Continuous flow preparation method of lenalidomide and derivative thereof

Abstract

The invention discloses a continuous flow preparation method of lenalidomide and derivatives thereof, and belongs to the technical field of medical chemistry. According to the preparation method, acetonitrile is adopted as a solvent, a substrate solution A and a brominating agent solution B are prepared respectively, the substrate solution A and the brominating agent solution B are mixed online to obtain a first mixed solution, the first mixed solution is introduced into a continuous flow photochemical reactor for a photo-bromination reaction, and the continuous flow photochemical reactor is provided with an LED light source with an integrated circulating cooling function; the method comprises the following steps: mixing 3-aminopiperidine-2, 6-dione hydrochloride with alkali to obtain a bluish violet pre-activated solution, mixing the pre-activated solution with light bromination reaction effluent on line, and carrying out condensation and cyclization reaction in a flowing state; and continuously carrying out hydrogenation reduction reaction in a flowing state, and collecting effluent to obtain the target compound lenalidomide or the derivative thereof. According to the continuous flow preparation method disclosed by the invention, the total retention time of the three-step reaction is shortened to 42 minutes from more than 40 hours of the traditional process, and the production capacity in unit time is remarkably improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to a continuous flow preparation method for lenalidomide and its derivatives. Background Technology

[0002] Lenalidomide, a first-line drug for the treatment of multiple myeloma, typically undergoes three key steps in its industrial synthesis: bromination, cyclization, and reduction. Currently, most mainstream processes employ traditional batch processing, which suffers from cumbersome operations, long production cycles, and batch-to-batch quality fluctuations.

[0003] Despite the significant advantages of continuous flow chemistry in improving mass and heat transfer and process safety, its application in the total synthesis of lenalidomide still faces considerable challenges: (1) Problems of intermediate purification and impurity accumulation: In the existing process, the single-step conversion rate and selectivity of the above three reaction steps are often unsatisfactory, resulting in a large number of by-products in the reaction solution. In the batch process, impurities can be removed by separating and purifying intermediates (such as crystallization and extraction); however, in the continuous flow process, if efficient online purification cannot be achieved, the impurities and unreacted raw materials remaining in the previous step will directly enter the subsequent unit, resulting in a serious impurity accumulation effect, which not only poisons the subsequent catalysts or reagents, but also drastically reduces the yield and purity of the final product.

[0004] (2) Incompatibility of the reaction system: The solvent system, pH environment and reagent type required for the three-step reaction are very different. For example, the strong oxidizing or acidic reagents remaining in the previous step may conflict with the reducing agent or catalyst in the subsequent step. Developing a solvent / reagent system that can be compatible with the three-step reaction or can be easily switched online without intermediate separation has a very high technical threshold.

[0005] Therefore, there is an urgent need to develop a new strategy for the continuous flow synthesis of lenalidomide that can overcome the aforementioned multi-step tandem barrier and achieve both high yield and high purity. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention proposes a continuous flow preparation method for lenalidomide and its derivatives.

[0007] This invention provides a continuous flow preparation method for lenalidomide and its derivatives, comprising the following steps: Step S1. Using acetonitrile as a solvent, substrate solution A and brominating agent solution B are prepared separately. Substrate solution A and brominating agent solution B are mixed online to obtain a first mixture, which is then introduced into a continuous flow photochemical reactor to carry out photobromination reaction under flowing conditions. The continuous flow photochemical reactor is equipped with an LED light source with integrated circulating cooling function. The power of the LED light source is 230W-460W, and the irradiation wavelength is 455-465nm. After the reaction is completed, the first reaction effluent is continuously output. Step S2. Mix the solution containing 3-aminopiperidine-2,6-dione hydrochloride with an alkali to obtain a blue-purple pre-activated solution. Mix the pre-activated solution with the first reaction effluent online. The resulting second mixture is continuously fed into a tubular reactor to carry out condensation and cyclization reactions in a flowing state. After the reaction is completed, the second reaction effluent is continuously output. Step S3. The second reaction effluent and hydrogen gas are fed into a fixed-bed reactor packed with catalyst to carry out a hydrogenation reduction reaction under flowing conditions. The effluent is collected to obtain the target compound. The target compound is selected from , , , , ; The substrate solution A contains a substrate corresponding to the selected target compound, with the general formula: Where R is selected from H (hydrogen), X (halogen), Ph (phenyl), Bz (benzoyl), R1; X is selected from F (fluorine), Cl (chlorine), Br (bromine); R1 is selected from Me (methyl), Et (ethyl), n-Pr (n-propyl), i-Pr (isopropyl), t-Bu (tert-butyl).

[0008] A schematic diagram of the all-continuous flow synthesis of lenalidomide is shown below. Figure 1 .

[0009] In some embodiments, the substrate is selected from methyl 2-methyl-3-nitrobenzoate, methyl 4-methyl-5-nitro-1,1'-biphenyl-3-carboxylate, methyl 4'-(tert-butyl)-4-methyl-5-nitro-[1,1'-biphenyl]-3-carboxylate, methyl 5-fluoro-2-methyl-3-nitrobenzoate, and methyl 2'-fluoro-4-methyl-5-nitro-[1,1'-biphenyl]-3-carboxylate.

[0010] In some embodiments, the brominating agent solution B is an acetonitrile solution of N-bromosuccinimide, wherein the molar ratio of N-bromosuccinimide to the substrate is (1.3-1.8):1. Preferably, the molar ratio of N-bromosuccinimide to the substrate is 1.5:1.

[0011] In some embodiments, the continuous flow photochemical reactor in step S1 is a pulsed plate photochemical reactor.

[0012] In some embodiments, the photobromination reaction in step S1 is carried out at a temperature of 20-60°C and a residence time of 10-30 min.

[0013] In some embodiments, the tubular reactor in step S2 is a tubular reactor made of PTFE material.

[0014] In some embodiments, in step S2, a solution containing 3-aminopiperidine-2,6-dione hydrochloride is mixed with an alkali and treated at 40-60°C for 8-15 minutes to obtain a blue-purple pre-activated solution.

[0015] In some embodiments, in step S2, the solvent of the solution containing 3-aminopiperidine-2,6-dione hydrochloride is selected from N,N-dimethylformamide.

[0016] In some embodiments, the base in step S2 is selected from at least one of triethylamine, sodium carbonate, potassium carbonate, and N,N-diisopropylethylamine; preferably N,N-diisopropylethylamine; and / or; In some embodiments, in step S2, the molar ratio of 3-aminopiperidine-2,6-dione hydrochloride, base, and substrate described in step S1 is (1.0-1.3):(3.0-4.0):1.

[0017] The reaction temperature for the condensation and cyclization reaction in step S2 is 80-100℃, and the residence time is 30-60 min; preferably, the reaction temperature is 80-90℃, and the residence time is 30-45 min.

[0018] In some embodiments, the catalyst in step S3 is selected from 5% palladium / activated carbon, 20% nickel / silica, Raney nickel, and palladium alumina. Preferably, the catalyst is palladium alumina.

[0019] In some embodiments, in the hydrogenation reduction reaction described in step S3, the hydrogen flow rate is 20-30 sccm, the reaction temperature is 100-120℃, the system back pressure is 0.4-0.6 MPa, and the residence time is 1.5-2.5 min. Preferably, the reaction temperature of the hydrogenation reduction reaction in step S3 is 100-110°C.

[0020] In some embodiments, after the reaction in step S2 is completed, the solvent in the second reaction effluent (containing compound 4) continuously output is N,N-dimethylformamide (DMF), which is directly used in the continuous flow hydrogenation reduction reaction in the fixed-bed reactor in step S3.

[0021] In some embodiments, the catalyst in step S3 is selected from at least one of palladium / activated carbon, nickel / silica, Raney nickel, and palladium alumina.

[0022] Preferably, the catalyst is selected from at least one of 20% nickel / silica, Raney nickel, and 5% palladium alumina.

[0023] In some embodiments, the second reaction effluent is continuously fed into the fixed-bed reactor packed with catalyst at a flow rate of 0.5-2 mL / min.

[0024] In summary, compared with the prior art, this application achieves the following technical effects: This application presents a fully continuous synthesis method for lenalidomide and its derivatives based on an optimized continuous flow apparatus. Through a highly integrated three-step cascade reaction, it overcomes the limitations of traditional batch reactors where intermediate products must be separated and purified due to solvent incompatibility. This technical solution utilizes the high mixing efficiency and excellent solvent compatibility of continuous flow to significantly reduce the total residence time of the three-step reaction from over 40 hours in traditional processes to 42 minutes, greatly increasing production capacity per unit time. Simultaneously, due to the significant inhibition of side reactions by the process flow, the final product does not require cumbersome column chromatography purification; high-purity target compounds can be obtained through simple post-processing, significantly reducing production costs.

[0025] In the critical free radical bromination stage, this application utilizes the large specific surface area and superior light transmittance of a flowing photochemical device to effectively overcome the light efficiency degradation problem caused by the Lambert-Beer law during scale-up production in traditional batch reactors. Through precise control of light intensity, temperature, and residence time via an online control system, accurate control of the degree of bromination is achieved, significantly suppressing the formation of dibromination byproducts and resolving the technical pain point of poor selectivity during industrial scale-up. This digital process feedback mechanism ensures high consistency in conversion rate and purity across batches, achieving steady-state control of product quality.

[0026] Regarding production safety and process reproducibility, this application replaces free radical initiators such as BPO and AIBN, which pose potential risks of thermal decomposition and explosion, with a photoinitiation mechanism, significantly improving the safety level of the bromination reaction. Simultaneously, the continuous flow hydrogenation process utilizes the small volume of the microreactor to minimize the instantaneous hydrogen holdup within the system, fundamentally reducing the risk of high-pressure hydrogen leakage and deflagration. Combined with an automated monitoring system for real-time monitoring and adjustment of key parameters such as pressure and flow rate, this process effectively avoids production accidents caused by human error or environmental fluctuations, providing a safer and more stable technical path for the large-scale production of lenalidomide drugs. Attached Figure Description

[0027] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0028] Figure 1 This is a schematic diagram of the fully continuous flow synthesis of lenalidomide.

[0029] Figure 2 This is a diagram of a lenalidomide continuous flow synthesis apparatus. In the diagram, (a, d) are the feed storage bottles; (b, e) are the plunger pumps; (c) is the continuous flow photochemical system; (f) is the polytetrafluoroethylene (PTFE) coil reactor and heating device; (g, j) is the reaction liquid storage bottle; (h) is the hydrogen generator; and (i) is the continuous flow hydrogenation reaction system.

[0030] Figure 3 The image shows the proton NMR spectrum of lenalidomide 5a.

[0031] Figure 4 The 1H NMR spectrum of lenalidomide 5b is shown.

[0032] Figure 5 The image shows the 1H NMR spectrum of lenalidomide 5C. Detailed Implementation

[0033] To enable those skilled in the art to better understand the present invention, the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

[0034] Currently, there are no reports of continuous flow synthesis of lenalidomide in existing technologies, nor are there any related continuous flow devices.

[0035] This application presents an adaptive modification of an existing continuous flow apparatus. For the synthetic route of lenalidomide and its derivatives, this study employs a stepwise optimization-system integration strategy: first, using purified intermediates from each step as raw materials, the parameters and conditions of each unit reaction are independently validated and optimized; subsequently, the reaction units are coupled, achieving a fully continuous flow synthesis without intermediate separation. The technical solution of this application was ultimately established through apparatus operation verification. A diagram of the lenalidomide fully continuous flow synthesis apparatus is shown below. Figure 2 .

[0036] Step 1: Bromination reaction Bromination reactions face two major challenges in industrial scale-up: firstly, poor selectivity, with a tendency for over-bromination to generate dibromo byproducts; and secondly, low safety, with traditional thermally initiated free radical processes (such as those using AIBN or BPO) posing an explosion risk. This application utilizes a constructed continuous-flow photocatalytic reaction system, using methyl 2-methyl-3-nitrobenzene (compound 1) as the raw material, and optimizes the reaction solvent, light intensity, and residence time. The results are shown in Table 1.

[0037] The route of the bromination reaction is shown below: Table 1 Through optimization, the optimal reaction conditions were finally determined in this application: acetonitrile was used as the reaction solvent, and after the two materials were mixed, compound 2 was synthesized with a separation yield of 96% under irradiation with 460 nm blue light at 403.2 W for 10 min.

[0038] Step 2: Condensation and Ringing In the second step, the isolated compound 2 was used as a starting material for the optimized continuous-flow synthesis of the lenalidomide precursor (compound 4). This application screened different organic and inorganic bases and pre-activated the hydrochloride substrate. The results are shown in Table 2.

[0039] The condensation and cyclization reaction routes are as follows: Table 2 This application established the optimal continuous flow process conditions for synthesizing compound 4 by pre-activating the hydrochloride substrate and systematically optimizing the organic base and its dosage. The results showed that the separation yield reached 83% after a residence time of 30 minutes. Compared to the traditional batch reaction (12 h), this process significantly shortens the reaction time while maintaining high yield, greatly improving production efficiency.

[0040] Step 3: Hydrogenation reduction reaction In traditional batch hydrogenation processes, methanol or water is commonly used as the solvent. This is because methanol and water have good hydrogen solubility and are easy to process afterward. However, the substrate has extremely poor solubility in these solvents, easily leading to a heterogeneous slurry state in the reaction system. In continuous flow processes, this solid-liquid mixture can cause blockages in the pipelines and packed beds, even completely interrupting the production process. Particularly challenging is the difficulty in mixing the solid-liquid-gas three phases; resistance leads to low mass transfer efficiency, preventing the reaction from proceeding effectively. Furthermore, to avoid solvent switching and potential compatibility issues arising from different solvents, this application successfully used DMF (dimethylformamide) from cyclization reactions as the reaction solvent.

[0041] DMF is a strongly polar aprotic solvent with excellent solubility for compounds containing polar structures such as amides and heterocycles. This allows reactants to enter the reactor as a homogeneous solution, which is fundamental to achieving stable and continuous flow.

[0042] The solvent used in the second step of condensation and cyclization reaction includes N,N-dimethylformamide (DMF). Therefore, the second reaction effluent continuously output after the second step reaction is completed can be directly used in the hydrogenation reduction reaction in the third step fixed-bed reactor.

[0043] The results are shown in Table 3.

[0044] The hydrogenation reduction reaction route is as follows: Table 3 Through optimization, the optimal catalyst, flow rate, and reaction temperature were finally determined. Using 5% Pd / Al2O3 as the catalyst, with a hydrogen flow rate of 20 sccm, and under the conditions of a reaction pressure of 0.5 MPa and 100℃, the reaction residence time was shortened to 2 min, and lenalidomide was obtained with a separation yield of 99%.

[0045] Based on optimized stepwise continuous flow conditions, this application designed and constructed a fully continuous flow synthesis apparatus. Using methyl 2-methyl-3-nitrobenzoate as the starting material, the various materials were fed into a continuous flow reactor, and the three-step reaction was completed within a total residence time of 42 minutes, yielding lenalidomide in a total yield of 63%. Compared with the three-step batch synthesis that takes more than 40 hours, the fully continuous flow synthesis method of this application eliminates the post-processing separation steps of intermediates, and the final product, lenalidomide, can be obtained as a pure product without column chromatography purification.

[0046] To evaluate the practicality of the continuous flow apparatus, this application further conducted gram-scale synthesis of lenalidomide. After 2 hours of continuous operation, 1.03 g of 5a was obtained, representing a production rate of 0.515 g of product per hour. Furthermore, four lenalidomide derivatives 5b-5e were synthesized using the same continuous flow synthesis apparatus, with overall separation yields between 40% and 45%.

[0047] The target compounds of this application, lenalidomide and its derivatives, have the following structural formulas: Lenalidomide 5a: ; Lenalidomide derivative 5b: ; Lenalidomide derivative 5c: ; Lenalidomide derivative 5d: ; Lenalidomide derivative 5e: .

[0048] The reagents used in the examples, their Chinese and English names are listed below: N-Bromosuccinimide (NBS); Acetonitrile (MeCN); Polytetrafluoroethylene (PTFE).

[0049] The present invention will be further illustrated below with reference to specific embodiments and comparative embodiments. The following specific embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the following embodiments, and are not in particular limited to the types of raw materials used in the following specific embodiments.

[0050] Example 1: Synthesis of Lenalidomide 5a The starting material methyl 2-methyl-3-nitrobenzoate was dissolved in acetonitrile (MeCN) to prepare a substrate solution with a concentration of 0.6 M (1.0 equivalent).

[0051] N-bromosuccinimide (NBS) was dissolved in acetonitrile to prepare a brominating agent solution with a concentration of 0.9 M (1.5 equivalents).

[0052] Feed A and feed B are introduced into the continuous flow reaction system separately via high-pressure constant flow pumps (such as plunger pumps). The two streams merge in a T-mixer and then enter the continuous flow photochemical system. This continuous flow photochemical system consists of an 11 mL HANU continuous flow photochemical reactor I (abbreviated as HANU reactor I) and an LED light source equipped with a circulating cooling device. The light source has a power of 403.2 W and an illumination wavelength of 460 nm (blue light). During reaction operation, the flow rates of feed A and B are set to 0.55 mL / min and 0.55 mL / min respectively, the reaction temperature is room temperature, and the residence time of the reaction system is maintained at 10 min. The resulting effluent (containing compound 2) ), which is used directly in subsequent reactions.

[0053] Simultaneously, a DMF solution of compound 3 (0.39 M, 1.3 equivalents) and DIPEA (0.90 M, 3.0 equivalents) was preheated at 50°C for 10 minutes to form a blue-violet pre-activated solution. Then, the pre-activated solution was combined with the effluent from the first step via a T-type mixer, and the mixture was directly introduced into PTFE reactor II (1.6 mm inner diameter, 66 mL working volume) and held at 80°C for 30 minutes.

[0054] The effluent from the second step reaction (containing compound 4) was collected in bottle G (Stirring device) equipped with a stirrer, serving as the feed liquid for continuous-flow hydrogenation. The continuous-flow hydrogenation reaction system was then started, with the hydrogen flow rate set to 20 sccm. The feed liquid was pumped at a flow rate of 1 mL / min into fixed-bed reactor III (working volume 2 mL) packed with 5% Pd / Al₂O₃ via a built-in feed pump. During the reaction, the system pressure was maintained at 0.5 MPa via a back pressure valve (BPR), the reaction temperature was controlled at 100°C, and the residence time was 2 minutes. The process continued until all the reaction liquid had flowed out.

[0055] Collect the reaction liquid flowing out of the reactor and continuously monitor the effluent using a TLC (Transient Chromatography) plate. When the TLC shows no organic spots or the spots have disappeared, it is determined that all the reaction liquid has flowed out, and the reaction is stopped. Finally, the collected reaction solution was evaporated, then water was added to precipitate the precipitate, and the mixture was washed with a small amount of ethyl acetate to obtain lenalidomide (5a). The 1H NMR spectrum of lenalidomide 5a is shown below. Figure 3 .

[0056] Compared to the traditional three-step batch synthesis that takes over 40 hours, the continuous flow synthesis strategy of this application eliminates the post-processing and separation steps of intermediates, and completes the three-step continuous flow reaction within a total residence time of 42 minutes, preparing lenalidomide in an overall yield of 63%. Notably, this technique greatly simplifies the purification process: the final step does not require column chromatography purification; after removing a large amount of solvent by rotary evaporation, the reaction solution is precipitated with water, and then washed with a small amount of ethyl acetate to obtain the final product.

[0057] To evaluate the scalability of this continuous flow system, a gram-scale synthesis of 5a was performed. After 2 hours of continuous operation, 1.03 g of 5a was obtained, corresponding to a productivity of 0.515 g / h.

[0058] Example 2: Synthesis of lenalidomide derivative 5b 4-Methyl-5-nitro-1,1'-biphenyl-3-carboxylate for the synthesis of 5b was synthesized by the following method: 1.0 eq. of methyl 5-bromo-2-methyl-3-nitrobenzoate, 1.5 eq. of phenylboronic acid, 0.03 eq. of tetrakis(triphenylphosphine)palladium, and 3.0 eq. of potassium carbonate were weighed into a reaction tube at room temperature. The mixture was purged three times with an inert gas (nitrogen or argon). 50 mL of solvent (dioxane / water = 4:1) was added, and the mixture was refluxed and stirred at 90 °C for 8 h to obtain methyl 4-methyl-5-nitro-1,1'-biphenyl-3-carboxylate.

[0059] The photobromination of methyl 4-methyl-5-nitro-1,1'-biphenyl-3-carboxylate (0.6 M, 1.0 equivalent) was carried out using NBS (0.9 M, 1.5 equivalent) and MeCN as solvent. The liquid stream was irradiated at 460 nm at room temperature (lamp power 403.2 W), with two separate flow paths at a flow rate of 0.55 mL / min and a residence time of 10 min.

[0060] Prior to mixing, a DMF solution of compound 3 (0.39 M, 1.3 equivalents) and DIPEA (0.90 M, 3.0 equivalents) was preheated at 50°C for 10 minutes to form a blue-violet color. This pre-activated solution was then combined with the reaction stream (bromine 2) from the first step via a T-type mixer. The combined stream was then directly fed into PTFE reactor II (1.6 mm inner diameter, 66 mL working volume) and held at 80°C for 30 minutes.

[0061] Subsequently, the effluent solution from reactor II (containing compound 4) was treated with H2 (20 sccm) and flowed through a 5% Pd / Al2O3 packed bed reactor (working volume 2 mL) for reaction at 100 °C, residence time 2 min, and back pressure 0.5 MPa. Finally, the collected reaction mixture was collected by evaporation and then precipitated with water to obtain 5b. The 1H NMR spectrum of lenalidomide derivative 5b is shown below. Figure 4 .

[0062] Example 3: Synthesis of lenalidomide derivative 5c 4'-(tert-butyl)-4-methyl-5-nitro-[1,1'-biphenyl]-3-carboxylate methyl ester for 5C synthesis was synthesized by the following method: methyl 5-bromo-2-methyl-3-nitrobenzoate (1.0 eq.), tert-butylphenylboronic acid (1.5 eq.), tetrakis(triphenylphosphine)palladium (0.03 eq.), and potassium carbonate (3.0 eq.) were weighed into a reaction tube at room temperature, purged three times with an inert gas (nitrogen or argon), and 50 mL of solvent (dioxane / water = 4:1) was added. The mixture was refluxed and stirred at 90 °C for 8 h to obtain 4'-(tert-butyl)-4-methyl-5-nitro-[1,1'-biphenyl]-3-carboxylate methyl ester.

[0063] The photobromination of methyl 4'-(tert-butyl)-4-methyl-5-nitro-[1,1'-biphenyl]-3-carboxylate (0.6 M, 1.0 equivalent) was carried out using NBS (0.9 M, 1.5 equivalent) as solvent and MeCN as solvent. The liquid stream was irradiated at 460 nm wavelength at room temperature (lamp power 403.2 W), with two streams flowing at a rate of 0.55 mL / min and a residence time of 10 min.

[0064] Prior to mixing, a DMF solution of compound 3 (0.39 M, 1.3 equivalents) and DIPEA (0.90 M, 3.0 equivalents) was preheated at 50°C for 10 minutes to form a blue-violet color. This pre-activated solution was then combined with the reaction stream (bromine 2) from the first step via a T-type mixer. The combined stream was then directly fed into PTFE reactor II (1.6 mm inner diameter, 66 mL working volume) and held at 80°C for 30 minutes.

[0065] Subsequently, the effluent solution from reactor II (containing compound 4) was treated with H2 (20 sccm) and flowed through a 5% Pd / Al2O3 packed bed reactor (working volume 2 mL) for reaction at 100 °C, residence time 2 min, and back pressure 0.5 MPa. Finally, the collected reaction mixture was collected by evaporation and then precipitated with water to obtain 5c. The 1H NMR spectrum of lenalidomide derivative 5c is shown below. Figure 5 .

[0066] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A continuous flow preparation method for lenalidomide and its derivatives, characterized in that, Includes the following steps: Step S1. Using acetonitrile as a solvent, substrate solution A and brominating agent solution B are prepared separately. Substrate solution A and brominating agent solution B are mixed online to obtain a first mixture, which is then introduced into a continuous flow photochemical reactor for photobromination reaction. The continuous flow photochemical reactor is equipped with an LED light source with integrated circulating cooling function. The power of the LED light source is 230W-460W, and the irradiation wavelength is 455-465nm. After the reaction is completed, the first reaction effluent is continuously output. Step S2. Mix the solution containing 3-aminopiperidine-2,6-dione hydrochloride with an alkali to obtain a blue-purple pre-activated solution. Mix the pre-activated solution with the first reaction effluent online. The resulting second mixture is continuously fed into a tubular reactor to carry out condensation and cyclization reactions in a flowing state. After the reaction is completed, the second reaction effluent is continuously output. Step S3. The second reaction effluent and hydrogen gas are fed into a fixed-bed reactor packed with catalyst to carry out a hydrogenation reduction reaction under flowing conditions. The effluent is collected to obtain the target compound. The target compound is selected from , , , , ; The substrate solution A contains a substrate corresponding to the selected target compound, with the general formula: R is selected from H, X, Ph, Bz, R1; X is selected from F, Cl, Br; R1 is selected from Me, Et, n-Pr, i-Pr, t-Bu.

2. The continuous flow preparation method according to claim 1, characterized in that, The substrate is selected from methyl 2-methyl-3-nitrobenzoate, methyl 4-methyl-5-nitro-1,1'-biphenyl-3-carboxylate, methyl 4'-(tert-butyl)-4-methyl-5-nitro-[1,1'-biphenyl]-3-carboxylate, methyl 5-fluoro-2-methyl-3-nitrobenzoate, and methyl 2'-fluoro-4-methyl-5-nitro-[1,1'-biphenyl]-3-carboxylate. The brominating agent solution B is an acetonitrile solution of N-bromosuccinimide.

3. The continuous flow preparation method according to claim 1, characterized in that, The continuous flow photochemical reactor mentioned in step S1 is a pulsed plate photochemical reactor, and / or, The reaction temperature for the photobromination reaction in step S1 is 20-60℃, and the residence time is 10-30 min.

4. The continuous flow preparation method according to claim 1, characterized in that, The tubular reactor mentioned in step S2 is a tubular reactor made of PTFE material.

5. The continuous flow preparation method according to claim 1, characterized in that, In step S2, a solution containing 3-aminopiperidine-2,6-dione hydrochloride is mixed with alkali and treated at 40-60°C for 8-15 minutes to obtain a blue-purple pre-activated solution.

6. The continuous flow preparation method according to claim 1 or 5, characterized in that, In step S2, the solvent of the solution containing 3-aminopiperidine-2,6-dione hydrochloride is selected from N,N-dimethylformamide.

7. The continuous flow preparation method according to claim 1, characterized in that, The base in step S2 is selected from at least one of triethylamine, sodium carbonate, potassium carbonate, and N,N-diisopropylethylamine, and / or... In step S2, the molar ratio of 3-aminopiperidine-2,6-dione hydrochloride, base, and substrate described in step S1 is (1.0-1.3):(3.0-4.0):

1.

8. The continuous flow preparation method according to claim 1, characterized in that, The reaction temperature for the condensation and cyclization reaction in step S2 is 80-100℃, and the residence time is 30-60 min.

9. The continuous flow preparation method according to claim 1, characterized in that, In the hydrogenation reduction reaction described in step S3, the hydrogen flow rate is 20-30 sccm, the reaction temperature is 100-120℃, the system back pressure is 0.4-0.6 MPa, and the residence time is 1.5-2.5 min.

10. The continuous flow preparation method according to claim 1, characterized in that, The catalyst in step S3 is selected from at least one of palladium / activated carbon, nickel / silica, Raney nickel, and palladium alumina.

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