A process for the preparation of lenalidomide

Abstract

The application discloses a preparation method of lenalidomide, which comprises the following steps: S1, methyl 2-bromomethyl-3-nitrobenzoate, 3-aminopiperidine-2,6-dione hydrochloride and a base are dissolved in a polar solvent, and reaction is carried out at 50-60 DEG C for 5-8 h; after the reaction is completed, the obtained mixed product is refined and purified to obtain 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione; S2, 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione, ammonium formate and a palladium-carbon catalyst are added into a mixed solvent, and reaction is carried out at 35-45 DEG C for 4-7 h; after the reaction is completed, the obtained crude product is further treated; S3, the crude product is stirred and dissolved in a polar solvent, and then filtered; ammonium formate and sodium mercaptoacetate are added into the filtrate, and reaction is carried out under stirring for 2-5 h; after the reaction is completed, the obtained mixed solution is refined and purified to obtain lenalidomide.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine and chemical industry, and particularly relates to a preparation method of lenalidomide. BACKGROUND

[0002] Lenalidomide, with the chemical name of 3-(7-amino-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione, is developed by the American Celgene Company and approved for marketing by the FDA of the United States in December 2005. Lenalidomide is an immunomodulatory drug, which can activate T lymphocytes, produce interleukin-2 (IL-2), change the number and function of natural killer cells (NK cells), and then enhance the NK cell-dependent cytotoxic activity. Lenalidomide is an analog of thalidomide, which has the effects of immunomodulation, anti-angiogenesis and anti-tumor, and almost no neurotoxicity and teratogenicity. Lenalidomide is mainly used for treating multiple myeloma, myelodysplastic syndrome, chronic lymphocytic leukemia and solid tumors and other diseases.

[0003] At present, there are many synthesis routes of lenalidomide, and a commonly used synthesis route is as follows: 1, 3-aminopiperidine-2,6-dione and its salt are subjected to condensation reaction with 2-bromomethyl-3-nitrobenzoic acid methyl ester to obtain 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione, and finally subjected to catalytic hydrogenation reaction to obtain lenalidomide. This is a three-phase reaction, that is, the hydrogen gas as the hydrogen donor is in the gas phase, the palladium-carbon catalyst is in the solid phase, and the raw material solution is in the liquid phase. It is not easy to fully react, and even if the reaction is carried out in a high-pressure kettle under pressure, it still needs 3-4 hours to completely react. There are problems of complicated operation, long reaction time and safety. In addition, the method has the following two problems: 1, methanol is used as the solvent, which leads to incomplete reduction of lenalidomide, poor purity and low yield; 2, the amount of palladium-carbon catalyst used is large, and the palladium is not completely removed by the general palladium removal method, and the content of palladium is too high, which does not meet the requirements of drugs. SUMMARY

[0004] Based on the above prior art, the application provides a preparation method of lenalidomide, which simplifies the operation, improves the safety of operation, and improves the yield and purity of lenalidomide.

[0005] The technical scheme adopted to achieve the above-mentioned purposes of the application is as follows:

[0006] A preparation method of lenalidomide, comprising the following steps:

[0007] S1. Methyl 2-bromomethyl-3-nitrobenzoate, 3-aminopiperidine-2,6-dione hydrochloride and base are dissolved in a polar solvent, heated to 50-60℃, and reacted at 50-60℃ for 5-8 hours. After the reaction is completed, water is added to the resulting mixed product, stirred to precipitate crystals, filtered, washed and dried to obtain 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione.

[0008] S2. 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione, ammonium formate, and palladium on carbon catalyst are added to a mixed solvent, which is a mixture of tetrahydrofuran and dioxane. The temperature is raised to 35-45℃, and the reaction is carried out at 35-45℃ for 4-7 hours. After the reaction is completed, the temperature is lowered, the mixture is filtered, and the filter cake is washed with a mixture of tetrahydrofuran and dioxane to obtain the crude product.

[0009] S3. Dissolve the crude product with a polar solvent by stirring, filter, add ammonium formate and sodium mercaptoacetate to the filtrate, stir and react for 2-5 hours. After the reaction is complete, add water to the resulting mixture, stir to precipitate crystals, filter, wash the filter cake, and dry to obtain lenalidomide.

[0010] Furthermore, the alkali is triethylamine.

[0011] Furthermore, the polar solvent is N,N-dimethylformamide.

[0012] Furthermore, the molar ratio of methyl 2-bromomethyl-3-nitrobenzoate, 3-aminopiperidine-2,6-dione hydrochloride, and base is 1:1.1-1.5:1.5-2.

[0013] Furthermore, the molar ratio of 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione and ammonium formate is 1:5.9-8.6.

[0014] Furthermore, the mass of the palladium catalyst added is 8.6-11.0% of the mass of 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione.

[0015] Furthermore, the total mass of ammonium formate and sodium mercaptoacetate added is 0.4-0.6% of the crude product mass, and the mass ratio of ammonium formate to mercaptoacetate is 1:2.

[0016] Furthermore, the volume ratio of tetrahydrofuran to dioxane is 1:1-2.

[0017] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows:

[0018] 1. This invention uses ammonium formate as a reducing agent and hydrogen donor, replacing hydrogen gas, which simplifies the operation, improves the safety of the operation, and at the same time transforms the three-phase reaction into a two-phase reaction, allowing the reaction to proceed fully and improving the yield of lenalidomide.

[0019] 2. In this invention, a mixture of tetrahydrofuran and dioxane is used instead of methanol as a solvent, which makes the reduction of lenalidomide more complete and further improves the yield and purity of lenalidomide.

[0020] 3. This invention uses ammonium formate and sodium thioglycolate as reagents to remove palladium, which can remove palladium completely, with a palladium concentration of less than 5 ppm, meeting the requirements for pharmaceuticals. Detailed Implementation

[0021] The present invention will now be described in detail with reference to specific embodiments.

[0022] Example 1

[0023] 1. Add 60 kg of DMF to a 200 L glass reactor, and while stirring, add 10.68 kg of methyl 2-bromomethyl-3-nitrobenzene and 7.05 kg of... 3-Aminopiperidine-2,6-dione hydrochloride and 6.90 kg of triethylamine were heated to 60 °C and reacted at 60 °C for 6 h. After the reaction was completed, 70 L of drinking water was slowly added to the resulting mixture, and the mixture was stirred to crystallize for 1 h. The mixture was then filtered, and the filter cake was washed twice with DMF (15 kg + 15 kg), once with dichloromethane, once with drinking water, and once with methanol. The washed filter cake was spread evenly in a stainless steel pan and transferred to a vacuum drying oven at 70 °C. The cake was turned over every hour, and the weight of the material was recorded. The mixture was dried to constant weight, and the resulting solid was pulverized to 60 mesh to obtain a white solid 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione, abbreviated as IM1, with a yield of 93.07% and a purity of 98.8%.

[0024] 1 HNMR(DMSO)δ11.04(S,1H),8.48(dd,1H),8.19(d,1H),7.85(t,1H),5.16(dd ,1H), 4.87(dd,2H), 2.92~2.83(m,1H), 2.63~2.48(m,2H), 2.01~1.99(m,1H).

[0025] 2. Add 50L of tetrahydrofuran and 65L of dioxane to a reactor. Under stirring, add 6.5kg of IM1, 10.5kg of ammonium formate and 0.9kg of Pd / C catalyst. Heat to 40℃ and react at 40℃ for 5.5h. After the reaction is complete, cool to 20℃, filter, and wash the filter cake with a mixture of 2L of tetrahydrofuran and 3L of dioxane. After washing, weigh to obtain 5.53kg of crude product.

[0026] 3. Add 82.9 kg DMF to a 300 L reactor, add the crude product while stirring, and stir to dissolve at 60 °C for 1 h. Then filter with a tubular filter. Add 9.21 g ammonium formate and 18.42 g sodium mercaptoacetate to the filtrate and stir to react for 4 h. After the reaction is complete, filter and add the filtrate to a 500 L reactor. Slowly add 223.83 kg purified water and stir to crystallize for 6 h. Filter by suction. Wash the filter cake successively with a mixture of tetrahydrofuran and dioxane, purified water and acetone. Then spread it evenly in a stainless steel tray and dry in a vacuum drying oven at 70 °C. Turn it once every hour and record the weight of the material. Dry to constant weight to obtain a pale yellow solid lenalidomide with a yield of 87.8%, a purity of 99.9% and a palladium content of 3 ppm.

[0027] 1 HNMR(DMSO)δ10.97(S,1H), 7.18(t,1H), 6.98(d,1H), 6.85(dd,1H),

[0028] 5.43(s,2H), 5.10(dd,1H), 4.23~4.15(m,2H), 2.95~2.88(m,1H), 2.65~2.49(m1H), 2.34~2.21(m1H), 2.03~2.0(m1H).

[0029] Comparative Example 1

[0030] 1. Add 60 kg of DMF to a 200 L glass reactor, and while stirring, add 10.68 kg of methyl 2-bromomethyl-3-nitrobenzene and 7.05 kg of... 3-Aminopiperidine-2,6-dione hydrochloride and 6.90 kg of triethylamine were heated to 60 °C and reacted at 60 °C for 6 h. After the reaction was completed, 70 L of drinking water was slowly added to the resulting mixture, and the mixture was stirred to crystallize for 1 h. The mixture was then filtered, and the filter cake was washed twice with DMF (15 kg + 15 kg), once with dichloromethane, once with drinking water, and once with methanol. The washed filter cake was spread evenly in a stainless steel pan and transferred to a vacuum drying oven at 70 °C. The cake was turned over every hour, and the weight of the material was recorded. The mixture was dried to constant weight, and the resulting solid was pulverized to 60 mesh and weighed to obtain a white solid 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione, abbreviated as IM1, with a yield of 93.2% and a purity of 98.5%.

[0031] 2. Add 115L of methanol to the reactor, and add 6.5kg of IM1, 10.5kg of ammonium formate and 0.9kg of Pd / C catalyst under stirring. Heat to 40℃ and react at 40℃ for 5.5h. After the reaction is completed, cool down to 20℃, filter, and wash the filter cake with 5L of methanol. After washing, weigh to obtain 4.89kg of crude product.

[0032] 3. Add 73.35 kg DMF to a 300 L reactor, add the crude product while stirring, and stir to dissolve at 60 °C for 1 h. Then filter with a tubular filter. Add 8.15 g ammonium formate and 16.3 g sodium mercaptoacetate to the filtrate and stir to react for 4 h. After the reaction is complete, filter and add the filtrate to a 500 L reactor. Slowly add 198.05 kg purified water and stir to crystallize for 6 h. Filter by suction. Wash the filter cake successively with a mixture of tetrahydrofuran and dioxane, purified water and acetone. Then spread it evenly in a stainless steel tray and dry in a vacuum drying oven at 70 °C. Turn it once per hour and record the weight of the material. Dry to constant weight to obtain a white lenalidomide product with a purity of 98.9%, a yield of 73.5%, and a palladium content of 5 ppm.

[0033] Comparative Example 2

[0034] 1. Add 60 kg of DMF to a 200 L glass reactor, and while stirring, add 10.68 kg of methyl 2-bromomethyl-3-nitrobenzene and 7.05 kg of... 3-Aminopiperidine-2,6-dione hydrochloride and 6.90 kg of triethylamine were heated to 60 °C and reacted at 60 °C for 6 h. After the reaction was completed, 70 L of drinking water was slowly added to the resulting mixture, and the mixture was stirred to crystallize for 1 h. The mixture was then filtered, and the filter cake was washed twice with DMF (15 kg + 15 kg), once with dichloromethane, once with drinking water, and once with methanol. The washed filter cake was spread evenly in a stainless steel pan and transferred to a vacuum drying oven at 70 °C. The cake was turned over every hour, and the weight of the material was recorded. The mixture was dried to constant weight, and the resulting solid was pulverized to 60 mesh and weighed to obtain a white solid 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione with a yield of 92.82% and a purity of 99.05%, abbreviated as IM1.

[0035] 2. Add 50L of tetrahydrofuran and 65L of dioxane to a reactor. Under stirring, add 6.5kg of IM1, 10.5kg of ammonium formate and 0.9kg of Pd / C catalyst. Heat to 40℃ and react at 40℃ for 5.5h. After the reaction is complete, cool to 20℃, filter, and wash the filter cake with a mixture of 2L of tetrahydrofuran and 3L of dioxane. After washing, weigh to obtain 5.48kg of crude product.

[0036] 3. Add 82.2 kg DMF to a 300 L reactor, add the crude product while stirring, and stir to dissolve at 60 °C for 1 h. Then filter with a tubular filter. Add 27.4 g sodium mercaptoacetate to the filtrate and stir to react for 4 h. After the reaction is complete, filter and add the filtrate to a 500 L reactor. Slowly add 221.94 kg purified water and stir to crystallize for 6 h. Filter by suction. Wash the filter cake successively with a mixture of tetrahydrofuran and dioxane, purified water and acetone. Then spread it evenly in a stainless steel tray and dry in a vacuum drying oven at 70 °C. Turn it once every hour and record the weight of the material. Dry to constant weight to obtain white lenalidomide product with a yield of 87.1%, purity of 99.8% and palladium content of 28 ppm.

[0037] Comparative Example 3

[0038] 1. Add 60 kg of DMF to a 200 L glass reactor, and while stirring, add 10.68 kg of methyl 2-bromomethyl-3-nitrobenzene and 7.05 kg of... 3-Aminopiperidine-2,6-dione hydrochloride and 6.90 kg of triethylamine were heated to 60 °C and reacted at 60 °C for 6 h. After the reaction was completed, 70 L of drinking water was slowly added to the resulting mixture, and the mixture was stirred to crystallize for 1 h. The mixture was then filtered, and the filter cake was washed twice with DMF (15 kg + 15 kg), once with dichloromethane, once with drinking water, and once with methanol. The washed filter cake was spread evenly in a stainless steel pan and transferred to a vacuum drying oven at 70 °C. The cake was turned over once per hour, and the weight of the material was recorded. The mixture was dried to constant weight, and the resulting solid was pulverized to 60 mesh and weighed to obtain a white solid 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione with a yield of 92.95% and a purity of 98.96%, abbreviated as IM1.

[0039] 2. Add 50L of tetrahydrofuran and 65L of dioxane to a reactor. Under stirring, add 6.5kg of IM1, 10.5kg of ammonium formate and 0.9kg of Pd / C catalyst. Heat to 40℃ and react at 40℃ for 5.5h. After the reaction is complete, cool to 20℃, filter, and wash the filter cake with a mixture of 2L of tetrahydrofuran and 3L of dioxane. After washing, weigh to obtain 5.45kg of crude product.

[0040] 3. Add 81.75 kg DMF to a 300 L reactor, add the crude product while stirring, and stir to dissolve at 60 °C for 1 h. Then filter with a cartridge filter, filter the filtrate through a 3M filter to remove palladium, add the resulting filtrate to a 500 L reactor, slowly add 220.73 kg purified water, stir to crystallize for 6 h, filter, and wash the filter cake successively with a mixture of tetrahydrofuran and dioxane, purified water and acetone. Then spread it evenly in a stainless steel tray and dry in a vacuum drying oven at 70 °C, turning it once per hour, recording the weight of the material, and drying to constant weight to obtain a white lenalidomide product with a yield of 87.3%, purity of 99.7%, and palladium content of 75 ppm.

Claims

1. A method for preparing lenalidomide, characterized in that... Includes the following steps: S1. Methyl 2-bromomethyl-3-nitrobenzene, 3-aminopiperidine-2,6-dione hydrochloride and triethylamine are dissolved in N,N-dimethylformamide, heated to 50-60℃, and reacted at 50-60℃ for 5-8 hours. After the reaction is completed, water is added to the resulting mixture, stirred to precipitate crystals, filtered, washed and dried to obtain 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione. S2. 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione, ammonium formate, and palladium on carbon catalyst are added to a mixed solvent, which is a mixture of tetrahydrofuran and dioxane. The mass of palladium on carbon catalyst added is 8.6-11.0% of the mass of 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione. The temperature is raised to 35-45℃, and the reaction is carried out at 35-45℃ for 4-7 hours. After the reaction is completed, the temperature is lowered, the mixture is filtered, and the filter cake is washed with a mixture of tetrahydrofuran and dioxane to obtain the crude product. The volume ratio of tetrahydrofuran to dioxane is 1:1-2; S3. Dissolve the crude product with N,N-dimethylformamide by stirring, filter, add ammonium formate and sodium mercaptoacetate to the filtrate, stir and react for 2-5 hours. After the reaction is complete, add water to the resulting mixture, stir to precipitate crystals, filter, wash the filter cake, and dry to obtain lenalidomide. The total mass of ammonium formate and sodium thioacetate added is 0.4-0.6% of the crude product mass, and the mass ratio of ammonium formate to sodium thioacetate is 1:

2.

2. The method for preparing lenalidomide according to claim 1, characterized in that: The molar ratio of methyl 2-bromomethyl-3-nitrobenzoate, 3-aminopiperidine-2,6-dione hydrochloride and triethylamine is 1:1.1-1.5:1.5-2.

3. The method for preparing lenalidomide according to claim 1, characterized in that: The molar ratio of 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione and ammonium formate is 1:5.9-8.6.