Synthesis method of lenalidomide carbohydrate derivative
By catalyzing the reaction of lenalidomide and monosaccharides in ethanol solvents by ammonium sulfate, the problems of strict reaction conditions and high economic costs in the prior art are solved, and the efficient synthesis of lenalidomide sugar derivatives is achieved, metal residues are avoided, and it is suitable for a wide range of reaction substrates.
Patent Information
- Application Number
- CN202510239006.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-03
- Publication Date
- 2025-05-23
AI Technical Summary
The existing lenalidomide sugar derivative synthesis methods require strict chemical reaction conditions and high economic costs, and there is the use of precious metal catalysts, resulting in metal residue problems.
The reaction of lenalidomide and monosaccharides in an ethanol solvent was catalyzed by ammonium sulfate, and lenalidomide sugar derivatives were generated by mild reaction conditions (90°C, 24 hours) and metal-free catalyzed methods. The process includes the reaction in an air atmosphere, using ammonium sulfate and ethanol as catalyst and solvent, and purifying by filtration and amino column chromatography to obtain the product.
The mildening of reaction conditions, the improvement of yield and the reduction of cost are achieved, and the metal residue problem is avoided. It is suitable for a wide range of reaction substrates and is easy to operate.
Smart Images
Figure CN120025385A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of chemical organic synthesis, and specifically relates to a synthesis reaction in which an amine compound and a monosaccharide are catalyzed by ammonium sulfate to generate corresponding sugar derivatives. Background Art
[0002] Lenalidomide is a new type of immunomodulator with anti-tumor activity, which is mainly manifested in inhibiting the proliferation of cancer cells and promoting their death, blocking the nutrient supply of tumor matrix to malignant cells. Carbohydrate compounds have multiple biological activities and extensive recognition and binding capabilities in the body. Therefore, after combining with lenalidomide, lenalidomide sugar derivatives may produce new biological activities and targets, providing new directions for drug research and development. Lenalidomide sugar derivatives may have stronger anti-tumor activity and can more effectively inhibit the growth and spread of tumor cells, thereby improving the treatment effect, helping to reduce the resistance of tumor cells to lenalidomide, and prolonging the effective treatment time of the drug. It may also reduce the side effects of lenalidomide, such as gastrointestinal reactions and rashes, thereby improving the quality of life of patients. Summary of the invention
[0003] In view of the fact that existing synthesis methods require harsh conditions and high economic costs, the present invention can provide a synthesis method with mild reaction conditions, good functional group compatibility, low cost, and no heavy metal involvement. The method is simple to operate, has a high yield, low cost, no metal residue, and is applicable to a wide range of reaction substrates.
[0004] In order to achieve the above object, the present invention adopts the following technical solutions: A method for synthesizing a lenalidomide sugar derivative catalyzed by ammonium sulfate, which uses lenalidomide shown in formula I and a monosaccharide shown in formula II as raw materials, and reacts under the action of ammonium sulfate and ethanol solvent to obtain the corresponding lenalidomide sugar derivative.
[0005]
[0006] In one embodiment of the present invention, the raw material monosaccharides are D-glucose, D-galactose, D-mannose, D-xylose and D-ribose.
[0007] In one embodiment of the invention, the catalyst is ammonium sulfate.
[0008] In one embodiment of the present invention, the reaction is carried out in an organic solvent, specifically ethanol.
[0009] In one embodiment of the present invention, the ratio of the amount of the reactants is: lenalidomide: ammonium sulfate: monosaccharide is 10:1:15.
[0010] In one embodiment of the present invention, the reaction is carried out in an air atmosphere, the reaction temperature is 90° C., and the reaction time is 24 hours.
[0011] In one embodiment of the present invention, after the reaction is completed for 24 hours, it is cooled to room temperature, filtered, the solid is heated and dissolved with methanol, and finally purified by amino column chromatography using methanol / water as eluent to obtain the desired product.
[0012] Beneficial effects: The present invention has the following advantages. First, it can avoid severe chemical reaction conditions, the raw materials are all commercial reagents, cheap and easy to obtain, and the use of precious metal catalysts is avoided. The absence of metal catalysts can avoid metal residues and the reaction yield is high. Therefore, it is of great significance to develop a method for synthesizing lenalidomide sugar derivatives with mild reaction conditions and no metal catalysis. BRIEF DESCRIPTION OF THE DRAWINGS
[0013] Figure 1 It is a brief schematic diagram of the invention content, wherein the left side of the arrow is the raw material, the upper and lower sides of the arrow are the abbreviations of the synthetic reaction additives and conditions, and the right side of the arrow is a simplified diagram summarizing the structural formula of the product.
[0014] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of Example 1.
[0015] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of Example 2.
[0016] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of Example 3.
[0017] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of Example 4.
[0018] Figure 6 This is the hydrogen nuclear magnetic resonance spectrum of Example 5. DETAILED DESCRIPTION
[0019] The technical solution of the present invention is further described below in conjunction with specific embodiments.
[0020] The reagents involved in the present invention are all commercial reagents and can be purchased directly. The present invention provides the following synthesis method: under air conditions, a magnetic stirrer, lenalidomide (1 mmol), ammonium sulfate (0.1 mmol) and a monosaccharide (1.5 mmol) are added to a sealed reaction tube, 10 mL of ethanol is added, and the reaction is carried out under air protection at 90°C under magnetic stirring and heating conditions for 24 hours, and the degree of reaction is monitored by thin layer chromatography. After the reaction is completed for 24 hours, it is cooled to room temperature, filtered, and the solid is heated and dissolved with methanol, and finally purified by amino column chromatography, using methanol / water as an eluent to obtain the desired product.
[0021] In the embodiment of the present invention, the specific monosaccharide is selected from: Example
[0022] The structural formula of the lenalidomide sugar derivative prepared in this example is as follows:
[0023] Preparation method: Lenalidomide (1mmol), D-glucose (1.5mmol) and ammonium sulfate (0.1mmol) are added to a sealed reaction tube, and 10mL of ethanol is added. The reaction is carried out under air and heated at 90℃ with magnetic stirring for 24 hours. The reaction is monitored by thin layer chromatography. After the reaction is completed, it is cooled to room temperature and filtered. The solid is heated and dissolved with methanol, and finally purified by amino column chromatography using methanol / water as eluent to obtain the desired product. The product is a yellow solid with a yield of 90%. NMR characterization data: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.38-7.25 (m, 1H), 7.20 – 7.11(m, 1H), 7.00 (dd, J = 7.6, 2.4 Hz, 1H), 5.02 (dt, J = 12.4, 3.2 Hz, 1H),4.55 – 4.15 (m, 3H), 3.81 – 3.71 (m, 1H), 3.64 – 3.56 (m, 1H), 3.52 – 3.37(m, 3H), 3.36 – 3.30 (m, 1H), 2.87 – 2.67 (m, 2H), 2.40 (qd, J = 12.8, 4.8Hz, 1H), 2.20 – 2.07 (m, 1H). Example
[0024] The structural formula of the lenalidomide sugar derivative prepared in this example is as follows:
[0025] Preparation method: Lenalidomide (1mmol), D-galactose (1.5mmol) and ammonium sulfate (0.1mmol) are added to a sealed reaction tube, and 10mL of ethanol is added. The reaction is carried out under air and heated at 90℃ with magnetic stirring for 24 hours. The reaction is monitored by thin layer chromatography. After the reaction is completed, it is cooled to room temperature and filtered. The solid is heated and dissolved with methanol, and finally purified by amino column chromatography using methanol / water as eluent to obtain the desired product. The product is a yellow solid with a yield of 88%. NMR characterization data: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.32-7.24 (m, 1H), 7.15-7.08 (m,1H), 6.98 (dd, J = 7.6, 5.2 Hz, 1H), 4.98 (dt, J = 13.2, 5.2 Hz, 1H), 4.49 –4.18 (m, 3H), 3.90 – 3.84 (m, 1H), 3.72 – 3.66 (m, 1H), 3.64 – 3.58 (m, 4H),2.79-2.66 (m, 2H), 2.35 (qd, J = 12.8, 5.2 Hz, 1H), 2.14-2.04 (m, 1H). Example
[0026] The structural formula of the lenalidomide sugar derivative prepared in this example is as follows:
[0027] Preparation method: Lenalidomide (1mmol), D-mannose (1.5mmol) and ammonium sulfate (0.1mmol) are added to a sealed reaction tube, and 10mL of ethanol is added. The reaction is carried out under air and heated at 90℃ with magnetic stirring for 24 hours. The reaction is monitored by thin layer chromatography. After the reaction is completed, it is cooled to room temperature and filtered. The solid is heated and dissolved with methanol, and finally purified by amino column chromatography using methanol / water as eluent to obtain the desired product. The product is a yellow solid with a yield of 89%. NMR characterization data: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.33 – 7.20 (m, 1H), 7.09 (ddd, J = 15.2, 7.2, 4.8 Hz, 1H), 6.92 (dd, J= 12.4, 8.0 Hz, 1H), 5.12 – 4.95 (m,1H), 4.87 (d, J = 10.8 Hz, 1H), 4.37 – 4.10 (m, 2H), 3.92 (dd, J = 8.8, 3.6Hz, 1H), 3.78 (d, J = 11.2 Hz, 1H), 3.67 – 3.56 (m, 2H), 3.50 (t, J = 9.6 Hz,1H), 3.40 (ddd, J = 9.2, 5.6, 2.0 Hz, 1H), 2.90 – 2.68 (m, 2H), 2.37 (qd, J =13.2, 5.6 Hz, 1H), 2.19 – 2.03 (m, 1H). Example
[0028] The structural formula of the lenalidomide sugar derivative prepared in this example is as follows:
[0029] Preparation method: Lenalidomide (1mmol), D-ribose (1.5mmol) and ammonium sulfate (0.1mmol) are added to a sealed reaction tube, and 10mL of ethanol is added. The reaction is carried out under air and heated at 90℃ with magnetic stirring for 24 hours. The reaction is monitored by thin layer chromatography. After the reaction is completed, it is cooled to room temperature and filtered. The solid is heated and dissolved with methanol, and finally purified by amino column chromatography using methanol / water as eluent to obtain the desired product. The product is a yellow solid with a yield of 83%. NMR characterization data: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.36 – 7.22 (m, 1H), 7.22 – 7.08 (m,1H), 7.07 – 6.89 (m, 1H), 5.02 (dd, J = 13.6, 5.6 Hz, 1H), 4.32 – 4.24 (m,1H), 3.96 – 3.28 (m, 5H), 2.88 – 2.66 (m, 2H), 2.51 – 2.32 (m, 1H), 2.21-2.07(m, 1H). Example
[0030] The structural formula of the lenalidomide sugar derivative prepared in this example is as follows:
[0031] Preparation method: Lenalidomide (1mmol), D-xylose (1.5mmol) and ammonium sulfate (0.1mmol) are added to a sealed reaction tube, and 10mL of ethanol is added. The reaction is carried out under air and heated at 90℃ with magnetic stirring for 24 hours. The reaction is monitored by thin layer chromatography. After the reaction is completed, it is cooled to room temperature and filtered. The solid is heated and dissolved with methanol, and finally purified by amino column chromatography using methanol / water as eluent to obtain the desired product. The product is a yellow solid with a yield of 80%. NMR characterization data: 1 H NMR (400 MHz, Deuterium Oxide) δ 7.34 – 7.18 (m, 1H), 7.15 – 7.07 (m,1H), 7.06 – 6.83 (m, 1H), 4.99 (dd, J = 13.2, 4.8 Hz, 1H), 4.41-4.11 (m, 3H), 3.83 – 3.69 (m, 1H), 3.57 – 3.20 (m, 4H), 2.80 – 2.64 (m, 2H), 2.44 – 2.27(m, 1H), 2.16 – 2.04 (m, 1H). Finally, it should be noted that the above embodiments are used to illustrate the technical solutions of the present invention rather than to limit it. Those skilled in the art should understand that simple modifications or equivalent replacements of the solutions of the present invention are all within the scope of the claims of the present invention.
Claims
1. A method for synthesizing a lenalidomide sugar derivative, characterized in that: Lenalidomide shown in formula I and monosaccharide shown in formula II are used as raw materials, and the reaction is carried out in an air atmosphere under the action of catalyst ammonium sulfate and ethanol solvent to obtain the lenalidomide sugar derivative shown in formula III: Among them, the raw material monosaccharide that can be used for preparation of formula II can be the following structure: The preparation steps of the lenalidomide sugar derivatives are as follows: The reaction substrate (amine), monosaccharide and ammonium sulfate were placed in a pressure-resistant tube of a specific specification with a magnetic stirrer, and an appropriate amount of ethanol solvent was added through a syringe; the reaction mixture was stirred at 90° C. for 24 hours; After 24 hours of reaction, cool to room temperature, filter, heat and dissolve the solid with methanol, and finally purify by amino column chromatography using methanol / water as eluent to obtain the desired product; The product was separated by gradient elution to obtain compound II.
2. The synthesis method according to claim 1, characterized in that The reaction solvent is ethanol, the catalyst is ammonium sulfate, and the reaction temperature is 90°C.
3. The synthesis method according to claim 1 or 2, characterized in that The molar ratio of amine, catalyst (ammonium sulfate) and monosaccharide is: amine: ammonium sulfate: monosaccharide = 10:1:
15.
4. The synthesis method according to claim 1, characterized in that The reaction time in air atmosphere is 24 hours.