Synthesis of (1‐(Aminomethyl)‐2,3‐dihydro‐1H‐inden‐3‐yl)methanol: Structural Confirmation of the Main Band Impurity Found in Varenicline^® Starting Material

Abstract

Described here is the synthesis of (1‐(aminomethyl)‐2,3‐dihydro‐1H‐inden‐3‐yl)methanol 1, the previously unidentified impurity found in the synthesis of 2,1 providing a confirmation of the structure. Fabbrica Italiano Sintetici (FIS), working in conjunction with Pfizer Groton, reported an unidentified impurity, referred to as the “main band impurity”, in 2 at levels of 0.4 to 0.8%. The structure was postulated to be 1, the open‐ring product of the lithium aluminum hydride (LAH) reduction of 3 to 2. Although the cis isomer of 1 was previously reported in the literature,2 a much shorter racemic synthesis was developed using intermediates employed for the production of Varenicline^®. Several reducing agents were screened for the synthesis of 1, with LiAlH₄ followed by basic workup conditions giving optimal results. High performance liquid chromatography (HPLC) analysis ultimately confirmed the structure of 1 as the main band impurity generated during the synthesis of 2.

Keywords:

• Varenicline
• amino alcohol
• reduction

Acknowledgment

We thank Jotham Coe, Michael Vetelino, and Paige Brooks for all the preliminary chemistry and Kyle Leeman for his analytical support.