Preparation method of tetrahydronaphthalene benzamide key intermediate

A technology of tetralin and intermediates, applied in the field of medicine, can solve the problems of long reaction time, complicated operation, low yield and the like, and achieve the effects of reducing by-products, shortening the reaction time, and improving time efficiency

Pending Publication Date: 2022-03-01
LIAONING UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

According to the above two patents, it is desired to obtain N-(3-iodo-4-methylphenyl)-5-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene -2-Carboxamide needs to go through two-step experiments, and the yield is low, the operation is cumbersome, and the reaction time is long. Therefore, it is necessary to simplify the experimental operation process, and there is an urgent need for a preparation method that is easy to operate and has a high recovery rate.

Method used

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  • Preparation method of tetrahydronaphthalene benzamide key intermediate
  • Preparation method of tetrahydronaphthalene benzamide key intermediate
  • Preparation method of tetrahydronaphthalene benzamide key intermediate

Examples

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Effect test

Embodiment 1

[0033] Add 5-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (1g, 3mmol) into the reaction vessel, add 10mL of toluene to dissolve , control the temperature at 20°C, add 3-iodo-4-methylaniline (0.806g, 3.3mmol), and stir to dissolve. The resulting reaction system was evacuated, under nitrogen protection, and under stirring at room temperature, trimethylaluminum toluene solution (2.1ml, 2mol / L) was slowly added dropwise. After the addition was complete, the reaction system was heated to 100°C, reacted for 3h, and cooled to room temperature. Add 10 mL of water and 10 mL of dichloromethane to the resulting reaction mixture for extraction, separate the organic phase, wash with 5% aqueous potassium sodium tartrate solution twice, wash with water three times, wash with saturated brine once, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure and filter with suction to obtain 1.58 g of a white solid with a yield of 93.3% and...

Embodiment 2

[0037] Add 5-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (1g, 3mmol) into the reaction vessel, add 10mL of toluene to dissolve , control the temperature at 20°C, add 3-iodo-4-methylaniline (0.806g, 3.3mmol), and stir to dissolve. The resulting reaction system was evacuated, under nitrogen protection, and under stirring at room temperature, trimethylaluminum toluene solution (2.1ml, 2mol / L) was slowly added dropwise. After the addition was complete, the reaction system was heated to 90°C, reacted for 3h, and cooled to room temperature. Add 10 mL of water and 10 mL of dichloromethane to the resulting reaction mixture for extraction, separate the organic phase, wash with 5% aqueous potassium sodium tartrate solution twice, wash with water three times, wash with saturated brine once, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure and filter with suction to obtain 1.52 g of a white solid with a yield of 90.2% and ...

Embodiment 3

[0039]Add 5-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (1g, 3mmol) into the reaction vessel, add 10mL of toluene to dissolve , control the temperature at 20°C, add 3-iodo-4-methyl-aniline (0.806g, 3.3mmol), and stir to dissolve. The resulting reaction system was evacuated, under nitrogen protection, and under normal temperature stirring, trimethylaluminum toluene solution (2.1ml, 2mol / L) was slowly added dropwise. After the dropwise addition, the reaction system was heated to 80°C, reacted for 3h, and cooled to room temperature. 10 mL of water and 10 mL of dichloromethane were added to the resulting reaction mixture for extraction, the organic phase was separated and washed twice with 5% potassium sodium tartrate aqueous solution, three times with water, once with saturated brine, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure and filter with suction to obtain 1.34 g of a white solid with a yield of 79.2% ...

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Abstract

The invention discloses a preparation method of a tetrahydronaphthalene benzamide key intermediate. The preparation method comprises the following steps: adding a compound a into a reaction container, adding a reaction solvent for dissolving, and adding 3-iodine-4-methylaniline while controlling the temperature at 5-45 DEG C; vacuumizing the obtained reaction system, introducing nitrogen for protection, controlling the temperature at 15-25 DEG C, slowly dropwise adding a catalyst, heating the reaction system to 80-110 DEG C after dropwise adding, and reacting for 3-4 hours to obtain a reaction mixture; and adding an extraction system into the obtained reaction mixture for extraction, separating and taking an organic phase, washing, drying and evaporating or concentrating and crystallizing to obtain the tetrahydronaphthalene benzamide key intermediate. According to the method disclosed by the invention, the reaction time is greatly shortened, the yield is improved, the use of a catalyst is reduced, byproducts in the reaction are reduced, and the cost is greatly saved.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of a key intermediate for synthesizing novel substituted benzamide compounds that inhibit tumor cell growth and exert antitumor effects. Background technique [0002] Chinese patent CN102295635A discloses the synthesis of 5-(4-methylpiperazine-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester as raw material The method of oxazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid, the reaction steps are as follows: 5-(4-methylpiperazin-1-yl)-5,6 , Dissolve methyl 7,8-tetrahydronaphthalene-2-carboxylate in methanol and tetrahydrofuran solution, add 2N sodium hydroxide solution, react at room temperature for 16 hours, adjust pH to 4 with 2N hydrochloric acid aqueous solution, spin under reduced pressure Remove the organic solvent, add ethyl acetate and wash with saturated brine, dry filter, evaporate to dryness, and separate the product b...

Claims

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Application Information

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IPC IPC(8): C07D295/155
CPCC07D295/155
Inventor 陈烨刘举丁实胡思雨史建涛魏浩张亚东
Owner LIAONING UNIVERSITY
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