Improved Methods for the Synthesis of Irbesartan, an Antihypertensive Active Pharmaceutical Ingredient

Abstract

New methods for the preparation of irbesartan 1 have been described. The dehydration and tetrazole formation in one step from substituted cyclopentane derivative 7 with tributyltin chloride and sodium azide is described. Selective hydrolysis of nitrile 3 with HCl has also been described in the preparation of N-acylaminocyclopentane-2-carboxylic acid 4, which is the key intermediate for the preparation of irbesartan. The impurity profiling of irbesartan has also been discussed.

Critical Analysis of Drug Product Recalls due to Nitrosamine Impurities

“…Two major approaches have been reported for the synthesis of irbesartan with the most extensively used process introducing the tetrazole ring during the last step. The pharmaceutical companies Sanofi, 69,70 Arabindo, 71 and Alembic Ltd. 72 follow this approach but installation of the tetrazole moiety is associated with nitrosamine contamination. Thus, the introduction of this moiety earlier in the synthesis appears to be beneficial to avoid such impurities.…”

“…Lee’s group from Chonnam National University also employed a similar approach wherein the tetrazole ring formation was completed as the last step using Me 3 SiN 3 as a reagent instead of Bu 3 SnN 3 . Aurobindo Pharma and Alembic Ltd. (2007) synthesized irbesartan starting from 1-aminocyclopentanecarbonitrile and employed tetrazole ring formation as a last step using Bu 3 SnCl/NaN 3 or Bu 3 SnN 3 . Teva Pharmaceuticals (2004) employed a completely different approach in which the tetrazole moiety was incorporated in the starting material itself.…”

Rational Design and Synthesis of AT1R Antagonists

“…Irbesartan was approved from the FDA and released to the US market at 1996 under the name of Avapro. A similar strategy was used for the synthesis of irbesartan ( Scheme 7 and Scheme 8 , [ 33 , 34 , 35 ]). In particular, irbesartan was synthesized through dehydration and tetrazole formation in one step from a substituted cyclopentane derivative 6 with tributyltin chloride and sodium azide.…”

“…The purity of the compound was 99.85% as confirmed by HPLC analysis. Minimization of the impurities was the mail focus of this synthetic methodology ( Scheme 7 , [ 33 , 34 ]).…”

“… Synthesis of irbesartan by Prasada Rao et al through nitrile derivative 6 , tributyltin chloride and sodium azide in the presence of DMF [ 33 , 34 ]. …”