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Improved process

一种来那度胺、硝基的技术，应用在制备3--哌啶-2领域，能够解决低产率、差可行性、危险等问题

Inactive Publication Date: 2012-04-11
GENERICS UK LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] (1) low yield of final product;
[0009] (2) low yield of nitro intermediate; and
[0012] (1) is dangerous; and
[0013] (2) Poor commercial viability due to large solvent:substance ratio and low yield of final product lenalidomide

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0140] Example 1 : Preparation of 3-(1-oxo-4-nitro-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione

[0141]Add triethylamine (140.8g, 2.29mol) to 3-amino-piperidine-2,6-dione hydrochloride (100g, 0.61mol) in N,N-dimethylformamide at 25-30°C (800ml) in solution. A solution of methyl 2-bromomethyl-3-nitro-benzoate (186.0 g, 1.13 mol) in acetonitrile (200 ml) was then added under stirring and nitrogen atmosphere and the reaction mixture was heated to 50-55°C, Lasts for 8-10 hours. After completion of the reaction, approximately 60% of the solvent was removed by distillation under reduced pressure (100 mbar) at 50-60°C. Water (1000ml) was added to the remaining mixture at 50-55°C and stirred at this temperature for 1 hour. The obtained solid product was cooled to 25-30°C and filtered. The solid was washed with water (500ml) at 50-55°C, cooled at ambient temperature and filtered again. Finally, the solid was washed with methanol (500 ml) at 50-55°C, cooled at 25-30°C and fil...

Embodiment 2

[0144] Example 2 : Preparation of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (I) (lenalidomide)

[0145] Dissolve 3-(1-oxo-4-nitro-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (100 g, 0.35 mol) in acetonitrile and methanol mixture (7000ml, 1:1, v / v). A catalyst comprising a slurry of 10% palladium on carbon (5.0 g) in methanol (25 ml) with a water content of approximately 50% was added under a nitrogen atmosphere. The nitrogen was replaced with hydrogen and bubbled through the reaction mixture with stirring. The reaction mixture was maintained at 30-35°C. After 1 hour, a second amount of catalyst was added and hydrogen sparging was continued until the reaction was complete after a total time of about 2-2.5 hours. The completion of the reaction was monitored by TLC. The catalyst was completely removed by filtration. The filtrate was concentrated and approximately two-thirds of the solvent was removed by distillation at a temperature of 45-50°C an...

Embodiment 3

[0149] Example 3 : Further purification of lenalidomide

[0150] Lenalidomide was prepared as described above.

[0151] Lenalidomide (70 g) was suspended in a mixture of acetonitrile and methanol (700 ml, 1:1, v / v) and an equimolar portion of a crude lenalidomide in hydrogen chloride solution in isopropanol was added slowly. The reaction mixture was stirred at ambient temperature for 45 minutes, then slowly cooled to 5-10 °C and held at this temperature for 45 minutes. The precipitated solid was filtered and dried. The solid was washed in methanol (100ml) at ambient temperature and filtered, then dried to remove all solvent.

[0152] Lenalidomide hydrochloride was suspended in methanol (350 ml), and 1.1 molar equivalents of triethylamine were slowly added with stirring. The reaction mixture was stirred at ambient temperature for 45 minutes, then cooled at 5-10 °C and maintained at this temperature for a further 45 minutes. The precipitated solid was filtered and dried. ...

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Abstract

The present invention relates to improved processes for preparing 3-(4-amino-1-oxo-1,3- dihydro-isoindol-2-yl)-piperidine-2,6-dione (I) (lenalidomide) and its intermediate 3-(1-oxo- 4-nitro-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. The present invention further relates to improved processes for preparing lenalidomide crystalline form A, use of said crystalline form A as an active pharmaceutical ingredient or as an intermediate in the preparation of further crystalline or amorphous forms of lenalidomide, compositions comprising lenalidomide crystalline form A and their use in the treatment of disease.

Description

technical field [0001] The present invention relates to the preparation of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (I) (lenaldil Amine) and its intermediate 3-(1-oxo-4-nitro-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione improved method. The present invention also relates to an improved process for the preparation of lenalidomide crystalline form A for use as an active pharmaceutical ingredient or as an intermediate in the preparation of another crystalline or amorphous form of lenalidomide, comprising lenalidomide Compositions of amine form A and their use in the treatment of diseases. [0002] Background technique [0003] 3-(4-Amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (I) having the common name lenalidomide is a A non-polypeptide compound that antagonizes TNFα and is believed to increase levels of adenosine 3',5'-cyclic monophosphate. Lenalidomide and various structural analogs are useful in the treatment of a wide range o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04A61K31/45
CPCC07D401/04A61P29/00A61P31/12A61P35/00A61P37/00A61P37/06
Inventor 维纳亚克·戈文德·戈雷维纳伊·库玛·舒克拉希尔雅斯·布安达里苏雷什·哈斯贝
Owner GENERICS UK LTD
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