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Anti-cancer drug ceritinib intermediate 2-chlorine(bromine)-4-fluorine-5-nitrotoluene synthetic method

A technology of ceritinib and anticancer drugs, which is applied in the field of drug synthesis, can solve the problems of a large amount of wastewater and low yield, and achieve the effect of reducing the pressure of wastewater treatment

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

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved in the present invention is: in view of the problems in the existing technical scheme that a large amount of waste water is easily produced and the yield is low, an anticancer drug ceritinib intermediate 2- Synthetic method of chloro(bromo)-4-fluoro-5-nitrotoluene

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] Add concentrated sulfuric acid (723g) to the reaction flask, drop the ice-salt bath to 0°C, slowly add 2-chloro-4-fluorotoluene (144.6g, 1.0moL) dropwise, control the temperature at 0-10°C, and then add dropwise 65 % Concentrated nitric acid (97g, 1.0moL), after the dropwise addition, keep at 0-10°C for 1.0h, the central control 2-chloro-4-fluorotoluene disappears, the reaction is completed, extract with dichloromethane (650g*3), separate Concentrated sulfuric acid was removed, the organic layers were combined, washed with saturated sodium bicarbonate until neutral, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 163.1 g of crude 2-chloro-4-fluoro-5-nitrotoluene, yield 86.0 %, it can be directly used in the next reaction without further purification.

Embodiment 2

[0015] Into the reaction bottle, add the concentrated sulfuric acid recovered in Example 1, drop the ice-salt bath to 0°C, slowly add 2-chloro-4-fluorotoluene (144.6g, 1.0moL) dropwise, control the temperature at 0-10°C, and then 65% concentrated nitric acid (97g, 1.0moL) was added dropwise. After the addition was completed, the reaction was maintained at 0-10°C for 1.0h. The central control 2-chloro-4-fluorotoluene disappeared, and the reaction ended. Extract with dichloromethane (723g*3), separate concentrated sulfuric acid, combine organic layers, wash with saturated potassium bicarbonate until neutral, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 165.4g of 2-chloro-4- The crude product of fluoro-5-nitrotoluene, with a yield of 87.2%, was directly used in the next reaction without further purification.

Embodiment 3

[0017] Into the reaction bottle, add the concentrated sulfuric acid recovered in Example 2, drop the ice-salt bath to 0°C, slowly add 2-chloro-4-fluorotoluene (144.6g, 1.0moL) dropwise, control the temperature at 0-10°C, and then 65% concentrated nitric acid (97g, 1.0moL) was added dropwise. After the addition was completed, the reaction was maintained at 0-10°C for 1.0h. The central control 2-chloro-4-fluorotoluene disappeared, and the reaction ended. Extract with dichloromethane (868g*3), separate concentrated sulfuric acid, combine organic layers, wash with saturated sodium bicarbonate until neutral, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 170.6g 2-chloro-4- The crude product of fluoro-5-nitrotoluene, with a yield of 90%, was directly used in the next reaction without further purification.

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Abstract

The invention relates to the technical field of medicine synthesis, and especially relates to an anti-cancer drug ceritinib intermediate 2-chlorine(bromine)-4-fluorine-5-nitrotoluene synthetic method. The method takes concentrated sulfuric acid as a solvent and takes concentrated nitric acid as a nitrating agent, after the reaction is complete, ice water is not added for quenching, a solvent is directly used for extracting the product, an organic layer is washed to neutrality, then the material is condensed to the crude product, the residual concentrated sulfuric acid after extraction can be repeatedly used for three times, water volume used for quenching the concentrated sulfuric acid is reduced, generation of massive waste water due to processing of the concentrated sulfuric acid can be avoided, the method has the advantages of energy saving and environmental protection, waste water processing pressure is greatly reduced, crude yield can reach 85-90%, and the method is suitable for large-scale industrial production, and is further for popularization and application.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing an anticancer drug ceritinib intermediate 2-chloro(bromo)-4-fluoro-5-nitrotoluene. Background technique [0002] 2-Chloro-4-fluoro-5-nitrotoluene, CAS NO 112108-73-3; 2-bromo-4-fluoro-5-nitrotoluene, CAS NO64695-96-1, both are anticancer drugs Xerui The key intermediate of Tini, the structural formula is as follows: 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 For the treatment of patients with metastatic non-small cell lung cancer (NSCLC), the FDA has previously granted Zykadia Breakthrough Therapy Designation. Zykadia is an oral, selective anaplastic lymphoma kinase (ALK) inhibitor. In the clinical treatment of lung cancer, ALK is an im...

Claims

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Application Information

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IPC IPC(8): C07C201/08C07C205/12
CPCC07C201/08
Inventor 孙海波钱春国卞春亭冯亚兵
Owner 常州安迪沃克医药科技有限公司
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