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Preparation method of pomalidomide

A technology of polilidomide and amides, which is applied in the field of preparation of polilidomide, can solve the problems of low purity, large amount of solvent consumption, and low yield, and achieve high purity, low solvent consumption, and high yield. Effect

Active Publication Date: 2015-04-29
SHANGHAI INST OF PHARMA IND +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The technical problem to be solved by the present invention is to provide a kind of polilidomide in order to overcome the defects of many impurities, low yield, large amount of solvent, low purity and not suitable for large-scale industrial production in the existing polilidomide preparation method. The preparation method of amine

Method used

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  • Preparation method of pomalidomide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 14

[0032] Preparation of Example 14-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0033] Mix 5 g of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-nitroisoindoline and 0.4 g of 10% palladium carbon into 50 mL of N,N - in dimethylacetamide, then carry out hydrogenation reaction at 30°C at 0.45Mpa for 7 hours, remove the catalyst by filtration, concentrate the filtrate under vacuum, beat the concentrate with water overnight to obtain 3.6g of a yellow solid, the target compound. The yield is 80%, the purity measured by HPLC is 99.4%, and the melting point is 236-238°C.

[0034] 1 HNMR (DMSO-d 6 )δ:10.99(s,1H),7.42-7.47(m,1H),6.92-7.00(m,2H),6.52(s,2H),2.55-2.71(m,3H),1.88-2.05(m, 4H).

Embodiment 24

[0035] Preparation of Example 24-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0036] Mix 5 g of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-nitroisoindoline and 0.4 g of 10% palladium carbon into 150 mL of N,N -in a mixed solvent of dimethylacetamide and ethanol (volume ratio 1:1), then carry out hydrogenation reaction at 50°C at 0.4Mpa for 7 hours, filter the catalyst, and concentrate the filtrate under vacuum, The concentrate was slurried with water overnight to obtain 3.4 g of a yellow solid, namely the target compound. The yield was 75%, and the purity measured by HPLC was 99%. NMR data is the same as in Example 1.

Embodiment 34

[0037] Preparation of Example 34-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0038] Mix 5 g of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-nitroisoindoline and 0.1 g of 10% palladium carbon into 105 mL of N,N -in a mixed solvent of dimethylacetamide and water (volume ratio 20:1), then hydrogenation reaction was carried out at 0.4Mpa at 40°C for 7 hours, the catalyst was filtered off, the filtrate was concentrated under vacuum, and the concentrated The mixture was slurried with water overnight to obtain 3.2 g of a yellow solid, namely the target compound. The yield was 71%, and the purity measured by HPLC was 99.2%. NMR data is the same as in Example 1.

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Abstract

The invention discloses a preparation method of pomalidomide. The preparation method of pomalidomide comprises the following step; in N,N-dimethylacetamide or a mixed solvent of N,N-dimethylacetamide and other solvents, carrying out reduction reaction shown in the formula (described in the specification) on hydrogen and a compound shown in a formula II in the presence of palladium on activated carbon, wherein other solvents can be alcohol solvents, ketone solvents or water. The preparation method of pomalidomide has the advantages of high yield, low solvent consumption and high purity and is also applicable to industrial large-scale production. The formula II is described in the specification.

Description

technical field [0001] The invention relates to a preparation method of polilidomide. Background technique [0002] Pomalidomide, the English name is Pomalidomide, the chemical name is 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, and its chemical structure is as follows: [0003] [0004] Polidomide is a new immunomodulator originally developed by Celgene. Polidomide is a derivative of thalidomide, which can regulate T cells and inhibit their proliferation, and play an immune regulatory role; by activating natural killer ( natural killer) cells, promote the apoptosis of tumor cells, and are mainly used clinically for the treatment of multiple myeloma. [0005] US Patent Nos. 6,395,754 and 5,635,517 disclose methods for the synthesis of unsubstituted and substituted 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione compounds. Although these two patents mention that 1,4-dioxane can be used as a solvent for the preparation of unsubstituted and substituted...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 刘航袁哲东杨玉雷胡志张颢
Owner SHANGHAI INST OF PHARMA IND
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