Uses
5-Dehydro Tolvaptan is an impurity of Tolvaptan (T536650), a selective, competitive arginine vasopressin V2 receptor antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH g
Uses
5-Dehydro Tolvaptan is an impurity of Tolvaptan (T536650), a selective, competitive arginine vasopressin V2 receptor antagonist
ngestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH).
Preparation
To a 3 L reactor was added 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine (70. 0 g, 212.90 mmol), dichloromethane (560 ml) and distilled water (140 ml), and the mixture was stirred for 1 hour. Magnesium hydroxide (14.90 g, 14.90 mmol) was added to the reaction mixture at 10 ° C. or lower, and the mixture was stirred for 30 minutes. 2-Methylbenzoyl chloride (30.42 ml) was gradually added to the reaction mixture, stirring for 3 hours. The reaction mixture was filtered to remove magnesium hydroxide, and the pH of the reaction mixture was adjusted to pH 8 to 9 using an aqueous sodium hydroxide solution, and then the organic layer was separated. The obtained organic layer was dried with sodium sulfate (Na 2 SO 4), filtered, and concentrated under reduced pressure to give 5-Dehydro Tolvaptan (yield: 96 percent).
Synthesis
To a 3 L reactor was added 1-(4-amino-2-methylbenzoyl)-7-chloro-3,4-dihydro-1H-benzo[b]azepin-5(2H)-one (70.0 g, 212.90 mmol), dichloromethane (560 mL), and distilled water (140 mL), and the reaction mixture was stirred for 1 hour. Magnesium hydroxide (14.90 g, 14.90 mmol) was slowly added to the reaction mixture at a temperature controlled below 10 °C and stirring was continued for 30 min. Subsequently, o-toluoyl chloride (30.42 mL) was slowly added dropwise and the reaction was continued with stirring for 3 hours after the dropwise addition. After completion of the reaction, the magnesium hydroxide was removed by filtration and the pH of the filtrate was adjusted to 8-9 with aqueous sodium hydroxide to separate the organic layer. The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine 91.35 g in 96% yield.
References
[1] Patent: JP2018/12690, 2018, A. Location in patent: Paragraph 0029; 0030
[2] Patent: CN105315169, 2016, A. Location in patent: Paragraph 0170; 0224; 0225
[3] Patent: CN105753735, 2016, A. Location in patent: Paragraph 0181; 0217; 0218
[4] Patent: CN106883175, 2017, A. Location in patent: Paragraph 0017; 0018
[5] Patent: CN108503586, 2018, A. Location in patent: Paragraph 0044; 0045; 0054; 0055; 0056
