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

• Published in: Synthetic communications 2008-01, Vol.38 (3), p.441-447
• Main Authors: Busch, Frank R., Concannon, Paul E., Handfield, Robert E., McKinley, Jason D., McMahon, Megan E., Singer, Robert A., Watson, Timothy J., Withbroe, Gregory J., Stivanello, Mariano, Leoni, Lucia, Bezze, Chiara
• Format: Article
• Language: English
• Subjects: amino alcohol; reduction; Varenicline
• ISSN: 0039-7911; 1532-2432
• DOI: 10.1080/00397910701771231

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 LiAlH 4 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.