Chemical Properties
Off-White Solid
Uses
Candesartan analog as angiotensin II antagonist.
Uses
2-Ethoxy-1-((2''-(1-trityl-1H-tetrazol-5-yl)-[1,1''-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylic Acid can be used as reagent/reactant in preparation of the anti-hypertensive drug candesartan cilexetil.
Synthesis
I. 1-((2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylic acid (10 kg) was added to the reaction kettle along with dichloromethane (100 kg), and cooled down to 15°C. The temperature of the reaction system was increased to 15°C by adding triethylamine (4.5 kg). Triethylamine (4.5 kg) was slowly added dropwise, and after the dropwise addition was completed, the temperature of the reaction system was raised to 23 °C. Triphenylchloromethane (7kg) was added in batches and after completion of addition, the reaction was maintained at 23°C for 3.5 hours. The reaction progress was monitored by TLC (unfolding agent: dichloromethane/methanol=10:1, v/v, Rf=0.78). After completion of the reaction, the pH of the system was adjusted to 5.4 by adding 0.1 mol/L HCl (30 L), then 5 L of 9 mol/L HCl was added slowly to pH=2.2, and the reaction was allowed to stand for stratification to separate the aqueous and organic layers. The organic layer (about 60 L) was washed with saturated saline, transferred to a reduced pressure distillation unit, and dichloromethane was recovered under reduced pressure. Ethanol (65L) was added to the residue, warmed to 45°C and stirred for 3 hours until a large amount of white solid precipitated. The heating was stopped, cooled to room temperature, filtered, the filter cake was washed with a small amount of ethanol, and dried at 50°C under normal pressure for 12 hours to obtain 2-ethoxy-1-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylic acid (white crystalline powder, 14.5 kg, yield 94.0%).
References
[1] Patent: CN105153124, 2018, B. Location in patent: Paragraph 0005; 0054; 0055; 0076; 0090
[2] Patent: WO2009/7986, 2009, A1. Location in patent: Page/Page column 13
[3] Patent: US2010/210852, 2010, A1. Location in patent: Page/Page column 5
[4] Patent: WO2009/7986, 2009, A1. Location in patent: Page/Page column 14
