Method for preparing mozavaptan

A technology of formula and halogenated alkanes, which is applied in the field of preparation of mozavaptan, can solve the problems of low yield and achieve the effects of high reaction yield, simple post-treatment and short reaction time

Inactive Publication Date: 2009-11-04
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of the present invention is to overcome the problem of low yield in the existing mozavaptan synthesis method, to provide a silver salt that can be dissolved

Method used

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  • Method for preparing mozavaptan
  • Method for preparing mozavaptan
  • Method for preparing mozavaptan

Examples

Experimental program
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Embodiment 1

[0029] 1.9 g of 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzazepine (Formula 1) was dissolved with 3 g of 4-(o-methylbenzamido)-benzoyl chloride In 20 ml of dichloromethane, 5 ml of tetrahydrofuran solution in which 2.3 g of silver trifluoromethanesulfonate was dissolved was added dropwise at 0 to -5°C, and after the addition was complete, the reaction was carried out at room temperature for 30 minutes. Add 10 ml of saturated sodium bicarbonate solution and stir for 10 minutes, filter, wash the filter cake with a small amount of dichloromethane, combine the organic phases, wash twice with 10 ml of water, and dry overnight with 5 g of anhydrous sodium sulfate. After recovering the solvent, the solid was recrystallized from ethanol to obtain 3.4 g of mozavaptan, with a yield of 79.6%.

Embodiment 2

[0031] 1.9 g of 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzazepine (Formula 1) was dissolved with 3 g of 4-(o-methylbenzamido)-benzoyl chloride In 20 ml of 1,2-dichloroethane, 10 ml of dioxane solution in which 2.1 g of silver trifluoroacetate was dissolved was added dropwise at 0 to -5°C. After the addition was complete, the reaction was carried out at room temperature for 30 minutes. Add 10 ml of saturated potassium bicarbonate solution and stir for 10 minutes, filter, wash the filter cake with a small amount of 1,2-dichloroethane, combine the organic phases, wash twice with 10 ml of water, and dry overnight with 5 g of anhydrous sodium sulfate. After recovering the solvent, the solid was recrystallized from ethanol to obtain 3.3 g of mozavaptan, with a yield of 77.3%.

Embodiment 3

[0033] Dissolve 1.9 g of 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzazepine (Formula 1) and 1.6 g of p-nitrobenzoyl chloride in 20 ml of 1,2-dichloro In ethane, at 0~-5°C, 5 ml of tetrahydrofuran solution in which 2.3 g of silver trifluoromethanesulfonate was dissolved was added dropwise, and after the addition was completed, the reaction was carried out at room temperature for 30 minutes. Add 10 ml of saturated sodium bicarbonate solution and stir for 10 minutes, filter, wash the filter cake with a small amount of dichloromethane, combine the organic phases, wash twice with 10 ml of water, and dry overnight with 5 g of anhydrous sodium sulfate. After recovering the solvent, the solid was recrystallized from ethanol to obtain 2.7 g of formula II, which was reduced in 30 ml of absolute ethanol with 0.2 g of 5% palladium carbon hydrogenation under normal pressure. After recovering the solvent, dissolve it in 20ml of dichloromethane, add 1.3 grams of o-toluyl chloride, and add dro...

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Abstract

The invention discloses a method for preparing mozavaptan, which comprises the following steps: dissolving reactants of 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzodiazepine and 4-(ortho-methyl-benzamido) benzoyl chloride in an alkylogen solvent; adding an anhydrous aprotic solvent dissolved with a silver salt to the mixture; and reacting the mixture at a temperature of between 10 and 30 DEG C. The invention also discloses another method which comprises the following steps: reacting the 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzodiazepine with paranitrobenzoyl chloride under the action of a soluble silver salt; and after deoxidizing nitro groups, reacting the mixture with ortho-methyl benzoyl chloride under the action of the soluble silver salt. The methods have short reaction time without column chromatography purification on a product, the product can be purified through recrystallization after the solvent is reclaimed, the post-treatment is simple, the reaction yield is high, and the yield after the recrystallization can reach more than 70 percent.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of mozavaptan. Background technique [0002] Mozavaptan is a non-peptide V2 receptor antagonist, which is mainly used for the rare disease of hyponatremia in the syndrome of insufficient secretion of antidiuretic hormone associated with malignant tumors. There are two main methods for the preparation of mozavaptan. [0003] Method 1: 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzazepine is added dropwise to 4-(o-methylbenzamido)benzoyl chloride solution in a solvent, Catalyzed by base (potassium carbonate, sodium carbonate, triethylamine, etc.), mozavaptan is obtained. [0004] [0005] Method 2: 5-dimethylamino-2,3,4,5-tetrahydro-1H-benzazepine is catalyzed with 4-nitrobenzoyl chloride in a solvent using a base (triethylamine, pyridine, etc.) The amide is generated, and the nitro group is reduced by palladium-carbon hydrogenation, and mozavap...

Claims

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Application Information

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IPC IPC(8): C07D223/16
Inventor 吴永平徐群杰卢定强
Owner NANJING UNIV OF TECH
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