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Method for preparing high-purity pomalidomide

A pomalidomide and high-purity technology is applied in the field of preparation of high-purity pomalidomide, which can solve the problems of unmentioned intermediate and product purity, inability to meet the requirements of the pharmaceutical industry, and high requirements for purity and impurity content, Achieve the effect of less waste, low price and high safety

Active Publication Date: 2014-05-21
TIANJIN WEIJIE TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Pomalidomide is an active pharmaceutical ingredient, and the pharmaceutical industry has high requirements for its purity and impurity content. This report does not mention the purity of intermediates and products, which cannot meet the requirements of the pharmaceutical industry

Method used

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  • Method for preparing high-purity pomalidomide
  • Method for preparing high-purity pomalidomide
  • Method for preparing high-purity pomalidomide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add 24.0g (0.124mol, 1.0eq) of 3-nitrophthalic anhydride, 21.5g (0.130mol, 1.05eq) of 3- Aminopiperidine-2,6-dione hydrochloride and 240mL of toluene as a solvent were stirred to form a suspension, then 15.0g (0.148mol, 1.2eq) of triethylamine was added, and the temperature was slowly raised to reflux to separate water, and the reaction solution Turn into a purple suspension, continue to reflux and divide water for 8 hours, HPLC central control: when the content of 3-nitrophthalic anhydride in the raw material is 1 H NMR characterization, showing the following chemical shifts: (DMSO-d6)δ: 11.122(s, 1H), 8.342(d, J=8.1Hz, 1H), 8.229(d, J=7.2Hz, 1H), 8.122( t,J=7.8Hz,1H),5.215(dd,J=12.6,5.4Hz,1H),2.946-2.825(m,1H),2.631-2.571(m,2H),2.093-1.981(m,1H) ;MS(ESI)(m / z):274.4[M+H] + .

[0031] Add 31.7g (wet product 48.2g, 0.105mol, 1.0eq) 3-nitro-N-(2,6-dioxo-3 -piperidinyl)-phthalimide, 1.6g of 10% palladium on carbon and 395mL of 1,4-dioxane as a solvent, stirred to form a...

Embodiment 2

[0033] Add 24.0g (0.124mol, 1.0eq) of 3-nitrophthalic anhydride, 21.5g (0.130mol, 1.05eq) of 3- Aminopiperidine-2,6-dione hydrochloride and 240mL of toluene as a solvent were stirred to form a suspension, then 15.0g (0.148mol, 1.2eq) of triethylamine was added, and the temperature was slowly raised to reflux to separate water, and the reaction solution Turn into a purple suspension, continue to reflux and divide water for 8 hours, and control in the HPLC: when the content of the raw material 3-nitrophthalic anhydride is <0.5%, and the temperature of the reaction solution drops to 15-25°C, add 10.0g N,N'-carbonyldiimidazole (0.062mol, 0.5eq), slowly heat up to reflux and stir for 2 hours, HPLC central control: when the intermediate state content is less than 0.5%, and the temperature of the reaction solution drops to 15-25°C, pump Filter, transfer the filter cake to another 250mL reaction bottle, add a mixture of 60mL methanol and 60mL water to make a slurry for 2 hours, filter...

Embodiment 3

[0036] Add 24.0g (0.124mol, 1.0eq) of 3-nitrophthalic anhydride, 21.5g (0.130mol, 1.05eq) of 3- Aminopiperidine-2,6-dione hydrochloride and 240mL of toluene as a solvent were stirred to form a suspension, then 18.8g (0.186mol, 1.5eq) of triethylamine was added, and the temperature was slowly raised to reflux to separate water, and the reaction solution Turn into a purple suspension, continue to reflux and divide water for 8 hours, and control in the HPLC: when the content of the raw material 3-nitrophthalic anhydride is <0.5%, and the temperature of the reaction solution drops to 15-25°C, add 10.0g N,N'-carbonyldiimidazole (0.062mol, 0.5eq), slowly heat up to reflux and stir for 2 hours, HPLC central control: when the intermediate state content is less than 0.5%, and the temperature of the reaction solution drops to 15-25°C, pump Filter, transfer the filter cake to another 250mL reaction bottle, add a mixture of 60mL methanol and 60mL water for beating for 2 hours, filter with...

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Abstract

The invention discloses a method for preparing high-purity pomalidomide. The method comprises the following steps: by taking 3-nitrophthalicanhydride and 3-aminopiperidine-2,6-diketone hydrochloride as raw materials, methylbenzene as a solvent, triethylamine as an acid attaching agent and N,N'-carbonyldimidazole as a condensing agent, carrying out a condensation reaction, thereby obtaining 3-nitro-N-(2,6-dioxo-3-piperidyl)-phthalimide; carrying out a hydrogenation reaction under catalysis of a palladium carbon catalyst, and recrystallizing to obtain the high-purity pomalidomide. The total yield is 62%, and the materials used in the reaction are low in price, simple and easily available; the second-step catalytic hydrogenation is performed under normal pressure, simple operations such as pulping, distilling and performing suction filtration are only used in the two-step reaction, and the operations are conventional production operations; intense heat release phenomena in the reaction process and after-treatment process are avoided, the operation is simple, and the safety is high; a mother solution obtained by after-treatment in the first-step reaction can be directly recycled, the amount of three wastes generated after after-treatment is small, and the operation is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a preparation method of high-purity pomalidomide. Background technique [0002] Pomalidomide is a derivative of Thalidomide. It has the same stability as Thalidomide. It is the most active immunomodulatory drug so far, which can regulate T cells and inhibit their proliferation. , by activating natural killer cells, promoting the apoptosis of tumor cells, and exerting an immunoregulatory effect, it is mainly used clinically for the treatment of multiple myeloma. Multiple myeloma, a type of blood cancer that starts in plasma cells in the bone marrow, mainly affects the elderly. According to the National Cancer Institute, approximately 21,700 Americans are diagnosed with multiple myeloma each year and 10,710 die from the disease. The US Food and Drug Administration (FDA) approved Pomalyst (pomalidomide) on February 8, 2013 for the treatment of multiple myeloma patients whose dise...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 宋洪海赵建新魏彦宇郭心富林松
Owner TIANJIN WEIJIE TECH
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