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Method for preparing pomalidomide by one-pot process

A pomalidomide and compound technology, applied in the field of pomalidomide preparation, can solve the problems of compound III instability, large environmental pollution, harsh reaction conditions, etc., reduce material transfer and unit operations, reduce production costs, The effect of reagent safety and environmental protection

Active Publication Date: 2015-03-11
HANGZHOU XINBOSI BIOMEDICAL CO LTD
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  • Abstract
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  • Claims
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AI Technical Summary

Problems solved by technology

[0006] The first step reaction in route 1 requires the use of highly toxic ethyl chloroformate, and a class of solvent dichloroethane has been used many times in the reaction, which has great environmental pollution
The fourth step reaction requires a low temperature of -40°C, the reaction conditions are relatively harsh, and the final hydrogenation reduction with Pd / C is relatively expensive
But compound III in this route is unstable and easy to degrade
The last step of the reaction is to use heavy metal palladium to reduce the cost, and it is easy to cause the heavy metal to exceed the standard, making it difficult for the final product to meet the pharmaceutical standard
More importantly, this method involves multiple material transfers, which is not conducive to industrial production

Method used

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  • Method for preparing pomalidomide by one-pot process
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  • Method for preparing pomalidomide by one-pot process

Examples

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example 1

[0034] Example 1: One-pot preparation of pomalidomide

[0035] Add 211g of 3-nitrophthalic acid into the reaction flask, add 100ml of acetic anhydride and 650ml of acetic acid, stir and mix, and heat to reflux at 120°C for 16h. Add 165g of 3-aminopiperidine-2,6-dione hydrochloride, 90g of sodium acetate, and 2500ml of acetic acid, heat to reflux at 120°C for 8 hours, then cool to 75±2°C. Add 240g of iron powder in batches, control the reaction temperature not to exceed 105°C, stir the reaction for 5 hours, and cool to room temperature. After filtering, the filter cake was washed with water, and then beaten and washed with sodium bicarbonate solution, and the crude product was obtained after filtration. The crude product was dissolved by heating with 2400ml dimethyl sulfoxide and filtered. Water was added dropwise to the filtrate, the precipitated solid was collected by filtration, and air-dried at 60° C. for 4 h. 216.7 g of yellow solid was obtained, yield: 79.3%, purity: 9...

example 2

[0038] Example 2: One-pot preparation of pomalidomide

[0039] Add 21.1g of 3-nitrophthalic acid into the reaction flask, add 10ml of acetic anhydride and 65ml of acetic acid, stir and mix, and heat to reflux at 120°C for 15h. Add 16.5g of 3-aminopiperidine-2,6-dione hydrochloride, 10g of sodium acetate, and 250ml of acetic acid, heat to reflux at 120°C for 6 hours, then cool to 75±2°C. Add 24g of iron powder in batches, control the reaction temperature not to exceed 105°C, stir the reaction for 5 hours, and cool to room temperature. Filtrate, wash the filter cake with water, and then beat and wash with sodium bicarbonate solution. After filtration, the crude product is obtained. The crude product is heated and dissolved in 240ml of dimethyl sulfoxide, filtered, and water is added dropwise to the filtrate. 20.8 g of yellow solid was obtained, yield: 76.2%, purity: 99.96%.

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Abstract

The invention relates to a method for preparing pomalidomide (compound I) by a one-pot process. The method comprises the following steps: reacting a raw material 3-nitrophthalic acid disclosed as Formula (II) with acetic anhydride in an acidic solvent to prepare 3-nitrophthalic anhydride disclosed as Formula (III), carrying out condensation reaction with 3-aminopiperidyl-2,6-dione hydrochloride disclosed as Formula (IV) under the action of an alkali, and finally, reducing with iron powder, thereby preparing the pomalidomide (compound I) by the one-pot process. The method has the advantages of high efficiency, high yield, low cost, high safety and environmental protection.

Description

technical field [0001] The invention relates to the technical field of preparation methods of pomalidomide. Background technique [0002] Pomalidomide, the chemical name is 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione, manufactured by Celgene Developed by the company, it was approved for marketing by the FDA on February 8, 2013, and was approved by the EMA for listing in the UK and Ireland on August 9, 2013. Pomalidomide + low-dose dexamethasone for the treatment of multiple myeloma. As a novel immunomodulator, pomalidomide has shown great activity and great potential in the treatment of relapsed multiple myeloma. [0003] The method for preparing pomalidomide (compound I) reported in the literature mainly contains the following several kinds at present: [0004] Route 1 (EP 0925294; EP 0984955; US 5635517; WO 9803502; WO 9854170): [0005] [0006] The highly toxic ethyl chloroformate is used in the first step of the reaction in route one, and a class of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 杜焕达杨俊胡畏王万青刘艳华
Owner HANGZHOU XINBOSI BIOMEDICAL CO LTD
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