Method for industrially producing EOC 317

A technology of methyl etherification and intermediates, applied in the field of pharmaceutical production, can solve the problems of long preparation time, high preparation cost, unsuitable production, etc., and achieve the effects of low production cost, short preparation cycle and safe production method

Inactive Publication Date: 2019-06-25
TAIZHOU EOC PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] However, in the existing preparation methods, toxic solvents are used, and the preparation time is long, the pr

Method used

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  • Method for industrially producing EOC 317
  • Method for industrially producing EOC 317
  • Method for industrially producing EOC 317

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0130] Example 1 Synthesis of EOC317

[0131] 1.1 Synthesis of Intermediate 3

[0132] Into the 5.0L glass reactor, add 2.0L dichloromethane, add 4-amino-5-(4-amino-3-fluorophenyl)pyrrole[1,2-f][1,2,4]triazine- Ethyl 6-carboxylate (250.0g, 0.79mol), the reaction system was cooled to 5-10°C under nitrogen protection, 2-fluoro-5-(trifluoromethyl)benzene isocyanate (324.1g, 1.58mol) was added dropwise ), the temperature was controlled below 15 °C during the dropping process, and the reaction system was heated to 25-30 °C after the dropping, and the reaction system gradually became a brown solution during the process, and after stirring for about 20min, a white solid was gradually precipitated in the system, and Gradually becoming viscous, HPLC monitoring to ethyl 4-amino-5-(4-amino-3-fluorophenyl)pyrro[1,2-f][1,2,4]triazine-6-carboxylate After the reaction was completed, 2.0 L of dimethyl sulfoxide was added to the reaction system, 350 mL of 2.1N hydrochloric acid was added, th...

Example Embodiment

[0152] Example 2 Synthesis of EOC317

[0153] 2.1 Synthesis of Intermediate 3

[0154] Add 2.0L of tetrahydrofuran to the 5.0L glass reactor, add 4-amino-5-(4-amino-3-fluorophenyl)pyrrole[1,2-f][1,2,4]triazine-6-carboxyl Ethyl acid (250.0g, 0.79mol), the reaction system was cooled to 5-10°C under nitrogen protection, 2-fluoro-5-(trifluoromethyl)benzene isocyanate (405.1g, 1.98mol) was added dropwise, During the addition, the temperature was controlled below 15°C. After the dripping, the reaction system was heated to 25-30°C. During this process, the reaction system gradually turned into a brown solution. After stirring for about 20 minutes, a white solid was gradually precipitated in the system, and gradually changed Viscous, HPLC monitoring showed that the reaction of ethyl 4-amino-5-(4-amino-3-fluorophenyl)pyrrole[1,2-f][1,2,4]triazine-6-carboxylate was completed, 2.0L of N,N-dimethylformamide was added to the reaction system, 350mL of 2.1N hydrochloric acid was added, the...

Example Embodiment

[0170] Example 3 Synthesis of EOC317

[0171] 3.1 Synthesis of Intermediate 3

[0172] Add 2.0L of tetrahydrofuran to the 5.0L glass reactor, add 4-amino-5-(4-amino-3-fluorophenyl)pyrrole[1,2-f][1,2,4]triazine-6- Ethyl carboxylate (250.0g, 0.79mol), the reaction system was cooled to 5-10°C under nitrogen protection, 2-fluoro-5-(trifluoromethyl)benzene isocyanate (453.7g, 2.21mol) was added dropwise, During the dropping process, the temperature was controlled below 15 °C. After the dropping, the reaction system was heated to 25-30 °C. During this process, the reaction system gradually turned into a brown solution. After stirring for about 20 minutes, a white solid gradually precipitated in the system, and gradually changed The viscosity of 4-amino-5-(4-amino-3-fluorophenyl) pyrrole[1,2-f][1,2,4]triazine-6-carboxylate ethyl ester was monitored by HPLC. , add 2.0L of dimethyl sulfoxide to the reaction system, add 350mL of 2.1N hydrochloric acid, heat the reaction system to 75-8...

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Abstract

The application relates to a method for preparing N-{4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-yl-methyl) pyrrolo [2,1-f] [1,2,4] triazine-5-yl]-2-fluorophenyl}-N'-[2-fluoro-5-(trifluoromethyl) phenyl] urea, and the method comprises the following steps: a) obtaining an intermediate 1, wherein the intermediate 1 is 1-(4-(4-amino-6-(methoxymethyl) pyrrole [1,2-f] [1,2,4] triazine-yl)-2-fluorophenyl)-3-(2-fluoro-5-(trifluoromethyl) phenyl) urea; and b) reacting the intermediate 1 with N-methylenemorpholin-N-chloride to obtain N-{4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-yl-methyl) pyrrolo [2,1-f] [1,2,4] triazine-5-yl]-2-fluorophenyl}-N'-[2-fluoro-5-(trifluoromethyl) phenyl] urea.

Description

technical field [0001] This application relates to the field of pharmaceutical production. Specifically, the application relates to a method for preparing N-{4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f] [1,2,4]Triazin-5-yl]-2-fluorophenyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea method. Background technique [0002] N-{4-[4-amino-6-(methoxymethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine -5-yl]-2-fluorophenyl}-N'-[2-fluoro-5-(trifluoromethyl)phenyl]urea (also known as EOC317) is a new type of kinase developed by Bayer in Germany Inhibitor oral preparations can target cancer cells through multiple mechanisms of action. EOC317 performed well in preclinical experiments and toxicity experiments, and has the potential to become the latest generation of targeted anticancer drugs. [0003] However, in the existing preparation methods, toxic solvents are used, and the preparation time is long, the preparation cost is high, and the yield is...

Claims

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Application Information

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IPC IPC(8): C07D487/04
Inventor 于洪瑞李合亭邹晓明
Owner TAIZHOU EOC PHARMA CO LTD
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