A method for preparing lauroyl aripiprazole

Abstract

This invention belongs to the technical field of drug synthesis methods, and provides a method for preparing lauroyl aripiprazole, comprising: (1) hydroxymethylation reaction: reacting aripiprazole, a 35-40 wt% formaldehyde aqueous solution, and an alkali in an organic solvent to obtain hydroxymethyl aripiprazole; (2) lauroylation reaction: reacting the hydroxymethyl aripiprazole, an organic alkali, and lauroyl chloride in a water-immiscible solvent at 20-30°C, and then recrystallizing in a crystallization solvent to obtain lauroyl aripiprazole. This method not only improves the yield and product purity of the two-step hydroxymethylation and lauroylation reactions, but also shortens the reaction time, simplifies the post-processing, and reduces material costs.

Description

Technical Field

[0001] This invention belongs to the technical field of drug synthesis methods, and particularly relates to a method for preparing lauroyl aripiprazole. Background Technology

[0002] Aripiprazole lauroyl is a prodrug of the active drug aripiprazole. Its long-acting suspension injection is an atypical antipsychotic developed by Alkermes plc using the LinkeRx technology platform and was approved by the FDA in October 2015 for the treatment of schizophrenia. The efficacy and safety of this product are similar to aripiprazole. It is administered once every 1-2 months to meet the needs of different individuals. Common adverse reactions include insomnia, akathisia, and headache. The molecular structure of this compound is as follows:

[0003]

[0004] Patent document US20140221653 discloses the synthetic route of lauroyl aripiprazole, as follows:

[0005] Route 1:

[0006] The synthetic route uses aripiprazole as a starting material, and the product is obtained through a two-step reaction involving hydroxymethylation and lauroylation.

[0007] Route 2:

[0008] Patent document US20140221653 also discloses a process route for synthesizing similar compounds, namely, using aripiprazole as the starting material, and under the conditions of sodium hydrogen as a base and 1,4-dioxane as a solvent, condensing it with the corresponding chloromethyl ester in one step to obtain the target product, which is then purified by column chromatography.

[0009] However, the above synthetic route has the following drawbacks:

[0010] Disadvantages of Route 1:

[0011] In the hydroxymethylation reaction, (1) the conversion rate of raw materials is not high and the purity is low. The product contains 25% aripiprazole, which is not conducive to the purification of the finished product after the next step; (2) the operation is not conducive to industrial production. Since the solvent is high-boiling-point DMF, the post-treatment method of water and ethyl acetate separation extraction will cause part of the product to remain in the water layer, the extraction yield is not high, and the residual DMF in the ethyl acetate layer is not easy to remove; (3) the reaction time is long and the energy consumption is high.

[0012] In the laurylation reaction, (1) lauryl anhydride is expensive and not suitable for industrial production; (2) the reaction time is long and the energy consumption is high; (3) the product purification is carried out by column chromatography, which is not convenient for large-scale industrial production; and (4) the product yield is low.

[0013] Disadvantages of Route 2:

[0014] (1) The sodium hydrogen used in the reaction is a highly active inorganic strong base that produces flammable and explosive hydrogen gas when it comes into contact with water, which is highly dangerous; (2) 1,4-dioxane has a high boiling point and is not easy to completely desolvate; (3) The product purification is carried out by column chromatography, which is not convenient for industrial production. Summary of the Invention

[0015] The purpose of this invention is to address the problems existing in the synthesis process of lauroyl aripiprazole by providing a method for preparing lauroyl aripiprazole that can not only improve the yield and product purity of the two-step reaction of hydroxymethylation and lauroylation, but also shorten the reaction time, simplify the post-processing, and reduce material costs.

[0016] To achieve the above objectives, the present invention provides a method for preparing lauroyl aripiprazole, comprising the following steps:

[0017] (1) Hydroxymethylation reaction: Aripiprazole, a 35-40 wt% aqueous formaldehyde solution, and an alkali (e.g., an organic alkali) are reacted in an organic solvent to prepare hydroxymethyl aripiprazole (i.e., 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinoline-2(1H)-one);

[0018] (2) Lauroylation reaction: At 20-30℃, the hydroxymethyl aripiprazole, organic base and lauroyl chloride are reacted in a solvent that is immiscible with water, and then recrystallized in a crystallization solvent to obtain the lauroyl aripiprazole (i.e., dodecanoic acid (7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl ester).

[0019] According to the preparation method provided by the present invention, preferably, in step (1), the mass of aripiprazole: volume of formaldehyde aqueous solution: volume of organic solvent is 1g:1.5-5ml:1-10ml, more preferably 1g:1.5-5ml:1-8ml; more preferably 1g:2-3.5ml:1.5-4ml; particularly preferably 1g:2-3.5ml:1.5-3ml; the molar equivalent of the base (e.g., an organic base) relative to aripiprazole is 0.05-1.00eq, preferably 0.10-1.00eq, and more preferably 0.15-0.50eq. In the present invention, the molar equivalent of the base relative to aripiprazole refers to the ratio of the amount of base to the amount of aripiprazole.

[0020] Preferably, the process conditions for the hydroxymethylation reaction in step (1) include: a reaction temperature of 70-90°C and a reaction time of 2-3 hours. The organic solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran (THF), acetonitrile, and 1,4-dioxane, more preferably N,N-dimethylformamide.

[0021] In the hydroxymethylation reaction, a dynamic equilibrium exists between the reactants and products under the reaction conditions. Specifically, the product degrades back into the reactants under alkaline conditions. This invention breaks this dynamic equilibrium by reducing the amount of organic solvent used, causing the product to precipitate from the reaction system. This allows the reaction to continue in the forward direction, ultimately improving the conversion rate of the reactants. Furthermore, in existing synthetic methods, the product can only be obtained through extraction. In contrast, this invention not only simplifies the post-processing, improves conversion and yield, but also reduces the residual organic solvent in the product. The alkali in the reaction system acts as a catalyst, and its amount can affect the degree of product degradation.

[0022] In one example of the present invention, in step (1), the product obtained from the hydroxymethylation reaction is purified to obtain hydroxymethyl aripiprazole. The purification includes: cooling the product obtained from the hydroxymethylation reaction to room temperature and filtering it, washing it 1-4 times with a washing solvent, and then drying it at 40-65°C for 8-16 hours to obtain hydroxymethyl aripiprazole.

[0023] The mass of aripiprazole: the single volume of the washing solvent used is 1g: 0.5-1.3mL.

[0024] The room temperature range described in this invention is 25±5℃.

[0025] Preferably, the washing solvent is selected from one or more of dichloromethane, acetone, acetonitrile, and C1-C3 alcohols.

[0026] As described above, the present invention avoids cumbersome steps such as solvent removal and extraction in the preparation of the intermediate product (hydroxymethylaripiprazole), and the solid intermediate product can be obtained simply by filtration. The key to controlling the yield and purity of the intermediate product (hydroxymethylaripiprazole) in this invention is the amount of organic solvent used. Using a small volume ensures the reaction continues in the forward direction. The main purpose of washing after filtration is to reduce the residual organic solvent and water in the filter cake, thus minimizing the impact of residual water on product degradation and shortening the drying time. Therefore, using a water-miscible washing solvent can improve the purity of the product and make it easier to dry.

[0027] In another example of the present invention, the purification further includes: purifying the hydroxymethyl aripiprazole obtained by filtration and washing by pulping in a pulping solvent;

[0028] Preferably, the pulping solvent is selected from one or more of dichloromethane, acetone, tetrahydrofuran, acetonitrile, ethyl acetate, ethanol, and isopropanol, and more preferably from one or more of dichloromethane, acetone, acetonitrile, ethyl acetate, ethanol, and isopropanol;

[0029] Preferably, the process conditions for pulping and purification include: pulping temperature of 5-85℃, more preferably 10-40℃; pulping time of 1-3 hours, more preferably 1-2 hours; and the mass of the product obtained from the hydroxymethylation reaction is 1g: 4-20mL of the volumetric volume of the pulping solvent.

[0030] According to the preparation method provided by the present invention, inexpensive lauroyl chloride is used as the acylation reagent to improve the conversion rate of hydroxymethylaripiprazole. Preferably, in step (2), the amount of lauroyl chloride is 1-3 times the molar amount of hydroxymethylaripiprazole, more preferably 1.3-2 times; the amount of organic base is 1-1.5 times the molar amount of hydroxymethylaripiprazole; the mass ratio of hydroxymethylaripiprazole to the volume ratio of the water-immiscible solvent is 1g:5-15mL, more preferably 1g:8-10mL; the mass ratio of lauroylaripiprazole to the volume ratio of the crystallization solvent is 1g:1-5mL, more preferably 1g:2-3mL. In the present invention, the volume ratio of the crystallization solvent is calculated based on the amount of the final product (lauroylaripiprazole). The amounts of lauroyl chloride, organic base, and water-immiscible solvent are all calculated based on the amount of the pure intermediate product (hydroxymethyl aripiprazole) finally obtained in step (1).

[0031] Step (2) can be filtered and washed before recrystallization. The main purpose of filtration is to remove the hydrochloride of the base generated in the reaction. The next step is to wash with brine to quench the excess acyl chloride and remove the residual hydrochloride of the base and the free base (excess). The solid product obtained after filtration and washing is recrystallized with a crystallization solvent. The purpose of recrystallization is to remove lauric acid and organic impurities generated in the reaction.

[0032] Preferably, the base in step (1) is an inorganic base or an organic base. The inorganic base is selected from one or more of cesium carbonate, sodium hydroxide, and potassium hydroxide. The organic base is selected from one or more of sodium alkoxide, 4-dimethylaminopyridine, N-methylmorpholine, triethylenediamine, N,N-diisopropylethylamine, pyridine, and triethylamine. More preferably, it is selected from pyridine and / or triethylamine.

[0033] Preferably, the organic base in step (2) is selected from one or more of sodium alkoxide, 4-dimethylaminopyridine, N-methylmorpholine, triethylenediamine, N,N-diisopropylethylamine, pyridine and triethylamine, more preferably, selected from pyridine and / or triethylamine.

[0034] In this invention, acyl chloride is used as the acylating reagent to generate HCl after the reaction. An organic base with a molar equivalent greater than that of the substrate is used to ensure that all HCl is converted into the hydrochloride salt of the organic base. In other words, the organic base acts as an acid-binding agent to ensure that the reaction proceeds smoothly.

[0035] Preferably, the water-immiscible solvent is selected from ethyl acetate and / or dichloromethane. Hydroxymethylaripiprazole has poor solubility; only a few solvents such as THF and dioxane are readily soluble in it. When anhydrides are used as reactants in the acylation reaction, their reactivity is low, thus requiring a homogeneous system. Therefore, using a solvent that readily dissolves hydroxymethylaripiprazole is essential. However, in this invention, acyl chlorides are used as the acylation reagent, resulting in higher reactivity. The reaction can be carried out in a heterogeneous system, and the use of non-polar solvents does not affect the conversion rate. Furthermore, the product is readily soluble. More importantly, the triethylamine salt generated in the reaction has poor solubility in non-polar solvents and can be removed by filtration and subsequent water washing.

[0036] Preferably, the crystallization solvent is selected from one or more of methanol, ethanol, isopropanol, acetonitrile, acetone and n-heptane; more preferably, it is selected from one or more of methanol, ethanol, isopropanol and n-heptane; and more preferably, it is ethanol.

[0037] The beneficial effects of the technical solution of this invention are as follows:

[0038] 1) Compared with the prior art, the present invention significantly improves the reaction yield and purity by reducing the amount of organic solvent used in the preparation of hydroxymethyl aripiprazole, while also reducing the safety risks to experimental operators and environmental pollution. The reaction yield and purity of hydroxymethyl aripiprazole are both above 90%. At the same time, the post-processing of the product is greatly simplified. With further purification steps, hydroxymethyl aripiprazole with a purity of 95%-99% can be obtained.

[0039] 2) This invention uses lauroyl chloride as the acylation reagent, which not only saves material costs, but also greatly improves the conversion rate of the hydroxymethylation intermediate and the yield of the final product lauroyl aripiprazole, from less than 30% to 70-80%. The reaction time is shortened by selecting the acylation reagent, and the solidification and purification process is optimized.

[0040] 3) The method of the present invention shortens the hydroxymethylation reaction time from 20 hours to 2-3 hours; the lauroylation reaction time is also reduced from 16 hours to 1-2 hours, and the temperature is reduced from 60°C to room temperature, which greatly reduces production costs;

[0041] 4) The method of the present invention simplifies the solidification and purification of lauroyl aripiprazole, which can be obtained by direct recrystallization of the residue after solvent removal from the reaction solution, avoiding column chromatography operation and making it suitable for industrial production. Detailed Implementation

[0042] To provide a detailed understanding of the technical features and content of this invention, preferred embodiments will be described in more detail below. While preferred embodiments of the invention are described in the examples, it should be understood that the invention can be implemented in various forms and should not be limited to the embodiments set forth herein.

[0043] Raw material source:

[0044] 37% formaldehyde aqueous solution, analytical grade, purchased from Chengdu Kelong Chemical Reagent Factory;

[0045] Triethylamine, analytical grade, purchased from Chengdu Kelong Chemical Reagent Factory;

[0046] Pyridine, analytical grade, purchased from Chengdu Kelong Chemical Reagent Factory;

[0047] Lauroyl chloride, analytical grade, purchased from Chengdu Dingdang Times Pharmaceutical Technology Co., Ltd.;

[0048] Lauric anhydride, analytical grade, purchased from Shanghai Teber Chemical Technology Co., Ltd.;

[0049] Aripiprazole, industrial grade, commercially available, Nanjing Qike Pharmaceutical Co., Ltd.

[0050] All other common organic solvents were purchased from Chengdu Kelong Chemical Reagent Factory.

[0051] Test method:

[0052] (1) The structure of the compound was determined by nuclear magnetic resonance (NMR). NMR chemical shifts (δ) are expressed in terms of 10⁻¹⁰. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0053] (2) The purity of the compound was determined by high performance liquid chromatography (HPLC). The HPLC determination was performed using an Agilent 1260 high performance liquid chromatograph (YMC C18 150×4.6mm, 3um column) with a detection wavelength of 254nm.

[0054] Example 1

[0055] Preparation of intermediate 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinoline-2(1H)-one (hydroxymethyl aripiprazole):

[0056] A mixture of aripiprazole (45 g, 100.63 mmol), formaldehyde aqueous solution (37% by mass, 120 mL), triethylamine (7 mL, 50.32 mmol, molar equivalent to aripiprazole of 0.50 eq), and N,N-dimethylformamide (135 mL) was heated to 80 °C and reacted for 2.5 h. After cooling to room temperature, the mixture was filtered. The filter cake was washed twice with acetonitrile, 30 mL each time, and dried by forced air to obtain 53.6 g of product, with a yield of 96% and a purity of 90.12%.

[0057] 1 H NMR (CDCl3, 400MHZ) δ1.62~1.78(m, 2H), 1.77~1.91(m, 2H), 2.43~2.77(m, 8H), 2.82(t, 2H), 3.11(s, 4H), 3.71(s, 1H) ), 4.01 (t, 2H), 5.33 (s, 2H), 6.57 (dd, 1H), 6.86 (d, 1H), 6.96 (m, 1H), 7.04 (d, 1H), 7.10~7.20 (m, 2H); m / z (M+H)=478.

[0058] Example 2

[0059] Preparation of intermediate 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinoline-2(1H)-one (hydroxymethyl aripiprazole):

[0060] A mixture of aripiprazole (26 g, 58.15 mmol), formaldehyde aqueous solution (37% by mass, 90 mL), triethylamine (4 mL, 29.07 mmol, molar equivalent to aripiprazole of 0.50 eq), and N,N-dimethylformamide (78 mL) was heated to 80 °C and reacted for 2.5 h. After cooling to room temperature, the mixture was filtered, and the filter cake was washed twice with 26 mL of acetone each time. The product was dried by forced air to obtain 26.1 g of product, with a yield of 94% and a purity of 91.34%.

[0061] The obtained product has essentially the same proton spectrum information as that in Example 1.

[0062] Example 3

[0063] Preparation of intermediate 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinoline-2(1H)-one (hydroxymethyl aripiprazole):

[0064] A mixture of aripiprazole (26 g, 58.15 mmol), formaldehyde aqueous solution (37% by mass, 90 mL), triethylamine (4 mL, 29.07 mmol, molar equivalent to aripiprazole of 0.50 eq), and N,N-dimethylformamide (78 mL) was heated to 80 °C and reacted for 2.5 h. After cooling to room temperature, the mixture was filtered, and the filter cake was washed twice with 26 mL of ethanol each time. The product was dried by forced air to obtain 24.2 g of product, with a yield of 87.2% and a purity of 91.05%.

[0065] The obtained product has essentially the same proton spectrum information as that in Example 1.

[0066] Example 4

[0067] Preparation of intermediate 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinoline-2(1H)-one (hydroxymethyl aripiprazole):

[0068] A mixture of aripiprazole (50 g, 111.61 mmol), formaldehyde aqueous solution (37% by mass, 175 mL), triethylamine (7.8 mL, 55.80 mmol, molar equivalent to aripiprazole of 0.50 eq), and N,N-dimethylformamide (400 mL) was heated to 80 °C and reacted for 2.5 h. After cooling to room temperature, the mixture was filtered, and the filter cake was washed twice with 65 mL of acetone each time. The product was dried by forced air to obtain 49.6 g of product, with a yield of 93% and a purity of 91.25%.

[0069] The obtained product has essentially the same proton spectrum information as that in Example 1.

[0070] Example 5

[0071] Preparation of intermediate 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinoline-2(1H)-one (hydroxymethyl aripiprazole):

[0072] A mixture of aripiprazole (50 g, 111.61 mmol), formaldehyde aqueous solution (37% by mass, 175 mL), pyridine (1.8 mL, 22.32 mmol, molar equivalent to aripiprazole of 0.20 eq), and N,N-dimethylacetamide (75 mL) was heated to 80 °C and reacted for 2.0 h. After cooling to room temperature, the mixture was filtered, and the filter cake was washed twice with 65 mL of dichloromethane each time. The product was dried by forced air to obtain 48.2 g of product, with a yield of 90% and a purity of 91.51%.

[0073] The obtained product has essentially the same proton spectrum information as that in Example 1.

[0074] Example 6

[0075] Preparation of intermediate 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinoline-2(1H)-one (hydroxymethyl aripiprazole):

[0076] A mixture of aripiprazole (5 g, 11.16 mmol), formaldehyde aqueous solution (37% by mass, 17.5 mL), cesium carbonate (0.58 g, 1.78 mmol, 0.16 eq), and N,N-dimethylformamide (40 mL) was heated to 80 °C and reacted for 3 h. After cooling to room temperature, the mixture was filtered, and the filter cake was washed twice with 10 mL of acetone each time. The product was then dried by forced air to obtain 4.85 g of product, with a yield of 91.0% and a purity of 94.82%. The obtained product had essentially the same 1H NMR spectrum as that in Example 1.

[0077] Example 7

[0078] Preparation of intermediate 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinoline-2(1H)-one (hydroxymethyl aripiprazole):

[0079] A mixture of aripiprazole (5 g, 11.16 mmol), formaldehyde aqueous solution (37% by mass, 17.5 mL), sodium hydroxide (0.071 g, 1.78 mmol, 0.16 eq), and N,N-dimethylformamide (40 mL) was heated to 80 °C and reacted for 3 h. After cooling to room temperature, the mixture was filtered, and the filter cake was washed twice with 10 mL of acetone each time. The product was then dried by forced air to obtain 4.39 g of product, with a yield of 82.4% and a purity of 91.34%. The obtained product had essentially the same 1H NMR spectrum as that in Example 1.

[0080] Example 8

[0081] Slurry purification of intermediate 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinoline-2(1H)-one:

[0082] 53.6 g of the intermediate with a purity of 90.12% obtained in Example 1 was refluxed with 500 mL of acetone and stirred for 1 hour. The mixture was then filtered under reduced pressure to obtain 49.3 g of white solid, with a yield of 92% and a purity of 92.26%.

[0083] Example 9

[0084] Slurry purification of intermediate 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinoline-2(1H)-one:

[0085] 26.1 g of the intermediate with a purity of 91.34% obtained in Example 2 was slurried with 130 mL of acetonitrile at room temperature for 1 hour, and then filtered under reduced pressure to obtain 22.2 g of white solid with a yield of 85% and a purity of 95.53%.

[0086] Example 10

[0087] Slurry purification of intermediate 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinoline-2(1H)-one:

[0088] 24.2 g of the intermediate with a purity of 91.05% obtained in Example 3 was slurried in 200 mL of dichloromethane at room temperature for 1 hour, and filtered under reduced pressure to obtain 20.3 g of white solid, with a yield of 84% and a purity of 97.40%.

[0089] Example 11

[0090] Preparation of methyl dodecanoate (7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-yl) ester (lauroyl aripiprazole):

[0091] A mixture of the intermediate hydroxymethylaripiprazole (5 g, 10.48 mmol), triethylamine (1.5 mL, 10.48 mmol), and dichloromethane (50 mL) obtained in Example 9 was stirred at room temperature for 5 min. Lauroyl chloride (3.44 g, 15.72 mmol) was slowly added dropwise while maintaining the reaction temperature at 20–30 °C. After the addition was complete, the mixture was stirred at 25 °C ± 5 °C for 1 h. The mixture was filtered under reduced pressure, and the filter cake was washed three times with 50 mL of saturated brine each time. The filtrate was separated, and the organic layer was dried and desoluble using anhydrous sodium sulfate. The residue was recrystallized from 21 mL of isopropanol, filtered, and the filter cake was washed with a small amount of isopropanol and dried by forced air to obtain 5.2 g of white powder, with a yield of 75% and a purity of 98.86%.

[0092] 1 H NMR (CDCl3, 400MHZ) δ0.87 (t, 3H), 1.18 ~ 1.37 (m, 16H), 1.58 ~ 1.89 (m, 6H), 2.35 (t, 2H), 2.49 (t, 2H), 2.59 ~ 2.77 (m, 6H), 2.86 (dd, 2 H), 3.02~3.14 (m, 4H), 3.97 (t, 2H), 5.91 (s, 2H), 6.56~6.65 (m, 2H), 6.95 (dd, 1H), 7.07 (dd, 1H), 7.11~7.19 (m, 2H); m / z (M+H)=660.

[0093] Example 12

[0094] Preparation of methyl dodecanoate (7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-yl) ester (lauroyl aripiprazole):

[0095] A mixture of the intermediate hydroxymethylaripiprazole (5 g, 10.48 mmol), pyridine (0.85 mL, 10.48 mmol), and ethyl acetate (25 mL) obtained in Example 9 was stirred at room temperature for 5 min. Lauroyl chloride (3.44 g, 15.72 mmol) was slowly added dropwise while maintaining the reaction temperature at 20–30 °C. After the addition was complete, the mixture was stirred at 25 °C ± 5 °C for 1 h. The mixture was filtered under reduced pressure, and the filter cake was washed three times with 25 mL of saturated brine each time. The filtrate was separated, and the organic layer was dried and dissolved using anhydrous sodium sulfate. The residue was recrystallized from 15 mL of ethanol, filtered, and the filter cake was washed with a small amount of ethanol and dried by forced air to obtain 5.4 g of white powder, with a yield of 78% and a purity of 99.07%.

[0096] The obtained product has essentially the same proton spectrum information as that in Example 11.

[0097] Example 13

[0098] Preparation of methyl dodecanoate (7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-yl) ester (lauroyl aripiprazole):

[0099] A mixture of the intermediate hydroxymethyl aripiprazole (5 g, 10.48 mmol), triethylamine (1.5 mL, 10.48 mmol), and dichloromethane (50 mL) obtained in Example 10 was stirred at room temperature for 5 min. Lauroyl chloride (4.59 g, 20.96 mmol) was slowly added dropwise while maintaining the reaction temperature at 20–30 °C. After the addition was complete, the mixture was stirred at 25 °C ± 5 °C for 1 h. The mixture was filtered under reduced pressure, and the filter cake was washed three times with 50 mL of saturated brine each time. The filtrate was separated, and the organic layer was dried and desoluble using anhydrous sodium sulfate. The residue was recrystallized from 15 mL of ethanol, filtered, and the filter cake was washed with a small amount of ethanol and dried by forced air to obtain 5.7 g of white powder, with a yield of 83% and a purity of 99.42%.

[0100] The obtained product has essentially the same proton spectrum information as that in Example 11.

[0101] Comparative Example 1

[0102] Preparation of intermediate 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinoline-2(1H)-one:

[0103] In a 500 mL three-necked flask, aripiprazole (6.00 g, 11.15 mmol), 17.5 mL of 37% formaldehyde aqueous solution (formalin), triethylamine (0.18 g, 1.78 mmol), and 50 mL of DMF were added. The mixture was heated to 80 °C and reacted for 20 hours. After the reaction was complete, the mixture was allowed to cool naturally to room temperature, diluted with 100 mL of ethyl acetate, and extracted and washed three times with 125 mL of water / saturated brine (1:1). The organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 5.32 g of a white solid containing 70.0% hydroxymethylaripiprazole and 29.2% aripiprazole as the remainder, with a yield of 58.2% hydroxymethylaripiprazole.

[0104] Comparative Example 2

[0105] Preparation of methyl dodecanoate (7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-yl) ester (lauroyl aripiprazole):

[0106] Add 5.32 g (11.15 mmol) of hydroxymethyl aripiprazole (prepared in Comparative Example 1), 6.40 g (16.72 mmol) and 8 mL of anhydrous tetrahydrofuran to a 100 mL three-necked flask. After stirring at 60 °C for 2 hours, add triethylamine (0.15 g, 0.15 mmol) and maintain the reaction at 60 °C for 16 hours. After the reaction was complete, the clarified solution was desolventized. 16 mL of ethyl acetate and 5 mL of n-hexane were added to the remaining crude product. The organic layer was washed with 26 mL of 5% sodium bicarbonate aqueous solution. The mixture was separated, and the pH of the aqueous layer was adjusted to 7. The organic layer was then extracted once more. The mixture was separated, and the organic layer was washed successively with 5% sodium bicarbonate solution, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (ethyl acetate: n-hexane = 1:1) to obtain a pale yellow oil. The oil was dissolved in dichloromethane and washed three times with 5% sodium bicarbonate solution. Desolventization yielded 1.6 g of a pale yellow-white solid, with a yield of 31% and a purity of 98.08%.

[0107] 1 H NMR (CDCl3, 400MHZ) δ0.87 (t, 3H), 1.18 ~ 1.37 (m, 16H), 1.58 ~ 1.89 (m, 6H), 2.35 (t, 2H), 2.49 (t, 2H), 2.59 ~ 2.77 (m, 6H), 2.86 (dd, 2 H), 3.02~3.14 (m, 4H), 3.97 (t, 2H), 5.91 (s, 2H), 6.56~6.65 (m, 2H), 6.95 (dd, 1H), 7.07 (dd, 1H), 7.11~7.19 (m, 2H); m / z (M+H)=660.

[0108] Comparative Example 3

[0109] Preparation of methyl dodecanoate (7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-yl) ester (lauroyl aripiprazole):

[0110] Aripiprazole (2.0 g, 4.45 mmol), dichloromethane (10 ml), and 60% NaH (1.68 g, 42.0 mmol) were added to a 100 ml three-necked flask and stirred at 25 ± 5 °C for 20 min. KI (0.37 g, 2.22 mmol) was added, followed by the slow addition of chloromethyl lauryl ester (2.21 g, 8.92 mmol). After the addition was complete, the mixture was heated to reflux and reacted for 20 h. The mixture was allowed to cool naturally to 25 °C, and the reaction was quenched by slowly adding 40 ml of pure water. The mixture was separated, and the organic layer was concentrated under reduced pressure to obtain an oil containing 53.7% lauroyl aripiprazole and 42.8% aripiprazole. This oil was recrystallized from 8 ml of ethanol to give 1.54 g of a white solid product, with a yield of 52.3%, containing 90.76% lauroyl aripiprazole and 8.00% aripiprazole.

[0111] The obtained product has essentially the same proton spectrum information as that in Comparative Example 2.

[0112] Comparative Example 4

[0113] Preparation of methyl dodecanoate (7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-yl) ester (lauroyl aripiprazole):

[0114] The hydroxymethyl aripiprazole (5.00 g, 10.48 mmol), lauric anhydride (6.02 g, 15.72 mmol), and 8 mL of anhydrous tetrahydrofuran prepared in Example 8 were added to a 100 mL three-necked flask. After stirring at 60 °C for 2 hours, triethylamine (0.14 g, 0.14 mmol) was added, and the reaction was maintained at 60 °C for 16 hours. After the reaction was complete, the clarified solution was desolventized. 15 mL of ethyl acetate and 5 mL of n-hexane were added to the remaining crude product. The organic layer was washed with 30 mL of 5% sodium bicarbonate aqueous solution. The mixture was separated, and the pH of the aqueous layer was adjusted to 7. The organic layer was then extracted once more. The mixture was separated, and the organic layer was washed successively with 5% sodium bicarbonate solution, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (ethyl acetate: n-hexane = 1:1) to obtain a pale yellow oily substance. The oily substance was dissolved in dichloromethane and washed three times with 5% sodium bicarbonate solution. Desolventization yielded 2.0 g of a white solid, with a yield of 28.9% and a purity of 98.26%.

[0115] The obtained product has essentially the same proton spectrum information as that in Comparative Example 2.

[0116] The various embodiments of the present invention have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments.

Claims

1. A method for preparing lauroyl aripiprazole, characterized in that, Includes the following steps: (1) Hydroxymethylation reaction: Aripiprazole, a 35-40 wt% formaldehyde aqueous solution, and an inorganic base are reacted in an organic solvent to prepare hydroxymethyl aripiprazole; The mass ratio of aripiprazole to the volume of formaldehyde aqueous solution to the volume of organic solvent is 1g: 2-3.5ml: 1.5-3ml. The inorganic base has a molar equivalent of 0.15-0.50 eq relative to aripiprazole; The reaction temperature is 70-90℃, and the reaction time is 2-3 hours; The organic solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, acetonitrile, and 1,4-dioxane; The inorganic base is selected from one or more of cesium carbonate, sodium hydroxide, and potassium hydroxide; In step (1), the product obtained from the hydroxymethylation reaction is purified to obtain hydroxymethyl aripiprazole; the purification includes: cooling the product obtained from the hydroxymethylation reaction to room temperature and filtering it, then washing and drying it with a washing solvent to obtain hydroxymethyl aripiprazole; The mass of aripiprazole: the single volume of the washing solvent used is 1g: 0.5-1.3mL; The purification process also includes: purifying the hydroxymethyl aripiprazole obtained by filtration and washing by pulping in a pulping solvent; The pulping solvent is selected from one or more of dichloromethane, acetone, tetrahydrofuran, acetonitrile, ethyl acetate, ethanol, and isopropanol; The process conditions for pulping and purification include: pulping temperature of 5-85℃; pulping time of 1-3 hours; The mass of the product obtained from the hydroxymethylation reaction is: the volume of the pulping solvent used is 1g: 4-20mL; (2) Lauroylation reaction: The hydroxymethyl aripiprazole, organic base and lauroyl chloride are reacted in a solvent that is immiscible with water at 20-30℃, and then recrystallized in a crystallization solvent to obtain the lauroyl aripiprazole; The amount of lauroyl chloride used is 1-3 times the molar amount of hydroxymethyl aripiprazole; The amount of the organic base used is 1-1.5 times the molar amount of the hydroxymethyl aripiprazole; The mass of the hydroxymethyl aripiprazole is 1g: 5-15mL, and the mass of the lauroyl aripiprazole is 1g: 1-5mL, where the volume of the crystallization solvent is 1g. The solvent that is immiscible with water is selected from ethyl acetate and / or dichloromethane; The lauroylation reaction time is 1-2 hours.

2. A method for preparing lauroyl aripiprazole, characterized in that, Includes the following steps: (1) Hydroxymethylation reaction: Aripiprazole, a 35-40 wt% aqueous formaldehyde solution, and an organic base are reacted in an organic solvent to prepare hydroxymethyl aripiprazole; The mass ratio of aripiprazole to the volume of formaldehyde aqueous solution to the volume of organic solvent is 1g: 2-3.5ml: 1.5-3ml. The molar equivalent of the organic base relative to aripiprazole is 0.15-0.50 eq; The reaction temperature is 70-90℃, and the reaction time is 2-3 hours; The organic solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, acetonitrile, and 1,4-dioxane; The organic base is selected from one or more of sodium alkoxide, 4-dimethylaminopyridine, N-methylmorpholine, triethylenediamine, N,N-diisopropylethylamine, pyridine, and triethylamine; In step (1), the product obtained from the hydroxymethylation reaction is purified to obtain hydroxymethyl aripiprazole; the purification includes: cooling the product obtained from the hydroxymethylation reaction to room temperature and filtering it, then washing and drying it with a washing solvent to obtain hydroxymethyl aripiprazole; The mass of aripiprazole: the single volume of the washing solvent used is 1g: 0.5-1.3mL; The purification process also includes: purifying the hydroxymethyl aripiprazole obtained by filtration and washing by pulping in a pulping solvent; The pulping solvent is selected from one or more of dichloromethane, acetone, tetrahydrofuran, acetonitrile, ethyl acetate, ethanol, and isopropanol; The process conditions for pulping and purification include: pulping temperature of 5-85℃; pulping time of 1-3 hours; The mass of the product obtained from the hydroxymethylation reaction is: the volume of the pulping solvent used is 1g: 4-20mL; (2) Lauroylation reaction: The hydroxymethyl aripiprazole, organic base and lauroyl chloride are reacted in a solvent that is immiscible with water at 20-30℃, and then recrystallized in a crystallization solvent to obtain the lauroyl aripiprazole; The amount of lauroyl chloride used is 1-3 times the molar amount of hydroxymethyl aripiprazole; The amount of the organic base used is 1-1.5 times the molar amount of the hydroxymethyl aripiprazole; The mass of the hydroxymethyl aripiprazole is 1g: 5-15mL, and the mass of the lauroyl aripiprazole is 1g: 1-5mL, where the volume of the crystallization solvent is 1g. The solvent that is immiscible with water is selected from ethyl acetate and / or dichloromethane; The lauroylation reaction time is 1-2 hours.

3. The preparation method according to claim 2, characterized in that, The organic base in step (1) is selected from pyridine and / or triethylamine.

4. The preparation method according to any one of claims 1-3, characterized in that, The washing solvent is selected from one or more of dichloromethane, acetone, acetonitrile, and C1-C3 organic alcohols.

5. The preparation method according to any one of claims 1-3, characterized in that, The pulping solvent is selected from one or more of dichloromethane, acetone and acetonitrile; the pulping temperature is 10-40℃; and the pulping time is 1-2 hours.

6. The preparation method according to any one of claims 1-3, characterized in that, In step (2), the amount of lauroyl chloride used is 1.3-2 times the molar amount of hydroxymethyl aripiprazole; the volume of the water-immiscible solvent used is 1g: 8-10mL; the mass of lauroyl aripiprazole: the volume of the crystallization solvent used is 1g: 2-3mL.

7. The preparation method according to any one of claims 1-3, characterized in that, The crystallization solvent is selected from one or more of methanol, ethanol, isopropanol, acetonitrile, acetone and n-heptane.

8. The preparation method according to any one of claims 1-3, characterized in that, The crystallization solvent is selected from ethanol.

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