Preparation method of piperaspirone hydrochloride intermediate

Abstract

The invention belongs to the technical field of medicines, and relates to a preparation method of a piperaspirone hydrochloride intermediate. According to the preparation method provided by the invention, a specific amount of isopropanol is used as a solvent, the high-purity compound shown in the formula I can be obtained by directly carrying out hot filtration, crystallization, filtration and drying after the reaction is finished, subsequent operations such as concentration and the like are not needed, the operation is simple and time-saving, the yield is high, the product purity is good, and the method is suitable for industrial production. And the removal effect of 1, 4-dibromobutane (genotoxic impurities) is good (the detection amount is less than 4ppm).

Description

Technical Field

[0001] The invention belongs to the technical field of medicines and relates to a method for preparing a perospirone hydrochloride intermediate. Background Art

[0002] Perospirone hydrochloride tablets were developed by Sumitomo Corporation of Japan and approved by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on December 22, 2000. They are marketed by Sumitomo Corporation of Japan under the trade name Lullan. Perospirone hydrochloride is an atypical antipsychotic that exerts its therapeutic effects by affecting dopamine metabolic pathways and blocking dopamine-2 and 5-HT2 receptors. It is effective for behavioral abnormalities caused by dopamine and serotonin systems. Clinical studies have shown that perospirone is effective for various problematic behaviors caused by hyperactivity of the dopaminergic nervous system and significantly improves negative symptoms and mood disorders that are resistant to traditional antipsychotics. It is widely used in the clinical treatment of schizophrenia. Compared with haloperidol, perospirone hydrochloride has stronger selectivity for the striatum, is less likely to cause extrapyramidal reactions, or causes fewer extrapyramidal side effects, and has better selectivity, clinical safety, and efficacy.

[0003] The preparation of perospirone hydrochloride involves the reaction of cis-hexahydrophthalimide with 1,4-dibromobutane to produce the intermediate cis-N-4-bromobutyl-hexahydrophthalimide. In this reaction, the molar ratio of 1,4-dibromobutane (mutagen): cis-hexahydrophthalimide is greater than 5 to avoid the formation of disubstituted byproducts. However, the large-scale use of 1,4-dibromobutane (mutagen) can affect the health of operators and compromise product purity and safety. Therefore, it is necessary to develop a new method for preparing perospirone hydrochloride to improve its purity and yield while effectively controlling the safety limit of 1,4-dibromobutane.

[0004] CN115873005A discloses a method for preparing 8-(benzisothiazol-3-yl)-5,8-diazaspiro[4,5]decane-5-ammonium bromide. After the reaction is completed, the reaction is filtered hot and the filtrate is concentrated. After concentration, the reaction is crystallized and filtered again. The resulting solid needs to be stirred with solvents such as 1,2-dichloroethane, filtered again, and dried to obtain the intermediate. The operation is complex, many types of organic solvents are required, the amount used is large, and the production cycle is long. Summary of the Invention

[0005] The object of the present invention is to provide a method for preparing and purifying a high-purity compound of formula I, comprising the following steps:

[0006] The compound of formula II (3-(1-piperazinyl)-1,2-benzisothiazole) and 1,4-dibromobutane are dissolved in isopropanol, an inorganic base is added, and a cyclization reaction is carried out under heating conditions to obtain the compound of formula I (8-(benzisothiazol-3-yl)-5,8-diazaspiro[4,5]decane-5-ammonium bromide);

[0007]

[0008] In one or more embodiments of the present application, the mass volume ratio of the 3-(1-piperazinyl)-1,2-benzisothiazole to isopropyl alcohol is 1:15 to 1:30 g / ml, preferably 1:18 to 1:25 g / ml.

[0009] In one or more embodiments of the present application, the mass volume ratio of the 3-(1-piperazinyl)-1,2-benzisothiazole to isopropyl alcohol is 1:19 to 1:24 g / ml, preferably 1:20 to 1:22 g / ml, preferably 1:20 g / ml.

[0010] In one or more embodiments of the present application, the inorganic base is one or more of potassium carbonate, sodium carbonate, and cesium carbonate, preferably potassium carbonate.

[0011] In one or more embodiments of the present application, the molar ratio of 3-(1-piperazinyl)-1,2-benzisothiazole to the inorganic base is 1:1.5 to 1:3.5, preferably 1:1.8 to 1:3.0, and preferably 1:1.8 to 1:2.8.

[0012] In one or more embodiments of the present application, the molar ratio of 3-(1-piperazinyl)-1,2-benzisothiazole to the inorganic base is preferably 1:1.8 to 1:2.5, preferably 1:2.0 to 1:2.5, preferably 1:2.5. In one or more embodiments of the present application, the cyclization reaction is carried out at a temperature of 70 to 85°C, preferably 80 to 85°C.

[0013] In one or more embodiments of the present application, after the cyclization reaction, the steps of heat filtration, crystallization, filtration and drying are further included.

[0014] In one or more embodiments of the present application, the crystallization is carried out at a temperature of -5 to 40°C, preferably -5 to 30°C.

[0015] In one or more embodiments of the present application, the crystallization is carried out at a temperature of 5-25°C, 10-25°C, or 20-25°C.

[0016] In one or more embodiments of the present application, the crystallization temperature is -5 to 25°C, preferably -5 to 20°C, preferably -5 to 15°C, preferably -5 to 10°C, preferably -5 to 5°C.

[0017] In one or more embodiments of the present application, the drying temperature is 40-80°C, preferably 45-70°C, and more preferably 55-65°C.

[0018] Beneficial technical effects of the present invention:

[0019] The preparation method provided by the present invention uses a specific amount of isopropyl alcohol as a solvent. After the reaction is completed, the compound of formula I can be directly obtained by hot filtration, crystallization, filtration, and drying. No subsequent operations such as concentration or re-slurrying are required. The operation is simple and time-saving, the amount of organic solvent used is small, the product yield is high, the purity is good, and the removal effect of 1,4-dibromobutane (a genotoxic impurity) is good (detection amount <4ppm). If other solvents such as methanol or ethanol are used without concentration, the yield is lower. DETAILED DESCRIPTION

[0020] Example

[0021] Comparative Example 1:

[0022] Methanol (400 mL), sodium carbonate (60.4 g), 3-(1-piperazinyl)-1,2-benzisothiazole (50.0 g), and 1,4-dibromobutane (51.5 g) were added to a reaction flask and heated to 60-65°C for reaction. After the reaction, the mixture was filtered hot, and the filtrate was cooled to -5-5°C and stirred for crystallization for 2 hours. The mixture was then filtered and the filter cake was air-dried at 55-65°C to constant weight to obtain 8-(benzisothiazol-3-yl)-5,8-diazaspiro[4,5]decane-5-ammonium bromide. The yield was 41.2%, the liquid phase purity was 99.72%, and the 1,4-dibromobutane content was 36 ppm.

[0023] Comparative Example 2:

[0024] Isopropyl alcohol (400 mL), potassium carbonate (78.6 g), 3-(1-piperazinyl)-1,2-benzisothiazole (50.0 g), and 1,4-dibromobutane (54.2 g) were added to a reaction flask and heated to 80-85°C for reaction. After completion of the reaction, the mixture was filtered hot, and the filtrate was cooled to -5-5°C and stirred for crystallization for 2 hours. The mixture was then filtered, and the filter cake was rinsed with isopropyl alcohol. The filter cake was then air-dried at 55-65°C to constant weight to obtain 8-(benzisothiazol-3-yl)-5,8-diazaspiro[4,5]decane-5-ammonium bromide with a yield of 48.7% and a liquid phase purity of 99.83%. The detected amount of 1,4-dibromobutane was 40 ppm.

[0025] Comparative Example 3:

[0026] Isopropyl alcohol (2000 mL), potassium carbonate (78.6 g), 3-(1-piperazinyl)-1,2-benzisothiazole (50.0 g), and 1,4-dibromobutane (54.2 g) were added to a reaction flask and heated to 80-85°C for reaction. After completion of the reaction, the mixture was filtered hot, and the filtrate was cooled to -5-5°C and stirred for crystallization for 2 hours. The mixture was filtered, and the filter cake was rinsed with isopropyl alcohol. The filter cake was air-dried at 55-65°C to constant weight to obtain 8-(benzisothiazol-3-yl)-5,8-diazaspiro[4,5]decane-5-ammonium bromide with a yield of 63.9% and a liquid phase purity of 99.95%. The detected amount of 1,4-dibromobutane was less than 4 ppm.

[0027] Comparative Example 4

[0028] Methanol (180 mL), sodium carbonate (60.4 g), 3-(1-piperazinyl)-1,2-benzisothiazole (50.0 g), and 1,4-dibromobutane (51.5 g) were added to a reaction flask and heated to 60-65°C for reaction. After the reaction, the mixture was filtered hot, and the filtrate was cooled to -5-5°C and stirred for crystallization for 2 hours. The mixture was then filtered and the filter cake was air-dried at 55-65°C to constant weight to obtain 8-(benzisothiazol-3-yl)-5,8-diazaspiro[4,5]decane-5-ammonium bromide. The yield was 55.3%, the liquid phase purity was 98.99%, and the 1,4-dibromobutane detection level was 120 ppm.

[0029] Example 1:

[0030] Isopropyl alcohol (1000 mL), potassium carbonate (78.6 g), 3-(1-piperazinyl)-1,2-benzisothiazole (50.0 g), and 1,4-dibromobutane (54.2 g) were added to a reaction flask and heated to 80-85°C for reaction. After completion of the reaction, the mixture was filtered hot, and the filtrate was cooled to -5-5°C and stirred for crystallization for 2 hours. The mixture was then filtered, and the filter cake was rinsed with isopropyl alcohol. The filter cake was then air-dried at 55-65°C to constant weight to obtain 8-(benzisothiazol-3-yl)-5,8-diazaspiro[4,5]decane-5-ammonium bromide with a yield of 87.6% and a liquid phase purity of 99.97%. The detected amount of 1,4-dibromobutane was <4 ppm.

[0031] Example 2:

[0032] Isopropyl alcohol (750 mL), potassium carbonate (78.6 g), 3-(1-piperazinyl)-1,2-benzisothiazole (50.0 g), and 1,4-dibromobutane (54.2 g) were added to a reaction flask and heated to 80-85°C for reaction. After the reaction, the mixture was filtered hot, and the filtrate was cooled to -5-5°C and stirred for crystallization for 2 hours. The mixture was filtered, and the filter cake was rinsed with isopropyl alcohol. The filter cake was air-dried at 55-65°C to constant weight to obtain 8-(benzisothiazol-3-yl)-5,8-diazaspiro[4,5]decane-5-ammonium bromide with a yield of 85.3% and a liquid phase purity of 99.96%. The detected amount of 1,4-dibromobutane was less than 4 ppm.

[0033] Example 3:

[0034] Isopropyl alcohol (1500 mL), potassium carbonate (78.6 g), 3-(1-piperazinyl)-1,2-benzisothiazole (50.0 g), and 1,4-dibromobutane (54.2 g) were added to a reaction flask and heated to 80-85°C for reaction. After completion of the reaction, the mixture was filtered hot, and the filtrate was cooled to -5-5°C and stirred for crystallization for 2 hours. The mixture was then filtered, and the filter cake was rinsed with isopropyl alcohol. The filter cake was then air-dried at 55-65°C to constant weight to obtain 8-(benzisothiazol-3-yl)-5,8-diazaspiro[4,5]decane-5-ammonium bromide with a yield of 84.4% and a liquid phase purity of 99.98%. The detected amount of 1,4-dibromobutane was <4 ppm.

[0035] Example 4:

[0036] Isopropyl alcohol (1000 mL), potassium carbonate (78.6 g), 3-(1-piperazinyl)-1,2-benzisothiazole (50.0 g), and 1,4-dibromobutane (54.2 g) were added to a reaction flask and heated to 70-80°C for reaction. After completion of the reaction, the mixture was filtered hot, and the filtrate was cooled to -5-5°C and stirred for crystallization for 2 hours. The mixture was then filtered, and the filter cake was rinsed with isopropyl alcohol. The filter cake was then air-dried at 55-65°C to constant weight to obtain 8-(benzisothiazol-3-yl)-5,8-diazaspiro[4,5]decane-5-ammonium bromide with a yield of 86.4% and a liquid phase purity of 99.95%. The detected amount of 1,4-dibromobutane was <4 ppm.

[0037] Example 5:

[0038] Isopropyl alcohol (1000 mL), potassium carbonate (78.6 g), 3-(1-piperazinyl)-1,2-benzisothiazole (50.0 g), and 1,4-dibromobutane (54.2 g) were added to a reaction flask and heated to 80-85°C for reaction. After completion of the reaction, the mixture was filtered hot, and the filtrate was cooled to 20-30°C and stirred for crystallization for 2 hours. The mixture was filtered, and the filter cake was rinsed with isopropyl alcohol. The filter cake was air-dried at 55-65°C to constant weight to obtain 8-(benzisothiazol-3-yl)-5,8-diazaspiro[4,5]decane-5-ammonium bromide with a yield of 84.7% and a liquid phase purity of 99.96%. The detected amount of 1,4-dibromobutane was less than 4 ppm.

[0039] Example 6:

[0040] Isopropyl alcohol (1000 mL), sodium carbonate (60.4 g), 3-(1-piperazinyl)-1,2-benzisothiazole (50.0 g), and 1,4-dibromobutane (54.2 g) were added to a reaction flask and heated to 80-85°C for reaction. After the reaction, the mixture was filtered hot, and the filtrate was cooled to 20-30°C and stirred for crystallization for 2 hours. The mixture was filtered, and the filter cake was rinsed with isopropyl alcohol. The filter cake was air-dried at 55-65°C to constant weight to obtain 8-(benzisothiazol-3-yl)-5,8-diazaspiro[4,5]decane-5-ammonium bromide with a yield of 85.4% and a liquid phase purity of 99.96%. The detected amount of 1,4-dibromobutane was less than 4 ppm.

Claims

1. A method for preparing a compound of formula I, characterized in that: The method comprises the following steps: dissolving a compound of formula II and 1,4-dibromobutane in isopropanol, adding an inorganic base, and performing a cyclization reaction to obtain a compound of formula I.

2. The preparation method according to claim 1, characterized in that The mass volume ratio of the 3-(1-piperazinyl)-1,2-benzisothiazole to isopropyl alcohol is 1:15 to 1:30 g / ml, preferably 1:18 to 1:25 g / ml.

3. The preparation method according to claim 2, characterized in that The mass volume ratio of the 3-(1-piperazinyl)-1,2-benzisothiazole to isopropyl alcohol is 1:19 to 1:24 g / ml, preferably 1:20 to 1:22 g / ml, preferably 1:20 g / ml.

4. The preparation method according to claim 1, characterized in that The inorganic base is one or more of potassium carbonate, sodium carbonate and cesium carbonate, preferably potassium carbonate.

5. The preparation method according to claim 1, characterized in that The molar ratio of the 3-(1-piperazinyl)-1,2-benzisothiazole to the inorganic base is 1:1.5 to 1:3.5, preferably 1:1.8 to 1:3.0, and preferably 1:1.8 to 1:2.

8.

6. The preparation method according to claim 5, characterized in that The molar ratio of 3-(1-piperazinyl)-1,2-benzisothiazole to the inorganic base is preferably 1:1.8 to 1:2.5, preferably 1:2.0 to 1:2.5, and preferably 1:2.

5.

7. The preparation method according to claim 1, characterized in that The temperature of the cyclization reaction is 70-85°C, preferably 80-85°C.

8. The preparation method according to any one of claims 1 to 7, characterized in that After the cyclization reaction, the method further comprises the steps of heat filtration, crystallization, filtration and drying.

9. The preparation method according to claim 8, characterized in that The crystallization temperature is -5 to 40°C, preferably -5 to 30°C, -5 to 25°C, -5 to 20°C, -5 to 15°C, -5 to 10°C, -5 to 5°C or 20 to 25°C.

10. The preparation method according to claim 8, characterized in that The drying temperature is 40-80°C, preferably 45-70°C, more preferably 55-65°C.

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