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A ceritinib preparing method

A technology of ceritinib and isopropoxy, which is applied in the field of synthesis of organic compounds, achieves the effects of easy availability of raw materials, low cost, low synthetic route, mild reaction conditions and easy control

Active Publication Date: 2017-04-19
常州市勇毅生物药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to solve the problem of ceritinib synthesis in the prior art, and provide a method for preparing ceritinib that is more suitable for industrial production, has lower cost and is easier to operate

Method used

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Experimental program
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Effect test

Embodiment 1

[0020] The first step: put 4-bromo-2-isopropoxy-5-methylaniline (56G, ​​231.1mmol) into the 1000ml reaction flask, add in 200ml glacial acetic acid at room temperature, start stirring, add dropwise acetic anhydride ( 26.2ml, 277mmol), then heated to reflux for 30min, cooled to room temperature, poured into 500ml of ice water, stirred for 10min, filtered with suction, washed with water, and dried to obtain N-(4-bromo-2-isopropoxy-5-toluene base) acetamide 62.7 g (95% yield).

[0021] Step 2: Add 4-piperidone (99.13g, 1mol), potassium carbonate (138g, 1mol), DMF 500ml in turn into a 2000ml reaction flask, start stirring, stir at room temperature for 30min, dropwise add chlorobenzene (112g, 1mol ), after the dropwise addition, heat to 80° and keep warm for 5H, then cool down to room temperature, add 1000ml of water, stir for 30min, extract with 800ml*3 ethyl acetate, wash the ethyl acetate layer twice with 300ml brine, add anhydrous sulfuric acid It was dried over sodium and con...

Embodiment 2

[0027] The first step: put 4-bromo-2-isopropoxy-5-methylaniline (56G, ​​231.1mmol) into the 1000ml reaction flask, add in 200ml glacial acetic acid at room temperature, start stirring, add dropwise acetic anhydride ( 26.2ml, 277mmol), then heated to reflux for 45min, cooled to room temperature, poured into 500ml ice water, stirred for 10min, filtered with suction, washed with water, and dried to obtain N-(4-bromo-2-isopropoxy-5-toluene base) acetamide 62.7 g (95% yield).

[0028] Step 2: Add 4-piperidone (99.13g, 1mol), potassium carbonate (138g, 1mol), DMF 500ml in turn into a 2000ml reaction flask, start stirring, stir at room temperature for 30min, dropwise add chlorobenzene (112g, 1mol ), after the dropwise addition, heat to 80° and keep warm for 6H, then cool down to room temperature, add 1000ml of water, stir for 60min, extract with 800ml*3 ethyl acetate, wash the ethyl acetate layer twice with 300ml brine, add anhydrous sulfuric acid It was dried over sodium and concen...

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Abstract

The invention relates to a ceritinib preparing method. The method includes (1) reacting 4-bromo-2-isopropoxy-5-methylaniline and acetic anhydride to generate N-(4-bromo-2-isopropoxy-5-cresyl) acetamide, (2) reacting 4-piperidone to generate N-benzyl-4-piperidone, (3) subjecting the N-(4-bromo-2-isopropoxy-5-cresyl) acetamide and the N-benzyl-4-piperidone to a docking reaction, (4) subjecting a product of the former step to dehydroxylation and (5) generating a finally product that is ceritinib from N-(4-(1-phenyl-1,2,3,6-tetrahydropyridin-4-yl)-2-isopropoxy-5-cresyl) acetamide under the existence of a catalyst. The novel ceritinib preparing method is provided. The synthesis route is low in cost, reaction conditions are mild and easy to control, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing organic compounds, in particular to a method for preparing ceritinib. Background technique [0002] Ceritinib is an anticancer drug approved by the FDA on April 29, 2014. Ceritinib is an ALK inhibitor (Anaplastic Lymphoma Kinase), indicated for the treatment of patients with anaplastic lymphoma kinase-positive (ALK+) metastatic non-small cell lung cancer (NSCLC) who have progressed after crizotinib treatment or who are intolerant to crizotinib. The trade name is Zykadia, developed by Novartis Pharmaceuticals. [0003] The synthesis of ceritinib uses the convergence method, first synthesizing two fragments with similar molecular weights, and then splicing the two fragments (JMC, 2013, 5675). The first fragment starts from compound 1, after nitration by SNAr reaction with isopropanol to give 2, 2 and 3 PtO after Suzuki coupling 2 Fragment 4 was obtained by catalytic hydrogenation to reduce the nitro g...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/26C07D401/12
CPCC07D211/26C07D401/12
Inventor 潘勇夏晓丽
Owner 常州市勇毅生物药业有限公司
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