Preparation method of paliperidone

Abstract

The invention relates to the technical field of organic chemical synthesis, in particular to a preparation method of paliperidone. According to the invention, the paliperidone crude product is synthesized by adopting a one-pot method, and reaction parameters in synthesis of the first intermediate, the second intermediate and the paliperidone crude product and purification of the paliperidone crude product are optimized, so that the reaction time is shortened, the reaction process is simplified, the purity and yield of the paliperidone are improved, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemical synthesis, and in particular to a method for preparing paliperidone. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] As representatives of antipsychotic drugs, benzisoxazole compounds and their derivatives have excellent antipsychotic activity and are often used as drug intermediates. They are widely used in medicine, pesticides, and preservation.

[0004] Paliperidone, also known as paliperidone and 9-hydroxyrisperidone, is a commonly used antipsychotic drug and a derivative of the benzisoxazole antipsychotic drug. It was originally developed by Johnson & Johnson in the United States and is a second-generation antipsychotic drug. It was first approved for marketing by the US FDA in December 2006 and was approved by the CFDA in China in 2008 for the treatment of adult schizophrenia. Its trade name is It was subsequently approved by CFDA in 2017 for the treatment of adolescent schizophrenia.

[0005] There are many reports on the preparation methods of paliperidone, however, these preparation methods have the following problems: first, they are obtained by multi-step processes, and each reaction step requires separation and purification, resulting in a long production cycle, high production energy consumption and labor costs, and poor atom economy; second, the amount of "three wastes" generated is large, the total yield is low, and the production cost is very high; in addition, the preparation reaction time is long, the purity of the obtained paliperidone product is poor, and the yield of the refining process is low. These problems are key technical issues that restrict the large-scale production of paliperidone. Summary of the invention

[0006] In order to solve the deficiencies of the prior art, the present invention provides a preparation method of paliperidone, which utilizes a one-pot synthesis method, has a short production cycle, a small amount of three wastes output, is green and environmentally friendly, has a high yield, and has good process safety; the mixed solvent refining and impurity removal process has a high yield, and the purity of the prepared paliperidone product can reach more than 99.93%. 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.

[0007] In order to achieve the above technical objectives, the present invention adopts the following technical solutions:

[0008] A method for preparing paliperidone comprises the following steps:

[0009] (1) dispersing the raw materials 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and hydroxylamine hydrochloride in 2-methyltetrahydrofuran, adjusting the pH of the reaction system to 5-6, and reacting to obtain a first intermediate;

[0010] (2) adjusting the pH of the reaction system to 8-12, and reacting to obtain a second intermediate;

[0011] (3) adding water to the reaction system, separating the liquids, and collecting the organic phase; adding a base and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one to the organic phase to react and generate a crude paliperidone;

[0012] The structural formula of the first intermediate is as follows:

[0013]

[0014] The structural formula of the second intermediate is as follows:

[0015]

[0016] In one or more embodiments, in step (1), the base used to adjust the pH of the reaction system is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate and triethylamine, preferably sodium hydroxide.

[0017] Preferably, the mass fraction of the sodium hydroxide, potassium hydroxide, potassium carbonate and cesium carbonate aqueous solution is 25-35%; the mass fraction of lithium hydroxide is 5-10%.

[0018] In one or more embodiments, in step (1), the molar ratio of the raw materials 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and hydroxylamine hydrochloride is 1:(1.1-2.0), preferably 1:(1.5-1.7), and more preferably 1:1.5.

[0019] In one or more embodiments, in step (1), the amount of 2-methyltetrahydrofuran added is 5 to 25 times the volume of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride, preferably 10 to 20 times the volume, and more preferably 15 times the volume.

[0020] In one or more embodiments, in step (1), the reaction temperature is 50 to 80° C., preferably 60 to 80° C., and more preferably 70 to 80° C.; the reaction time is 1 to 5 hours, and preferably 2 to 3 hours.

[0021] In one or more embodiments, in step (2), the base used to adjust the pH of the reaction system is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate and triethylamine, preferably sodium hydroxide.

[0022] Preferably, the mass fraction of the sodium hydroxide, potassium hydroxide, potassium carbonate and cesium carbonate aqueous solution is 25-35%; the mass fraction of lithium hydroxide is 5-10%.

[0023] In one or more embodiments, in step (2), the pH of the reaction system is adjusted to 8-12, preferably 10-11.

[0024] In one or more embodiments, in step (2), the reaction temperature is 30 to 80° C., preferably 50 to 80° C., and more preferably 50 to 60° C.; the reaction time is 1 to 5 h, and preferably 2 to 3 h.

[0025] In one or more embodiments, in step (3), the base is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, pyridine, and sodium hydroxide; preferably cesium carbonate, potassium carbonate, or sodium carbonate, and more preferably cesium carbonate.

[0026] Preferably, the concentrations of the aqueous solutions of sodium hydroxide, potassium carbonate and cesium carbonate are 25-35%; the concentration of the aqueous solution of sodium carbonate is 10-17%; and the concentration of the aqueous solution of sodium bicarbonate is 5-10%.

[0027] In one or more embodiments, in step (3), the molar ratio of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride to 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is 1:(1 to 1.7), preferably 1:(1.4 to 1.7), and more preferably 1:1.5.

[0028] In one or more embodiments, in step (3), the molar ratio of the base to 4-(2,4-difluorobenzoyl)-piperidine hydrochloride is (1.3-3.0):1, preferably (1.5-2.5):1, and more preferably (1.9-2):1.

[0029] In one or more embodiments, in step (3), water is added after the reaction system is cooled to 20-30°C.

[0030] In one or more embodiments, the crude paliperidone is recrystallized to obtain paliperidone.

[0031] Preferably, the recrystallization temperature is first raised to 60-80°C and the crude paliperidone is added, and then the temperature is lowered to 0-5°C and kept warm; wherein the keeping time is 2-6h.

[0032] Preferably, the solvent used for recrystallization is selected from methanol, anhydrous ethanol, isopropanol, 60% ethanol (volume ratio), isopropanol / water, NMP (N-methyl-2-pyrrolidone), isopropanol / water / NMP, preferably isopropanol, 60% ethanol, isopropanol / water or isopropanol / water / NMP, further preferably isopropanol / water / NMP (N-methyl-2-pyrrolidone).

[0033] Further preferably, in isopropanol / water / NMP, the volume ratio of isopropanol, water and NMP is (12-20):(3-8):(0.5-1.5), preferably 15:(5-8):(0.5-1), and further preferably 15:5:1.

[0034] Preferably, in step (4), the amount of the recrystallization solvent added is 5 to 15 times the volume of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride, preferably 7 to 10 times the volume, and more preferably 9 to 11 times the volume.

[0035] The beneficial effects of the present invention are:

[0036] (1) The present invention adopts a "one-pot method" to synthesize the crude paliperidone. By optimizing the reaction parameters in the synthesis of the first intermediate, the second intermediate, the crude paliperidone and the purification of the crude paliperidone, not only the reaction time is shortened and the reaction process is simplified, but also the purity and yield of paliperidone are improved, which is suitable for industrial production.

[0037] (2) In the present invention, by specifically screening different alkaline reagents, a common alkaline reagent for synthesizing the first intermediate and the second intermediate is obtained, which saves a lot of post-processing time and post-processing materials, reduces the use of volatile alkaline reagents, greatly reduces the cost of paliperidone preparation, and improves the operability of the process. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0039] Figure 1 The synthetic route for preparing paliperidone in the present invention;

[0040] Figure 2 is the H NMR spectrum of paliperidone prepared in Example 13;

[0041] Figure 3 is the liquid phase spectrum of paliperidone prepared in Example 13;

[0042] Figure 4is the mass spectrum of paliperidone prepared in Example 13. DETAILED DESCRIPTION

[0043] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0044] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and / or "including" are used in this specification, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.

[0045] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0046] Figure 1 For the synthetic route of paliperidone preparation in the present invention, refer to Figure 1 Synthesis of paliperidone.

[0047] Example 1: Effect of different reaction solvents on the preparation of paliperidone

[0048] (1) Add 300 mL of reaction solvent to a 500 mL three-necked reaction bottle, start stirring, add 20.0 g of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and 7.97 g of hydroxylamine hydrochloride. Add 30% sodium hydroxide aqueous solution to adjust the pH to 5, heat to 75±5°C after the addition, and react for 2 h.

[0049] (2) The reaction system was cooled to 55±5°C, 30% sodium hydroxide aqueous solution was added dropwise to adjust the pH to 11, and the reaction was kept warm for 2 h.

[0050] (3) The reaction system was cooled to 25±5°C, 80 mL of purified water was added under stirring, the liquids were separated, and the aqueous phase was discarded. The organic phase was transferred to a 500 mL three-necked reaction bottle, 165.0 g of 30% cesium carbonate aqueous solution was added under stirring, 28.6 g of TMP was added, and the reaction was heated to 75±5°C for 5 h, cooled to 5±5°C, stirred for crystallization for 2 h, filtered, and the filter cake was dried to obtain the crude product of paliperidone.

[0051] (4) Add 150 mL of isopropanol, 50 mL of purified water, and 10 mL of DMSO to a 500 mL three-necked reaction flask, heat the system to 65±5°C, add 10.0 g of crude paliperidone, stir until dissolved, cool to 0°C, keep stirring for 4 h, filter, and dry the filter cake to obtain paliperidone.

[0052] Detection method: High performance liquid chromatography

[0053] Method source: USP NF 2024 Paliperidone

[0054] The effects of using different types of solvents in step (1) on the yield and purity of paliperidone are shown in Table 1.

[0055] Table 1

[0056]

[0057]

[0058] The experimental results show that the target product cannot be prepared using anhydrous ethanol, isopropanol and methanol as reaction solvents. The target product can be obtained using 2-methyltetrahydrofuran, n-butanol, toluene and chloroform, but the yield and quality are quite different. Using 2-methyltetrahydrofuran has the best effect.

[0059] Example 2: Effect of different bases 1 on the preparation of paliperidone

[0060] (1) Add 300 mL of 2-methyltetrahydrofuran to a 500 mL three-necked reaction bottle, start stirring, add 20.0 g of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and 7.97 g of hydroxylamine hydrochloride. Add base 1 dropwise to adjust the pH to 5. After the addition is complete, heat to 75±5°C and react for 2 h.

[0061] (2) The reaction system was cooled to 55±5°C, and alkali 1 was added dropwise to adjust the pH to 11. The reaction was kept warm for 2 h.

[0062] (3) The reaction system was cooled to 25±5°C, 80 mL of purified water was added under stirring, the liquids were separated, and the aqueous phase was discarded. The organic phase was transferred to a 500 mL three-necked reaction bottle, 165.0 g of 30% cesium carbonate aqueous solution was added under stirring, 28.6 g of TMP was added, and the reaction was heated to 75±5°C for 5 h, cooled to 5±5°C, stirred for crystallization for 2 h, filtered, and the filter cake was dried to obtain the crude product of paliperidone.

[0063] (4) Add 150 mL of isopropanol, 50 mL of purified water, and 10 mL of DMSO to a 500 mL three-necked reaction flask, heat the system to 65±5°C, add 10.0 g of crude paliperidone, stir until dissolved, cool to 0°C, keep stirring for 4 h, filter, and dry the filter cake to obtain paliperidone.

[0064] Detection method: High performance liquid chromatography

[0065] Method source: USP NF 2024 Paliperidone

[0066] The effect of using base 1 in step (1) on the yield and purity of paliperidone is shown in Table 2.

[0067] Table 2

[0068]

[0069]

[0070] The experimental results show that the target product can be obtained by selecting 30% sodium hydroxide aqueous solution, 30% potassium hydroxide aqueous solution, 30% potassium carbonate aqueous solution, 30% cesium carbonate aqueous solution, 10% lithium hydroxide aqueous solution and triethylamine, but the yield and quality are quite different. The use of 30% sodium hydroxide aqueous solution has the best effect.

[0071] Example 3: Effect of different step (1) reaction temperatures on the preparation of paliperidone

[0072] (1) Add 300 mL of 2-methyltetrahydrofuran to a 500 mL three-necked reaction bottle, start stirring, add 20.0 g of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and 7.97 g of hydroxylamine hydrochloride. Add 30% sodium hydroxide aqueous solution dropwise to adjust the pH to 5. After the addition is complete, heat to the reaction temperature and react for 2 h.

[0073] (2) Adjust the reaction liquid temperature to 55±5°C, add 30% sodium hydroxide aqueous solution to adjust the pH to 11, and keep the reaction warm for 2 hours.

[0074] (3) The reaction system was cooled to 25±5°C, 80 mL of purified water was added under stirring, the liquids were separated, and the aqueous phase was discarded. The organic phase was transferred to a 500 mL three-necked reaction bottle, 165.0 g of 30% cesium carbonate aqueous solution was added under stirring, 28.6 g of TMP was added, and the reaction was heated to 75±5°C for 5 h, cooled to 5±5°C, stirred for crystallization for 2 h, filtered, and the filter cake was dried to obtain the crude product of paliperidone.

[0075] (4) Add 150 mL of isopropanol, 50 mL of purified water, and 10 mL of DMSO to a 500 mL three-necked reaction flask, heat the system to 65±5°C, add 10.0 g of crude paliperidone, stir until dissolved, cool to 0°C, keep stirring for 4 h, filter, and dry the filter cake to obtain paliperidone.

[0076] Detection method: High performance liquid chromatography

[0077] Method source: USP NF 2024 Paliperidone

[0078] The effect of the reaction temperature in step (1) on the yield and purity of paliperidone is shown in Table 3.

[0079] Table 3

[0080] Serial number Step (1) Reaction temperature (°C) Yield (%) purity(%) 1 35±5(30～40) — — 2 40±5(40～50) — — 3 55±5(50～60) 27.5 76.74 4 65±5(60～70) 45.2 90.66 5 75±5(70～80) 75.6 99.93

[0081] The experimental results show that the target product can be obtained in step (1) at a temperature within the range of 50 to 80°C. Taking into account factors such as yield and quality, the optimal condition is 75±5°C.

[0082] Example 4: Effect of different step (1) feed ratios on the preparation of paliperidone

[0083] (1) Add 300 mL of 2-methyltetrahydrofuran to a 500 mL three-necked reaction bottle, start stirring, add 20.0 g of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride, and different amounts of hydroxylamine hydrochloride. Add 30% sodium hydroxide aqueous solution to adjust the pH to 5. After the addition is complete, heat to 75±5°C and react for 2 h.

[0084] (2) Adjust the temperature of the reaction solution to 55±5°C, add 30% sodium hydroxide aqueous solution to adjust the pH to 11, and keep the temperature to react for 2 hours.

[0085] (3) The reaction system was cooled to 25±5°C, 80 mL of purified water was added under stirring, the liquids were separated, and the aqueous phase was discarded. The organic phase was transferred to a 500 mL three-necked reaction bottle, 165.0 g of 30% cesium carbonate aqueous solution was added under stirring, 28.6 g of TMP was added, and the reaction was heated to 75±5°C for 5 h, cooled to 5±5°C, stirred for crystallization for 2 h, filtered, and the filter cake was dried to obtain the crude product of paliperidone.

[0086] (4) Add 150 mL of isopropanol, 50 mL of purified water, and 10 mL of DMSO to a 500 mL three-necked reaction flask, heat the system to 65±5°C, add 10.0 g of crude paliperidone, stir until dissolved, cool to 0°C, keep stirring for 4 h, filter, and dry the filter cake to obtain paliperidone.

[0087] Detection method: High performance liquid chromatography

[0088] Method source: USP NF 2024 Paliperidone

[0089] The effect of the molar ratio of step (1) 4-(2,4-difluorobenzoyl)-piperidine hydrochloride:hydroxylamine hydrochloride on the yield and purity of paliperidone is shown in Table 4.

[0090] Table 4

[0091]

[0092] The experimental results show that the target product can be obtained in the range of 1:(1.1-2.0) for the molar ratio of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride:hydroxylamine hydrochloride in step (1), and a target product of higher quality can be obtained in the range of 1:(1.5-2.0). Considering the comprehensive yield, quality and other factors, the optimal condition is 1:1.5.

[0093] Example 5: Effect of different step (2) reaction pH on the preparation of paliperidone

[0094] (1) Add 300 mL of 2-methyltetrahydrofuran to a 500 mL three-necked reaction bottle, start stirring, add 20.0 g of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and 7.97 g of hydroxylamine hydrochloride. Add 30% sodium hydroxide aqueous solution dropwise to adjust the pH to 5. After the addition is complete, heat to 75±5°C and react for 2 h.

[0095] (2) The reaction system was cooled to 55±5°C, 30% sodium hydroxide aqueous solution was added dropwise to adjust the pH value to the target value, and the reaction was kept warm for 2 h.

[0096] (3) The reaction system was cooled to 25±5°C, 80 mL of purified water was added under stirring, the liquids were separated, and the aqueous phase was discarded. The organic phase was transferred to a 500 mL three-necked reaction bottle, 165.0 g of 30% cesium carbonate aqueous solution was added under stirring, 28.6 g of TMP was added, and the reaction was heated to 75±5°C for 5 h, cooled to 5±5°C, stirred for crystallization for 2 h, filtered, and the filter cake was dried to obtain the crude product of paliperidone.

[0097] (4) Add 150 mL of isopropanol, 50 mL of purified water, and 10 mL of DMSO to a 500 mL three-necked reaction flask, heat the system to 65±5°C, add 10.0 g of crude paliperidone, stir until dissolved, cool to 0-5°C, keep stirring for 4 h, filter, and dry the filter cake to obtain paliperidone.

[0098] Detection method: High performance liquid chromatography

[0099] Method source: USP NF 2024 Paliperidone

[0100] The effect of the reaction pH value in step (2) on the yield and purity of paliperidone is shown in Table 4.

[0101] Table 5

[0102] Serial number Step (2) pH value of reaction solution Yield (%) purity(%) 1 7 — — 2 8 24.4 87.20 3 9 30.4 92.47 4 10 55.2 97.82 5 11 75.6 99.93 6 12 44.6 93.47

[0103] It should be noted that, unless it is a special process, the actual controlled value of the pH value of the reaction liquid in the actual production process is a range value rather than a specific value.

[0104] The experimental results show that the target product can be obtained when the pH value of step (2) is in the range of 8 to 12, and a target product of higher quality can be obtained in the range of 8 to 12. Considering factors such as yield and quality, the optimal pH value is 10 to 11.

[0105] Example 6: Effect of different step (2) reaction temperatures on the preparation of paliperidone

[0106] (1) Add 300 mL of 2-methyltetrahydrofuran to a 500 mL three-necked reaction bottle, start stirring, add 20.0 g of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and 7.97 g of hydroxylamine hydrochloride. Add 30% sodium hydroxide aqueous solution dropwise to adjust the pH to 5. After the addition is complete, heat to 75±5°C and react for 2 h.

[0107] (2) The reaction system was adjusted to the reaction temperature, 30% sodium hydroxide aqueous solution was added dropwise to adjust the pH to 11, and the reaction was kept warm for 2 hours.

[0108] (3) The reaction system was cooled to 25±5°C, 80 mL of purified water was added under stirring, the liquids were separated, and the aqueous phase was discarded. The organic phase was transferred to a 500 mL three-necked reaction bottle, 165.0 g of 30% cesium carbonate aqueous solution was added under stirring, 28.6 g of TMP was added, and the reaction was heated to 75±5°C for 5 h, cooled to 5±5°C, stirred for crystallization for 2 h, filtered, and the filter cake was dried to obtain the crude product of paliperidone.

[0109] (4) Add 150 mL of isopropanol, 50 mL of purified water, and 10 mL of DMSO to a 500 mL three-necked reaction flask, heat the system to 65±5°C, add 10.0 g of crude paliperidone, stir until dissolved, cool to 0°C, keep stirring for 4 h, filter, and dry the filter cake to obtain paliperidone.

[0110] Detection method: High performance liquid chromatography

[0111] Method source: USP NF 2024 Paliperidone

[0112] The effect of the reaction temperature in step (2) on the yield and purity of paliperidone is shown in Table 5.

[0113] Table 6

[0114] Serial number Step (2) reaction temperature (°C) Yield (%) purity(%) 1 15±5(10～20) — — 2 25±5(20～30) — — 3 30±5(30～40) 27.2 90.63 4 40±5(40～50) 39.7 92.83 5 55±5(50～60) 75.6 99.93 6 60±5(60～70) 58.7 96.86 7 70±5(70～80) 50.5 95.95

[0115] The experimental results show that the target product can be obtained in step (2) at a temperature in the range of 30 to 80°C, and a target product of higher quality can be obtained in the range of 50 to 80°C. Considering the yield, quality and other factors, the optimal condition is 55±5°C.

[0116] Example 7: Effect of different bases 2 on the preparation of paliperidone

[0117] (1) Add 300 mL of 2-methyltetrahydrofuran to a 500 mL three-necked reaction bottle, start stirring, add 20.0 g of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and 7.97 g of hydroxylamine hydrochloride. Add 30% sodium hydroxide aqueous solution dropwise to adjust the pH to 5. After the addition is complete, heat to 75±5°C and react for 2 h.

[0118] (2) The reaction system was cooled to 55±5°C, 30% sodium hydroxide aqueous solution was added dropwise to adjust the pH to 11, and the reaction was kept warm for 2 h.

[0119] (3) The reaction system was cooled to 25±5°C, 80 mL of purified water was added under stirring, the liquids were separated, and the aqueous phase was discarded. Different bases 2 were added to the reaction system in an amount of 0.15 mol, 28.6 g of TMP was added, the reaction was heated to 75±5°C for 5 h, the temperature was cooled to 5±5°C, stirred for crystallization for 2 h, filtered, and the filter cake was dried to obtain the crude product of paliperidone.

[0120] (4) Add 150 mL of isopropanol, 50 mL of purified water, and 10 mL of DMSO to a 500 mL three-necked reaction flask, heat the system to 65±5°C, add 10.0 g of crude paliperidone, stir until dissolved, cool to 0°C, keep stirring for 4 h, filter, and dry the filter cake to obtain paliperidone.

[0121] Detection method: High performance liquid chromatography

[0122] Method source: USP NF 2024 Paliperidone

[0123] The effect of using base 2 in step (3) on the yield and purity of paliperidone is shown in Table 6.

[0124] Table 7

[0125] Serial number Base 2 Yield (%) purity(%) 1 30% cesium carbonate aqueous solution 75.6 99.95 2 30% potassium carbonate aqueous solution 43.5 93.25 3 30% sodium hydroxide aqueous solution 20.3 84.47 4 10% sodium carbonate aqueous solution 35.0 90.84 5 6% sodium bicarbonate aqueous solution 18.3 79.69 6 Triethylamine 27.3 88.46 7 Pyridine 27.9 86.11 8 Potassium tert-butoxide — — 9 Sodium Methanol — —

[0126] The experimental results show that the target product 2 cannot be prepared using potassium tert-butoxide and sodium methoxide as base 2. The target product can be obtained by using 30% cesium carbonate aqueous solution, 30% sodium hydroxide aqueous solution, 30% potassium carbonate aqueous solution, 10% sodium carbonate aqueous solution, 6% sodium bicarbonate aqueous solution, triethylamine and pyridine. Considering the comprehensive yield, quality and other factors, 30% cesium carbonate aqueous solution has the best effect.

[0127] Example 8: Effect of different feed ratios of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and TMP on the preparation of paliperidone

[0128] (1) Add 300 mL of 2-methyltetrahydrofuran to a 500 mL three-necked reaction bottle, start stirring, add 20.0 g of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and 7.97 g of hydroxylamine hydrochloride. Add 30% sodium hydroxide aqueous solution dropwise to adjust the pH to 5. After the addition is complete, heat to 75±5°C and react for 2 h.

[0129] (2) The reaction system was cooled to 55±5°C, 30% sodium hydroxide aqueous solution was added dropwise to adjust the pH to 11, and the reaction was kept warm for 2 h.

[0130] (3) The reaction system was cooled to 25±5°C, 80 mL of purified water was added under stirring, the liquids were separated, and the aqueous phase was discarded. 165.0 g of 30% cesium carbonate aqueous solution was added to the reaction system, and different amounts of TMP were added. The reaction system was heated to 75±5°C for 5 h, cooled to 5±5°C, stirred for crystallization for 2 h, filtered, and the filter cake was dried to obtain the crude product of paliperidone.

[0131] (4) Add 150 mL of isopropanol, 50 mL of purified water, and 10 mL of DMSO to a 500 mL three-necked reaction flask, heat the system to 65±5°C, add 10.0 g of crude paliperidone, stir until dissolved, cool to 0°C, keep stirring for 4 h, filter, and dry the filter cake to obtain paliperidone.

[0132] Detection method: High performance liquid chromatography

[0133] Method source: USP NF 2024 Paliperidone

[0134] The effects of different feed molar ratios of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride to TMP on the yield and purity are shown in Table 7.

[0135] Table 8

[0136]

[0137]

[0138] The experimental results show that the target product can be obtained when the molar ratio of the starting material to TMP is in the range of 1 to 1.7, among which the target product with a higher yield can be obtained in the range of 1:1.4 to 1.7. Considering the yield, quality and other factors, the optimal molar ratio is 1:1.5.

[0139] Example 9: Effect of reaction temperature ratio in step (3) on the preparation of paliperidone

[0140] (1) Add 300 mL of 2-methyltetrahydrofuran to a 500 mL three-necked reaction bottle, start stirring, add 20.0 g of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and 7.97 g of hydroxylamine hydrochloride. Add 30% sodium hydroxide aqueous solution dropwise to adjust the pH to 5. After the addition is complete, heat to 75±5°C and react for 2 h.

[0141] (2) The reaction system was cooled to 55±5°C, 30% sodium hydroxide aqueous solution was added dropwise to adjust the pH to 11, and the reaction was kept warm for 2 h.

[0142] (3) The reaction system was cooled to 25±5°C, 80 mL of purified water was added under stirring, the liquid was separated, and the aqueous phase was discarded. 165.0 g of 30% cesium carbonate aqueous solution and 28.6 g of TMP were added to the reaction system, the reaction system was heated to the reaction temperature for 5 h, the reaction solution was cooled to 5±5°C and stirred for crystallization for 2 h, filtered, and the filter cake was dried to obtain the crude product of paliperidone.

[0143] (4) Add 150 mL of isopropanol, 50 mL of purified water, and 10 mL of DMSO to a 500 mL three-necked reaction flask, heat the system to 65±5°C, add 10.0 g of crude paliperidone, stir until dissolved, cool to 0°C, keep stirring for 4 h, filter, and dry the filter cake to obtain paliperidone.

[0144] Detection method: High performance liquid chromatography

[0145] Method source: USP NF 2024 Paliperidone

[0146] The effect of step (3) reaction temperature on the yield and purity of paliperidone is shown in Table 8.

[0147] Table 9

[0148] Serial number Step (3) Reaction temperature (°C) Yield (%) purity(%) 1 35±5(30～40) — — 2 55+5(50～60) 23.1 86.46 3 65±5(60～70) 58.6 95.23 4 75±5(70～80) 75.6 99.93

[0149] The experimental results show that the target product can be obtained in step (3) at a reaction temperature in the range of 50 to 80°C, among which the target product with a better yield can be obtained at 60 to 80°C. Considering the yield, quality and other factors, the optimal condition is 75±5 (70 to 80)°C.

[0150] Example 10: Effect of the crystallization temperature ratio in step (3) on the preparation of paliperidone

[0151] (1) Add 300 mL of 2-methyltetrahydrofuran to a 500 mL three-necked reaction bottle, start stirring, add 20.0 g of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and 7.97 g of hydroxylamine hydrochloride. Add 30% sodium hydroxide aqueous solution dropwise to adjust the pH to 5. After the addition is complete, heat to 75±5°C and react for 2 h.

[0152] (2) The reaction system was cooled to 55±5°C, 30% sodium hydroxide aqueous solution was added dropwise to adjust the pH to 11, and the reaction was kept warm for 2 h.

[0153] (3) The reaction system was cooled to 25±5°C, 80 mL of purified water was added under stirring, the liquid was separated, and the aqueous phase was discarded. 165.0 g of 30% cesium carbonate aqueous solution and 28.6 g of TMP were added to the reaction system, the reaction solution was heated to 75±5°C, reacted for 5 h, the reaction solution was cooled to the crystallization temperature, stirred and crystallized for 2 h, filtered, and the filter cake was dried to obtain the crude product of paliperidone.

[0154] (4) Add 150 mL of isopropanol, 50 mL of purified water, and 10 mL of DMSO to a 500 mL three-necked reaction flask, heat the system to 65±5°C, add 10.0 g of crude paliperidone, stir until dissolved, cool to 0°C, keep stirring for 4 h, filter, and dry the filter cake to obtain paliperidone.

[0155] Detection method: High performance liquid chromatography

[0156] Method source: USP NF 2024 Paliperidone

[0157] The effect of the crystallization temperature in step (3) on the yield and purity of paliperidone is shown in Table 9.

[0158] Table 10

[0159] Serial number Step (3) Crystallization temperature (°C) Yield (%) purity(%) 1 -5±5(-10～0) 75.3 97.43 2 5±5(0～10) 75.6 99.93 3 15±5(10～20) 56.5 99.16

[0160] The experimental results show that the target product can be obtained in the crystallization temperature range of -10 to 20°C in step (3), and the target product with a higher yield can be obtained in the range of -10 to 10°C. Considering the yield, quality and other factors, the optimal crystallization temperature is 5±5°C.

[0161] Example 11: Effect of the type of refining solvent in step (4) on the preparation of paliperidone

[0162] (1) Add 300 mL of 2-methyltetrahydrofuran to a 500 mL three-necked reaction bottle, start stirring, add 20.0 g of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and 7.97 g of hydroxylamine hydrochloride. Add 30% sodium hydroxide aqueous solution dropwise to adjust the pH to 5. After the addition is complete, heat to 75±5°C and react for 2 h.

[0163] (2) The reaction system was cooled to 55±5°C, 30% sodium hydroxide aqueous solution was added dropwise to adjust the pH to 11, and the reaction was kept warm for 2 h.

[0164] (3) The reaction system was cooled to 25±5°C, 80 mL of purified water was added under stirring, the liquid was separated, and the aqueous phase was discarded. 165.0 g of 30% cesium carbonate aqueous solution and 28.6 g of TMP were added to the reaction system, the reaction solution was heated to 75±5°C, reacted for 5 h, the reaction solution was cooled to 5±5°C, stirred and crystallized for 2 h, filtered, and the filter cake was dried to obtain the crude product of paliperidone.

[0165] (4) Add 210 mL of refined solvents of different types to a 500 mL three-necked reaction bottle, add 10.0 g of crude paliperidone under stirring, heat the system to 65±5° C., adjust the amount of solvent and stir until dissolved, cool to 0° C., keep warm and stir for 4 h, filter, and dry the filter cake to obtain paliperidone.

[0166] Detection method: High performance liquid chromatography

[0167] Method source: USP NF 2024 Paliperidone

[0168] The effect of the type of refining solvent in step (4) on the preparation of paliperidone is shown in Table 11.

[0169] Table 11

[0170] Serial number Types of Refining Solvents Yield (%) purity(%) 1 Methanol 65.7 98.71 2 Anhydrous ethanol 75.6 98.55 3 Isopropyl alcohol 80.3 98.11 4 60% ethanol 88.7 98.31 5 Isopropyl alcohol:water (V / V=3:1) 90.2 99.13 6 N-Methyl-2-pyrrolidone (NMP) 35.6 99.36 7 Isopropyl alcohol: water: NMP (V / V / V = 15:5:1) 95.6 99.93

[0171] The experimental results show that the use of methanol, anhydrous ethanol, isopropanol, 60% ethanol, isopropanol / water, NMP, isopropanol / water / NMP as refining solvents all have certain purification effects. Among them, isopropanol, 60% ethanol, isopropanol / water or isopropanol / water / NMP can obtain the target product with better yield, and the best solvent system is isopropanol / water / NMP.

[0172] Example 12: Effect of the Refining Solvent Ratio in Step (4) on the Preparation of Paliperidone

[0173] (1) Add 300 mL of 2-methyltetrahydrofuran to a 500 mL three-necked reaction bottle, start stirring, add 20.0 g of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and 7.97 g of hydroxylamine hydrochloride. Add 30% sodium hydroxide aqueous solution dropwise to adjust the pH to 5. After the addition is complete, heat to 75±5°C and react for 2 h.

[0174] (2) The reaction system was cooled to 55±5°C, 30% sodium hydroxide aqueous solution was added dropwise to adjust the pH to 11, and the reaction was kept warm for 2 h.

[0175] (3) The reaction system was cooled to 25±5°C, 80 mL of purified water was added under stirring, the liquid was separated, and the aqueous phase was discarded. 165.0 g of 30% cesium carbonate aqueous solution and 28.6 g of TMP were added to the reaction system, the reaction solution was heated to 75±5°C, reacted for 5 h, the reaction solution was cooled to 5±5°C, stirred and crystallized for 2 h, filtered, and the filter cake was dried to obtain the crude product of paliperidone.

[0176] (4) Add different proportions of isopropanol / water / NMP to a 500 mL three-necked reaction flask, wherein the total volume of isopropanol / water / NMP is 210 mL, add 10.0 g of crude paliperidone under stirring, heat the system to 65±5° C., adjust the amount of solvent and stir until dissolved, cool to 0° C., keep warm and stir for 4 h, filter, and dry the filter cake to obtain paliperidone.

[0177] Detection method: High performance liquid chromatography

[0178] Method source: USP NF 2024 Paliperidone

[0179] The effect of the type of refining solvent in step (4) on the preparation of paliperidone is shown in Table 11.

[0180] Table 12

[0181] Serial number Isopropyl alcohol / water / NMP solvent volume ratio Yield (%) purity(%) 1 12:3:0.5 82.7 99.91 2 12:5:0.7 85.6 99.55 3 15:5:1 95.6 99.93 4 20:5:1 88.7 99.31 5 15:8:0.5 92.2 99.13 6 15:5:1.5 80.6 99.76 7 20:8:1.5 86.9 99.92

[0182] The experimental results show that a better refining effect is achieved when the volume ratio of isopropanol, water and NMP is 12-20:3-8:0.5-1.5, among which the yield exceeds 90% when the volume ratio is 15:(5-8):(0.5-1), and the optimal solvent ratio is 15:5:1.

[0183] Example 13: Preparation of paliperidone by the best technical solution of the present invention

[0184] (1) Add 300 mL of 2-methyltetrahydrofuran to a 500 mL three-necked reaction bottle, start stirring, add 20.0 g of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and 7.97 g of hydroxylamine hydrochloride. Add 30% sodium hydroxide aqueous solution dropwise to adjust the pH to 5. After the addition is complete, heat to 75±5°C and react for 2 h.

[0185] (2) The reaction system was cooled to 55±5°C, 30% sodium hydroxide aqueous solution was added dropwise to adjust the pH to 11, and the reaction was kept warm for 2 h.

[0186] (3) The reaction system was cooled to 25±5°C, 80 mL of purified water was added under stirring, the liquid was separated, and the aqueous phase was discarded. 165.0 g of 30% cesium carbonate aqueous solution and 28.6 g of TMP were added to the reaction system, the reaction solution was heated to 75±5°C, reacted for 5 h, the reaction solution was cooled to 5±5°C, stirred and crystallized for 2 h, filtered, and the filter cake was dried to obtain the crude product of paliperidone.

[0187] (4) To a 500-mL three-necked reaction flask, add 210 mL of isopropanol / water / NMP (V / V / V=15:5:1), add 10.0 g of crude paliperidone under stirring, heat the system to 65±5° C., stir until dissolved, cool to 0° C., keep stirring for 4 h, filter, and dry the filter cake to obtain paliperidone.

[0188] Figure 2 is the H NMR spectrum of paliperidone prepared in this example; Figure 3 is the liquid phase spectrum, Figure 4 For the mass spectrum.

[0189] The experimental results show that the one-pot method for preparing paliperidone reported in the present invention has significantly improved yield and purity compared with the prior art. The present invention reduces the amount of "three wastes" generated, improves atom economy, shortens the production cycle, improves production efficiency, greatly reduces the cost of paliperidone, and is suitable for industrial production.

[0190] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing paliperidone, characterized in that: The following steps are involved: (1) dispersing the raw materials 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and hydroxylamine hydrochloride in 2-methyltetrahydrofuran, adjusting the pH of the reaction system to 5-6, and reacting to obtain a first intermediate; (2) adjusting the pH of the reaction system to 8-12, and reacting to obtain a second intermediate; (3) adding water to the reaction system, separating the liquids, and collecting the organic phase; adding a base and 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one to the organic phase to react and generate a crude paliperidone; The structural formula of the first intermediate is as follows: The structural formula of the second intermediate is as follows:

2. The preparation method according to claim 2, characterized in that: In step (1), the base used to adjust the pH of the reaction system is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, and triethylamine, preferably sodium hydroxide; Preferably, the mass fraction of the sodium hydroxide, potassium hydroxide, potassium carbonate and cesium carbonate aqueous solution is 25-35%; the mass fraction of lithium hydroxide is 5-10%.

3. The preparation method according to claim 2, characterized in that: In step (1), the molar ratio of the raw material 4-(2,4-difluorobenzoyl)-piperidine hydrochloride to hydroxylamine hydrochloride is 1:(1.1-2.0), preferably 1:(1.5-1.7), and more preferably 1:1.5; Alternatively, in step (1), the amount of 2-methyltetrahydrofuran added is 5 to 25 times the volume of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride, preferably 10 to 20 times the volume, and more preferably 15 times the volume.

4. The preparation method according to claim 2, characterized in that: In step (1), the reaction temperature is 50 to 80° C., preferably 60 to 80° C., and more preferably 70 to 80° C.; the reaction time is 1 to 5 h, and preferably 2 to 3 h.

5. The preparation method according to claim 2, characterized in that: In step (2), the base used to adjust the pH of the reaction system is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, and triethylamine, preferably sodium hydroxide; preferably, the mass fraction of sodium hydroxide, potassium hydroxide, potassium carbonate, and cesium carbonate aqueous solution is 25-35%; the mass fraction of lithium hydroxide is 5-10%. Alternatively, in step (2), the pH of the reaction system is adjusted to 8-12, preferably 10-11.

6. The preparation method according to claim 2, characterized in that: In step (2), the reaction temperature is 30 to 80° C., preferably 50 to 80° C., and more preferably 50 to 60° C.; the reaction time is 1 to 5 h, and preferably 2 to 3 h.

7. The preparation method according to claim 2, characterized in that: In step (3), the base is selected from one or more of cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, pyridine, and sodium hydroxide; preferably cesium carbonate, potassium carbonate or sodium carbonate, and more preferably cesium carbonate; preferably, the concentration of sodium hydroxide, potassium carbonate and cesium carbonate aqueous solution is 25-35%; the concentration of sodium carbonate aqueous solution is 10-17%; the concentration of sodium bicarbonate aqueous solution is 5-10%.

8. The preparation method according to claim 2, characterized in that: In step (3), the molar ratio of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride to 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is 1:(1 to 1.7), preferably 1:(1.4 to 1.7), and more preferably 1:1.5; Or, in step (3), the molar ratio of the base to 4-(2,4-difluorobenzoyl)-piperidine hydrochloride is (1.3-3.0):1, preferably (1.5-2.5):1, and more preferably (1.9-2):

1.

9. The preparation method according to claim 2, characterized in that: In step (3), after the reaction system is cooled to 20-30° C., water is added.

10. The preparation method according to claim 2, characterized in that: The crude paliperidone is recrystallized to obtain paliperidone; Preferably, the recrystallization temperature is first raised to 60-80°C and the crude paliperidone is added, and then the temperature is lowered to 0-5°C and kept warm; wherein the keeping time is 2-6h; Preferably, the solvent used for recrystallization is selected from methanol, anhydrous ethanol, isopropanol, 60% ethanol (volume ratio), isopropanol / water, NMP (N-methyl-2-pyrrolidone), isopropanol / water / NMP, preferably isopropanol, 60% ethanol, isopropanol / water or isopropanol / water / NMP, and further preferably isopropanol / water / NMP (N-methyl-2-pyrrolidone); further preferably, in isopropanol / water / NMP, the volume ratio of isopropanol, water and NMP is (12-20):(3-8):(0.5-1.5), preferably 15:(5-8):(0.5-1), and further preferably 15:5:

1. Preferably, in step (4), the amount of the recrystallization solvent added is 5 to 15 times the volume of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride, preferably 7 to 10 times the volume, and more preferably 9 to 11 times the volume.

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