A method for continuously preparing pioglitazone intermediates using microtubules

Abstract

The present invention relates to a method for continuously preparing a pioglitazone intermediate in a microtubule reactor. The method uses 5-ethyl-2-(2-hydroxyethyl)pyridine as a starting material, and continuously reacts in a microtubule reactor through nucleophilic substitution and Knoevenagel condensation to prepare a pioglitazone intermediate 5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione. The method has the advantages of enhanced mass transfer and heat transfer, overcomes the problems of inconvenient operation, low degree of automation, and high energy consumption cost in traditional intermittent reactor processes, significantly shortens the production cycle, improves the total yield, and is suitable for industrialized scale-up production.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a method for continuously preparing 5-[4-[2-(5-ethyl-2-pyridyl)-ethoxy]benzylidene]-2,4-thiazolidinedione, an intermediate of pioglitazone, by microtubule continuous method. Background Art

[0002] Pioglitazone is a thiazolidinedione drug commonly used in clinical treatment of type 2 diabetes. The preparation process of pioglitazone is mainly based on chemical synthesis. The compound 5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione is a key intermediate in the preparation of pioglitazone. Therefore, achieving efficient preparation of this intermediate is of great significance.

[0003] The existing process route of the intermediate is to use 5-ethyl-2-(2-hydroxyethyl)pyridine (1) as the starting material and undergo a two-step intermittent reaction of nucleophilic substitution and Knoevenagel condensation to obtain the target product (3). The synthesis route is as follows:

[0004]

[0005] The first step of the nucleophilic substitution reaction is a key step in the synthesis of pioglitazone intermediates. The prior art reports improvements to the first step, such as those reported in US4812570, EP0506273, and the literature ( Eur. J. Med. Chem. 2006,41, 841-846, Org. Process Res. Dev. 2009, 13, 1190-1194) Lett. Org. Chem. , 2014, 11, 197-202) both used sulfonyl chloride to activate the hydroxyl group in 5-ethyl-2-(2-hydroxyethyl)pyridine, and then reacted it with p-hydroxybenzaldehyde to obtain the intermediate 4-[2-(5-ethyl-2-pyridyl)-ethoxy]benzaldehyde (compound (2)), but there are many reaction steps. 、 The reaction time is long and the atom economy is poor. The prior art has reported that the two-step reaction is used to synthesize compound (2), but the total yield is low, such as in the literature ( Chem. Pharm. Bull. , 1991, 39(6), 1440-1445) reported a total yield of approximately 30%, which is insufficient to meet the requirements of industrial production. The use of a one-step reaction to synthesize compound (2) appears to shorten the synthetic route and simplify the process, but it uses a strong base reagent, which poses a significant safety risk (EP0816340), the activator is expensive (JP2013028577), and the photosensitizer has a complex structure (CN108484488), making it inadequate for large-scale production.

[0006] In industry, the two-step method of methanesulfonyl chloride activation and substitution is often used to prepare the intermediate compound (2). However, these processes are batch operations and have problems such as low efficiency and insufficient automation control.

[0007] Continuous Microtubular Reaction is a chemical reaction technology based on microchannel design. Its core is to achieve continuous flow, mixing and reaction of materials through micron-scale pipe structures (usually with an inner diameter of tens of microns to several millimeters). Compared with traditional batch reactions, although it greatly enhances the efficiency of mass and heat transfer (CN113896622), the process requires precise control of reaction conditions, which increases the complexity and has technical difficulties such as difficulty in monitoring and the risk of thermal runaway. MSA Palma et al. ( Chem. Eng. Technol. , 2019,42(2): 465-473; Chem. Eng. Technol ., 2018, 41(9): 1800-1807.) Microreactor technology was used to improve the second-step Knoevenagel condensation reaction. Although it was proposed that the microreactor could replace the batch reaction, the yield was not ideal under the optimal reaction solvent, time, and temperature conditions. Moreover, it was shown that the yield decreased when the reaction temperature exceeded 140°C. BR102021006604 described the use of a microreactor operating in a continuous flow to carry out the second-step Knoevenagel condensation reaction to obtain thiazolidinediones, but the reaction yield was below 50%, and the yield decreased when the temperature rose above 120°C.

[0008] The above process has significant limitations. Only the second step, the Knoevenagel condensation reaction, is used for microtubule continuity. In fact, it is a semi-continuous reaction, and the reaction process has not achieved full continuity. Full continuity means that in the entire production process from raw material input to product output, each process is operated in a continuous and uninterrupted manner to form an integrated production process. At the same time, due to problems such as insufficient raw material mixing efficiency and imprecise control of reaction conditions, the reaction yield is low, which makes it difficult to meet the needs of industrial production for efficient and large-scale production. Therefore, there is an urgent need to develop a full-continuous preparation process to significantly improve the reaction yield of thiazolidinedione compounds, simultaneously optimize reaction efficiency, shorten production cycle and reduce costs, and achieve the goal of industrial-scale production. Summary of the Invention

[0009] The present invention provides a method for preparing thiazolidinediones, an intermediate of pioglitazone, by microtubule continuous reaction, which significantly improves the reaction yield of thiazolidinediones, improves reaction efficiency, and shortens the production cycle, wherein the microtubule continuous reaction is fully continuous. The difficulty of microtubule continuous reaction lies in catalyst efficiency and catalyst immobilization. Microtubule continuous reaction generally requires a fast reaction. The reaction involved in the present invention has a long reaction time and low yield. It is difficult to achieve microtubule continuous reaction in the existing technology. The present invention significantly improves the reaction yield and reaction rate by premixing raw materials, designing steps, selecting and immobilizing catalysts, and the synergistic effect of various reaction parameters, thereby achieving the goal of efficient continuous reaction.

[0010] In a first aspect, the present invention provides a method for preparing a pioglitazone intermediate thiazolidinedione by microtubule continuous reaction, the method comprising: performing a microtubule continuous reaction; the thiazolidinedione is compound I: 5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione.

[0011] The present invention also provides a method for preparing a pioglitazone intermediate compound I by continuous microtubule reaction, which comprises the following steps:

[0012] Step S100: 5-ethyl-2-(2-hydroxyethyl)pyridine and p-fluorobenzaldehyde are respectively dissolved in a first solvent to prepare a solution, which is pumped into a microtube at the same flow rate, mixed in a mixer, and then reacted in a reaction module of an inorganic base particle-packed column to obtain an effluent;

[0013] Step S200: dissolving the thiazolidine-2,4-dione and the condensing agent in a second solvent to prepare a mixed solution, pumping the solution into a mixer at the same flow rate as the effluent from step S100, and then mixing the solution into a reaction module of a microtubular reactor for reaction. The reaction solution is collected, concentrated, and recrystallized to obtain Compound I.

[0014] Wherein, the compound I is 5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione.

[0015] In some embodiments, the concentration ratio of the 5-ethyl-2-(2-hydroxyethyl)pyridine solution to the p-fluorobenzaldehyde solution in step S100 is 7:10 to 12:10, preferably 9:10.

[0016] In some embodiments, the concentration of 5-ethyl-2-(2-hydroxyethyl)pyridine in step S100 is 0.1-1.0 mol / L, preferably 0.25-0.3 mol / L, more preferably 0.25 mol / L;

[0017] The concentration of p-fluorobenzaldehyde in step S100 is 0.1-1.0 mol / L, preferably 0.25-0.3 mol / L, and more preferably 0.28 mol / L.

[0018] In some embodiments, the material pumping flow rate in step S100 is 0.01-5.0 mL / min, preferably 0.075-0.15 mL / min, and more preferably 0.1 mL / min.

[0019] In some embodiments, the retention time of the material in step S100 in the packed column reaction module is 5 to 180 min, preferably 10 to 30 min, preferably 10 min.

[0020] In some embodiments, the reaction temperature in step S100 is 0-80°C, preferably 20-30°C, and more preferably 25°C.

[0021] In some embodiments, in step S100, the concentration ratio of the 5-ethyl-2-(2-hydroxyethyl)pyridine solution to the p-fluorobenzaldehyde solution is 9:10, the material pumping flow rate is 0.075-0.15 mL / min, the retention time is 10-30 min, and the reaction temperature is 20-30°C.

[0022] In some embodiments, in step S100, the concentration of 5-ethyl-2-(2-hydroxyethyl)pyridine is 0.25 mol / L, the concentration of p-fluorobenzaldehyde is 0.28 mol / L, the material pumping flow rate is 0.1 mL / min, the retention time is 10 min, and the reaction temperature is 25°C.

[0023] In some embodiments, the first solvent in step S100 is selected from dimethyl sulfoxide, N , N - one or more of dimethylformamide, tetrahydrofuran, acetonitrile, ethanol, methanol, toluene, isopropanol, ethyl acetate, preferably N , N -Dimethylformamide (DMF).

[0024] In some embodiments, the inorganic base filled in the filling column in step S100 is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, and cesium carbonate, preferably potassium hydroxide.

[0025] In some embodiments, the inorganic base particle filling column in step S100 is a stainless steel straight tube with an inner diameter of 7 mm, a length of 150 mm, a visual inner cavity volume of 6 mL, and a filling amount of inorganic base of 8 g.

[0026] In some embodiments, step S100 is to dissolve 5-ethyl-2-(2-hydroxyethyl)pyridine in DMF to prepare a 0.25 mol / L solution, and dissolve p-fluorobenzaldehyde in DMF to prepare a 0.28 mol / L solution. The two solutions are simultaneously pumped into the microtube at the same flow rate of 0.1 mL / min, enter the first mixer 3 for mixing, and then pass into the inorganic base filling column 4 with a set temperature of 25°C for reaction. After the reaction is retained for 10 minutes, a flask is connected to the inorganic base filling column 4 to continuously collect the effluent.

[0027] In some embodiments, the reaction molar yield of step S100 is greater than 90%.

[0028] In some embodiments, the reaction in step S100 is a nucleophilic substitution reaction.

[0029] In some embodiments, the condensing agent in step S200 is selected from one or more of ammonium acetate, ammonium formate, piperidine, pyridine, pyrrolidine, quinoline and other primary amines and secondary amines, preferably piperidine.

[0030] In some embodiments, the molar ratio of thiazolidine-2,4-dione to the condensing agent in step S200 is 100-5:1, preferably 45-50:1, and more preferably 50:1.

[0031] In some embodiments, the molar concentration of the thiazolidine-2,4-dione solution in the mixed solution of step S200 is 0.1 to 0.6 mol / L, preferably 0.3 mol / L;

[0032] In some embodiments, the molar concentration of the condensing agent in the mixed solution in step S200 is 0.001-0.02 mol / L, preferably 0.006 mol / L.

[0033] In some embodiments, the molar concentration of the mixed solution in step S200 is 0.3 mol / L based on thiazolidine-2,4-dione.

[0034] In some embodiments, the pumping flow rate in step S200 is 0.01-5.0 mL / min, preferably 0.1-0.3 mL / min, and more preferably 0.2 mL / min.

[0035] In some embodiments, the reaction temperature in step S200 is 100-200°C, preferably 130-200°C, and more preferably 180°C.

[0036] In some embodiments, the retention time of the reaction material in step S200 in the reaction module is 10-100 min, preferably 13-27 min, and more preferably 20 min.

[0037] In some embodiments, the reaction pressure in step S200 is 0.5-2.5 MPa, preferably 1.7-2.0 MPa, and more preferably 1.7 MPa.

[0038] In some embodiments, the molar ratio of thiazolidine-2,4-dione to the condensing agent in step S200 is 45-50:1, the pumping flow rate is 0.1-0.3 mL / min, the reaction temperature is 130-200° C., the retention time is 13-27 min, and the reaction pressure is 1.7-2.0 MPa.

[0039] In some embodiments, the second solvent in step S200 is selected from dimethyl sulfoxide, N , N - one or more of dimethylformamide, tetrahydrofuran, acetonitrile, ethanol, methanol, toluene, isopropanol, ethyl acetate, preferably methanol.

[0040] In some embodiments, the reaction in step S200 is a Knoevenagel condensation reaction.

[0041] In some embodiments, the mixer in step S100 and step S200 is a T-type mixer or a Y-type mixer, preferably a T-type mixer.

[0042] In some embodiments, the microtubes in step S100 and step S200 are cylindrical channels without internal fine structures and are made of stainless steel; the inner diameter of the microtubes is 100-1000 μm, preferably 400 μm;

[0043] In some embodiments, the inner diameter of the microtube reactor in step S200 is 100-1000 μm, preferably 400 μm; the volume of the microtube reactor is 5-10 mL, preferably 8 mL.

[0044] In some embodiments, the injection pump in step S100 and step S200 is a high-pressure PTFE pump.

[0045] In some embodiments, step S200 is to dissolve thiazolidine-2,4-dione and piperidine in methanol at a molar ratio of 50:1 to form a solution with a molar concentration of 0.3 mol / L based on thiazolidine-2,4-dione, and pump it into the microtube at the same flow rate of 0.2 mL / min as the effluent of step S100. After mixing in the second mixer 8, it enters the microtube reactor for reaction, is heated to 180° C. in an oil bath, the first back pressure valve 10 is set to 1.7 MPa, the retention time is 20 min, and a Knoevenagel condensation reaction is carried out. A flask is connected after the first back pressure valve 10, and the reaction liquid is continuously collected after the reaction equilibrium, concentrated, and recrystallized to obtain compound I.

[0046] In some embodiments, the reaction molar yield of step S200 is greater than 90%.

[0047] In some embodiments, the present invention further provides a method for continuously preparing Compound I using microtubules, wherein the method comprises the following steps:

[0048] Step S100: 5-ethyl-2-(2-hydroxyethyl)pyridine was dissolved in DMF to prepare a 0.25 mol / L solution, and the solution was connected to the first syringe pump 1; p-fluorobenzaldehyde was dissolved in DMF to prepare a 0.28 mol / L solution, and the solution was connected to the second syringe pump 2; the two solutions were simultaneously pumped into the microtube at the same flow rate of 0.1 mL / min, entered the T-type first mixer 3 for mixing, and then passed into a potassium hydroxide packed column set at a temperature of 25°C for reaction. After the reaction was retained for 10 minutes, a flask was connected from the inorganic base packed column 4, and the effluent was continuously collected for 24 hours; the inorganic base packed column 4 was a stainless steel straight tube with an inner diameter of 7 mm, a length of 150 mm, a visual inner cavity volume of 6 mL, and a potassium hydroxide filling amount of 8 g;

[0049] Step S200: dissolving thiazolidine-2,4-dione and piperidine in methanol at a molar ratio of 50:1, the molar concentration of the thiazolidine-2,4-dione solution in the mixed solution is 0.3 mol / L; the molar concentration of the piperidine is 0.006 mol / L, the mixed solution is connected to the fourth syringe pump 7, the effluent of step S100 is connected to the second back pressure valve 12, and simultaneously pumped into the microtube at the same flow rate of 0.2 mL / min, after mixing in the T-type second mixer 8, entering the microtube reactor for reaction, heating to 180°C in an oil bath, setting the first back pressure valve 10 to 1.7 MPa, and performing a Knoevenagel condensation reaction with a retention time of 20 min. A flask is connected after the first back pressure valve 10. After the reaction reaches equilibrium, the reaction solution is continuously collected for 24 hours, concentrated, and recrystallized to obtain compound I; the inner diameter of the microtube reactor is 400 μm and the volume is 8 mL;

[0050] The microtubes in step S100 and step S200 are circular tubular channels without internal fine structures and are made of stainless steel; the inner diameter of the microtubes is 400 μm;

[0051] The compound I is 5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione.

[0052] Beneficial effects:

[0053] According to the specific embodiments provided by the present invention, the present invention discloses the following technical effects:

[0054] (1) For the first time, a microtubule continuous reaction process was used to prepare the pioglitazone intermediate 5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione, overcoming the defect of the prior art that the yield decreased when the Knoevenagel condensation reaction temperature was increased to 120°C. The optimal reaction conditions and continuous control conditions were screened out. By synergizing the material concentration, flow rate, pressure, retention time and other reaction condition parameters in the first and second steps, the reaction efficiency was maximized, the reaction cycle was shortened, and the molar yield of each step was controlled at more than 90%, which was significantly higher than that of the traditional batch reaction, producing unexpected technical effects.

[0055] (2) The micro-tube continuous reaction process is easy to monitor and control the reaction process. By adjusting the reaction parameters, the reaction materials of each reaction unit can be fully mixed and the reaction can be precisely controlled. This greatly improves the degree of automation, reduces manual operation, and reduces energy consumption costs, making it suitable for industrial production.

[0056] (3) The micro-tube continuous reaction device has a smaller characteristic size, which enhances the mass transfer effect of the reaction materials, has excellent heat exchange capacity, short reaction time, small equipment footprint, and can be produced on a large scale. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 : Schematic diagram of continuous nucleophilic substitution microtubules; wherein 1 is the first injection pump, 2 is the second injection pump, 3 is the first mixer, 4 is the inorganic base filling column, and 5 is the first receiving device.

[0058] Figure 2 : Schematic diagram of Knoevenagel condensation microtubule continuous process; wherein, 6 is the third injection pump, 7 is the fourth injection pump, 8 is the second mixer, 9 is the microtubule reactor, 10 is the first back pressure valve, and 11 is the second receiving device.

[0059] Figure 3 : Schematic diagram of the microtubule continuous reaction of intermediate compound I; wherein 12 is the second back pressure valve. DETAILED DESCRIPTION

[0060] The present invention will be further described in detail with reference to the following specific examples and reaction formulas, and the protection of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, variations and advantages that those skilled in the art can think of are included in the present invention, and are protected by the appended claims. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the content specifically mentioned below, are common knowledge and common common sense in the art, and the present invention has no particular restrictions. The following examples are helpful for understanding the present invention, but do not limit the scope of protection of the present invention.

[0061] Unless otherwise specified, the raw materials and equipment used in the examples were purchased from the market.

[0062] Example 1: Optimization of reaction conditions for continuous nucleophilic substitution of microtubules

[0063] like Figure 1 As shown, 5-ethyl-2-(2-hydroxyethyl)pyridine is dissolved in the first solvent DMF to prepare a solution (x mol / L), which is then connected to the first syringe pump 1. 4-Fluorobenzaldehyde is dissolved in the first solvent DMF to prepare a solution (y mol / L), which is then connected to the second syringe pump 2. The two solutions are simultaneously injected into the microtube at the same flow rate (R μL / min), mixed in the T-shaped first mixer 3, and then passed into the inorganic base-filled column 4 (inner diameter 7 mm, length 150 mm, volume 6 mL) set at a temperature of 25°C for reaction. The reaction liquid flows out of the inorganic base-filled column 4 and is collected by the first receiving device 5. The yield of the product 4-[2-(5-ethyl-2-pyridyl)-ethoxy]benzaldehyde (compound (2)) is determined by gas chromatography. The reaction conditions under different reaction conditions are shown in Table 1.

[0064] Table 1. Screening of reaction conditions for nucleophilic substitution microtubule continuation

[0065]

[0066] From the data analysis results in Table 1, it can be seen that the reaction performance is best when the concentration of the 5-ethyl-2-(2-hydroxyethyl)pyridine solution is 0.25 mol / L and the concentration of the p-fluorobenzaldehyde solution is 0.28 mol / L. When the two materials are reacted at the same flow rate, the molar ratio is 9:10. The reaction flow rate is preferably 100 μL / min. Reducing the flow rate significantly reduces the yield of the reaction product, and increasing the flow rate also slightly reduces the yield of the reaction product. Increasing the retention time to 30 minutes has no significant effect on the reaction, so 10 minutes is preferred to shorten the reaction cycle.

[0067] Example 2: Optimization of Knoevenagel Condensation Microtubule Continuous Reaction Conditions

[0068] like Figure 2As shown, 4-[2-(5-ethyl-2-pyridinyl)-ethoxy]benzaldehyde was dissolved in the first solvent, DMF, to prepare a 0.2 mol / L stock solution, which was then connected to the third syringe pump 6. Thiazolidine-2,4-dione (x mol / L) and piperidine (condensing agent) (y mol / L) were dissolved in the second solvent, MeOH, at a specific ratio to prepare a stock solution, which was then connected to the fourth syringe pump 7. These two solutions were simultaneously injected into a microtube at the same flow rate, mixed in a second T-shaped mixer 8, and then fed into a stainless steel microtube reactor (reactor volume 8 mL) 9 for the Knoevenagel condensation reaction. The reaction pressure was set by a first backpressure valve 10. The reaction solution, flowing out of the first backpressure valve 10, was collected by a second receiving device 11, and the yield of the product, 5-[[4-[2-(5-ethyl-2-pyridinyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione, was determined by gas chromatography. The reaction conditions under different reaction conditions are shown in Table 2.

[0069] Table 2. Screening of reaction conditions for Knoevenagel condensation microtubule serialization

[0070]

[0071] The data analysis results in Table 2 show that the best reaction conditions were achieved when the concentrations of 4-[2-(5-ethyl-2-pyridyl)-ethoxy]benzaldehyde in DMF were 0.2 mol / L, the concentrations of thiazolidine-2,4-dione in methanol were 0.3 mol / L, and the concentrations of piperidine in methanol were 0.006 mol / L. The two materials reacted at the same flow rate, and the reaction temperature was preferably 180°C. Lowering the temperature significantly decreased the product yield. Increasing the temperature did not affect the reaction yield, but it resulted in significant vaporization of the reactants, increasing safety risks. The optimal reaction flow rate was 200 μL / min, with a retention time of 20 min. Both decreasing and increasing the flow rate significantly reduced the product yield.

[0072] Example 3: Microtubule Continuous Synthesis of 4-[2-(5-ethyl-2-pyridyl)-ethoxy]benzaldehyde

[0073] 5-Ethyl-2-(2-hydroxyethyl)pyridine was dissolved in DMF to prepare a stock solution (0.25 mol / L) and connected to the first syringe pump 1. 4-Fluorobenzaldehyde was dissolved in DMF to prepare a stock solution (0.28 mol / L) and connected to the second syringe pump 2. The two stock solutions were simultaneously injected into the microtube at the same flow rate (100 μL / min), mixed in the T-type first mixer 3, and then passed into the inorganic base-filled column 4 (inner diameter 7 mm, length 150 mm, volume 6 mL) set at 25°C for reaction. The retention time was 10 minutes. A flask was connected to the back of the inorganic base-filled column 4, and the reaction solution was collected continuously for 24 hours. 8.36 g of the intermediate 4-[2-(5-ethyl-2-pyridyl)-ethoxy]benzaldehyde (compound (2)) was obtained by column chromatography with a molar yield of 96%.

[0074] Comparative Example 1: Kettle Synthesis of 4-[2-(5-ethyl-2-pyridyl)-ethoxy]benzaldehyde

[0075] Following the method disclosed in Chinese patent CN116496207, 5-ethyl-2-(2-hydroxyethyl)pyridine (5.46 g, 36 mmol) and p-fluorobenzaldehyde (5.0 g, 40.3 mmol) were added to a reaction flask under a nitrogen atmosphere. 20 ml of water and potassium hydroxide (KOH) (4.0 g, 72.0 mmol) were then added. The reaction solution was heated to 100°C and stirred vigorously for 8 hours. The flask was then cooled to room temperature and separated by column chromatography to yield 7.32 g of 4-[2-(5-ethyl-2-pyridyl)-ethoxy]benzaldehyde. The molar yield was 79.7%.

[0076] Example 4: Microtubule-based continuous synthesis of 5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione

[0077] 4-[2-(5-ethyl-2-pyridyl)-ethoxy]benzaldehyde was dissolved in DMF to prepare a 0.2 mol / L stock solution, which was connected to the third syringe pump 6. Thiazolidine-2,4-dione and piperidine (condensing agent) were dissolved in MeOH at a molar ratio of 50:1 to prepare a stock solution (molar concentration of 0.3 mol / L based on thiazolidine-2,4-dione) and connected to the fourth syringe pump 7. Both solutions were simultaneously injected into the microtube at the same flow rate (200 μL / min). After mixing in the second T-shaped mixer 8, they were introduced into a microtube reactor (stainless steel, 400 μm inner diameter, 8 mL reactor volume). The Knoevenagel condensation reaction was carried out by heating to 180°C in an oil bath. The first backpressure valve 10 was set to 1.7 MPa. A flask was connected to the backpressure valve 10. After the reaction reached equilibrium, the reaction solution was continuously collected for 24 hours. Column chromatography separation gave 18.93 g of 5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione in a molar yield of 93%.

[0078] Comparative Example 2: Kettle Synthesis of 5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione

[0079] Referring to the method disclosed in Chinese patent CN 102731429, 4-[2-(5-ethyl-2-pyridyl)-ethoxy]benzaldehyde (14.7 g, 57.6 mmol), thiazolidine-2,4-dione (7.59 g, 64.8 mmol), and anhydrous sodium acetate (5.91 g, 72.0 mmol) were added to a reaction flask. The reaction was heated to 125°C in an oil bath. The solid raw material melted rapidly and then thickened. The reaction was stopped when the solidification was complete. An appropriate amount of DMF was added while hot to completely dissolve the solid. Water was then added to precipitate a large amount of solid. The pH was adjusted to 5-6 with dilute hydrochloric acid solution. The mixture was stirred at room temperature for 1 hour, then cooled in an ice bath, allowed to stand for 10 minutes, and filtered. The filter cake was washed with water and dried at 100°C. The crude product was purified by column chromatography to obtain 12.45 g of 5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione with a molar yield of 61.2%.

[0080] Example 5: Full-process microtubule continuous synthesis of 5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione ( Figure 3 )

[0081] A stock solution (0.25 mol / L) of 5-ethyl-2-(2-hydroxyethyl)pyridine was dissolved in DMF and connected to the first syringe pump 1. A stock solution (0.28 mol / L) of p-fluorobenzaldehyde was dissolved in DMF and connected to the second syringe pump 2. Both stock solutions were injected simultaneously into the microtube at the same flow rate of 0.1 mL / min. After thorough mixing in the first T-type mixer 3, they were introduced into a KOH-packed column (25°C, 6.0 mL, retention time 10 min). The reaction solution exiting the KOH-packed column was further connected via the second backpressure valve 12. Another stock solution (thiazolidine-2,4-dione and piperidine dissolved in MeOH at a molar ratio of 45:1, with a molar concentration of 0.3 mol / L based on thiazolidine-2,4-dione) was introduced into the fourth syringe pump 7 at a flow rate of 0.2 mL / min. All materials were thoroughly mixed in a T-shaped second mixer 8 and then connected to an 8 mL microtube reactor for a Knoevenagel condensation reaction at 180°C and 1.7 MPa. The reaction liquid, which flowed out of the first backpressure valve 10, was collected in a flask. After the reaction reached equilibrium, the reaction liquid was collected continuously for 24 hours. After concentration, the final target intermediate (5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione) was isolated by recrystallization, yielding 18.32 g of the final product (5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione) in a molar yield of 90%).

[0082] Comparative Example 3: Full-process microtubule continuous synthesis of 5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione

[0083] The same process as in Example 5 was used, but the flow rates of the substrate stock solution for the nucleophilic substitution reaction were adjusted to 0.15 mL / min, the flow rate for the Knoevenagel condensation reaction was adjusted to 0.3 mL / min, the reaction temperature was adjusted to 210°C, and the retention time was increased to 27 minutes. The final target intermediate (5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione) was obtained, yielding 10.17 g in a molar yield of 50%.

[0084] The present invention discloses a method for continuously preparing a pioglitazone intermediate 5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione by using a microtubule continuous reaction system. The method precisely controls the reaction conditions and coordinates the material concentration, flow rate, time, pressure and retention time in each reaction to improve the reaction efficiency, significantly reduce the amount of reagents used, greatly improve the degree of automation, reduce manual operation, and reduce energy consumption costs. The method is suitable for industrial production.

[0085] Compared with traditional batch reactor process technology, the method for preparing pioglitazone intermediates using a continuous reaction system including a mixer and a continuous reactor connected in sequence proposed in the present invention has excellent mass transfer, heat transfer and material molecular mixing performance, and solves the problems of low reaction efficiency, long production cycle and inconvenient operation of traditional processes.

[0086] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for continuously preparing pioglitazone intermediate compound I by microtubules, characterized in that The method is carried out by using a microtubule continuous reaction and comprises the following steps: Step S100: 5-ethyl-2-(2-hydroxyethyl)pyridine and p-fluorobenzaldehyde are respectively dissolved in a first solvent to prepare a solution, which is pumped into a microtube at the same flow rate, mixed in a mixer, and then reacted in a reaction module of an inorganic base particle-packed column to obtain an effluent; Step S200: dissolving the thiazolidine-2,4-dione and the condensing agent in a second solvent to prepare a mixed solution, pumping the solution into a mixer at the same flow rate as the effluent from step S100, and then mixing the solution into a reaction module of a microtubular reactor for reaction. The reaction solution is collected, concentrated, and recrystallized to obtain Compound I. Wherein, the compound I is 5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methylene]-2,4-thiazolidinedione; In step S100, the material pump flow rate is 0.1-0.15 mL / min; the retention time of the material in the packed column reaction module is 10-30 min; the first solvent is selected from N,N-dimethylformamide; the concentration of 5-ethyl-2-(2-hydroxyethyl)pyridine is 0.25 mol / L, and the concentration of p-fluorobenzaldehyde is 0.28 mol / L; the reaction temperature is 20-30°C; In step S200, the condensing agent is selected from piperidine; the molar concentration of the thiazolidine-2,4-dione solution in the mixed solution is 0.3 mol / L; the molar concentration of the condensing agent in the mixed solution is 0.006 mol / L; the pumping flow rate is 0.1~0.3 mL / min; the reaction temperature is 180~200°C; the retention time of the reaction material in the reaction module is 13-27 min; the reaction pressure is 1.7~2.0 MPa; and the second solvent is selected from methanol.

2. The method according to claim 1, wherein The inorganic base filled in the filling column in step S100 is selected from one of potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, and cesium carbonate.

3. The method according to claim 1, wherein: The inorganic base particle filling column in step S100 is a stainless steel straight tube with an inner diameter of 7 mm, a length of 150 mm, a visual inner cavity volume of 6 mL, and an inorganic base filling amount of 8 g.

4. The method according to claim 1, wherein: In step S100, the 5-ethyl-2-(2-hydroxyethyl)pyridine solution and the p-fluorobenzaldehyde solution are simultaneously pumped into the microtube at the same flow rate of 0.1 mL / min, mixed in the first mixer (3), and then passed into the inorganic base filling column (4) set at a temperature of 25°C for reaction. After the reaction is retained for 10 minutes, a flask is connected to the inorganic base filling column (4) to continuously collect the effluent.

5. The method according to claim 1, wherein: The mixer in step S100 and step S200 is a T-type mixer or a Y-type mixer; The microtubes in step S100 and step S200 are circular tubular channels without internal fine structures and are made of stainless steel; the inner diameter of the microtubes is 100-1000 μm; In step S200, the inner diameter of the microtube reactor is 100-1000 μm; the volume of the microtube reactor is 5-10 ml; The injection pump in step S100 and step S200 is a high-pressure PTFE pump.

6. The method according to claim 1, wherein: In step S200, thiazolidine-2,4-dione and piperidine are dissolved in methanol and pumped into the microtube at the same flow rate of 0.2 mL / min as the effluent from step S100. After mixing in the second mixer (8), the mixture enters the microtube reactor for reaction, is heated to 180° C. in an oil bath, and the first back pressure valve (10) is set to 1.7 MPa with a retention time of 20 min to carry out a Knoevenagel condensation reaction. A flask is connected after the first back pressure valve (10). After the reaction reaches equilibrium, the reaction solution is continuously collected, concentrated, and recrystallized to obtain compound I.

7. The method according to claim 1, wherein: The specific steps of the method are as follows: Step S100: 5-ethyl-2-(2-hydroxyethyl)pyridine is dissolved in DMF to prepare a 0.25 mol / L solution, and the solution is connected to the first injection pump (1); p-fluorobenzaldehyde is dissolved in DMF to prepare a 0.28 mol / L solution, and the solution is connected to the second injection pump (2); the two solutions are simultaneously pumped into the microtube at the same flow rate of 0.1 mL / min, enter the T-type first mixer (3) for mixing, and then pass into the potassium hydroxide packed column set at a temperature of 25°C for reaction. After the reaction is retained for 10 minutes, a flask is connected from the inorganic base packed column (4), and the effluent is continuously collected for 24 hours; the inorganic base packed column (4) is a stainless steel straight tube with an inner diameter of 7 mm, a length of 150 mm, a visual inner cavity volume of 6 mL, and a potassium hydroxide filling amount of 8 g; Step S200: dissolving thiazolidine-2,4-dione and piperidine in methanol at a molar ratio of 50:1, the molar concentration of thiazolidine-2,4-dione solution in the mixed solution is 0.3 mol / L; the molar concentration of piperidine is 0.006 mol / L, the mixed solution is connected to the fourth injection pump (7), the effluent of step S100 is connected to the second back pressure valve (12), and simultaneously pumped into the microtube at the same flow rate of 0.2 mL / min, after being mixed by the T-type second mixer (8), entering the microtube reactor for reaction, heating to 180°C in an oil bath, setting the first back pressure valve (10) to 1.7 MPa, the retention time is 20 min, and performing Knoevenagel condensation reaction, connecting a flask from the back of the first back pressure valve (10), collecting the reaction solution continuously for 24 hours after the reaction is balanced, concentrating, and recrystallizing to obtain compound I; the inner diameter of the microtube reactor is 400 μm and the volume is 8 mL; The microtubes in step S100 and step S200 are circular tubular channels without an internal fine structure and are made of stainless steel; the inner diameter of the microtubes is 400 μm; the first injection pump (1), the second injection pump (2), and the fourth injection pump (7) are all elite high-pressure PTFE pumps.

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