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Antitumor drug lenalidomide intermediate preparation method

An anti-tumor drug, the technology of lenalidomide, applied in the direction of organic chemistry, can solve the problems of low yield, unsatisfactory preparation, complex reaction, etc., to achieve simple and easy reaction, easy to obtain raw materials, and few reaction steps Effect

Inactive Publication Date: 2017-12-19
QINGDAO CHENDA BIOLOGICAL SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although the prior art has had more reports on the preparation of lenalidomide, the preparation of lenalidomide is still not ideal, especially its intermediate 3-(4-nitro-1-oxo-1 ,3-dihydroisoindol-2-yl)piperidine-2,6-dione preparation, there are still problems such as low yield and complex reaction

Method used

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  • Antitumor drug lenalidomide intermediate preparation method
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  • Antitumor drug lenalidomide intermediate preparation method

Examples

Experimental program
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Effect test

preparation example

[0026] Preparation of 4-nitroisoindoline

[0027] Under ice bath, add 80ml of concentrated nitric acid into 450ml of 98% concentrated sulfuric acid, stir for 10min, continue to keep the ice bath, add 50g of isoindoline under vigorous stirring, stir for 30min, continue to stir at room temperature for 8 hours, quench with ice water, and filter with suction , the filter cake is a crude product, the crude product is washed successively with water and saturated sodium bicarbonate, and recrystallized from petroleum ether to obtain 58.3g of light yellow solid 4-nitroisoindoline, the yield is 84.6%, and the HPLC purity is 99.11%; 1 HNMR (300MHz, DMSO-d 6 )δ: 7.51(d,1H), 7.43(d,1H), 7.22(t,1H), 4.04(s,2H), 3.98(s,2H), 3.47(br,1H).

Embodiment 1

[0029] Preparation of 3-(4-nitro-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione

[0030] Add 16.4g (100mmol) of 4-nitroisoindoline, 21.1g (110mmol) of 3-bromo-2,6-piperidinedione, 5.7g (30mmol) of cuprous iodide, and 53g (500mmol) of sodium carbonate In the flask, add 200ml of acetonitrile as the reaction solvent, raise the temperature to 55°C, stir and react for 5 hours, concentrate the reaction liquid, pour it into water, extract with dichloromethane, wash the organic phase with water, wash with saturated saline, dry over anhydrous sodium sulfate, and depressurize Concentrate and recrystallize from dichloromethane-n-hexane (volume ratio 1:10) to obtain 3-(4-nitro-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione 24.4g, the yield is 88.7%, the purity is 99.26%; 1 HNMR (300MHz, DMSO-d 6 )δ: 11.02(s,1H), 7.57(d,1H), 7.46(d,1H), 7.25(t,1H), 4.15(s,2H), 4.10(s,2H), 3.28(t,1H ), 2.40-2.48(m,2H), 1.91-1.95(m,2H). MS([M+H] + ): 276.11.

Embodiment 2

[0032] Preparation of 3-(4-nitro-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione

[0033] Add 16.4g (100mmol) of 4-nitroisoindoline, 23g (120mmol) of 3-bromo-2,6-piperidinedione, 7.6g (40mmol) of cuprous iodide, and 41.5g (300mmol) of potassium carbonate In the flask, add 200ml of tetrahydrofuran as a reaction solvent, raise the temperature to 60°C, stir and react for 6 hours, concentrate the reaction solution, pour it into water, extract with dichloromethane, wash the organic phase with water, wash with saturated saline, dry over anhydrous sodium sulfate, and depressurize Concentrate and recrystallize from dichloromethane-n-hexane (volume ratio 1:10) to obtain 3-(4-nitro-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione 24.9g, yield 90.4%, purity 99.44%.

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Abstract

The invention discloses an antitumor drug lenalidomide intermediate preparation method. The preparation method comprises the following steps: 1) under existence of cuprous iodide and organic alkali, performing contact reaction between 4-nitro indoline and 3-bromine-2,6-piperidine to obtain 3-(4-nitro-1,3-xylylenimine-2-yl)piperidine-2,6-diketone; 2) performing oxidizing reaction on the 3-(4-nitro-1,3-xylylenimine-2-yl)piperidine-2,6-diketone obtained in the step 1) to obtain lenalidomide intermediate of 3-(4-nitro-1-oxo-1,3-xylylenimine-2-yl)piperidine-2,6-diketone. The method disclosed by the invention has obviously smaller steps, the raw materials are easy to obtain, a yield is also improved, and the method is more suitable for industrial production.

Description

technical field [0001] The invention relates to the synthesis of drug intermediates, in particular to a method for preparing an anti-tumor drug lenalidomide intermediate. Background technique [0002] Lenalidomide, the chemical name is 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione, the drug mainly For the treatment of multiple myeloma bone marrow and dysplastic syndrome subtype diseases. Lenalidomide was developed by Celgene Biopharmaceutical Company of the United States. The application of lenalidomide in the treatment of multiple myeloma bone marrow and dysplastic syndrome subtype diseases has significantly improved the therapeutic effect of such diseases. [0003] In the prior art, the preparation of lenalidomide is usually through the intermediate 3-(4-nitro-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6- Lenalidomide and lenalidomide intermediate 3-(4-nitro-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6 obtained by diketone reduction - Diketones are s...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 杜文
Owner QINGDAO CHENDA BIOLOGICAL SCI & TECH
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