A continuous flow process for preparing Z-flupenthixol decanoate
By using multi-layer catalyst bed and online temperature control in the continuous flow preparation process of Z-flulpexoxanthol decanoate, the existing batch reactions have long reaction time, complex operation and poor product purity and yield, and high-efficiency, high-speed and low-cost preparation effects are achieved.
Patent Information
- Application Number
- CN202411922105.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-25
- Publication Date
- 2025-04-01
Smart Images
Figure CN119733444A_ABST
Abstract
Description
Technical Field
[0001] The present application relates to the field of preparation of Z-flupenthixol decanoate, and in particular to a process for preparing Z-flupenthixol decanoate by continuous flow. Background Art
[0002] Z-Flupentixol decanoate is a known antipsychotic drug, which is usually used to treat diseases such as schizophrenia. There are many methods for preparing Z-Flupentixol decanoate, and intermittent reaction is often used. This method has process problems such as long reaction time, complicated operation, poor product purity and yield.
[0003] With the development of modern pharmaceutical industry, the requirements for drug synthesis technology are increasing day by day. Traditional batch production methods have problems such as long reaction time, low yield and uneven purity. Continuous flow preparation technology has been widely used in the field of pharmaceutical synthesis in recent years. This technology realizes efficient and high-quality production of chemical reactions by means of continuous input of raw materials and online control of reaction conditions. Compared with intermittent reactions, continuous flow preparation technology has significant advantages, such as short reaction time, high product purity and yield, simple operation, and high energy utilization.
[0004] The continuous flow preparation of Z-flupenthixol decanoate requires sufficient mixing of the catalyst and the reaction solution and online temperature control to ensure high yield and purity of the product. However, increasing the length and capacity of the reactor will lead to multiple problems such as increased costs and difficult operation.
[0005] Therefore, it is particularly important to develop a continuous flow process for preparing Z-flupenthixol decanoate. Summary of the invention
[0006] In order to improve the yield and purity while reducing equipment costs, the present application provides a continuous flow process for preparing Z-flupenthixol decanoate.
[0007] On the one hand, the present application provides a device for preparing Z-flupenthixol decanoate by continuous flow, the device comprising a tubular reactor, a feeding system, a discharging system, and a temperature control system; a catalyst bed is arranged in the cross-sectional direction of the tubular reactor; the catalyst bed comprises catalyst bed layer I, catalyst bed layer II, and catalyst bed layer III arranged at intervals.
[0008] Preferably, the catalyst bed layer I is located at one end of the tubular reactor close to the feeding system; and the catalyst bed layer III is located at one end of the tubular reactor close to the discharging system.
[0009] Preferably, the catalyst bed I is formed by piling up granular catalysts.
[0010] Preferably, the catalyst bed II is formed by stacking hydrotalcite-supported catalysts.
[0011] Preferably, the catalyst bed II is formed by stacking hydrotalcite / kaolin supported catalysts.
[0012] The tubular reactor is a reactor body, usually a tubular container, used to install a catalyst bed and carry out chemical reactions. The feed system is responsible for evenly introducing the reactants into the tubular reactor and the catalyst bed. The discharge system is used to collect the reaction products and unreacted materials.
[0013] Temperature control system: For exothermic or endothermic reactions, the fixed catalyst bed needs to have an appropriate temperature control system to ensure that the reaction is carried out at the optimal temperature. The temperature control system of the present application is connected to the tubular reactor to meet the reaction requirements by controlling the temperature inside the tubular reactor.
[0014] The catalyst bed I is formed by the accumulation of granular catalysts. When the initial reaction solution passes through the bed, a certain amount of catalyst is obtained so that the reaction can be started at a set temperature, ensuring good fluid dynamics and heat transfer efficiency. The particle diameter is 2mm-6mm to maintain good catalyst contact and reaction efficiency.
[0015] Catalyst bed II is formed by the accumulation of hydrotalcite-loaded catalyst. Hydrotalcite is a multilayer structure. Its main body is composed of a metal hydroxide layer with a positive charge, and the interlayer is filled with exchangeable anions and water molecules. These layered structures are assembled together through the interaction of non-covalent bonds to form a stable hydrotalcite compound. The present application is carried on the hydrotalcite by allowing the catalyst to participate in the generation of hydrotalcite in situ, and the layered structure of the hydrotalcite prolongs the time for the reaction solution to flow, and prolongs the contact time between the reaction solution and the catalyst, thereby being able to improve the catalytic effect to a greater extent. Under the setting of the catalyst bed of the same thickness, the reaction solution has more contact with the catalyst and the reaction is more thorough.
[0016] The preparation process of the hydrotalcite-supported catalyst comprises the following steps: adding 4-6 parts of aluminum chloride hexahydrate and 7-9 parts of ferrous chloride tetrahydrate into 1L of deionized water, grinding the catalyst, adding 4-6 parts of the ground catalyst into the above solution, mixing evenly to obtain a hydrotalcite mixed solution, adding 30-34 parts of sodium hydroxide and 25-27 parts of sodium bicarbonate into 1L of deionized water to obtain an alkaline solution; dropping the hydrotalcite mixed solution and the alkaline solution into a container at the same time, stirring while reacting, keeping the reaction temperature at 63-67°C, keeping the pH of the system at 10, keeping the temperature for reaction for 20-26 minutes after the dropping is completed, raising the temperature, aging at 75-77°C for 32-36 hours, filtering the product, washing the solid product with water for 3 times, and drying it in an oven at 60°C overnight to obtain the hydrotalcite-supported catalyst.
[0017] Preferably, the method comprises the following steps: adding 5 parts of aluminum chloride hexahydrate and 8 parts of ferrous chloride tetrahydrate to 1L of deionized water, grinding the catalyst, adding 5 parts of the ground catalyst to the above solution, mixing evenly to obtain a hydrotalcite mixed solution, adding 32 parts of sodium hydroxide and 26 parts of sodium bicarbonate to 1L of deionized water to obtain an alkali solution; dripping the hydrotalcite mixed solution and the alkali solution into a container at the same time, stirring while reacting, keeping the reaction temperature at 65°C, keeping the pH of the system at 10, and keeping the reaction temperature for 24 minutes after the addition is completed, then raising the temperature, aging at 76°C for 34 hours, filtering the product, washing the solid product with water 3 times, and drying it in an oven at 60°C overnight to obtain a hydrotalcite-supported catalyst.
[0018] Catalyst bed III is formed by the accumulation of hydrotalcite / kaolin loaded catalyst. Hydrotalcite is a multilayer structure. Its main body is composed of positively charged metal hydroxide layers, and the interlayers are filled with exchangeable anions and water molecules. These layered structures are assembled together through non-covalent interactions to form stable hydrotalcite compounds. Kaolin crystals contain a large number of silicon-oxygen tetrahedrons and magnesium-aluminum octahedrons, which are closely arranged in layered structures to form a multilayer structure of kaolin. There is generally an oxygen ion layer in two adjacent layers of the layered structure, and there are also a large number of pore structures in kaolin.
[0019] The present application first obtains a dispersion by ultrasonic treatment of kaolin and a catalyst, and then uses the ultrasonic dispersion to participate in the formation of hydrotalcite in situ. Through the effects of charge, intercalation, and active groups between the layered structures of kaolin and hydrotalcite, a complex and loose structural path is formed. The catalyst is loaded in the structure. When it is filled in the catalyst bed, it takes a longer time for the reaction liquid to flow through. Therefore, the flow time of the reaction liquid can be further extended, and the contact time between the reaction liquid and the catalyst can be extended, thereby improving the catalytic effect to a greater extent. Under the setting of a catalyst bed with the same thickness, compared with catalyst bed II, the reaction liquid has more contact with the catalyst and the reaction is more thorough.
[0020] The preparation process of a hydrotalcite / kaolin supported catalyst comprises the following steps: adding 4-6 parts of aluminum chloride hexahydrate and 7-9 parts of ferrous chloride tetrahydrate to 1L of deionized water, mixing uniformly to obtain a hydrotalcite mixed solution, grinding the catalyst, putting 4-6 parts of the ground catalyst and 10-12 parts of kaolin into 500ml of water for ultrasonic dispersion for 2-4 hours to obtain a catalyst dispersion, adding 30-34 parts of sodium hydroxide and 25-27 parts of sodium bicarbonate to 1L of deionized water to obtain an alkaline solution; dripping the hydrotalcite mixed solution, the catalyst dispersion and the alkaline solution into a container at the same time, stirring while reacting, maintaining the reaction temperature at 63-67°C, maintaining the pH of the system at 10, and maintaining the reaction for 20-26 minutes after the dripping is completed, then raising the temperature, aging at 75-77°C for 32-36 hours, filtering the product, washing the solid product with water for 3 times, and drying it in an oven at 60°C overnight to obtain a hydrotalcite supported catalyst.
[0021] Preferably, the preparation process of the hydrotalcite / kaolin supported catalyst comprises the following steps: adding 5 parts of aluminum chloride hexahydrate and 8 parts of ferrous chloride tetrahydrate to 1L of deionized water, mixing evenly to obtain a hydrotalcite mixed solution, grinding the catalyst, putting 5 parts of the ground catalyst and 11 parts of kaolin into 500ml of water for ultrasonic dispersion for 3 hours to obtain a catalyst dispersion, adding 32 parts of sodium hydroxide and 26 parts of sodium bicarbonate to 1L of deionized water to obtain an alkali solution; dripping the hydrotalcite mixed solution, the catalyst dispersion and the alkali solution into a container at the same time, stirring while reacting, keeping the reaction temperature at 65°C, keeping the pH of the system at 10, and keeping the reaction for 24 minutes after the addition is completed, then raising the temperature, aging at 76°C for 34 hours, filtering the product, washing the solid product with water 3 times, and drying it in an oven at 60°C overnight to obtain a hydrotalcite / kaolin supported catalyst.
[0022] The present application improves the contact between the catalyst and the reaction liquid by combining three catalyst layers, namely catalyst bed I, catalyst bed II and catalyst bed III, while not affecting the continuous progress of the reaction. The final product prepared has high yield, high purity and few side reactions.
[0023] On the other hand, the present application provides a continuous flow process for preparing Z-flupenthixol decanoate, which is completed based on the above-mentioned device and comprises the following steps: dissolving Z-flupenthixol in a solvent to prepare a Z-flupenthixol solution, then adding decanoic anhydride and stirring to obtain a reaction solution, which enters a tubular reactor through a feeding system; reacts in the tubular reactor through a catalyst bed; discharges the material through a discharging system; and post-processes to obtain a product.
[0024] Preferably, the molar ratio of Z-flupenthixol to decanoic anhydride is 1:1.5.
[0025] Preferably, the reaction temperature is 45-50°C.
[0026] Preferably, the solvent is one or more of dichloromethane and ethyl acetate.
[0027] Preferably, the post-treatment includes cooling, extraction and distillation.
[0028] In a continuous chemical reactor, a solution containing Z-flupenthixol is reacted with decanoic anhydride (1:1.5). The reactants flow through a fixed catalyst bed at a controlled temperature of 45-50°C and pressure (2-3MPa), and the catalyst is 4-dimethylaminopyridine DMAP.
[0029] Preferably, the present application can also monitor the progress of the reaction through online analysis technology and adjust the reaction conditions in real time.
[0030] The synthetic route for preparing Z-flupenthixol decanoate is as follows: In summary, this application has the following beneficial technical effects: 1. The present application improves the contact between the catalyst and the reaction liquid by cooperating three catalyst layers, namely, catalyst bed layer I, catalyst bed layer II, and catalyst bed layer III, while not affecting the continuous progress of the reaction. The final product prepared has high yield, high purity, and few side reactions, thereby realizing continuous reaction to prepare Z-flupenthixol decanoate.
[0031] 2. The present application prepares a hydrotalcite-supported catalyst. The catalyst is supported on the hydrotalcite by in-situ participation of the catalyst in the formation of the hydrotalcite. The layered structure of the hydrotalcite prolongs the flow time of the reaction liquid and the contact time between the reaction liquid and the catalyst, thereby improving the catalytic effect to a greater extent. Under the setting of the catalyst bed layer of the same thickness, the reaction liquid has more contact with the catalyst and the reaction is more thorough.
[0032] 3. The present application prepares a hydrotalcite / kaolin supported catalyst. When it is filled in the catalyst bed, the reaction liquid needs a longer time to flow through, so the reaction liquid flow time can be further extended, and the contact time between the reaction liquid and the catalyst can be extended, so that the catalytic effect can be improved to a greater extent. Under the setting of the catalyst bed with the same thickness, the reaction liquid has more contact with the catalyst and the reaction is more thorough. BRIEF DESCRIPTION OF THE DRAWINGS
[0033] Figure 1 This is a diagram of the apparatus for preparing Z-flupenthixol decanoate by continuous flow in Example 1. DETAILED DESCRIPTION
[0034] The present application is further described in detail below through examples.
[0035] All raw materials in the examples are commercially available. Example
[0036] Example 1 Continuous flow preparation process of Z-flupenthixol decanoate: The catalyst bed I is formed by the accumulation of granular catalysts, and the particle diameter is 4 mm.
[0037] The catalyst bed II is formed by piling up the hydrotalcite-supported catalyst.
[0038] The preparation process of the hydrotalcite-supported catalyst comprises the following steps: adding 5 parts of aluminum chloride hexahydrate and 8 parts of ferrous chloride tetrahydrate into 1L of deionized water, grinding the catalyst, adding 5 parts of the ground catalyst into the above solution, mixing evenly to obtain a hydrotalcite mixed solution, adding 32 parts of sodium hydroxide and 26 parts of sodium bicarbonate into 1L of deionized water to obtain an alkaline solution; dripping the hydrotalcite mixed solution and the alkaline solution into a container at the same time, stirring while reacting, keeping the reaction temperature at 65°C, keeping the pH of the system at 10, keeping the temperature for reaction for 24 minutes after the dripping is completed, then raising the temperature, aging at 76°C for 34 hours, filtering the product, washing the solid product with water for 3 times, and drying it in an oven at 60°C overnight to obtain the hydrotalcite-supported catalyst.
[0039] Catalyst bed III is formed by stacking the hydrotalcite / kaolin supported catalyst.
[0040] The preparation process of a hydrotalcite / kaolin supported catalyst comprises the following steps: adding 5 parts of aluminum chloride hexahydrate and 8 parts of ferrous chloride tetrahydrate to 1L of deionized water, mixing uniformly to obtain a hydrotalcite mixed solution, grinding the catalyst, putting 5 parts of the ground catalyst and 11 parts of kaolin into 500ml of water for ultrasonic dispersion for 3 hours to obtain a catalyst dispersion, adding 32 parts of sodium hydroxide and 26 parts of sodium bicarbonate to 1L of deionized water to obtain an alkaline solution; dripping the hydrotalcite mixed solution, the catalyst dispersion and the alkaline solution into a container at the same time, stirring while reacting, keeping the reaction temperature at 65°C, keeping the pH of the system at 10, keeping the temperature for reaction for 24 minutes after the dripping is completed, then raising the temperature, aging at 76°C for 34 hours, filtering the product, washing the solid product with water for 3 times, and drying it in an oven at 60°C overnight to obtain a hydrotalcite / kaolin supported catalyst.
[0041] The catalyst bed I, catalyst bed II and catalyst bed III prepared according to the above method have a thickness of 1 / 7 of the length of the tubular reactor; the catalyst bed I is located at one end of the tubular reactor close to the feeding system; the catalyst bed III is located at one end of the tubular reactor close to the discharging system.
[0042] The specific steps are as follows: dissolving Z-flupenthixol in a solvent to prepare a Z-flupenthixol solution with a mass concentration of 20%, then adding decanoic anhydride and stirring to obtain a reaction solution, which enters a tubular reactor through a feeding system; reacts in the tubular reactor through a catalyst bed; discharges the material through a discharging system; cools to room temperature, extracts with water, and distills to obtain a product; and through testing and calculation, the yield of Z-flupenthixol decanoate is 90.6% and the purity is 97.5%.
[0043] The molar ratio of Z-flupenthixol to decanoic anhydride is 1:1.5.
[0044] The reaction temperature was controlled at 45°C and the pressure was 2MPa.
[0045] The solvent is a mixture of dichloromethane and ethyl acetate in a volume ratio of 1:1.
[0046] The catalyst is 4-dimethylaminopyridine DMAP.
[0047] Example 2 Continuous flow preparation process of Z-flupenthixol decanoate: The catalyst bed I is formed by the accumulation of granular catalysts, and the particle diameter is 4 mm.
[0048] The catalyst bed II is formed by piling up the hydrotalcite-supported catalyst.
[0049] The preparation process of the hydrotalcite-supported catalyst comprises the following steps: adding 5 parts of aluminum chloride hexahydrate and 8 parts of ferrous chloride tetrahydrate into 1L of deionized water, grinding the catalyst, adding 5 parts of the ground catalyst into the above solution, mixing evenly to obtain a hydrotalcite mixed solution, adding 32 parts of sodium hydroxide and 26 parts of sodium bicarbonate into 1L of deionized water to obtain an alkaline solution; dripping the hydrotalcite mixed solution and the alkaline solution into a container at the same time, stirring while reacting, keeping the reaction temperature at 65°C, keeping the pH of the system at 10, keeping the temperature for reaction for 24 minutes after the dripping is completed, then raising the temperature, aging at 76°C for 34 hours, filtering the product, washing the solid product with water for 3 times, and drying it in an oven at 60°C overnight to obtain the hydrotalcite-supported catalyst.
[0050] Catalyst bed III is formed by stacking the hydrotalcite / kaolin supported catalyst.
[0051] The preparation process of a hydrotalcite / kaolin supported catalyst comprises the following steps: adding 5 parts of aluminum chloride hexahydrate and 8 parts of ferrous chloride tetrahydrate to 1L of deionized water, mixing uniformly to obtain a hydrotalcite mixed solution, grinding the catalyst, putting 5 parts of the ground catalyst and 11 parts of kaolin into 500ml of water for ultrasonic dispersion for 3 hours to obtain a catalyst dispersion, adding 32 parts of sodium hydroxide and 26 parts of sodium bicarbonate to 1L of deionized water to obtain an alkaline solution; dripping the hydrotalcite mixed solution, the catalyst dispersion and the alkaline solution into a container at the same time, stirring while reacting, keeping the reaction temperature at 65°C, keeping the pH of the system at 10, keeping the temperature for reaction for 24 minutes after the dripping is completed, then raising the temperature, aging at 76°C for 34 hours, filtering the product, washing the solid product with water for 3 times, and drying it in an oven at 60°C overnight to obtain a hydrotalcite / kaolin supported catalyst.
[0052] The catalyst bed I, catalyst bed II and catalyst bed III prepared according to the above method have a thickness of 1 / 7 of the length of the tubular reactor; the catalyst bed I is located at one end of the tubular reactor close to the feeding system; the catalyst bed III is located at one end of the tubular reactor close to the discharging system.
[0053] The specific steps are as follows: dissolving Z-flupenthixol in a solvent to prepare a Z-flupenthixol solution with a mass concentration of 18%, then adding decanoic anhydride and stirring to obtain a reaction solution, which enters a tubular reactor through a feeding system; reacts in the tubular reactor through a catalyst bed; discharges the material through a discharging system; cools to room temperature, extracts with water, and distills to obtain a product; and through testing and calculation, the yield of Z-flupenthixol decanoate is 90.1% and the purity is 97.0%.
[0054] The molar ratio of Z-flupenthixol to decanoic anhydride is 1:1.6.
[0055] The reaction temperature was controlled at 47°C and the pressure was 2MPa.
[0056] The solvent is a mixture of dichloromethane and ethyl acetate in a volume ratio of 1:2.
[0057] The catalyst is 4-dimethylaminopyridine DMAP.
[0058] Comparative Example 1 The difference from Example 1 is that catalyst bed II and catalyst bed III are both replaced by catalyst bed I, that is, the catalyst bed is only catalyst bed I.
[0059] Continuous flow preparation process of Z-flupenthixol decanoate: The catalyst bed I is formed by the accumulation of granular catalysts, and the particle diameter is 4 mm.
[0060] The catalyst bed I, catalyst bed II and catalyst bed III prepared according to the above method have a thickness of 1 / 7 of the length of the tubular reactor; the catalyst bed I is located at one end of the tubular reactor close to the feeding system; the catalyst bed III is located at one end of the tubular reactor close to the discharging system.
[0061] The specific steps are as follows: dissolving Z-flupenthixol in a solvent to prepare a Z-flupenthixol solution with a mass concentration of 20%, adding decanoic anhydride and stirring to obtain a reaction solution, and entering the tubular reactor through a feeding system; reacting in the tubular reactor through a catalyst bed; discharging the material through a discharging system; cooling to room temperature, extracting with water, and distilling to obtain a product; and through testing and calculation, the yield of Z-flupenthixol decanoate is 77.1% and the purity is 93.7%.
[0062] The molar ratio of Z-flupenthixol to decanoic anhydride is 1:1.5.
[0063] The reaction temperature was controlled at 45°C and the pressure was 2MPa.
[0064] The solvent is a mixture of dichloromethane and ethyl acetate in a volume ratio of 1:1.
[0065] The catalyst is 4-dimethylaminopyridine DMAP.
[0066] Comparative Example 2 The difference from Example 1 is that both the catalyst bed I and the catalyst bed layer II are replaced by the catalyst bed layer II, that is, the catalyst bed is only one type of bed layer, namely, the catalyst bed layer II.
[0067] Continuous flow preparation process of Z-flupenthixol decanoate: The catalyst bed II is formed by piling up the hydrotalcite-supported catalyst.
[0068] The preparation process of the hydrotalcite-supported catalyst comprises the following steps: adding 5 parts of aluminum chloride hexahydrate and 8 parts of ferrous chloride tetrahydrate into 1L of deionized water, grinding the catalyst, adding 5 parts of the ground catalyst into the above solution, mixing evenly to obtain a hydrotalcite mixed solution, adding 32 parts of sodium hydroxide and 26 parts of sodium bicarbonate into 1L of deionized water to obtain an alkaline solution; dripping the hydrotalcite mixed solution and the alkaline solution into a container at the same time, stirring while reacting, keeping the reaction temperature at 65°C, keeping the pH of the system at 10, keeping the temperature for reaction for 24 minutes after the dripping is completed, then raising the temperature, aging at 76°C for 34 hours, filtering the product, washing the solid product with water for 3 times, and drying it in an oven at 60°C overnight to obtain the hydrotalcite-supported catalyst.
[0069] The catalyst bed I, catalyst bed II and catalyst bed III prepared according to the above method have a thickness of 1 / 7 of the length of the tubular reactor; the catalyst bed I is located at one end of the tubular reactor close to the feeding system; the catalyst bed III is located at one end of the tubular reactor close to the discharging system.
[0070] The specific steps are as follows: dissolving Z-flupenthixol in a solvent to prepare a Z-flupenthixol solution with a mass concentration of 20%, then adding decanoic anhydride and stirring to obtain a reaction solution, which enters a tubular reactor through a feeding system; reacts in the tubular reactor through a catalyst bed; discharges the material through a discharging system; cools to room temperature, extracts with water, and distills to obtain a product; and through testing and calculation, the yield of Z-flupenthixol decanoate is 84.4%, and the purity is 94.3%.
[0071] The molar ratio of Z-flupenthixol to decanoic anhydride is 1:1.5.
[0072] The reaction temperature was controlled at 45°C and the pressure was 2MPa.
[0073] The solvent is a mixture of dichloromethane and ethyl acetate in a volume ratio of 1:1.
[0074] The catalyst is 4-dimethylaminopyridine DMAP.
[0075] Comparative Example 3 The difference from Example 1 is that the catalyst bed II and the catalyst bed I are replaced by the catalyst bed III, that is, the catalyst bed is only one type of bed, which is the catalyst bed III.
[0076] Continuous flow preparation process of Z-flupenthixol decanoate: Catalyst bed III is formed by stacking the hydrotalcite / kaolin supported catalyst.
[0077] The preparation process of a hydrotalcite / kaolin supported catalyst comprises the following steps: adding 5 parts of aluminum chloride hexahydrate and 8 parts of ferrous chloride tetrahydrate to 1L of deionized water, mixing uniformly to obtain a hydrotalcite mixed solution, grinding the catalyst, putting 5 parts of the ground catalyst and 11 parts of kaolin into 500ml of water for ultrasonic dispersion for 3 hours to obtain a catalyst dispersion, adding 32 parts of sodium hydroxide and 26 parts of sodium bicarbonate to 1L of deionized water to obtain an alkaline solution; dripping the hydrotalcite mixed solution, the catalyst dispersion and the alkaline solution into a container at the same time, stirring while reacting, keeping the reaction temperature at 65°C, keeping the pH of the system at 10, keeping the temperature for reaction for 24 minutes after the dripping is completed, then raising the temperature, aging at 76°C for 34 hours, filtering the product, washing the solid product with water for 3 times, and drying it in an oven at 60°C overnight to obtain a hydrotalcite / kaolin supported catalyst.
[0078] The catalyst bed I, catalyst bed II and catalyst bed III prepared according to the above method have a thickness of 1 / 7 of the length of the tubular reactor; the catalyst bed I is located at one end of the tubular reactor close to the feeding system; the catalyst bed III is located at one end of the tubular reactor close to the discharging system.
[0079] The specific steps are as follows: dissolving Z-flupenthixol in a solvent to prepare a Z-flupenthixol solution with a mass concentration of 20%, then adding decanoic anhydride and stirring to obtain a reaction solution, which enters a tubular reactor through a feeding system; reacts in the tubular reactor through a catalyst bed; discharges the material through a discharging system; cools to room temperature, extracts with water, and distills to obtain a product; and through testing and calculation, the yield of Z-flupenthixol decanoate is 86.5%, and the purity is 94.6%.
[0080] The molar ratio of Z-flupenthixol to decanoic anhydride is 1:1.5.
[0081] The reaction temperature was controlled at 45°C and the pressure was 2MPa.
[0082] The solvent is a mixture of dichloromethane and ethyl acetate in a volume ratio of 1:1.
[0083] The catalyst is 4-dimethylaminopyridine DMAP.
[0084] As can be seen from Example 1 and Example 2, Comparative Example 1, by the device of the present application, the coordination of catalyst bed I, catalyst bed II, and catalyst bed III, the yield and output obtained by continuous production preparation of Z-flupenthixol decanoate are all higher. As can be seen from Example 1 and Comparative Examples 1-3, the coordination between catalyst bed I, catalyst bed II, and catalyst bed III is more conducive to the improvement of the yield and output of Z-flupenthixol decanoate, which may be due to the fact that the reaction solution and the catalyst are not in contact under the process of Comparative Examples 1 and Comparative Examples 2, resulting in yield and purity being lower than Example 1, and the amount of catalyst in Comparative Example 3 is not enough, and the initial reaction is incomplete, and the application provides a certain amount of catalyst in the reaction solution by catalyst bed I, to ensure that the catalyst in the whole reaction exists, and catalyst II improves the catalyst contact time, while further improving the catalyst content, the contact time can be lengthened, and the catalytic effect is further improved, and the basis of the catalyst is further improved by III, and the more thoroughness of the reaction before the final discharging is improved, thereby obtaining a higher yield and yield.
[0085] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make non-creative modifications to the present embodiment as needed, but as long as they are within the scope of the claims of the present application, they are protected by the patent law.
Claims
1. A device for preparing Z-flupenthixol decanoate by continuous flow, characterized in that: The device comprises a tubular reactor, a feeding system, a discharging system and a temperature control system; a catalyst bed is arranged in the cross-sectional direction of the tubular reactor; the catalyst bed comprises catalyst bed layer I, catalyst bed layer II and catalyst bed layer III arranged at intervals.
2. The device for preparing Z-flupenthixol decanoate by continuous flow according to claim 1, characterized in that: The catalyst bed layer I is located at one end of the tubular reactor close to the feeding system; the catalyst bed layer III is located at one end of the tubular reactor close to the discharging system.
3. The device for preparing Z-flupenthixol decanoate by continuous flow according to claim 2, characterized in that: The catalyst bed I is formed by the accumulation of granular catalysts.
4. The device for preparing Z-flupenthixol decanoate by continuous flow according to claim 3, characterized in that: The catalyst bed II is formed by the accumulation of hydrotalcite-supported catalysts.
5. The device for preparing Z-flupenthixol decanoate by continuous flow according to claim 4, characterized in that: The catalyst bed II is formed by piling up hydrotalcite / kaolin supported catalysts.
6. A continuous flow process for preparing Z-flupenthixol decanoate, based on the device as claimed in claim 5, characterized in that: The method comprises the following steps: dissolving Z-flupenthixol in a solvent to prepare a Z-flupenthixol solution, adding capric anhydride and stirring to obtain a reaction solution, and the solution enters a tubular reactor through a feeding system; reacts in the tubular reactor through a catalyst bed; discharges the solution through a discharging system; and obtains a product through post-processing.
7. The process for preparing Z-flupenthixol decanoate by continuous flow according to claim 6, characterized in that: The molar ratio of Z-flupenthixol to decanoic anhydride is 1:1.
5.
8. The process for preparing Z-flupenthixol decanoate by continuous flow according to claim 6, characterized in that: The reaction temperature is 45-50°C.
9. The process for preparing Z-flupenthixol decanoate by continuous flow according to claim 6, characterized in that: The solvent is one or more of dichloromethane and ethyl acetate.
10. The process for preparing Z-flupenthixol decanoate by continuous flow according to claim 6, characterized in that: The post-treatment includes cooling, extraction and distillation.