A process for the continuous preparation of mirabegron in a microchannel reactor

Abstract

This invention discloses a stepwise continuous flow method for preparing Miraberon using a microchannel reactor. Specifically, the method involves synthesizing Miraberon from p-nitrophenylethylamine hydrochloride and D-mandelic acid, followed by amide condensation, borane reduction, hydrogenation reduction, and a second amide condensation reaction to obtain the target product. Each step utilizes a continuous flow process for intermediate synthesis. This invention offers high reaction safety, short reaction time, and simple post-processing. It fundamentally eliminates the safety hazards caused by hydrogen leakage, reduces catalyst friction loss due to stirring in batch reactions, and avoids catalyst contact with air during post-processing, thus preserving catalyst activity, improving catalyst utilization efficiency, and significantly reducing economic costs.

Description

Technical Field

[0001] This invention belongs to the technical field of drug synthesis methods, specifically relating to a method for the continuous preparation of miraberione using a microchannel reactor. Background Technology

[0002] Mirabegron is a novel and selective β-reactive protein. 3 Mirabelon is an adrenergic receptor agonist used to treat overactive bladder (OAB) in adults. It was the first beta-agonist used to treat OAB. 3 Adrenergic receptor agonist drugs fill a gap in the treatment of OAB by beta-adrenergic receptor agonists.

[0003] Miraberon, chemically named 2-amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]-4-thiazolylacetamide, has the following structural formula:

[0004]

[0005] In 2004, Soichiro Kawazoe, Takayuki Suzuki, and others reported a method for preparing Miraberon, the specific route of which is as follows:

[0006]

[0007] This route uses the condensation reagent EDCI twice, resulting in slightly higher costs, but it offers convenient post-processing. However, it uses a highly toxic, flammable, and explosive BH3-THF solution. The reduction using palladium on carbon is also costly, making industrial-scale production difficult. To address the safety concerns of boranes, in 2018, Renzo Luisi's group used 2-methyltetrahydrofuran as a green alternative to traditional solvents, allowing for the safe transfer of borane complexes into microfluidic reactors. While using metal catalysts to reduce nitro groups to amino groups on an industrial scale offers advantages such as fewer byproducts and higher yields, the flammability and explosiveness of hydrogen pose significant safety hazards in the event of a leak, placing extremely high demands on equipment and safe operation, thus limiting the widespread application of this method.

[0008] Continuous flow chemistry refers to a chemical reaction process conducted under continuous flow conditions. Specifically, two or more reactants are first thoroughly mixed at appropriate flow rates using a mixing device before being pumped into tubular, packed bed, microchannel, or even batch reactors. The chemical reaction occurs simultaneously as the reactants flow through the reactor, and the reaction liquid is collected at the outlet or pumped to the next process. Generally, to meet production requirements, batch reactors are typically large, thus demanding high mass and heat transfer rates. Achieving uniform mixing is often difficult, posing a potential risk of localized overheating, and in some cases, severely impacting product recovery rates. In contrast, in continuous flow reactions, materials react in the reactor and immediately exit the system for cooling. The transport of reactants, the reaction itself, and the separation and post-processing of products are all completed under continuous flow conditions. The residence time of reactants in the equipment is short, the reaction process is rapid, and mass and heat transfer rates are fast. The reaction is more controllable, resulting in fewer side reactions, higher product selectivity, and greater environmental friendliness and safety. Summary of the Invention

[0009] To address the problems of long reaction time, significant safety hazards, and low catalyst reuse rates in traditional batch reactor synthesis of Mirabelon, the present invention aims to provide a method for the continuous preparation of Mirabelon using a microchannel reactor.

[0010] The specific technical solution is as follows:

[0011] A method for the continuous preparation of mirabeeron using a microchannel reactor includes the following steps:

[0012] Step 1: Compound 1, Compound 2, triethylamine, and HOBT were prepared into solution A, and EDCI was prepared into solution B. These solutions were then mixed separately using a plunger pump in a mixer, and then fed into a coil for reaction. The reaction solution was diluted with water until turbid, extracted with ethyl acetate, and the organic phase was washed with acid solution, then with alkaline solution, and finally with water. The solvent was then evaporated to obtain compound 3. Testing revealed that any method that pre-mixed EDCI with other reactants (whether compound 1, compound 2, triethylamine, or HOBT) resulted in a sharp decrease in yield. Under otherwise identical conditions, if EDCI, HOBT, and compound 2 were prepared into solution A, and compound 1 and triethylamine were prepared into solution B, the reaction yield was 38%. If compound 1, compound 2, triethylamine, and EDCI were prepared into solution A, and HOBT into solution B, the reaction yield was 42%. If EDCI and compound 1 were prepared into solution A, and compound 2, triethylamine, and HOBT were prepared into solution 2, the yield was only 32%.

[0013] The concentration of solution A is 0.1~0.5 mol / L, and the concentration of solution B is 0.11~0.55 mol / L.

[0014] Furthermore, the solvents used to prepare solutions A and B are DMF or a mixture of DMF and water.

[0015] Preferably, the solvent is DMF.

[0016] Furthermore, the reaction temperature inside the coil is 20-30°C, and the inner diameter of the coil is 1 / 16 inch.

[0017] Furthermore, the residence time of the material in the coil is 56~420s.

[0018] Preferably, the dwell time is 72 seconds.

[0019] Furthermore, the acid solution is 1N dilute hydrochloric acid, and the alkaline solution is saturated potassium carbonate or sodium bicarbonate solution.

[0020] Step 2: Compound 3 and the reducing agent BH3-DMS were dissolved in ultra-dry 2-methyltetrahydrofuran to prepare solutions C and D, respectively. The solutions were pumped through a Y-type mixer and then through a coil to obtain the reaction solution. The solution was then treated with concentrated hydrochloric acid to obtain the crude salt product, which was then treated with alkali and extracted to obtain compound 4.

[0021] Furthermore, the injector for the push-pump is made of glass, and the reaction coil has a diameter of 1 / 8 or 1 / 16 inch and is made of polytetrafluoroethylene.

[0022] Preferably, the pipe diameter is 1 / 8 inch.

[0023] Furthermore, the concentration of solution C is 0.2~0.8 mol / L, and the concentration of solution D is 0.4~10 mol / L.

[0024] Preferably, solution C has a concentration of 0.2 mol / L and solution D has a concentration of 0.44 mol / L.

[0025] Furthermore, the temperature of the borane reduction reaction is 70-90℃, the residence time of the material in the coil is 8-22 minutes, and the reaction pressure is 0-0.2MPa.

[0026] Preferably, the temperature is 80℃, the residence time is 13min, and the pressure is 0MPa.

[0027] Step 3: The compound 4 solution and hydrogen gas are introduced into a preheating coil through different pipelines. After being preheated in the preheating coil, the material enters a continuous flow microchannel fixed-bed reactor with a supported metal catalyst for hydrogenation reduction to obtain compound 5.

[0028] The concentration of compound 4 in the solution is 0.1~0.5 mol / L.

[0029] Furthermore, the solvent for the compound 4 solution is methanol or ethyl acetate.

[0030] Preferably, the solvent is methanol.

[0031] Furthermore, the pressure of hydrogen gas during the process is 0.1~3 MPa.

[0032] Preferably, the pressure is 1 MPa.

[0033] Furthermore, the continuous flow microchannel fixed bed reactor is a tubular reactor with a catalyst filling chamber inside. The outer periphery of the catalyst filling chamber is a heat exchange fluid channel. The catalyst filling wall is connected to the material inlet and the material outlet, respectively, and the heat exchange fluid channel is connected to the heat exchange fluid inlet and the heat exchange fluid outlet, respectively.

[0034] Furthermore, the catalyst filling cavity has a diameter of 100 μm-20 mm and a length of 10-16 cm, and is made of one of the following materials: glass, polytetrafluoroethylene, stainless steel, Hastelloy, tantalum, or zirconium.

[0035] Furthermore, the metal catalyst is Raney nickel, and the mass ratio of compound 4 to Raney nickel is 1:0.05~0.10.

[0036] Preferably, the mass ratio is 1:0.05.

[0037] Furthermore, the temperature of the hydrogenation reduction reaction is 25-50℃, and the residence time of the material in the continuous flow microchannel fixed bed reactor is 1 minute.

[0038] Preferably, the temperature is 50℃.

[0039] Step 4: Compound 5 and Compound 6 are prepared into corresponding salt solutions and mixed to form material F. EDCI is dissolved in water to prepare solution G. The reaction solution is pumped and flows out from the coil through a mixer to obtain the reaction liquid. After treatment with sodium hydroxide solution, it is filtered to obtain compound 7. Testing showed that any method that pre-mixes EDCI with the reactants (whether compound 5 or compound 6) leads to a sharp decrease in yield.

[0040] Furthermore, the molar ratio of compound 5 to compound 6 is 1-1.2:1, and the molar ratio of condensing agent to compound 6 is 1-1.2:1.

[0041] Furthermore, the reaction is carried out at a temperature of 15-30℃, with a coil inner diameter of 1 / 16, and the solution solvent is DMF, methanol, ethanol, or water.

[0042] Preferably, the reaction temperature is 25°C and the solvent is water.

[0043] Furthermore, the dwell time is 1 to 4 minutes.

[0044] Preferably, the dwell time is 1.75 min.

[0045] The beneficial effects of this invention are as follows:

[0046] 1) The present invention features high reaction safety, short reaction time, and simple post-processing purification;

[0047] 2) Reduces the frictional loss of catalyst caused by stirring in the batch reaction, eliminates the need to filter and separate the catalyst from the feed liquid, avoids contact between the catalyst and air during post-processing, preserves the activity of the catalyst, improves the continuous utilization efficiency of the catalyst, and significantly reduces economic costs.

[0048] 3) Continuous flow significantly reduces the number of times feed is required in batch reactors, saving labor costs. Attached Figure Description

[0049] Figure 1 This is an overall flowchart of the present invention;

[0050] Figure 2 This is a schematic diagram of the mixer structure used in this invention;

[0051] Figure 3 This is a schematic diagram of the continuous flow microchannel fixed bed reactor of the present invention.

[0052] In the diagram: 15 is the feed inlet, 16 is the discharge outlet, 17 is the microchannel inside the mixer; 21 is the catalyst filling chamber; 22 is the heat exchange fluid channel; 23 is the material inlet; 24 is the material outlet; 25 is the heat exchange fluid inlet; 26 is the heat exchange fluid outlet. Detailed Implementation

[0053] The present invention will be further described below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention is not limited to the following embodiments.

[0054] The reaction formula of this invention is as follows:

[0055]

[0056] The mixer used in the preparation of compounds 2 and 7 in this invention is as follows: Figure 2 As shown, the mixer is provided with two inlets 15 and one outlet 16, and an internal microchannel 17 is provided between the inlets 15 and the outlet 16.

[0057] The continuous flow microchannel fixed-bed reactor used in the preparation of compound 5 in this invention is a tubular reactor, such as... Figure 3 As shown, the catalyst filling chamber 21 is provided inside, and the outer periphery of the catalyst filling chamber 21 is a heat exchange fluid channel 22. The catalyst filling chamber 21 is connected to the material inlet 23 and the material outlet 24, respectively, and the heat exchange fluid channel 22 is connected to the heat exchange fluid inlet 25 and the heat exchange fluid outlet 26, respectively. In this embodiment of the invention, the catalyst filling chamber 21 has a diameter of 10 mm, a length of 15 cm, and is made of Hastelloy alloy.

[0058] Example 1 (Continuous flow synthesis of compound 3)

[0059] The process is as follows Figure 1 As shown in (a), the material solution was prepared by adding 4.05 g of p-nitrophenylethylamine hydrochloride, 3.35 g of D-mandelic acid, 2.03 g of triethylamine and 2.97 g of HOBT to a mixing tank and dissolving them in 100 mL of DMF to prepare a mixed solution, and dissolving 4.22 g of EDCI in 100 mL of DMF to prepare a 0.22 mol / L solution.

[0060] The materials were pumped into the mixer using two plunger pumps at a flow rate of 3 mL / min. After mixing in the mixer, the mixture was transferred to a coil with a liquid holding capacity of 7.2 mL (coil inner diameter of 1 / 16 inch). The mixture was held in the coil for 1.2 min at a reaction temperature of 25°C. The reaction solution was then collected, diluted with water until turbid, extracted with ethyl acetate, and then washed with 1N hydrochloric acid, followed by washing with saturated potassium carbonate solution and then with water. The organic phase was dried with anhydrous sodium sulfate and then distilled under reduced pressure to obtain compound 3 with a yield of 99%. Compared with the batch reaction time of 4 h, the continuous flow reaction was faster and more efficient.

[0061] Example 2

[0062] In this embodiment, the solvent DMF in Example 1 was replaced with a mixed solvent of DMF: H2O = 10:1 (volume ratio), and other operating conditions were the same as in Example 1. The yield of compound 3 was 91.5%.

[0063] Example 3

[0064] In this embodiment, the flow rate in Example 1 was changed to 4 mL / min, the residence time was 56 s, and other operating conditions were the same as in Example 1. The yield of compound 3 was 96%. In this embodiment, the flow rate in Example 1 was changed to 1 mL / min, the residence time was 430 s, and other operating conditions were the same as in Example 1. The yield of compound 3 was 94%.

[0065] Example 4 (Continuous flow synthesis of compound 4)

[0066] like Figure 1 As shown in (b), 2.4 g of compound 3 was dissolved in 40 mL of ultra-dry 2-methyltetrahydrofuran to prepare a 0.2 mol / L solution C (maximum concentration approximately 0.8 mol / L), and 1.8 mL of 10 mol / L BH3-DMS solution was dissolved in 38.2 mL of ultra-dry 2-methyltetrahydrofuran to prepare a 0.44 mol / L solution D.

[0067] Solutions C and D were fed using a push-jet pump (the push-jet pump syringe was made of glass) and mixed at room temperature using a Y-type mixer. The mixture was then fed into a coil with an inner diameter of 1 / 8 inch and made of polytetrafluoroethylene. The reaction temperature was 80°C, the pressure was 0 MPa, the flow rate was 0.5 mL / min, and the residence time was 13 min. The reaction solution was quenched with a small amount of water or methanol, and then concentrated hydrochloric acid was added to decomplex the mixture and precipitate the salt. The filtered salt was then treated with alkali and extracted. The organic phase was dried with anhydrous sodium sulfate and then distilled under reduced pressure to obtain compound 4 with a yield of 88%. Compared with the reaction time of 2 h in a batch reactor, the continuous flow reaction only required 13 min.

[0068] Example 5 (Continuous flow synthesis of compound 5)

[0069] like Figure 1 As shown in (c), 2.86 g of compound 4 was dissolved in 100 mL of methanol to prepare a 0.1 mol / L solution E, and 144 mg of Raney nickel was mixed with quartz sand and filled into the catalyst packing cavity.

[0070] Solution E and hydrogen gas were introduced into a preheating coil through different pipelines and preheated to 50°C. Then, the mixture was introduced into a continuous flow microchannel fixed-bed reactor for reaction at a pressure of 1 MPa. The residence time of the material in the continuous flow microchannel fixed-bed reactor was 1 min. The amount of H2 in the continuous flow microchannel fixed-bed reactor 2 was 10 equivalents relative to compound 4. After mixing, the material flow rate was 1.890 mL / min. Compound 5 was obtained by vacuum distillation of the reaction solution with a conversion rate of 100%. Compared with the 90% yield of the batch reaction, the continuous flow reaction has a higher yield and a faster reaction time.

[0071] Example 6 (Continuous flow synthesis of compound 7)

[0072] like Figure 1 As shown in (d), 0.51g of compound 5 and 0.35g of compound 6 were added to 4.2mL of 1N dilute hydrochloric acid and then water was added to prepare a 20mL mixed salt solution F (or compound 5 and compound 6 were added to water and then concentrated hydrochloric acid was added to prepare the solution). 0.43g of EDCI was dissolved in 20mL of water to prepare a 0.11mol / L solution G.

[0073] At room temperature and pressure, solutions F and G were pumped into a mixer by two pumps and then flowed out through a reaction coil (with an inner diameter of 1 / 16 inch). The flow rate of the solutions was 2 mL / min, and the residence time of the materials in the coil was 1.75 min (reaction temperature was 25 °C). The reaction solution was treated with 1.5 N sodium hydroxide solution and filtered to obtain a white solid compound 7 with a yield of 95%.

Claims

1. A method for the continuous preparation of Miraberon using a microchannel reactor, characterized in that, Includes the following steps: Step 1: Prepare solution A by mixing p-nitrophenylethylamine hydrochloride, D-mandelic acid, triethylamine and HOBT as the reaction raw materials, and prepare solution B by mixing EDCI separately. Mixture A and solution B are fed into a mixer by a plunger pump and then flow out after reaction in a coil. After simple post-treatment, compound 3 is obtained. Step 2: Compound 3 and reducing agent BH3-DMS were dissolved in 2-methyltetrahydrofuran to prepare solutions. The solutions were pumped into Y-type mixers and mixed before entering the coil. The reaction solution was treated with concentrated hydrochloric acid, and the resulting solid was treated with alkali and then extracted to obtain compound 4. Step 3: Compound 4 is dissolved in methanol or ethyl acetate and fed into a continuous flow microchannel fixed bed reactor via a plunger pump. Under the action of a catalyst, it reacts with hydrogen and then flows out through a coil to obtain compound 5. Step 4: Compound 5 and Compound 6 are separately prepared into salt solutions with hydrochloric acid and mixed into one liquid. Separately, condensing agent EDCI is dissolved in water to prepare a solution. The two liquids are mixed in a mixer and then flowed out through a coil. The reaction solution is treated with alkali and then filtered to obtain Compound 7. The reaction steps are as follows: ； In step one, the solvent used to prepare solutions A and B is DMF, and the reaction temperature in the coil is 20-30℃. In step one, the molar ratio of EDCI to p-nitrophenylethylamine hydrochloride is 1-1.1:1; In step one, the residence time of the material in the coil is 56s-420s, and the flow rate of solution A and solution B pumped in by the plunger pump is 3mL / min or 4mL / min.

2. The method for continuous preparation of Miraberon using a microchannel reactor as described in claim 1, characterized in that, In step two, the reaction temperature of the material in the coil is 70-90℃, the pressure is 0MPa, and the residence time is 10-22min.

3. The method for continuous preparation of Miraberon using a microchannel reactor as described in claim 1, characterized in that, In step two, the molar ratio of the reducing agent BH3-DMS to compound 3 is 2-2.5:

1.

4. The method for continuous preparation of Miraberon using a microchannel reactor as described in claim 1, characterized in that, In step three, the continuous flow microchannel fixed bed reactor is a tubular reactor with a catalyst filling chamber inside. The outer periphery of the catalyst filling chamber is a heat exchange fluid channel. The catalyst filling chamber is connected to the material inlet and the material outlet, and the heat exchange fluid channel is connected to the heat exchange fluid inlet and the heat exchange fluid outlet.

5. The method for continuous preparation of Miraberon using a microchannel reactor as described in claim 1, characterized in that, Step 3: The catalyst filling cavity has a diameter of 100 μm-20 mm and a length of 10-16 cm. The material is one of glass, polytetrafluoroethylene, stainless steel, Hastelloy, tantalum, or zirconium.

6. The method for continuous preparation of Miraberon using a microchannel reactor as described in claim 1, characterized in that, In step three, the metal catalyst is Raney nickel, and the mass ratio of compound 4 to Raney nickel is 1:0.05~0.10; the reaction temperature in step three is 25-50℃, and the residence time of the material in the continuous flow microchannel fixed bed reactor in step three is 1 minute.

7. The method for continuous preparation of Miraberon using a microchannel reactor as described in claim 1, characterized in that, In step four, the molar ratio of compound 5 to compound 6 is 1-1.2:1, and the molar ratio of condensing agent to compound 6 is 1-1.2:1; the residence time of the materials in the coil in step four is 1-4 min, and the reaction temperature is 15-30℃.

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