Method for preparing lenalidomide

A technology of lenalidomide and nitro group, applied in the field of preparing lenalidomide, can solve the problems of loss of lenalidomide components, time-consuming and laborious, influence on the total yield, etc., and achieve mild reaction conditions, improve the total yield, The effect of efficient preparation

Inactive Publication Date: 2012-12-26
CHONGQING TAIHAO PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the post-treatment process adopted in this patent after each step of the reaction, including the final refining process, is likely to cause the loss of lenalidomide components, especially in the final refining step, which repeatedly refines lenalidomide into hydrochloride, making The final total yield is affected
Simultaneously, the post-treatment and refining process of this method are complicated to operate, time-consuming and laborious, which is unfavorable for improving the production efficiency of lenalidomide

Method used

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  • Method for preparing lenalidomide
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  • Method for preparing lenalidomide

Examples

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Embodiment 1

[0031] Embodiment 1: the method of the present invention prepares lenalidomide

[0032] 1. Preparation of 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione

[0033] Add 20.0g of 3-aminopiperidine-2,6-dione hydrochloride and 160ml of DMF to a 500ml single-necked bottle, stir at room temperature for 5 minutes, then add 40ml of triethylamine to the system, stir for 5 minutes, then add 37.2g of 2-bromo Methyl-3-nitro-benzoic acid methyl ester, 40ml of acetonitrile, after addition, under nitrogen protection, stir the reaction at 53°C (the reaction temperature is between 20°C and the boiling point of the mixed solvent of DMF and acetonitrile) for 8 hours, then cool to room temperature Then pour it into 500ml water (2 times the volume of the reaction solution) under stirring, filter after stirring for 10 minutes, rinse and filter with 500ml water (2 times the volume of the reaction solution) and 500ml methanol (2 times the volume of the reaction solution) respectively. Cake, th...

Embodiment 2

[0042] Embodiment 2: the method of the present invention prepares lenalidomide

[0043] 1. Preparation of 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione

[0044] Add 20.0g of 3-aminopiperidine-2,6-dione hydrochloride and 300ml of acetonitrile into a 500ml single-necked bottle, stir at room temperature for 30 minutes, then add 40ml of triethylamine to the system, stir for 30 minutes, then add 37.2g of 2- Bromomethyl-3-nitro-methyl benzoate, after addition, stirred and reacted at 81°C (reaction temperature between 20°C and solvent boiling point) under nitrogen protection for 12 hours, cooled to room temperature and poured into 3000ml of water (9 times the volume of the reaction solution), stirred for 10 minutes and then filtered, followed by rinsing the filter cake with 3000ml of water (9 times the volume of the reaction solution) and 3000ml isopropanol (9 times the volume of the reaction solution). The cake was dried under reduced pressure at 50°C to obtain a blue-purp...

Embodiment 3

[0053] Embodiment 3: the method of the present invention prepares lenalidomide

[0054] 1. Preparation of 3-(7-nitro-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione

[0055] Add 20.0g of 3-aminopiperidine-2,6-dione hydrochloride and 200ml of DMF to a 500ml single-necked bottle, stir at room temperature for 5 minutes, then add 40ml of triethylamine to the system, stir for 5 minutes, then add 37.2g of 2-bromo After the addition of methyl-3-nitro-benzoic acid methyl ester, under nitrogen protection, stir the reaction at 60°C (the reaction temperature is between 20°C and the boiling point of the solvent) for 10 hours, and pour it into 1250ml under stirring after cooling to room temperature water (5 times the volume of the reaction solution), stirred for 10 minutes and then filtered, then rinsed the filter cake with 1250ml water (5 times the volume of the reaction solution) and 1250ml ethanol (5 times the volume of the reaction solution) respectively, and collected the filter cake in 5...

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PUM

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Abstract

The invention relates to the field of chemical synthesis, and discloses a method for preparing lenalidomide, which comprises the following steps: condensing 3-aminopiperidyl-2,6-diketohydrochloride with 2-halomethyl-3-nitro-methyl benzoate under weakly alkaline conditions, cooling the reaction solution to room temperature, adding into water, stirring, filtering to obtain a filter cake, sequentially washing with water and alcohol reagents, and drying to obtain 3-(7-nitro-3-oxo-1H-isoindazolyl-2-yl)piperidyl-2,6-dione; and carrying out nitro-amino reduction reaction, filtering the reaction solution, concentrating, crystallizing at -20 DEG C to room temperature, filtering, washing the filter cake with alcohol reagents, drying to obtain a lenalidomide crude product, and recrystallizing to obtain the lenalidomide finished product. By adjusting the after-treatment technique, the invention enhances the total yield of lenalidomide, and ensures the high purity; and the whole method has the advantages of mild reaction conditions and no high temperature or high pressure, and can be used for preparing lenalidomide in a simple and efficient way. 2-halomethyl-3-nitro-methyl benzoate.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a method for preparing lenalidomide. Background technique [0002] Multiple myeloma is a malignant plasma cell proliferative blood tumor. Plasma cells have the function of secreting immunoglobulin, but the hyperplastic plasma cells of most patients with multiple myeloma only produce a kind of immunoglobulin called paraprotein or M protein, which is not beneficial to the body, while normal plasma cells and Other white blood cells are replaced by malignant plasma cells, resulting in decreased normal immunoglobulin synthesis and secretion. Multiple myeloma cells also invade other tissues in the body, such as bone tissue, and cause tumors. Multiple myeloma is the second most common hematological malignancy, accounting for about 1% of all cancer patients and about 2% of all cancer deaths. [0003] Lenalidomide is a new immune-modulating, non-chemotherapy anti-cancer drug. Its chem...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
Inventor 王信见李靖姚全兴
Owner CHONGQING TAIHAO PHARM CO LTD
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