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Method for preparing intermediate 2-carboxylic acid-5-(2-methyl-benzoylamino)toluene for tolvaptan

A technology of methyl benzamido and tolvaptan, which is applied in the field of drug synthesis, can solve the problems of high cost, inconvenient industrial production, difficult recovery of precious metal reagents, etc., and achieve the effect of reducing the treatment of three wastes and reducing production costs

Inactive Publication Date: 2013-06-19
TIANJIN TAIPU PHARMA SCI & TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In this method, the method of carbon monoxide insertion is adopted. Although the method is simple, precious metal reagents such as palladium reagent and cesium acetate are used, which leads to high cost of this step, and the precious metal reagents are not easy to recycle in the treatment of three wastes. These are all for industrial production. brought some inconvenience

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Preparation of 2-formic acid-5-(2-methylbenzamido)toluene

[0016] Add 50g (0.16mol) of 2-bromo-5-(2-methylbenzamido)toluene and 200ml tetrahydrofuran into a 1L reaction flask, cool down to -78°C with acetone / dry ice system, and control the temperature -78~- Add 200ml of n-butyllithium hexane solution (1M / L) dropwise at 70°C for about 3 hours, then control the temperature at -78~-70°C for 1 hour, add about 20g of dry ice in portions, and slowly Raise the temperature to 0°C, pour the reaction solution into 200ml of water, separate the layers, and extract twice with 100ml of toluene; the aqueous layer is acidified with dilute hydrochloric acid solution, and the pH value is adjusted to 3-4, a large amount of solids are formed, filtered, and washed with normal water to obtain 41 g of the solid was refined with methanol / water and dried in vacuo to obtain 35 g of off-white solid, HPLC 98.2%, yield 79.2%, melting point 230-232°C.

[0017] 1 H NMR (400MHz, DMSO-de): δ = 2.39 ...

Embodiment 2

[0019] Preparation of 2-formic acid-5-(2-methylbenzamido)toluene

[0020] Add 5g (0.016mol) of 2-bromo-5-(2-methylbenzamido)toluene and 20ml of anhydrous ether into a 100ml reaction flask, cool down to -78°C with acetone / dry ice system, and control the temperature to -78°C Add 20ml of n-butyllithium hexane solution (1M / L) dropwise at ~-70°C for about 2 hours, then control the temperature at -78~-70°C for 1 hour, add about 2g of dry ice, and slow down for 1 hour Raise the temperature to 0°C, pour the reaction solution into 20ml of water, extract the layers twice with 20ml of toluene; acidify the aqueous layer with dilute hydrochloric acid solution, adjust the pH value to 3-4, and form a solid, filter, and wash with normal water to obtain a solid of 3.8 g, refined with methanol / water, and vacuum-dried to obtain 3.2 g of off-white solid, HPLC 98.9%, yield 72.4%, melting point 231-232°C.

Embodiment 3

[0022] Preparation of 2-formic acid-5-(2-methylbenzamido)toluene

[0023] Add 5g (0.016mol) of 2-bromo-5-(2-methylbenzamido)toluene and 20ml tetrahydrofuran into a 100ml reaction flask, cool down to -78°C with acetone / dry ice system, and control the temperature -78~- Add 30ml of n-butyllithium hexane solution (1M / L) dropwise at 70°C for about 2.5 hours, then control the temperature at -78~-70°C for 1 hour, add about 2g of dry ice, and slowly heat up to 0°C, pour the reaction solution into 20ml of water, extract the layers twice with 20ml of toluene; acidify the aqueous layer with dilute hydrochloric acid solution, adjust the pH value to 3-4, and generate a solid, filter, and wash with normal water to obtain 4.2g of solid, Purified with methanol / water and dried in vacuo to obtain 3.6 g of off-white solid, HPLC 99.2%, yield 81.4%, melting point 231-232°C.

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Abstract

The present invention provides a method for preparing an intermediate 2-carboxylic acid-5-(2-methyl-benzoylamino)toluene for tolvaptan. The method comprises: in an anhydrous organic solvent, 2-bromo-5-(2-methyl-benzoylamino)toluene is reacted with a n-butyllithium solution at a low temperature, then carbon dioxide is fed in or dry ice is added in, and the intermediate 2-carboxylic acid-5-(2-methyl-benzoylamino)toluene is obtained after treatment. The molar ratio of the 2-bromo-5-(2-methyl-benzoylamino)toluene to the n-butyllithium solution is 1:0.5-5. By using the method of the present invention, the prepared tolvaptan intermediate has characteristics of a low cost, few impurities, and high yields, thereby the method is more suitable for large-scale industrial 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 used for treating hypervolaemic or isovolemic hyponatremia with heart failure, liver cirrhosis, and syndrome of abnormal secretion of antidiuretic hormone. More specifically, it is a preparation method of tolvaptan intermediate 2-formic acid-5-(2-methylbenzamido)toluene. 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 associated with heart failure, liver cirrhosis, and syndrome of abnormal antidiuretic hormone secretion. [0003] Tolvaptan chemical name: N-[4-[(5R)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1-benzazepine-1-formyl] -3-methylphenyl]-2-methylbenzamide. Wherein 2-formic acid-5-(2-methylbenzamido)toluene is used as the key intermediate for ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/81C07C231/12C07D223/16
CPCY02P20/141
Inventor 陈滔陈华于玲丽范喜园
Owner TIANJIN TAIPU PHARMA SCI & TECH DEV
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