Method for preparing tolvaptan intermediate

A technology of tolvaptan and intermediates, which is applied in the field of drug synthesis and can solve problems such as difficult industrial production, difficulty in industrial production, and difficult amidation

Active Publication Date: 2010-09-01
天津泰普制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] In method A, because the high-purity general formula (3) could not be obtained before, there is no embodiment of the specific compound listed in the patent, but it is only a summary of the general method of this type of compound, specific to the compound general formula (3), general formula (2 ), the inventor has done relevant research according to the method disclosed in the literature, and the test results confirm that: the conversion rate of the active ester method has only about 3%, and the raw material cost is higher; the conversion rate of

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  • Method for preparing tolvaptan intermediate
  • Method for preparing tolvaptan intermediate
  • Method for preparing tolvaptan intermediate

Examples

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Embodiment 1

[0026] Add 6.4g (0.0238mol) of the general formula (3) into a 100ml four-necked bottle, add 60ml tetrahydrofuran, stir, and it becomes a cloudy liquid, add 1 drop of DMF, raise the temperature to 40°C and start adding 3.4g (0.0286mol) of thionyl chloride dropwise ), dropped in about 10 minutes, kept at 40°C, and reacted for 4 hours (TLC tracking, until the raw material point disappeared), evaporated the solvent under reduced pressure to obtain a brownish yellow oil; dissolved in 40ml of dichloromethane for subsequent use;

[0027] In a 250ml reaction flask, add 3.9g (0.02mol) of the compound of general formula (2) and add 80ml of dichloromethane to stir and dissolve, then add 2.8g (0.036mol) of pyridine, add dropwise the dichloromethane solution of the yellow oil, and control The temperature is below 0°C, the dropwise addition is completed, at 25°C, stir for 4 hours, stop stirring, pour the reaction solution into 120ml of ice water, add dilute hydrochloric acid under stirring, ...

Embodiment 2

[0030] Add 6.4 g (0.0238 mol) of general formula (3) into 40 ml of thionyl chloride and stir, raise the temperature and keep at 80 ° C, the reaction solids dissolve, react for 4 hours, evaporate the solvent under reduced pressure, and use 20 ml of toluene to remove the residual dichloride. Chlorothionyl, to obtain a brownish-yellow oil; dissolved in 40ml of dichloromethane for subsequent use;

[0031] In a 250ml reaction flask, add 3.9g (0.02mol) of the compound of general formula (2), add 80ml of dichloromethane and stir to dissolve, then add 2.8g (0.036mol) of n-butylamine, and add dropwise the dichloromethane solution of the yellow oil , control the temperature below 0°C, the dropwise addition is completed, 25°C, stir for 4 hours, stop stirring, pour the reaction solution into 120ml of ice water, add dilute hydrochloric acid while stirring, adjust the pH to 2, separate the organic layer and the water layer Extract with 50ml of chloroform, combine the organic layers, wash tw...

Embodiment 3

[0033] Add 6.4 g (0.0238 mol) of the general formula (3) into 160 ml of thionyl chloride, keep the room temperature at 60 ° C, react for 24 hours, evaporate the solvent under reduced pressure, and use 20 ml of toluene to remove the residual thionyl chloride to obtain brown Yellow oil; dissolved in 40ml of dichloromethane for later use;

[0034]In a 250ml reaction flask, add 3.9g (0.02mol) of the compound of general formula (2), add 80ml of chloroform, ethyl acetate and stir to dissolve, then add 2.8g (0.036mol) of 1,8-diazacyclo[5,4 , 0] Undecene-7, add dropwise the dichloromethane solution of the yellow oil, control the temperature below 0°C, the dropwise addition is completed, 25°C, stir and react for 6 hours, stop stirring, pour the reaction solution into 120ml of ice water, Add dilute hydrochloric acid under stirring, adjust the pH value to 2, separate the organic layer, extract the aqueous layer with 50ml ethyl acetate, combine the organic layer, wash twice with 100ml wat...

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Abstract

The invention provides a method for preparing tolvaptan intermediate 7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)-benzoyl]2,3,4,5-tetrahydro-1H-1-benzazepine-5-ketone, which comprises the following steps of: reacting a general formula (3) with thionyl chloride to form acetyl chloride solution; and then performing amidation reaction on a general formula (2) and the acetyl chloride solution in an organic solvent in the presence of de-acidifying agent, and treating the reaction product to obtain the tolvaptan intermediate shown in a general formula (1). The tolvaptan intermediate prepared by adopting the method of the invention has the characteristics of low cost, little impurity and high yield, and is more suitable for large-scale industrialized production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a preparation method of a tolvaptan intermediate for treating hyponatremia caused by congestive heart failure, liver cirrhosis and antidiuretic hormone deficiency syndrome. More specifically the tolvaptan intermediate 7-chloro-1-[2-methyl-4-(2-methylbenzamido)-benzoyl]-2,3,4,5-tetra Preparation method of hydrogen-1H-1-benzazepin-5-one. Background technique [0002] Tolvaptan (trade name of Tolvaptan: Samsca) is a non-peptide AVP2 receptor antagonist developed by Otsuka Corporation. It is mainly used for the treatment of hypervolemic or isovolemic hyponatremia with heart failure, liver cirrhosis, and syndrome of abnormal antidiuretic hormone secretion. Studies have found that when the concentration of sodium ions in plasma decreases, in order to maintain the balance of sodium ions inside and outside the cells, extracellular fluid will enter the cells, so that the cells will...

Claims

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Application Information

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IPC IPC(8): C07D223/16
Inventor 陈华赵健陈涛
Owner 天津泰普制药有限公司
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