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CN-122010899-A - Continuous flow preparation method of lenalidomide and derivatives thereof

CN122010899ACN 122010899 ACN122010899 ACN 122010899ACN-122010899-A

Abstract

The invention discloses a continuous flow preparation method of lenalidomide and derivatives thereof, and belongs to the technical field of medicinal chemistry. The preparation method comprises the steps of adopting acetonitrile as a solvent, respectively preparing a substrate solution A and a brominating agent solution B, mixing the substrate solution A and the brominating agent solution B on line to obtain a first mixed solution, introducing the first mixed solution into a continuous flow photochemical reactor for photo-bromination reaction, wherein the continuous flow photochemical reactor is provided with an LED light source with an integrated circulating cooling function, mixing 3-aminopiperidine-2, 6-dione hydrochloride and alkali to obtain a blue-violet preactivation solution, mixing the preactivation solution with photo-bromination reaction effluent on line, carrying out condensation and cyclization reaction in a flowing state, continuing to carry out hydrogenation reduction reaction in the flowing state, and collecting the effluent to obtain the target compound lenalidomide or a derivative thereof. According to the continuous flow preparation method, the total residence time of the three-step reaction is shortened from more than 40 hours to 42 minutes in the traditional process, and the production capacity in unit time is remarkably improved.

Inventors

  • HUANG JUNRONG
  • YOU HENGZHI
  • HOU TIANYI
  • ZHU YUXIANG
  • ZHAO YANG

Assignees

  • 深圳连续制药科技有限公司
  • 哈尔滨工业大学(深圳)(哈尔滨工业大学深圳科技创新研究院)

Dates

Publication Date
20260512
Application Date
20260114

Claims (10)

  1. 1. A continuous flow process for the preparation of lenalidomide and derivatives thereof, comprising the steps of: S1, acetonitrile is adopted as a solvent to prepare a substrate solution A and a brominating agent solution B respectively, the substrate solution A and the brominating agent solution B are mixed on line to obtain a first mixed solution, and the first mixed solution is introduced into a continuous flow photochemical reactor for carrying out a photo-bromination reaction, wherein the continuous flow photochemical reactor is provided with an LED light source with an integrated circulation cooling function, the power of the LED light source is 230W-460W, the irradiation wavelength is 455-465nm, and a first reaction effluent is continuously output after the reaction is completed; S2, mixing a solution containing 3-aminopiperidine-2, 6-dione hydrochloride with alkali to obtain a blue-violet preactivated solution, mixing the preactivated solution with the first reaction effluent on line, continuously introducing the obtained second mixed solution into a tubular reactor, performing condensation and cyclization reaction in a flowing state, and continuously outputting a second reaction effluent after the reaction is completed; S3, introducing the second reaction effluent and hydrogen into a fixed bed reactor filled with a catalyst together, performing hydrogenation reduction reaction in a flowing state, and collecting the effluent to obtain a target compound; The target compound is selected from 、 、 、 、 ; The substrate solution A comprises a substrate corresponding to the selected target compound, and the substrate has a general formula: Wherein R is H, X, ph, bz, R 1 , X is F, cl, br, R 1 is Me, et, n-Pr, i-Pr, t-Bu.
  2. 2. The continuous flow production process according to claim 1, characterized in that the substrate is selected from the group consisting of 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, 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. 3. The continuous flow preparation method according to claim 1, wherein the continuous flow photochemical reactor in step S1 is a pulse plate type photochemical reactor, and/or, The reaction temperature of the photo-bromination reaction in the step S1 is 20-60 ℃ and the residence time is 10-30 min.
  4. 4. The continuous flow preparation method according to claim 1, wherein the tubular reactor in step S2 is a tubular reactor made of PTFE.
  5. 5. The continuous flow preparation method according to claim 1, characterized in that in step S2, the solution containing 3-aminopiperidine-2, 6-dione hydrochloride is mixed with a base and treated for 8-15 minutes at 40-60 ℃ to obtain a blue-violet pre-activation solution.
  6. 6. The continuous flow preparation method according to claim 1 or 5, characterized in that in step S2, the solution containing 3-aminopiperidine-2, 6-dione hydrochloride is chosen from N, N-dimethylformamide as solvent.
  7. 7. The continuous flow preparation method according to claim 1, wherein 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 the 3-aminopiperidine-2, 6-dione hydrochloride and the base to the substrate in step S1 is (1.0-1.3): (3.0-4.0): 1.
  8. 8. The continuous flow preparation method according to claim 1, wherein the reaction temperature of the condensation and cyclization reaction in the step S2 is 80-100 ℃ and the residence time is 30-60min.
  9. 9. The continuous flow preparation method according to claim 1, wherein in the hydrogenation reduction reaction in the 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. 10. The continuous flow preparation method according to claim 1, wherein the catalyst in step S3 is selected from at least one of palladium/activated carbon, nickel/silica, raney nickel and palladium alumina.

Description

Continuous flow preparation method of lenalidomide and derivatives thereof Technical Field The invention belongs to the technical field of medicinal chemistry, and particularly relates to a continuous flow preparation method of lenalidomide and derivatives thereof. Background Lenalidomide (Lenalidomide) is a first-line drug for the treatment of multiple myeloma, and its industrial synthesis usually undergoes three key steps of bromination, cyclization and reduction. At present, the main stream technology mostly adopts the traditional kettle type (Batch) operation, and has the problems of complex operation, long production period, batch quality fluctuation and the like. Although continuous flow technology (Continuous Flow Chemistry) has significant advantages in terms of improving mass and heat transfer and process safety, its application to the total synthesis of lenalidomide still faces a great challenge: (1) The problems of intermediate purification and impurity accumulation are that in the prior art, the single-step conversion rate and selectivity of the three reaction steps are often unsatisfactory, so that more byproducts are caused in the reaction liquid. In the kettle type process, impurities can be removed through separation and purification (such as crystallization and extraction) of intermediates, but in the continuous flow process, if high-efficiency online purification cannot be realized, impurities and unreacted raw materials remained in the last step directly enter a subsequent unit, so that serious impurity accumulation effect is caused, subsequent catalysts or reagents are poisoned, and the yield and purity of a final product are rapidly reduced. (2) The compatibility of the reaction systems conflicts, and the solvent system, the pH environment and the reagent types required by the three-step reaction have huge differences. For example, the strong oxidizing or acidic reagent remaining from the previous step may interfere with the reducing agent or catalyst of the subsequent step (Incompatibility). Under the condition of not carrying out intermediate separation, a set of solvent/reagent system which can be compatible with three-step reaction or is easy to switch on line is developed, and the method has extremely high technical threshold. Therefore, there is a need to develop a new strategy for continuous flow synthesis of lenalidomide that overcomes the above-described multi-step cascade barrier, while achieving both high yields and high purity. Disclosure of Invention Aiming at the defects in the prior art, the invention provides a continuous flow preparation method of lenalidomide and derivatives thereof. The invention provides a continuous flow preparation method of lenalidomide and derivatives thereof, which comprises the following steps: S1, acetonitrile is adopted as a solvent to prepare a substrate solution A and a brominating agent solution B respectively, the substrate solution A and the brominating agent solution B are mixed on line to obtain a first mixed solution, and the first mixed solution is introduced into a continuous flow photochemical reactor to carry out photo-bromination reaction in a flowing state, wherein the continuous flow photochemical reactor is provided with an LED light source with an integrated circulation cooling function, the power of the LED light source is 230W-460W, the irradiation wavelength is 455-465nm, and a first reaction effluent is continuously output after the reaction is completed; S2, mixing a solution containing 3-aminopiperidine-2, 6-dione hydrochloride with alkali to obtain a blue-violet preactivated solution, mixing the preactivated solution with the first reaction effluent on line, continuously introducing the obtained second mixed solution into a tubular reactor, performing condensation and cyclization reaction in a flowing state, and continuously outputting a second reaction effluent after the reaction is completed; S3, introducing the second reaction effluent and hydrogen into a fixed bed reactor filled with a catalyst together, performing hydrogenation reduction reaction in a flowing state, and collecting the effluent to obtain a target compound; The target compound is selected from 、、、、; The substrate solution A comprises a substrate corresponding to the selected target compound, and the substrate has a general formula: Wherein R is selected from H (hydrogen), X (halogen), ph (phenyl), bz (benzoyl) and R 1, X is selected from F (fluorine), cl (chlorine) and Br (bromine), and R 1 is selected from Me (methyl), et (ethyl), n-Pr (n-propyl), i-Pr (isopropyl) and t-Bu (tert-butyl). The full continuous flow synthesis scheme of lenalidomide is shown in figure 1. In some embodiments, the substrate is selected from the group consisting of 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, meth