Anti-cancer drug ceritinib intermediate 1-amino-2-(isopropyl sulfonyl)benzene synthetic method

A technology of isopropylsulfonyl and ceritinib, applied in chemical instruments and methods, preparation of organic compounds, preparation of sulfides, etc., can solve the problems of cumbersome operation and high energy consumption, and achieve the improvement of reaction rate and energy consumption. Low, simple synthesis method

Inactive Publication Date: 2016-11-09
常州安迪沃克医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The technical problem to be solved by the present invention is: in view of the problems of high energy consumption and cumbersome operation of the existing technical solutions, it is necessary to provide a pure product obtained through iron powder reduction, salification, low-temperature oxidation, re-salification, and dissociation. The synthetic method of 1-amino-2-(isopropylsulfonyl)benzene with low energy consumption and higher production capacity

Method used

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  • Anti-cancer drug ceritinib intermediate 1-amino-2-(isopropyl sulfonyl)benzene synthetic method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] In the reaction bottle that is equipped with liquid caustic soda tail gas absorption device, add DMF (423.3g), 60% sodium hydride (44g, 1.1moL), o-fluoronitrobenzene (141.1g, 1.0moL), ice-salt bath drops to 0 Below ℃, add isopropyl mercaptan (91.4g, 1.2moL) dropwise, after the dropwise addition is completed, return to 25℃ and react for 2.0-3.0h, the central control o-fluoronitrobenzene disappears, and the reaction is completed, and the reaction solution is slowly poured into ice Water (1.41kg), extracted with toluene (280ml*3), organic solvent, washed with water and layered, dried and concentrated to obtain 209g of crude compound B, yield 105.9%, HPLC area normalization method 98.3%.

Embodiment 2

[0021] Add DMF (564.4g), 60% sodium hydride (48g, 1.2moL) and o-fluoronitrobenzene (141.1g, 1.0moL) to the reaction flask equipped with liquid caustic soda tail gas absorption device, and the ice-salt bath is reduced to 0 Below ℃, add isopropyl mercaptan (99g, 1.3moL) dropwise, return to 25℃ and react for 2.0~3.0h, the central control o-fluoronitrobenzene disappears, and the reaction is completed, slowly pour the reaction solution into ice water (1.41kg), extracted with ethyl acetate (280ml*3), organic solvent, washed with water and layered, dried and concentrated to obtain 212g of crude compound B, yield 107.4%, HPLC area normalization method 98.5%.

Embodiment 3

[0023] In the reaction bottle that is equipped with liquid caustic soda tail gas absorption device, add DMF (564.4g), 60% sodium hydride (60g, 1.5moL), o-fluoronitrobenzene (141.1g, 1.0moL), ice-salt bath drops to 0 Below ℃, add isopropyl mercaptan (114.2g, 1.5moL) dropwise. After the dropwise addition is completed, return to 25℃ and react for 2.0~3.0h. Water (1.41kg), extracted with dichloromethane (280ml*3), organic solvent, washed with water to separate layers, dried and concentrated to obtain 210g of crude compound B, yield 106.4%, HPLC area normalization method 98.3%.

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Abstract

The invention belongs to the technical field of medicine synthesis, and especially relates to a synthetic method of an anti-cancer drug ceritinib intermediate 1-amino-2-(isopropyl sulfonyl)benzene. The synthetic method comprises the following steps: employing o-fluoronitrobenzene, sodium hydride and isopropyl mercaptan to synthesize a 2-(isopropyl sulfide) nitrobenzene crude product, then directly reducing the crude product to iron powder, forming salt to obtain the 2-(isopropyl sulfide) aniline hydrochloride, and finally dropping hydrogen peroxide for oxidation in 2-(isopropyl sulfide) aniline hydrochloride for oxidation, forming salt, and dissociating to obtain a target product. The synthetic method has the advantages of simpleness, little sewage amount, low energy consumption, low production cost, and the product has the advantages of high purity, high yield, and easy industrial production, and is suitable for further popularization and application.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to a method for synthesizing an anticancer drug ceritinib intermediate 1-amino-2-(isopropylsulfonyl)benzene. Background technique [0002] 1-Amino-2-(isopropylsulfonyl)benzene, CAS.76697-50-2, is a key intermediate of anticancer drug ceritinib, and its structural formula is: Novartis (Novartis) announced on April 29, 2014 that the anticancer drug Zykadia (ceritinib) was approved by the FDA for anaplastic lymphoma kinase-positive (ALK+) who have progressed after treatment with Xalkori (crizotinib) or are intolerant to Xalkori Treatment of patients with metastatic non-small cell lung cancer (NSCLC). Previously, the FDA had granted Breakthrough Therapy Designation to Zykadia, an oral, selective anaplastic lymphoma kinase (ALK) inhibitor. In the clinical treatment of lung cancer, ALK is an important therapeutic target. The ALK gene can fuse with other genes to express an abno...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C317/36C07C315/02
CPCC07C315/02C07C319/14C07C319/20
Inventor 钱春国孙海波卞春亭冯亚兵
Owner 常州安迪沃克医药科技有限公司
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