Synthesis of deuterium-labeled losartan and losartan 5-carboxylic acid with improved isotopic enrichment

Losartan is a nonpeptide angiotensin II receptor antagonist undergoing substantial first-pass metabolism by cytochrome P450 enzymes,and it is converted,in part,to an active carboxylic acid metabolite-losartan 5-carboxylic acid.The synthesis of four-deuterium-labeled losartan and losartan 5-carboxylic acid were describedFour-deuterium-labeled 4-bromotoluene was chosen as the starting material.After Grignard reaction,oxidation,and substitution,intermediate（ 5 ）was obtained.Another key intermediate（ 7 ）was synthesized by condensation of intermediate（ 5 ）with 2-n-butyl-4-chloro-5-formylimidazole（ 6 ）.After compound（ 7 ）was reacted with sodium azide in reflux in toluene，the target compound（ 10 ）was obtained.Oxidant（ 9 ）was synthesized via reaction of tetrabutyl ammonium bromide（ 8 ）treated with potassium permanganate.Deuterium labeled losartan was converted to deuterium labeled losartan 5-carboxylic acid using oxidant（ 9 ）.The total yield of deuterium labeled losartan was 15.4% with 99.4% chemical purity and 98.4% isotopic enrichment.The total yield of deuterium labeled losartan 5-carboxylic acid was 8.2% with 96.4% chemical purity and 98.3% isotopic enrichment.The structures of the target compounds were confirmed by ¹H NMR and high-resolution MS.They are used as excellent internal standards for the pharmaceutical studies of losartan and losartan 5-carboxylic acid.