A continuous flow synthesis process for an ezetimibe intermediate

Abstract

This invention discloses a microchannel continuous flow process for preparing the key intermediate (S)-3-{(2R,5S)-5-(4-fluorophenyl)-2-((S)-[(4-fluorophenyl)amino]{4-(trimethylsilyl)oxy]phenyl}methyl)-5-[(trimethylsilyl)oxy]pentanoyl}-4-phenylazolidine-2-one (Ⅰ). The process involves two separate metering feeds of a silicon-protected substrate mixture and anhydrous titanium tetrachloride dichloromethane dilution for Mannich addition-condensation. Utilizing the ultra-high heat and mass transfer capabilities of the microchannel, the reaction can proceed stably under mild conditions of 0–5°C, with system temperature fluctuations ≤ ±1.5°C. This eliminates the need for the harsh cryogenic conditions of traditional batch reactors (-40–-30°C), significantly enhancing process operability. Simultaneously, it completely resolves the shortcomings of traditional batch reactors, such as localized overheating during titanium reagent addition, excessive steric impurities, long batch reaction times, and high safety risks associated with open-drip TiCl4 dispensing. The total residence time of materials in this continuous condensation process is only a dozen minutes, far less than the 4-hour reaction time of batch reactors. Compared with the traditional batch reactor condensation yield of about 60%, the yield of this process is increased to more than 85%, the three-dimensional impurities are significantly reduced, the raw material consumption is reduced, the batch purity consistency is greatly improved, TiCl4 is transported through a closed pipeline throughout the process, and there is no fugitive corrosion gas volatilization, making it suitable for stable industrial mass production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically to a continuous flow synthesis process for ezetimibe intermediate. Background Technology

[0002] Ezetimibe, chemically named (3R,4S)-1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azacyclobutanone, was jointly developed by Schering-Plough and Merck. It was first launched in Germany in 2002 and in the United States in the same year. It selectively inhibits cholesterol absorption and, when used in combination with statins, can effectively lower plasma cholesterol levels. It was the first novel oral lipid-lowering drug approved by the Food and Drug Administration (FDA).

[0003] The key technology for synthesizing ezetimibe is the construction of the four-membered ring in the molecular structure. This four-membered ring is generally formed by the cyclization of the compound (S)-3-{(2R,5S)-5-(4-fluorophenyl)-2-((S)-[(4-fluorophenyl)amino]{4-(trimethylsilyl)oxy]phenyl}methyl)-5-[(trimethylsilyl)oxy]valeryl}-4-phenylazolidine-2-one (Ⅰ). Therefore, compound Ⅰ is a key intermediate in the synthesis of ezetimibe.

[0004]

[0005] The existing industrial synthesis route, referencing patent CN1130342C, involves protecting the hydroxyl groups of compounds II and III with trimethylchlorosilane (TMSCl) in the presence of diisopropylethylamine (DIPEA). , A Mannich-like reaction was carried out under TiCl4 catalysis. After acid quenching, the hydroxyl group was removed and protected. Finally, N,O-bis(trimethylsilyl)acetamide (BSA) was added for hydroxyl protection to obtain product I.

[0006] Currently, the industry uses intermittent low-temperature autoclave process. Due to the limitations of heat and mass transfer in the autoclave, the system has large local temperature differences and uneven material mixing. The content of diastereosteric impurities in the by-product is high, and the crude product needs to be recrystallized and purified multiple times. Existing literature "Optimization of Synthesis of Ezetimibe" (China Pharmaceutical Industry Magazine, 2018, 49 (2), Zhang Yuncai and Zhang Fan) verified that when the reaction temperature is lowered to a harsh low temperature of -60 to -50℃, the stereosteric impurities can only be reduced to 9%, and the condensation molar yield is only about 60%.

[0007] The traditional batch reactor process has a total reaction time of 4 hours per batch. The manual open-top addition of titanium tetrachloride poses safety hazards such as material spraying and hydrogen chloride corrosion leakage. The low-temperature refrigeration unit has high energy consumption and large solvent consumption, resulting in large fluctuations in batch product quality, which is not conducive to stable large-scale production. Therefore, we propose a method for continuous synthesis of ezetimibe intermediates to solve the above problems. Summary of the Invention Purpose of the invention

[0008] To address the shortcomings of existing batch reactor methods for preparing key intermediate I of ezetimibe, which require cryogenic treatment at -40 to -30°C, resulting in poor heat and mass transfer, high content of steric impurities, a condensation yield of only 60%, a single-batch reaction cycle of up to 4 hours, significant safety and environmental hazards from open-drip TiCl4 delivery, large batch purity fluctuations, and cumbersome refining processes, this invention provides a continuous flow synthesis process for ezetimibe intermediates. This process utilizes a microchannel reactor to complete the core Mannich condensation reaction. Leveraging the ultra-high heat exchange and instantaneous mixing characteristics of the microchannel, the reaction temperature range is widened, steric impurity side reactions are suppressed, condensation yield is improved, and reaction time is significantly shortened. The process also employs a closed-loop pipeline for transporting high-risk titanium reagents, reducing energy consumption and safety risks, and enabling the continuous and stable industrial preparation of intermediate I.

[0009] Technical solution

[0010] A continuous flow synthesis process for ezetimibe intermediates includes the following steps: (1) Raw material pretreatment: 8-10 parts by weight of haloalkanes and 1 part of intermediate II were added to the nitrogen-protected preparation vessel. The organic base and silicon-based protective reagent were added at a temperature of ≤10℃. After reacting for 25 min, 0.8 parts of intermediate III were added and reacted at 10℃ for 1 h. The resulting silicon-protected substrate mixture was stored in storage tank A. 0.3 parts of anhydrous haloalkanes were added to the mixing vessel to dilute 0.65 parts of titanium tetrachloride. The mixture was then sealed at low temperature and stored in storage tank B. The haloalkanes were dichloromethane, trichloromethane or 1,2-dichloroethane. The organic bases were diisopropylethylamine, triethylamine, or N-methylmorpholine. The silicon-based protective reagents were trimethylchlorosilane or tert-butyldimethylchlorosilane.

[0011] (2) Continuous Mannich condensation: A high-precision plunger-type first feed pump delivers material from storage tank A at 380-420 mL / min, and a second feed pump delivers material from storage tank B at 90-110 mL / min. The flow rate error of the two pumps is ≤±1%, and the volumetric flow rate ratio is 4:1. The microchannel temperature is controlled at 0~5℃ with fluctuation ≤±1.5℃, the pressure is 0.1~0.15MPa, and the material residence time is 18~25min to obtain condensed crude liquid with diastereomeric impurities <2%. The microchannel material is silicon carbide, Hastelloy, or tantalum, with a heat transfer coefficient ≥6000W / (m²・K) and a mixing uniformity ≥98%.

[0012] (3) Post-treatment: The crude condensate is quenched at low temperature with glacial acetic acid or propionic acid, washed with 5% to 10% tartaric acid or citric acid aqueous solution, and extracted with dichloromethane or chloroform; after desolventizing the organic phase, BSA is refluxed, and crystallized with ethyl acetate / n-hexane or isopropyl acetate / petroleum ether; the solid is dried at 40 to 50℃ and vacuum degree -0.09 to -0.1MPa for 4 to 6 hours, and the moisture content of the finished product is ≤0.1% and the loss on drying is ≤0.5%. Beneficial effects

[0013] (1) Mild reaction conditions significantly reduce energy consumption and equipment investment: The microchannel reactor has mild reaction conditions, does not require deep cooling of -40 to -30℃, and can stably complete Mannich condensation at 0 to 5℃. It does not require a large-scale low-temperature refrigeration unit, reducing refrigeration energy consumption by more than 70%, reducing equipment investment by 20%, and significantly improving the operational fault tolerance.

[0014] (2) Excellent impurity control and significantly improved condensation yield: The microchannel provides instantaneous and uniform heat exchange and mixing, which inhibits the generation of three-dimensional impurities from the source. The three-dimensional impurities in the crude liquid are ≤2%, and can be reduced to less than 0.1% after a single crystallization. The condensation molar yield is stable at over 85%, which is 22 percentage points higher than the traditional process. The raw material consumption is reduced, and multiple recrystallization and refining processes are eliminated.

[0015] (3) High reaction efficiency, suitable for continuous large-scale production: The total reaction time of a single batch in a traditional batch reactor is 4 hours, while the material stays in the microchannel of this process for only 18 to 25 minutes, and can be continuously discharged 24 hours a day, increasing the unit equipment capacity by more than 5 times.

[0016] (4) Safe and environmentally friendly, solvent can be recycled: TiCl4 is transported in a closed storage tank and closed pipeline throughout the process, eliminating manual open dripping and completely eliminating the risk of spraying, corrosion and leakage; the reaction system is protected by nitrogen micro-positive pressure, greatly reducing the fugitive volatilization of hydrogen chloride; the extraction solvent can be recycled after distillation and dehydration, reducing the consumption of organic solvents and the discharge of waste liquid and solid waste by 35%. Detailed Implementation

[0017] The present invention will be further described in detail below with reference to specific embodiments. The described embodiments are only used to explain the present invention and are not intended to limit the scope of protection of the present invention. Example 1

[0018] (1) Raw material pretreatment: Under nitrogen protection, 160 kg of dichloromethane and 20 kg of ezetimibe intermediate II were added to a 1000 L drying preparation vessel and stirred until dissolved; 23.2 kg of diisopropylethylamine and 16 kg of trimethylchlorosilane were added at a temperature of ≤10℃ and stirred for 25 min; 16 kg of ezetimibe intermediate III solid was added and stirred at 10℃ for 1 h to obtain a silicon-protected substrate mixture, which was then transferred to storage tank A for low-temperature nitrogen-sealed storage; 6 kg of anhydrous dichloromethane was added to the mixing vessel and 13 kg of titanium tetrachloride was slowly added and stirred to dilute evenly, and then stored at low temperature in a sealed container to obtain the material in storage tank B.

[0019] (2) Continuous Mannich condensation reaction: The flow rate of the first feed pump of the high-precision plunger type is 400 mL / min, the flow rate of the second feed pump is 100 mL / min, the flow rate error is 0.7%, and the material volume ratio is stable at 4:1; the temperature of the microchannel reactor is controlled at 3℃, the temperature fluctuation is ≤1.2℃, the system pressure is 0.12MPa, the material residence time is 22min, and the Mannich addition condensation is completed. The diastereosteric impurities in the crude condensation liquid are 0.28%; the microchannel material is silicon carbide, the heat transfer coefficient is 6400W / (m²・K), and the mixing uniformity is 98.6%.

[0020] (3) Post-processing: The crude condensate was transported to a quenching vessel, quenched at low temperature with glacial acetic acid, washed with 7% tartaric acid aqueous solution, and extracted with dichloromethane; the organic phase was desolventized under reduced pressure, and after removing water with anhydrous dichloromethane, BSA was added and refluxed for 1 h; after desolventization, ethyl acetate-n-hexane mixed solvent was added and refluxed, and crystallization was performed by gradient cooling. After crystallization and purification, the diastereomeric stereoimpurities were reduced to 0.08%; after solid-liquid separation, the solid was dried at 45℃ and vacuum degree -0.095MPa for 5 h to obtain 34.35 kg of Ezetimibe key intermediate I product.

[0021] Test results: The molar yield of the condensation section was 85.6%, the content of the finished product was 99.1%, the diastereosteric impurities were 0.08%, the moisture content was 0.07%, and the loss on drying was 0.32%. Example 2

[0022] (1) Raw material pretreatment: Under nitrogen protection, 200 kg of dichloromethane and 20 kg of ezetimibe intermediate II were added to a 1000 L preparation vessel and stirred until dissolved; 23.2 kg of diisopropylethylamine and 16 kg of trimethylchlorosilane were added at a temperature of ≤10℃ and stirred for 25 min, then 16 kg of intermediate III was added and stirred at 10℃ for 1 h, and then transferred to storage tank A; 6 kg of anhydrous dichloromethane and 13 kg of titanium tetrachloride were added to the dissolving vessel for dilution and stored in storage tank B.

[0023] (2) Continuous Mannich condensation reaction: the flow rate of the first feed pump is 420 mL / min, the flow rate of the second feed pump is 105 mL / min, and the flow rate error is 0.9%; the microchannel temperature is controlled at 5℃ with fluctuation ≤1.4℃, the system pressure is 0.15 MPa, the material residence time is 25 min, and the diastereosteric impurities in the crude condensate are 0.31%; the microchannel is made of Hastelloy alloy with a heat transfer coefficient of 6100 W / (m²・K) and a mixing uniformity of 98.2%.

[0024] (3) The post-processing operation is the same as in Example 1. The vacuum drying temperature is 42℃, the vacuum degree is -0.09MPa, and the drying time is 6h. After crystallization, the diastereosteric impurities are 0.09%, and 34.07kg of Ezetimibe key intermediate I product is obtained.

[0025] Test results: The molar yield of the condensation section was 84.9%, the product content was 99.05%, the diastereosteric impurities were 0.09%, the moisture content was 0.08%, and the loss on drying was 0.35%. Comparative example (traditional batch reactor process)

[0026] 160 kg of dichloromethane and 20 kg of intermediate II were added to a 1000 L reactor under nitrogen protection. The silicon protection ratio was exactly the same as in Example 1. The silicon protection mixture was cooled to -40 to -35 °C, and a diluted titanium tetrachloride solution was slowly added dropwise. After the addition was completed, the mixture was kept at -40 °C for 4 hours. The quenching, water washing, BSA reaction, crystallization and drying were all consistent with those in Example 1. The crude liquid contained 10.2% diastereosteric impurities, and the impurities were still as high as 3.26% after a single crystallization. Finally, 25.20 kg of intermediate I was obtained.

[0027] Test results: The molar yield of the condensation section was 62.8%, the content of the finished product was 96.7%, the diastereomeric impurities were 3.26%, and the moisture content was 0.12%. Effect Comparison and Analysis

[0028] This invention achieves a mild condensation reaction at 0–5°C (compared to the harsh cryogenic conditions of -40–-35°C in traditional methods), reducing refrigeration energy consumption by over 70%; it eliminates the open-drip operation of titanium reagent, shortening the reaction time per batch by over 90%; the condensation molar yield is increased by 22.1–22.8 percentage points, and the finished product content is increased by 2.35–2.4 percentage points; the diastereosteric impurities in the crude liquid are reduced from 10.2% to 0.28%–0.31%, a reduction of over 97%, and the steric impurities can be stably controlled below 0.1% after a single crystallization. The raw material utilization rate is greatly improved, solvent loss and refining process costs are significantly reduced, and the overall production cost is significantly lowered, resulting in extremely obvious industrial economic advantages.

[0029] Although specific embodiments have been used to describe the technical solutions of the present invention in detail in this specification, any modifications or improvements made by those skilled in the art based on the inventive concept in terms of specific implementation methods and application scope are all within the scope of protection claimed by the present invention. Therefore, the content described in this specification should not be construed as a limitation of the present invention.

Claims

1. A condensation process for preparing key intermediate I of ezetimibe using microchannel continuous flow, characterized in that, Includes the following steps: (1) Raw material pretreatment: Under nitrogen protection, add 8-10 parts by weight of dichloromethane to the preparation vessel, then add 1 part by weight of ezetimibe intermediate II, and stir until dissolved; control the temperature ≤10℃ and add 1.16 parts by weight of diisopropylethylamine and 0.8 parts by weight of trimethylchlorosilane in sequence, stir and react for 25 min, then add 0.8 parts by weight of ezetimibe intermediate III solid, stir and react at 10℃ for 1 h to obtain a silicon-protected substrate mixture, which is then transferred to storage tank A for low-temperature nitrogen sealing and heat preservation; add 0.3 parts by weight of anhydrous dichloromethane to the mixing vessel, add 0.65 parts by weight of titanium tetrachloride, stir and dilute evenly, and keep it under low-temperature nitrogen sealing to obtain the material in storage tank B; (2) Continuous Mannich condensation reaction: A high-precision plunger-type first feed pump is used to transport the material from storage tank A to the microchannel reactor at a flow rate of 380-420 mL / min. A second feed pump is used to simultaneously transport the material from storage tank B to the microchannel reactor at a flow rate of 90-110 mL / min. The reaction temperature of the microchannel reactor is controlled at 0-5℃ (temperature fluctuation ≤ ±1.5℃), the reaction pressure is controlled at 0.1-0.15 MPa, and the residence time of the material in the reactor is 18-25 min to complete the Mannich addition condensation reaction and obtain the crude condensation reaction solution. Relying on the efficient heat and mass transfer of the microchannel, the generation of diastereosteric impurities is suppressed from the source, and the diastereosteric impurities in the obtained crude condensation reaction solution are less than 2%. (3) Post-processing: The crude condensation reaction solution was quenched at low temperature with glacial acetic acid, washed with tartaric acid, extracted with dichloromethane, and after desolventizing the organic phase, it was refluxed with BSA, crystallized with mixed solvent, and vacuum dried to obtain intermediate I finished product.

2. The condensation process for preparing key intermediate I of ezetimibe using microchannel continuous flow according to claim 1, characterized in that: In step (1), the haloalkane solvent is selected from dichloromethane, trichloromethane or 1,2-dichloroethane; the organic base is selected from diisopropylethylamine, triethylamine or N-methylmorpholine; and the silicon-based protecting agent is selected from trimethylchlorosilane or tert-butyldimethylchlorosilane.

3. The condensation process for preparing key intermediate I of ezetimibe using microchannel continuous flow according to claim 1, characterized in that: In step (2), the first feed pump delivers a flow rate of 380-420 mL / min, the second feed pump delivers a flow rate of 90-110 mL / min, the flow rate error between the two feed pumps is ≤±1%, and the volume flow rate ratio of the two materials is constant at 4:

1.

4. The condensation process for preparing key intermediate I of ezetimibe using microchannel continuous flow according to claim 1, characterized in that: In step (2), the temperature of the Mannich condensation reaction in the microchannel is 0-5℃, with temperature fluctuation ≤ ±1.5℃; the pressure of the reaction system is 0.1-0.15MPa; and the material residence time is 18-25min.

5. The condensation process for preparing key intermediate I of ezetimibe using microchannel continuous flow according to claim 1, characterized in that: In step (2), the microchannel reactor is made of silicon carbide, Hastelloy or tantalum, the reactor heat transfer coefficient is ≥6000W / (m²・K) and the material mixing uniformity is ≥98%.

6. The condensation process for preparing key intermediate I of ezetimibe using microchannel continuous flow according to claim 1, characterized in that: In step (3), glacial acetic acid and propionic acid are used to quench organic acids; 5% to 10% tartaric acid aqueous solution and citric acid aqueous solution are used as washing reagents; dichloromethane and chloroform are used as extraction solvents; and ethyl acetate / n-hexane and isopropyl acetate / petroleum ether are used as crystallization mixed solvents.

7. The condensation process for preparing key intermediate I of ezetimibe using microchannel continuous flow according to claim 1, characterized in that: In step (3), the vacuum drying temperature is 40-50℃, the vacuum degree is -0.09 to -0.1MPa, and the drying time is 4-6h; the moisture content of the finished product is ≤0.1%, and the drying loss is ≤0.5%.

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