An Efficient, Commercially Viable, and Safe Process for Preparation of Losartan Potassium, an Angiotensin II Receptor Antagonist

Abstract

An efficient, commercially viable and safe process for the preparation of losartan potassium, an antihypertensive drug substance, with an overall yield of 55.5% and ∼99.9% purity (including five chemical reactions and two recrystallizations) and meeting all other regulatory requirements is described. Formation and control of all the possible impurities are also described.

Controlling a Cohort: Use of Mirabilis-Based Purge Calculations to Understand Nitrosamine-Related Risk and Control Strategy Options

“…The high levels of NDMA identified within batches of Valsartan are likely due to the presence of dimethylamine in the tetrazole-forming reaction as a result of utilizing DMF as the solvent, which is subsequently exposed directly to high concentrations of nitrite in the reaction quenching process . The use of excess sodium azide and quenching with acidic sodium nitrite was similarly utilized in the preparation of Losartan, another drug that was subjected to recalls as a result of nitrosamine contamination. , Dimethylamine is known to be present within commercial DMF at a level greater than 15 ppm (dependent on manufacturer specification) , and is further generated through disproportionation of DMF when exposed to high temperatures, acidic conditions, and/or photolysis, and it is therefore likely to be generated to a reasonably high level during tetrazole formation and quenching. , The result is that the necessary conditions are now present for the formation of NDMA. Furthermore, a mechanism for formation of nitrosamines from tertiary amines has also been postulated (Figure ).…”

“…10 The use of excess sodium azide and quenching with acidic sodium nitrite was similarly utilized in the preparation of Losartan, another drug that was subjected to recalls as a result of nitrosamine contamination. 9,11 Dimethylamine is known to be present within commercial DMF at a level greater than 15 ppm (dependent on manufacturer specification) 12,13 and is further generated through disproportionation of DMF when exposed to high temperatures, acidic conditions, and/or photolysis, and it is therefore likely to be generated to a reasonably high level during tetrazole formation and quenching. 14,15 The result is that the necessary conditions are now present for the formation of NDMA.…”

Solubility and dissolution thermodynamic properties of 2-Cyano-4′-methylbiphenyl in binary solvent mixtures

“…OTBN), shown in Fig. 1, is an important drug intermediate to prepare sartans in organic synthesis [3][4][5][6][7][8].…”

An Efficient and Green Synthetic Route to Losartan

“…Hydrazoic acid is toxic and extremely explosive. 16 To minimise the cost constraint and the number of steps, we avoided the use of tributyltin azide and replaced tributyltin azide or triethylamine hydrochloride salt 17 with sodium azide and zinc trifluoromethanesulfonate. For the synthesis of the important intermediate 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde, we started from valeronitrile and methanol in the presence of acetyl chloride.…”