2-Ethoxy-1-[[2′-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1′-biphenyl]-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid

Off-White Solid

I. Candesartan (10kg) and methylene chloride (100kg) were added to the reactor, and the temperature was lowered to 15°C. Triethylamine (4.5kg) was slowly added dropwise; after the addition was completed, the temperature of the reaction system was raised to 23°C. Triphenylchloromethane (7kg) was added in portions; after the addition, the reaction system temperature was maintained at 23°C for 3.5 hours; TLC monitoring (developer dichloromethane:methanol = 10:1 (V/V), Rf = 0.78) After the reaction is complete, add 0.1 mol/L HCl 30L (system pH = 5.4) at a time, add 5L 9mol/L HCl slowly to pH = 2.2, and separate the aqueous and organic layers by standing. 60L for the organic layer. The saturated saline solution was washed, transferred to a vacuum vessel, and the dichloromethane was recovered under reduced pressure.The residue in the kettle was added with 65 L of ethanol, and the temperature was raised to 45° C. and stirred for 3 hours until a large amount of white solid precipitated. The heating was stopped, and the temperature was lowered to room temperature. The filter cake was washed with a small amount of ethanol and dried at normal pressure at 50° C. for 12 hours to obtain three. Phenyl candesartan (white crystalline powder, 14.5 kg). Calculated according to the following formula, the yield of this step is 94.0percent.Examples-l; Preparation of tritylated Candesartan acid (acetone) A mixture of Candesartan acid, triethylamine and acetone was heated to reflux temperature at 55-60A mixture of Candesartan acid, triethylamine and acetone was heated to reflux temperature at 55-60° C. To this trityl chloride solution in acetone was added and refluxed it for 4-8 hours. The reaction mixture was cooled at ambient temperature followed by addition of D. M. water and stirred for one hour. The reaction mixture was filtered and washed with mixture of acetone and D. M. water. To the solid, D. M water was added and stirred for 30 minutes at ambient temperature. The mixture was filtered and washed with D. M. water. The solid was dried to obtain tritylated Candesartan acid.Yield: 90percentPurity: 99percentExampIes-2; Preparation of tritylated Candesartan acid (MIBK)A mixture of Candesartan acid, triethylamine and methyl isobutyl ketone (MIBK) was heated to reflux temperature at 55-60Examples-3; Preparation of tritylated Candesartan acid (MEK) A mixture of Candesartan acid, triethylamine and methyl ethyl ketone (MEK) was heated to reflux temperature at 55-60Example-1: Preparation of Candesartan cilexetil (with isolation of cilexetil trityl candesartan); Step-I: Preparation of Trityl candesartanTo solution of Candesartan (10Og in 350 ml MDC) and triethyl amine (34.3 g) Trityl chloride (76.8g in 150 ml MDC) is added slowly at temperature of 25 - 3OTo a solution of 2-ethoxy-1-{[2'-(1H-tetrazol-5-yl)-1, 1'-biphenyl-4-yl]methyl}-benzimidazole-7-carboxylic acid (78 mg) in methylene chloride (1ml) were added trityl chloride (63 mg) and triethylamine (0.03ml). The mixture was stirred at room temperature for two hours thirty minutes. The reaction mixture was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica (eluant: cyclohexane /ethyl acetate: from to 90/10 to 0/100) to give 2-ethoxy-1-[{2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]-1, 1'-biphenyl-4-yl}methyl]-benzimidazole-7-carboxylic acid (60mg, 53percent yield) as a white solid. 250 g of tributyl tin azide was added into 600 ml of xylene. 100 g of candesartan cyclic compound (in formula II, R is ethyl) was added, heated to 140-150° C., and refluxed to react for 20 h. After the end of the reaction, the reaction mixture was cooled to 40-50° C. 600 ml of sodium hydroxide solution (48 g of sodium hydroxide dissolved in 600 ml of water) was added, and stirred under 20-35° C. (0032) The organic layer was removed. (0033) The alkaline aqueous layer was heated to 70-80° C. to completely hydrolyze candesartan ethyl ester. The temperature of the mixture was controlled at 25-35° C. 400 ml of dichloromethane was added. Glacial acetic acid was added dropwise to adjust pH of the mixture to 5-6 to precipitate candesartan. (0034) Triethylamine was added dropwise into the mixture until the candesartan solid was dissolved completely. The dichloromethane layer was separated. The aqueous layer was extracted by adding 200 ml of dichloromethane once again. The organic layers were combined. 68 g of triphenyl chloromethane was added into the organic layer. The temperature of the mixture was controlled at 25-35° C. to react until the content of candesartan was reduced to less than 1.0percent monitored by HPLC. After the end of the reaction, 100 ml of water was added for washing. The aqueous layer was removed. The organic layer was dried under reduced pressure. 600 ml of anhydrous ethanol was added to crystallize. The resulting crystals were collected by filtration, and dried to provide 125.5 g of trityl candesartan, yield 78.2percent, purity 97WORKING EXAMPLE 6

Candesartan analog as angiotensin II antagonist.

Molecular Weight:682.8
XLogP3:8.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:11
Exact Mass:682.26923897
Monoisotopic Mass:682.26923897
Topological Polar Surface Area:108
Heavy Atom Count:52
Complexity:1090
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes