.

[0012]

[0013] In the preparation process of 3,3-tetramethylene glutarimide potassium salt, nitrogen protection is required, and the reaction conditions are relatively harsh. In the preparation process of buspirone free base, butyl acetate reflux (125-126°C) is required for stirring for 6-8 hours, which is too high in temperature and too long in time, and the process safety is poor, which is not suitable for industrial mass production.

[0014] An Efficient Synthesis of Buspirone and its Analogues (Archiv der Pharmazie, 1992, 325(5): 313-315) discloses a method for preparing buspirone hydrochloride: 3,3-tetramethylene glutarimide is reacted with pyrimidinopiperazine quaternary ammonium salt in xylene with the addition of phase transfer catalyst 18-crown-6-6 reflux (137-140°C) for 6 hours to form buspirone, and then buspirone crude product is prepared by filtration and vacuum distillation. Buspirone is recrystallized from ethyl acetate to obtain buspirone. Buspirone is salted with hydrogen chloride in ethanol to obtain buspirone hydrochloride.

[0015]

[0016] This method requires the addition of an additional phase transfer catalyst to improve the reaction speed, which is high in production cost. Xylene is used as the reaction solvent, and the reaction temperature is 150-155°C, which is too high in temperature and poor in process safety, and is not suitable for industrial mass production. The purity of the prepared buspirone crude product is poor, and it needs to be refined to obtain qualified products.

[0017] Under the prior art, although there are many methods for preparing buspirone hydrochloride, most of them have problems such as high reaction temperature, long reaction time, low conversion rate and the like. In order to speed up the reaction, high-boiling reaction solvents are often used to increase the reaction temperature and / or phase transfer catalysts are added, which leads to poor process safety, low product purity and the like. In addition, due to the large number of production processes, there are problems such as low yield, large amount of three wastes and the like. Buspirone and buspirone hydrochloride are prepared in steps, the production cycle is long, the preparation process of buspirone hydrochloride has poor atom economy, and the production energy consumption and labor cost are high. These problems have been the key technical problems restricting the scale-up production of buspirone hydrochloride. SUMMARY

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

[0019] To achieve the above-mentioned purposes, the present application adopts the following technical solutions:

[0020] (1) 8-(2-pyrimidinyl)-8-azaspiro[4.5]decane hydrobromide (abbreviated as: pyrimidinyl piperazine quaternary ammonium salt) and 3,3-tetramethylene glutarimide are prepared into buspirone with a mixed solvent as a solvent in the presence of base 1.

[0021] (2) An acidic aqueous solution is added to the reaction liquid of step (1), adjusted to be acidic, stirred and separated, and the water phase is extracted with toluene to remove impurities.

[0022] (3) An organic solvent and an aqueous base 2 are added to the acidic aqueous liquid of step (2) buspirone, stirred and separated, and the buspirone organic phase is washed with water.

[0023] (4) Hydrogen chloride ethanol solution is added to the buspirone organic phase of step (3), stirred, and cooled to crystallize to obtain buspirone hydrochloride.

[0024] The specific synthesis 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 5-20:1, preferably 10-15:1.

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

[0029] The molar ratio of the pyrimidinopiperazine quaternary ammonium salt to 3,3-tetramethylene glutarimide in step (1) is 1:1.0-1.3, preferably 1:1.1.

[0030] The base 1 in step (1) is sodium carbonate.

[0031] The molar ratio of the pyrimidinopiperazine quaternary ammonium salt to the base 1 in step (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 an aqueous hydrochloric acid solution, an aqueous hydrobromic acid solution, an aqueous sulfuric acid solution, an aqueous phosphoric acid solution, an aqueous nitric acid solution, etc., preferably an aqueous hydrobromic acid solution.

[0033] The base 2 used for adjusting the pH to alkaline 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 salting temperature in step (4) is 40-70°C, preferably 50-60°C.

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

[0036] Compared with the prior art, the present application has the following advantages:

[0037] (1) The present application directly produces the buspirone hydrochloride by using the "one-pot" process, has a short production cycle and low production cost.

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

[0039] (3) The "one-pot" process effectively reduces the amount of "three wastes" produced, and is green and environmentally friendly.

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

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

[0042] Figure 1 The buspirone hydrochloride produced by the method of the present application has the following H-NMR spectrum.

[0043] Figure 2 The mass spectrum (HRMS) of the prepared buspirone hydrochloride according to the method of the present application.

[0044] Figure 3 The liquid chromatogram (HPLC) of the prepared buspirone hydrochloride according to the method of the present application (Fig. A is the liquid chromatogram of buspirone hydrochloride at 210 nm, and Fig. B is the liquid chromatogram of buspirone hydrochloride at 240 nm). DETAILED DESCRIPTION

[0045] The above description of the present application is further explained in detail by the following specific embodiments in the form of examples, but the examples should not be understood as any limitation of the present application, and the protection scope of the present application is subject to the claims, and except for the special description, the following examples are completed by using the conventional prior art. The specific embodiments are described as follows:

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

[0047] (1) 210 g of different reaction solvents were added to a 500 mL three-necked flask, and stirring was started. 20.0 g of pyrimidinopiperazine quaternary ammonium salt, 12.3 g of 3,3-tetramethylene glutarimide and 10.6 g of sodium carbonate were added, and heating was started to 100-105°C for 5 h.

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

[0049] (3) The liquid was separated, 200 g of toluene was added to the water phase, and stirring was started. The temperature was lowered to 0-10°C, and 10% sodium carbonate aqueous solution was added to adjust the pH to 9-10. The liquid was separated, and the organic phase was washed with 100 g of purified water to obtain a toluene solution of buspirone.

[0050] (4) 8.1 g of 30% hydrogen chloride ethanol solution was added to the toluene solution of buspirone, and the temperature was raised to 50-60°C. Stirring was continued for 1 h. The temperature was lowered to -5-5°C, and stirring was continued for 2 h. Filtration and drying gave buspirone hydrochloride, and the yield was calculated, and the purity was detected.

[0051] Detection method: high performance liquid chromatography.

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

[0053] The influence of different reaction solvents on the yield and purity of buspirone hydrochloride is shown in Table 1.

[0054] Table 1

[0055]

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

[0057] Example 2 Influence of different proportions of toluene / n-pentanol or toluene / n-hexanol mixed solution on the yield and purity of buspirone hydrochloride

[0058] (1) 210 g of different proportions of toluene / n-pentanol or toluene / n-hexanol mixed solution was added to a 500 mL three-necked flask, the stirring was started, 20.0 g of pyrimidinyl piperazine quaternary ammonium salt, 12.3 g of 3,3-tetramethylene glutarimide and 10.6 g of sodium carbonate were added, and heated to 100-105°C for 5 h.

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

[0060] (3) The aqueous phase was separated, 200 g of toluene was added to the aqueous phase, the stirring was started, and the temperature was lowered to 0-10°C. 10% sodium carbonate aqueous solution was added to adjust the system pH to 9-10. The organic phase was washed with 100 g of purified water to obtain a toluene solution of buspirone.

[0061] (4) 8.1 g of 30% hydrogen chloride ethanol solution was added to the toluene solution of buspirone, the temperature was raised to 50-60°C, and the stirring was continued for 1 h. The temperature was lowered to -5-5°C, and the stirring was continued for 2 h. The filter cake was dried to obtain buspirone hydrochloride, and the yield was calculated and the purity was detected.

[0062] Detection method: high performance liquid chromatography.

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

[0064] The influence of different proportions of toluene / n-pentanol or toluene / n-hexanol mixed solution on the yield and purity of buspirone hydrochloride is shown in Table 2.

[0065] Table 2

[0066]

[0067] The experimental results show that the yields and purities of the target product obtained from different proportions of toluene / n-pentanol and toluene / n-hexanol mixed solvents are quite different, and the yields and purities of the product obtained when the volume ratio of methanol / n-pentanol and toluene / n-hexanol is 10-15:1 are better.

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

[0069] (1) A 500 mL three-necked flask was charged with a toluene / n-pentanol mixed solution 210 g (V / V = 10:1), and stirring was started. Pyrimidinylpiperazine quaternary ammonium salt 20.0 g, 3,3-tetramethylene glutarimide 12.3 g and sodium carbonate 10.6 g were added, and heating was started to 100-105°C for reaction.

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

[0071] (3) The mixture was separated, 200 g of toluene was added to the aqueous phase, and stirring was started. The temperature was lowered to 0-10°C, and 10% sodium carbonate aqueous solution was added to adjust the pH to 9-10. The mixture was separated, and the organic phase was washed with 100 g of purified water to obtain a toluene solution of buspirone.

[0072] (4) 8.1 g of 30% hydrogen chloride ethanol solution was added to the toluene solution of buspirone, and the temperature was raised to 50-60°C. Stirring was continued for 1 h. The temperature was lowered to -5-5°C, and stirring was continued for 2 h. Filtration and drying gave buspirone hydrochloride, and the yield was calculated, and the purity was detected.

[0073] Detection method: high performance liquid chromatography.

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

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

[0076] Table 3

[0077]

[0078] The experimental results show that the yields and purities of the product obtained when the reaction time is 5-8 h are better and have little difference. The purity and yield of the product have a downward trend when the reaction time is further prolonged.

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

[0080] (1) Into a 500 mL flask, add toluene / n-pentanol mixed solution 210 g (V / V = 10:1), open the stirring, add pyrimidine piperazine quaternary ammonium salt 20.0 g, 3,3-tetramethylene glutarimide 12.3 g and sodium carbonate 10.6 g, heat to different temperatures and keep for 5 h.

[0081] (2) After the reaction is completed, add water 150 g, stir for 10 min, separate the liquid, add 10% hydrobromic acid aqueous solution to the organic phase to adjust the system pH = 1-2. Separate the liquid, and extract the water phase with 50 g of toluene for 3 times.

[0082] (3) Separate the liquid, add 200 g of toluene to the water phase, open the stirring, cool to 0-10°C, add 10% sodium carbonate aqueous solution to adjust the system pH = 9-10. Wash the organic phase with 100 g of purified water to obtain a butapenone toluene solution.

[0083] (4) Add 8.1 g of 30% hydrogen chloride ethanol solution to the butapenone toluene solution, heat to 50-60°C, continue to stir for 1 h. Cool to -5-5°C, continue to stir for 2 h, filter and dry to obtain hydrochloric acid butapenone. Calculate the yield and detect the purity.

[0084] Detection method: high performance liquid chromatography

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

[0086] The effect of different reaction temperatures on the yield and purity of hydrochloric acid butapenone in step (1) is 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°C are better, the yield and quality of the product obtained by reducing the reaction temperature are poor, and the yield and purity of the product obtained by increasing the reaction temperature are also significantly reduced.

[0090] The effect of different bases 1 on the yield and purity of hydrochloric acid butapenone in step (1) of Example 5

[0091] (1) Into a 500 mL flask, add toluene / n-pentanol mixed solution 210 g (V / V = 10:1), open the stirring, add pyrimidine piperazine quaternary ammonium salt 20.0 g, 3,3-tetramethylene glutarimide 12.3 g and different base 1. Heat to 100-105°C and keep for 5 h.

[0092] (2) Reaction completed, add 150 g water, stir for 10 min, separate the liquid, add 10% hydrobromic acid aqueous solution to the organic phase to adjust the system pH = 1-2. Separate the liquid, extract the water phase with 50 g of toluene for 3 times.

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

[0094] (4) Add 8.1 g of 30% hydrogen chloride ethanol solution to the butapenone toluene solution, heat to 50-60°C, continue stirring for 1 h. Cool to -5-5°C, continue stirring for 2 h, filter and dry to obtain hydrochloric acid butapenone, calculate the yield and detect the purity.

[0095] Detection method: high performance liquid chromatography

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

[0097] The influence of different bases 1 on the yield and purity of hydrochloric acid butapenone is shown in Table 5

[0098] Table 5

[0099]

[0100] The experimental results show that potassium carbonate, sodium tert-butoxide, triethylamine and DIEA are not selected as the base to generate the target product; sodium methoxide, sodium ethoxide and sodium hydroxide can obtain the target product, but the yield and purity of the product are poor, and sodium carbonate is the best base for the reaction.

[0101] The influence of different amounts of sodium carbonate on the yield and purity of hydrochloric acid butapenone in Example 6 step (1)

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

[0103] (2) Reaction completed, add 150 g water, stir for 10 min, separate the liquid, add 10% hydrobromic acid aqueous solution to the organic phase to adjust the system pH = 1-2. Separate the liquid, extract the water phase with 50 g of toluene for 3 times.

[0104] (3) Separation, 200 g of toluene was added to the water phase, stirring was started, and the temperature was lowered to 0-10 °C, 10% sodium carbonate solution was added to adjust the pH of the system to 9-10. The organic phase was washed with 100 g of purified water to obtain a solution of butyrospirolactone in toluene.

[0105] (4) 8.1 g of 30% hydrogen chloride ethanol solution was added to the butyrospirolactone toluene solution, the temperature was raised to 50-60 °C, and stirring was continued for 1 h. The temperature was lowered to -5-5 °C, and stirring was continued for 2 h, and then filtration and drying were performed to obtain hydrochloric acid butyrospirolactone, the yield was calculated, and the purity was detected.

[0106] Detection method: high performance liquid chromatography.

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

[0108] The effect of different amounts of sodium carbonate on the yield and purity of hydrochloric acid butyrospirolactone is shown in Table 6.

[0109] Table 6

[0110]

[0111]

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

[0113] Example 7 Step (1) Effect of different amounts of 3,3-tetramethylene glutarimide on the yield and purity of hydrochloric acid butyrospirolactone

[0114] (1) 210 g of toluene / n-pentanol mixed solution (V / V=10:1) was added to a 500 mL three-necked flask, stirring was started, 20.0 g of pyrimidinyl piperazine quaternary ammonium salt, different amounts of 3,3-tetramethylene glutarimide, and 10.6 g of sodium carbonate were added. The temperature was raised to 100-105 °C and the reaction was maintained for 5 h.

[0115] (2) After the reaction was completed, 150 g of water was added, stirring was continued for 10 min, and separation was performed. 10% hydrobromic acid aqueous solution was added to the organic phase to adjust the pH of the system to 1-2. Separation was performed, and the water phase was extracted with 50 g of toluene three times.

[0116] (3) Separation, 200 g of toluene was added to the water phase, stirring was started, and the temperature was lowered to 0-10 °C, 10% sodium carbonate solution was added to adjust the pH of the system to 9-10. The organic phase was washed with 100 g of purified water to obtain a solution of butyrospirolactone in toluene.

[0117] (4) To the solution of buspirone toluene, add 8.1 g of 30% hydrogen chloride ethanol solution, and heat to 50-60 °C, continue to stir for 1 h. Cool to -5-5 °C, continue to stir for 2 h, filter, dry to obtain buspirone hydrochloride, calculate the yield, and detect the purity.

[0118] Detection method: high performance liquid chromatography.

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

[0120] Step (1) The effect of different amounts of 3,3-tetramethylene glutarimide on the yield and purity of buspirone hydrochloride is shown in Table 7.

[0121] Table 7

[0122]

[0123] The experimental results show that different amounts of 3,3-tetramethylene glutarimide have great differences in the yield and purity of the product, and when the molar ratio of pyrimidinopiperazine quaternary ammonium salt to 3,3-tetramethylene glutarimide is 1:1.1, the yield and purity of the product are better.

[0124] Example 8 Step (2) The effect of pH value of acidic aqueous solution and water layer on the 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 pyrimidinopiperazine quaternary ammonium salt 20.0 g, 3,3-tetramethylene glutarimide 12.3 g and sodium carbonate 10.6 g. Heat to 100-105 °C and keep for 5 h.

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

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

[0128] (4) To the solution of buspirone toluene, add 8.1 g of 30% hydrogen chloride ethanol solution, and heat to 50-60 °C, continue to stir for 1 h. Cool to -5-5 °C, continue to stir for 2 h, filter, dry to obtain buspirone hydrochloride, calculate the yield, and detect the purity.

[0129] Detection method: high performance liquid chromatography.

[0130] Method source: EP 11.0 related substance detection method.

[0131] The influence of different pH values of the aqueous layer on the yield and purity of the butyrophenone hydrochloride in step (2) is shown in Table 8.

[0132] Table 8

[0133]

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

[0135] Influence of the type of extraction solvent of the aqueous layer in step (2) of Example 9 on the yield and purity of butyrophenone hydrochloride

[0136] (1) A 500 mL three-necked flask was charged with a toluene / n-pentanol mixed solution 210 g (V / V = 10:1), and stirring was started, and then pyrimidinyl piperazine quaternary ammonium salt 20.0 g, 3,3-tetramethylene glutarimide 12.3 g and sodium carbonate 10.6 g were added. Heating was started to 100-105°C, and the reaction was maintained for 5 h.

[0137] (2) After the reaction was completed, 150 g of water was added, and stirring was maintained for 10 min, and then the liquid was separated, and 10% aqueous hydrogen bromide solution was added to the organic phase to adjust the pH value of the system to 1-2. The liquid was separated, and the aqueous phase was extracted with 50 g of different solvents for 3 times.

[0138] (3) The liquid was separated, 200 g of toluene was added to the aqueous phase, and stirring was started, and then the temperature was lowered to 0-10°C, and 10% aqueous sodium carbonate solution was added to adjust the pH value of the system to 9-10. The liquid was separated, and the organic phase was washed with 100 g of purified water to obtain a toluene solution of butyrophenone.

[0139] (4) 8.1 g of 30% hydrogen chloride ethanol solution was added to the toluene solution of butyrophenone, and the temperature was raised to 50-60°C, and stirring was continued for 1 h. The temperature was lowered to -5-5°C, and stirring was continued for 2 h, and then filtration and drying were carried out to obtain butyrophenone hydrochloride, and the yield was calculated, and the purity was detected.

[0140] Detection method: high performance liquid chromatography.

[0141] Method source: EP 11.0 related substance detection method.

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

[0143] Table 9

[0144]

[0145] The experimental results show that the product yield and purity are better when toluene is used as the extraction solvent.

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

[0147] (1) A 500 mL three-necked flask was charged with a toluene / n-pentanol mixed solution 210 g (V / V = 10:1), and stirring was started. Pyrimidinylpiperazine quaternary ammonium salt 20.0 g, 3,3-tetramethylene glutarimide 12.3 g and sodium carbonate 10.6 g were added. The mixture was heated to 100-105°C and kept at this temperature for 5 h.

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

[0149] (3) The mixture was separated, and 200 g of different extraction solvents was added to the aqueous phase. Stirring was started, and the temperature was lowered to 0-10°C. 10% sodium carbonate aqueous solution was added to adjust the pH to 9-10. The organic phase was washed with 100 g of purified water to obtain a toluene solution of buspirone.

[0150] (4) 8.1 g of 30% hydrogen chloride ethanol solution was added to the toluene solution of buspirone, and the temperature was raised to 50-60°C. Stirring was continued for 1 h. The temperature was lowered to -5-5°C, and stirring was continued for 2 h. The mixture was filtered and dried to obtain buspirone hydrochloride. The yield was calculated, and the purity was determined.

[0151] Determination method: high performance liquid chromatography.

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

[0153] The effect of different extraction solvents on the yield and purity of buspirone hydrochloride in step (3) is 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 and purity are high.

[0157] Effect of two types of base and pH of water layer on the yield and purity of buspirone hydrochloride in step (3) of Example 11

[0158] (1) A 500 mL three-necked flask was charged with a toluene / n-pentanol mixed solution 210 g (V / V = 10:1), and stirring was started. Pyrimidinylpiperazine quaternary ammonium salt 20.0 g, 3,3-tetramethylene glutarimide 12.3 g and sodium carbonate 10.6 g were added. The mixture was heated to 100-105°C and kept at this temperature for 5 h.

[0159] (2) Reaction completed, add water 150 g, stir for 10 min, separate the liquid, add 10% hydrobromic acid aqueous solution to the organic phase to adjust the system pH = 1-2. Separate the liquid, extract the water phase with 50 g of toluene for 3 times.

[0160] (3) Separate the liquid, add 200 g of toluene to the water phase, start stirring, cool to 0-10°C, add different base 2 to adjust the system to different pH. Wash the organic phase with 100 g of purified water to obtain a butapenone toluene solution.

[0161] (4) Add 8.1 g of 30% hydrogen chloride ethanol solution to the butapenone toluene solution, heat to 50-60°C, continue stirring for 1 h. Cool to -5-5°C, continue stirring for 2 h, filter and dry to obtain hydrochloric acid butapenone. 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 effect of different base 2 types and water layer pH values on the yield and purity of hydrochloric acid butapenone in step (3) is 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 water layer pH value is 9-10, the yield and purity of the product are better.

[0169] Example 12 Step (4) Effect of salt formation temperature on the yield and purity of hydrochloric acid butapenone

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

[0171] (2) Reaction completed, add water 150 g, stir for 10 min, separate the liquid, add 10% hydrobromic acid aqueous solution to the organic phase to adjust the system pH = 1-2. Separate the liquid, extract the water phase with 50 g of toluene for 3 times.

[0172] (3) Separation, 200 g of toluene was added to the water phase, and the stirring was started. The temperature was lowered to 0-10°C, and 10% sodium carbonate solution was added to adjust the pH to 9-10. Separation, the organic phase was washed with 100 g of purified water to obtain a solution of butapen in toluene.

[0173] (4) 8.1 g of 30% hydrogen chloride ethanol solution was added to the solution of butapen in toluene, and the temperature was raised to different temperatures. The stirring was continued for 1 h. The temperature was lowered to -5-5°C, and the stirring was continued for 2 h. Filtration and drying gave hydrochloric acid butapen, the yield was calculated, and the purity was detected.

[0174] Detection method: high performance liquid chromatography.

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

[0176] The influence of different salt formation temperatures in step (4) on the yield and purity of hydrochloric acid butapen is shown in Table 12.

[0177] Table 12

[0178]

[0179] The experimental results show that when the salt formation temperature is 50-60°C, the yield and purity of the product are better.

[0180] Influence of crystallization temperature on the yield and purity of hydrochloric acid butapen in Example 13 step (4)

[0181] (1) 210 g of toluene / n-pentanol mixed solution (V / V=10:1) was added to a 500 mL three-necked flask, and the stirring was started. 20.0 g of pyrimidinyl piperazine quaternary ammonium salt, 12.3 g of 3,3-tetramethylene glutarimide and 10.6 g of sodium carbonate were added. The temperature was raised to 100-105°C, and the reaction was kept for 5 h.

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

[0183] (3) Separation, 200 g of toluene was added to the water phase, and the stirring was started. The temperature was lowered to 0-10°C, and 10% sodium carbonate solution was added to adjust the pH to 9-10. Separation, the organic phase was washed with 100 g of purified water to obtain a solution of butapen in toluene.

[0184] (4) 8.1 g of 30% hydrogen chloride ethanol solution was added to the solution of butapen in toluene, and the temperature was raised to 50-60°C. The stirring was continued for 1 h. The temperature was lowered to different temperatures, and the stirring was continued for 2 h. Filtration and drying gave hydrochloric acid butapen, the yield was calculated, and the purity was detected.

[0185] Detection method: high performance liquid chromatography.

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

[0187] The effect of different crystallization temperatures on the yield and purity of buspirone hydrochloride is 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, and the crystallization temperature is determined to be -5℃ to -5℃, which has better yield and purity. The H-NMR spectrum of buspirone hydrochloride prepared in sequence No. 2 is shown in Figure 1 , the mass spectrum (HRMS) is shown in Figure 2 , and the HPLC liquid phase diagram is shown in Figure 3 (Figure A is the liquid phase diagram of buspirone hydrochloride at 210 nm, and Figure B is the liquid phase diagram of buspirone hydrochloride at 240 nm).

Claims

1. A process for the preparation of buspirone hydrochloride, characterized in that Comprising the following steps: (1) The butadienfulone is prepared by reacting the compound of formula I with 3,3-tetramethylene glutarimide in a mixed solvent of toluene and a lower alcohol, the volume ratio of toluene to the lower alcohol is 10-15:1, the lower alcohol is n-pentanol and / or n-hexanol, in the presence of sodium carbonate at 100-105℃ for 5-8h, the molar ratio of the compound of formula I to 3,3-tetramethylene glutarimide is 1:1.0-1.3, the molar ratio of the compound of formula I to sodium carbonate is 1:1.2-1.5, and the structure of the compound of formula I is: ; (2) To the reaction solution of step (1), add aqueous hydrobromic acid, adjust pH to 1-2, stir and separate, and use toluene to extract the water phase to remove impurities; (3) To the acidic aqueous solution of step (2), add toluene and aqueous sodium carbonate, adjust pH to 9-10, stir and separate, and use water to wash the butapenem organic phase; (4) To the butapenem organic phase of step (3), add hydrogen chloride ethyl alcohol solution, stir, and obtain butapenem hydrochloride by salting-out at a temperature of 50-60°C and crystallization at a temperature of -5-5°C.

2. The production method according to claim 1, characterized by, The molar ratio of the compound of formula I to 3,3-tetramethylene glutarimide in step (1) is 1:1.1.

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