Synthesis of 2-methyl-6-(4-methylbenzenesulfonyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine*

A technology of methylbenzenesulfonyl and tetrahydroimidazole, applied in the field of pharmaceutical compound preparation, can solve the problems of difficult to repeat and achieve, harsh reaction conditions, long reaction time, etc., and achieves improved product purity, short reaction time, and reaction yield. rate increase effect

Active Publication Date: 2018-11-02
科贝源(北京)生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The inventor repeated the preparation method strictly according to this document, and limited the reaction conditions and reaction time to 3 hours. As a result, it was found that although the raw materials were completely reacted, the product was very complicated, resulting in an actual yield of only 17%, and a product purity of 98.5%.
Even if there are experimental differences, it also shows from another aspect that the reaction conditions of this document are very harsh, it is difficult to repeat in industrial production and achieve the yield declared by this document, and the heating temperature in this reaction is still too high, and the reaction time is longer

Method used

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  • Synthesis of 2-methyl-6-(4-methylbenzenesulfonyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine*
  • Synthesis of 2-methyl-6-(4-methylbenzenesulfonyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine*
  • Synthesis of 2-methyl-6-(4-methylbenzenesulfonyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine*

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Add the compound of formula I (100 g, 0.25 mol), toluene (3.6 L), and water (1 L) into a 5 L three-necked flask, and stir at room temperature for 2 h. Separate the liquid, add the organic phase into a 5L three-neck flask, heat and stir, T 内 =80°C, add acetamidine hydrochloride (120g, 1.27mol), water (24.6g, 1.37mol), cesium carbonate (520.6g, 1.6mol) in sequence, after the addition, heat up to 85-94°C for 1 hour, TLC detects that the reaction is complete (Developer: dichloromethane / methanol=10 / 1).

[0048] Stop heating, cool down, T 内 =25°C, add 1L methanol, 2L water, 300g concentrated hydrochloric acid, stir, separate the liquid, extract the organic phase with concentrated hydrochloric acid (150g) and water (1L), combine the water phase, adjust the pH of the water phase to 8-9 with sodium carbonate, and use Extract with ethyl acetate (1L×2), combine the organic phases, wash with water (800ml×2) and saturated NaCl (500ml×2) successively, dry over anhydrous sodium sulf...

Embodiment 2

[0050] Add the compound of formula I (100 g, 0.25 mol), chloroform (3.6 L), and water (1 L) into a 5 L three-neck flask, and stir at room temperature for 2 h. Separate the liquid, add the organic phase into a 5L three-neck flask, heat and stir, T 内 =81°C, add acetamidine hydrochloride (120g, 1.27mol), water (24.6g, 1.37mol), cesium carbonate (520.6g, 1.6mol) in turn, after adding, heat up to 85-94°C for 1 hour, TLC detects that the reaction is complete (Developer: dichloromethane / methanol=10 / 1).

[0051] Aftertreatment process is identical with embodiment 1, namely, stop heating, cooling, T 内 =25°C, add 1L methanol, 2L water, 300g concentrated hydrochloric acid, stir, separate the liquid, extract the organic phase with concentrated hydrochloric acid (150g) and water (1L), combine the water phase, adjust the pH of the water phase to 8-9 with sodium carbonate, and use Extract with ethyl acetate (1L×2), combine the organic phases, wash with water (800ml×2) and saturated NaCl (5...

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Abstract

The invention provides a synthetic method of 2-methyl-6-(4-methylphenyl)sulfonyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine. According to the invention, compound 4-bromo-1-[(4-methylphenyl) sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepine-5-one represented by formula I is reacted with acetamidine hydrochloride in the presence of cesium carbonate in a reaction solvent. The synthetic method comprises following advantages compared with the prior art, reaction temperature is lower, reaction time is shorter, and finished product yield and purity are both increased to certain degrees.

Description

technical field [0001] The present invention relates to 2-methyl-6-(4-methylbenzenesulfonyl)-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine The synthesis method belongs to the field of pharmaceutical compound preparation. Background technique [0002] Conivaptanhydrochkoride is a non-peptide dual inhibitor of arginine vasopressin (AVP) V1a and V2 receptors. Treatment of inpatients with diuretic hormone syndrome, hypothyroidism, adrenal hypofunction, or pulmonary disease). The injection of this drug was obtained on December 29, 2005 by the U.S. Food and Drug Administration (FDA) for approval to go on the market. The trade name is Vaprisol, which is produced by Astellas Pharma. The structural formula of Conivaptanhydrochkoride is as follows: [0003] [0004] The reported synthetic routes of conivaptan hydrochloride mainly contain two types: [0005] The first type of synthetic route is represented by the synthetic route reported in Chinese patent CN94192831.4. [000...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 郑祖爽梁飞吴坤君祝晓燕
Owner 科贝源(北京)生物医药科技有限公司
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