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Temperature effects on the stereospecificity of nucleophilic fluorination: formation of trans ‐[ 18 F]4‐fluoro‐ l ‐proline during the synthesis of cis ‐[ 18 F]4‐fluoro‐ l ‐proline
Author(s) -
Behnam Azad Babak,
Ashique Rezwan,
Labiris N. Renée,
Chirakal Raman
Publication year - 2012
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.1947
Subject(s) - chemistry , stereospecificity , diastereomer , hydrolysis , nucleophile , cis–trans isomerism , walden inversion , acid hydrolysis , stereochemistry , medicinal chemistry , organic chemistry , catalysis
Fluorine‐18 labeled (2 S ,4 S )‐4‐fluoro‐ l ‐proline ( cis ‐[ 18 F]4‐FPro) has been reported to be a potential positron emission tomography tracer to study abnormal collagen synthesis occurring in pulmonary fibrosis, osteosarcomas, mammary and colon carcinomas. In this paper, we report the stereospecific radiofluorination of (2 S ,4 R )‐ N‐tert ‐butoxycarbonyl‐4‐( p ‐toluenesulfonyloxy) proline methyl ester (at 110°C) to produce diastereomerically pure cis ‐[ 18 F]4‐FPro in 38% radiochemical yield at the end of a 90‐min synthesis. Investigation of the effect of temperature on the stereospecificity of nucleophilic fluorination showed that diasteriomerically pure cis ‐[ 18 F]4‐FPro or trans ‐[ 18 F]4‐FPro was produced at lower temperatures (85°C–110°C) during the fluorination of (2S,4R) or (2 S ,4 S ) precursors, respectively. However, at higher temperatures (130°C–145°C), fluorination of (2 S ,4 R ) precursor produced a mixture of cis ‐[ 18 F]4‐FPro and trans ‐[ 18 F]4‐FPro diastereomers with cis ‐[ 18 F]4‐FPro as the predominant isomer. Hydrolysis of the purified fluorinated intermediate was carried out either in one step, using 2 m triflic acid at 145°C for 10 min, or in two steps where the intermediate was heated in 1 m HCl at 110°C for 10 min followed by stirring at room temperature in 1 N NaOH for 5 min. The aqueous hydrolysis mixture was loaded onto an anion exchange column (acetate form for one‐step hydrolysis) or an ion retardation column (two‐step hydrolysis) followed by a C 18 Sep‐Pak® (Waters Corporation, Milford, MA, USA). Pure cis ‐[ 18 F]4‐FPro was then eluted with sterile water. We also report that epimerization of cis ‐[ 18 F]4‐FPro occurs during the two‐step hydrolysis (H + followed by OH − ) of the intermediate, resulting in 5 ± 3% trans ‐[ 18 F]4‐FPro, whereas the one‐step acid hydrolysis yielded pure cis ‐[ 18 F]4‐FPro in the final product. Copyright © 2011 John Wiley & Sons, Ltd.