Development of concise two-step catalytic approach towards lasofoxifene precursor nafoxidine |
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Authors: | Carin C.C. Johansson Seechurn Ivana Gazić Smilović Thomas Colacot Antonio Zanotti-Gerosa Zdenko Časar |
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Affiliation: | 1. Johnson Matthey Catalysis and Chiral Technologies, Orchard Road, Royston SG8 5HE, UK;2. Lek Pharmaceuticals, d.d., Sandoz Development Center Slovenia, Verov?kova ulica 57, 1526 Ljubljana, Slovenia;3. Johnson Matthey Catalysis and Chiral Technologies, Nolte Drive, West Deptford, USA;4. Johnson Matthey Catalysis and Chiral Technologies, Cambridge Science Park, Milton Road, Cambridge, UK;5. Faculty of Pharmacy, University of Ljubljana, A?ker?eva cesta 7, 1000 Ljubljana, Slovenia |
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Abstract: | We have elaborated a two-step catalytic approach to nafoxidine, a key precursor to lasofoxifene. Firstly, an efficient α-arylation of 6-methoxy-3,4-dihydronaphthalen-1(2H)-one with chlorobenzene was developed, which operates at low 0.1?mol% Pd-132 catalyst loading in the presence of 1.9 equivalents of sodium tert-butoxide at 60?°C in 1,4-dioxane and provides 6-methoxy-2-phenyl-3,4-dihydronaphthalen-1(2H)-one in 90% yield. Secondly, we have demonstrated that 6-methoxy-2-phenyl-3,4-dihydronaphthalen-1(2H)-one can be converted to nafoxidine in 61% yield via CeCl3 promoted reaction with (4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)lithium, which is formed in-situ from the corresponding arylbromide precursor and n-butyllithium. Altogether, the shortest two-step approach to nafoxidine from simple tetralone commodity starting material has been developed with overall 55% yield. The developed synthetic approach to nafoxidine has several beneficial aspects over the one used in the synthetic route primarily developed for the preparation of lasofoxifene. |
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Keywords: | Catalysis Palladium Cerium α-Arylation Addition of aryllithium to ketone Drugs |
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