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. 2013 Apr 22;4(6):514-6.
doi: 10.1021/ml400045j. eCollection 2013 Jun 13.

Metabolically Stable tert-Butyl Replacement

David Barnes-Seeman  1 , Monish Jain  2 , Leslie Bell  2 , Suzie Ferreira  2 , Scott Cohen  1 , Xiao-Hui Chen  2 , Jakal Amin  2 , Brad Snodgrass  2 , Panos Hatsis  2
Affiliations

Metabolically Stable tert-Butyl Replacement

David Barnes-Seeman et al. ACS Med Chem Lett. .

Abstract

Susceptibility to metabolism is a common issue with the tert-butyl group on compounds of medicinal interest. We demonstrate an approach of removing all the fully sp(3) C-Hs from a tert-butyl group: replacing some C-Hs with C-Fs and increasing the s-character of the remaining C-Hs. This approach gave a trifluoromethylcyclopropyl group, which increased metabolic stability. Trifluoromethylcyclopropyl-containing analogues had consistently higher metabolic stability in vitro and in vivo compared to their tert-butyl-containing counterparts.

Keywords: Metabolic stability; clearance; metabolism; t-butyl; tert-butyl; tertiary butyl.

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Figures

Figure 1
Figure 1
Finasteride and the Cp-CF3 analogue thereof.
Scheme 1
Scheme 1. General Synthesis of Compounds in Table 1 and 2
Reagents and conditions: (a) n-BuLi, THF, −78 to 0 °C, CO2; (b) (COCl)2, CH2Cl2; (c) iPr2NEt, CH3CN; (d) n-BuLi, THF, −78 to 0 °C, B(OMe)3; (e) SPhos, Pd(OAc)2, K3PO4, THF.
Scheme 2
Scheme 2. Synthesis of Cp-CF3-Containing Aryl Bromides
Reagents and conditions: (a) X = CH, MsCl, 18-crown-6, KF, DMF, 100 °C; X = N: Tebbe reagent; (b) CH2N2; (c) Xylenes reflux.
See this image and copyright information in PMC

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