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New intermediate of non-small-cell lung carcinoma treating drug Ceritinib, and preparation method thereof

A technology of non-small cell lung cancer and ceritinib, which is applied in organic chemistry and other fields, and can solve the problem of low literature yield

Inactive Publication Date: 2016-06-01
SHANGHAI SCIENPHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This step document yield is lower (60%), and when amplifying in kilogram scale, yield can only be maintained at 40~45%

Method used

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  • New intermediate of non-small-cell lung carcinoma treating drug Ceritinib, and preparation method thereof
  • New intermediate of non-small-cell lung carcinoma treating drug Ceritinib, and preparation method thereof
  • New intermediate of non-small-cell lung carcinoma treating drug Ceritinib, and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] The preparation of embodiment 1,2-isopropylsulfide nitrobenzene

[0026] Add 1.4kg of 2-fluoronitrobenzene, 0.77kg of isopropyl mercaptan, and 1.55kg of potassium carbonate into 8kg of N,N-dimethylformamide, raise the temperature to 80-90°C for 24 hours, and monitor the completion of the reaction by HPLC. Cool down to 20-25°C, and remove insoluble matter by filtration. Add the filtrate to 76 kg of purified water at 0-5°C that is vigorously stirred, and adjust the temperature to 5-10°C to adjust the pH to 6-7. Add 15 kg of petroleum ether: ethyl acetate = 2:1 mixed solvent for extraction twice. The extract phases were combined, concentrated under reduced pressure to remove petroleum ether, until the total volume was about 10 L, and directly injected into the next step.

Embodiment 2

[0027] The preparation of embodiment 2,2-isopropylsulfide aniline

[0028] Add 400 g of Egret Z activated carbon to the ethyl acetate solution obtained in the previous step, and stir at 30 to 40° C. for 15 to 16 hours. Remove gac by filtration, wash twice with 2kg ethyl acetate. Add 140g of 10% Pd / C to the ethyl acetate solution, 30-40°C, 1.6atm catalytic hydrogenation, the reaction is completed in about 19-20 hours, and the reaction is monitored by HPLC. The catalyst was removed by filtration, concentrated to dryness under reduced pressure to obtain 1.9 kg of red oily liquid.

Embodiment 3、2

[0029] Embodiment 3, the preparation of 2,5-dichloro-N-(2-(isopropyl sulfide) phenyl) pyrimidin-4-amine

[0030] Add 1.9kg of crude product from the previous step, 1.9kg of 2,4,5-trichloropyrimidine, and 2.4kg of diisopropylethylamine into 20kg of isopropanol, and heat up to reflux for reaction. HPLC monitors the end point of the reaction until the content of the raw material 2-isopropylsulfide aniline is lower than 6%. The temperature was lowered to 40-55° C., the dry reaction solution was concentrated under reduced pressure, and 20 kg of ethyl acetate was added for entrainment once. Add 20kg ethyl acetate, wash twice with 20kg purified water. The ethyl acetate phase was concentrated to dryness under reduced pressure, 10 kg of absolute ethanol was added to the black oily matter, and the crystallization was stirred at 20-25°C for 4 hours, and at 0-5°C for 16 hours. Filter and wash once with 1 kg of absolute ethanol. Vacuum drying at 40°C yielded 2.65kg of white powder solid...

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Abstract

The present invention relates to the field of pharmaceutical chemistry, to a preparation method of a new intermediate of 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidine-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (Ceritinib). According to the present invention, o-fluoronitrobenzene is adopted as a starting raw material, substitution, reduction and condensation are performed to obtain the new intermediate 2-X-5-chloro-N-(2-(isopropyl sulfide)phenyl)pyrimidine-4-amine (X is halogen, p-methyl benzene sulfonyloxy, methyl sulfonyloxy or trifluoromethylsulfonyloxy), the new intermediate can be oxidized to obtain a sulfonyl derivative, and the sulfonyl derivative and 2-isopropoxy-5-methyl-4-(piperidine-4-yl)aniline are subjected to condensation to finally obtain 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidine-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (Ceritinib); and the synthesis method has characteristics of readily available raw materials, high yield, mild reaction, simple operation and low production cost, and is suitable for industrial production.

Description

technical field [0001] The present invention relates to the pharmaceutical compound 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl) Phenyl)pyrimidine-2,4-diamine (ceritinib, LDK378) and key intermediate 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidine-4-amine method of preparation. [0002] The chemical name of ceritinib is: 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropyl (Sulphonyl)phenyl)pyrimidine-2,4-diamine, the chemical structure is as follows. [0003] Background technique [0004] Ceritinib (LDK378) is a small molecule ALK tyrosinase inhibitor originally developed by Novartis, and its trade name is Zykadia TM . In March 2013, the FDA granted it the status of "breakthrough drug" based on the results of its Phase I clinical trial. On April 29, 2014, it was approved for marketing by the FDA for the treatment of anaplastic lymphoma kinase (ALK)-positive patients treated with crizotinib. (C...

Claims

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Application Information

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IPC IPC(8): C07D239/42C07D401/12
Inventor 裴欣宇许全胜姜春阳谢军李惠
Owner SHANGHAI SCIENPHARM CO LTD
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