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Preparation method of N-(3-chlorine-4-(2-pyridine methoxy)phenyl)-2-cyanoacetamide

A technology of cyanoacetamide and pyridylmethoxyl, which is applied in the field of preparation of N-phenyl)-2-cyanoacetamide, can solve the problems of potential safety hazards, unsuitability for safe production, low yield, etc., and achieve easy Large-scale production, high product yield and simple steps

Active Publication Date: 2018-05-29
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses palladium carbon hydrogenation reduction in the synthesis, and there are certain safety hazards in actual production. The last step of reaction is carried out at a high temperature of 160-180 ° C, which is not only not suitable for safe production, but also has certain special requirements for equipment, and The total yield of the three-step reaction is about 50%, and the yield is relatively low

Method used

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  • Preparation method of N-(3-chlorine-4-(2-pyridine methoxy)phenyl)-2-cyanoacetamide
  • Preparation method of N-(3-chlorine-4-(2-pyridine methoxy)phenyl)-2-cyanoacetamide
  • Preparation method of N-(3-chlorine-4-(2-pyridine methoxy)phenyl)-2-cyanoacetamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] 1) Synthesis of N-(3-chloro-4-fluorophenyl)-2-cyanoacetamide

[0032] Add 14.6g of 3-chloro-4-fluoroaniline and 10.2g of cyanoacetic acid to 90ml of DMF, stir to dissolve, then add 12.1g of triethylamine, 1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride 25.9g and 1-hydroxybenzotriazole 15.5g, heated to 55°C, stirred for reaction, after the reaction was completed (TLC, dichloromethane: ethyl acetate 1:1), cooled to room temperature, Add 720ml of water, 200ml of dichloromethane to extract, leave the organic layer, add 200ml of water to wash the organic layer, dry the organic layer with anhydrous magnesium sulfate, filter the desiccant, and evaporate the organic layer under reduced pressure to obtain solid N-(3-chloro- 4-fluorophenyl)-2-cyanoacetamide 19.2g, the yield was 90.6%.

[0033] 2) Synthesis of N-(3-chloro-4-(2-pyridinemethoxy)phenyl)-2-cyanoacetamide

[0034] Add 10.5g of 2-pyridinemethanol and 2.8g of lithium hydroxide to 50ml of acetonitrile, add 19.2g...

Embodiment 2

[0036] 1) Synthesis of N-(3-chloro-4-fluorophenyl)-2-cyanoacetamide

[0037] Add 14.6g of 3-chloro-4-fluoroaniline and 10.2g of cyanoacetic acid to DMF 100ml, stir to dissolve, then add 12.3g of triethylamine, 1-(3-dimethylaminopropyl)-3-ethyl carbon 26.2g of diimine hydrochloride and 15.8g of 1-hydroxybenzotriazole, heated to 52°C, stirred for reaction, after the reaction was completed (TLC, dichloromethane: ethyl acetate 1:1), cooled to room temperature, Add 700ml of water and 200ml of dichloromethane for extraction, leave the organic layer, add 200ml of water to wash the organic layer, dry the organic layer with anhydrous magnesium sulfate, filter the desiccant, and evaporate the organic layer under reduced pressure to obtain solid N-(3-chloro- 4-fluorophenyl)-2-cyanoacetamide 19.2g, the yield was 90.6%.

[0038] 2) Synthesis of N-(3-chloro-4-(2-pyridinemethoxy)phenyl)-2-cyanoacetamide

[0039] Add 10.8 g of 2-pyridine methanol and 2.5 g of lithium hydroxide to 60 ml of acetonit...

Embodiment 3

[0041] 1) Synthesis of N-(3-chloro-4-fluorophenyl)-2-cyanoacetamide

[0042] Add 14.6g of 3-chloro-4-fluoroaniline and 10.2g of cyanoacetic acid to 90ml of DMF, stir to dissolve, then add 12.0g of triethylamine, 1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride 25.5g and 1-hydroxybenzotriazole 15.2g, heated to 55°C, stirred for reaction, after the reaction was completed (TLC, dichloromethane: ethyl acetate 1:1), cooled to room temperature, Add 700ml of water and 200ml of dichloromethane for extraction, leave the organic layer, add 200ml of water to wash the organic layer, dry the organic layer with anhydrous magnesium sulfate, filter the desiccant, and evaporate the organic layer under reduced pressure to obtain solid N-(3-chloro- 4-fluorophenyl)-2-cyanoacetamide 19.0 g, yield 89.6%.

[0043] 2) Synthesis of N-(3-chloro-4-(2-pyridinemethoxy)phenyl)-2-cyanoacetamide

[0044] Add 10.5 g of 2-pyridine methanol and 2.5 g of lithium hydroxide to 50 ml of acetonitrile, add 1...

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Abstract

The invention discloses a preparation method of N-(3-chlorine-4-(2-pyridine methoxy)phenyl)-2-cyanoacetamide. The method comprises the following steps: under the existence of 1-(3-dimethylaminopropyl)-3-ethylenediamine hydrochloride, 1-hydroxybenzotriazole and triethylamine, carrying out a reaction of 3-chlorine-4-fluoroaniline and cyanoacetic acid to generate N-(3-chlorine-4-fluorophenyl)-2-cyanoacetamide; under the existence of lithium hydroxide, continuously carrying out a reaction with 2-pyridylcarbinol to generate the N-(3-chlorine-4-(2-pyridine methoxy)phenyl)-2-cyanoacetamide. The method is simple in step, mild in reaction condition, high in product yield and easy in mass production. (The formula is shown in the description).

Description

Technical field [0001] The invention relates to a preparation method of N-(3-chloro-4-(2-pyridinemethoxy)phenyl)-2-cyanoacetamide, which belongs to the technical field of organic synthesis. Background technique [0002] With the continuous research on cancer, cancer-causing drugs are constantly innovating. WO2006127205 describes that receptor tyrosine kinase inhibitors have potential therapeutic value and can be used to treat cancer and other diseases characterized by uncontrolled or abnormal cell growth. Many studies have now been carried out to develop specific receptor tyrosine kinase inhibitors as possible anticancer therapeutic agents. [0003] Nonatinib, a surface growth factor tyrosine kinase inhibitor, patent CN102718749 describes its synthesis method, and the synthesis route is shown below. [0004] [0005] Lenatinib, an irreversible ErbB receptor tyrosine kinase inhibitor, patent CN103788067 introduces the synthesis method of lenatinib intermediates. The synthetic route ...

Claims

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Application Information

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IPC IPC(8): C07D213/30
CPCC07D213/30
Inventor 杨铎张杰
Owner SHANDONG BOYUAN PHARM CO LTD
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