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DOI: 10.1055/s-0037-1611845
Synthesis of 6-(Fluoromethyl)-19-norcholest-5(10)-en-3-ol, a Fluorinated Analogue of NP-59, using the Mild Fluorinating Reagent, TBAF(Pinacol)2
This work was supported by funding from the Center for the Discovery of New Medicine at the University of Michigan, Mi-Kickstart Award from The Michigan Translational Research and Commercialization (Viglianti and Brooks), and a University of Michigan Energy Institute Michigan Memorial Phoenix Project Seed Grant.Publication History
Received: 25 April 2019
Accepted after revision: 09 May 2019
Publication Date:
22 May 2019 (online)
Abstract
For 45 years, efforts to prepare a fluorinated analogue of the scintiscanning/SPECT agent 6-(iodomethyl)-19-norcholest-5(10)-en-3-ol (NP-59) for development of a PET imaging agent have failed due to undesired elimination reactions and unexpected rearrangements observed while utilizing a wide variety of fluorinating conditions (e.g., cesium fluoride, silver fluoride, (2-chloro-1,1,2-trifluoroethyl)diethylamine (FAR), diethylaminosulfur trifluoride (DAST), and hexafluoropropene diethylamine FPA). Herein, we report the full synthesis of NP-59, followed by the four-step synthesis of 6-(fluoromethyl)-19-norcholest-5(10)-en-3-ol (FNP-59) using a recently developed mild fluorinating reagent, less prone to producing elimination reactions in the preparation of primary fluorides, TBAF(pinacol)2, with an overall yield of 16% (four steps). Also included is an evaluation of the TBAF(pinacol)2 reagent on eight test substrates to investigate its scope.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1611845.
- Supporting Information
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References and Notes
- 1a Sarkar SD, Beierwaltes WH, Ice RD, Basmadjian GP, Hetzel KR, Kennedy WP, Mason MM. J. Nucl. Med. 1975; 16: 1038
- 1b Beierwaltes WH, Wieland DM, Yu T, Swanson DP, Mosley ST. Seminars in Nuclear Medicine 1978; 8: 5
- 2a Counsell RE, Ranade VV, Blair RJ, Beierwaltes WH, Weinhold PA. Steroids 1970; 16: 317
- 2b Maeda M, Kojima M, Ogawa H, Nitta K, Ito T. Steroids 1975; 26: 241
- 3a Freeman DA, Counsell RE. J. Nucl. Med. 1991; 32: 495
- 3b Yen R.-F, Wu V.-C, Liu K.-L, Cheng M.-F, Wu Y.-W, Chueh S.-C, Lin W.-C, Wu K.-D, Tzen K.-Y, Lu C.-C. J. Nucl. Med. 2009; 50: 1631
- 3c Chen Y.-C, Chiu J.-S, Tseng C.-E, Chen Y.-C. QJM 2014; 107: 233
- 3d Wong K.-K, Gandhi A, Viglianti BL, Fig LM, Rubello D, Gross MD. World J. Radiol. 2016; 8: 635
- 3e Wong KK, Komissarova M, Avram AM, Fig LM, Gross MD. Clin. Nucl. Med. 2010; 35: 865
- 4 Somawardhana CW, Amartey JK, Kojima M, Lambrecht RM. Int. J. Rad. Appl. Instrum. A. 1990; 41: 1223
- 5a Pandit-Taskar N, Zanzonico PB, Staton KD, Carrasquillo JA, Reidy-Lagunes D, Lyashchenko SK, Burnazi E, Zhang H, Lewis JS, Blasberg R, Larson SM, Weber WA, Modak S. J. Nucl. Med. 2017; 59: 147
- 5b U.S. Food and Drug Administration, Center for Drug Evaluation and Research. AdreView NDA 22-290, 2008.
- 6a Katzenellenbogen JA. J. Fluorine Chem. 2001; 109: 49
- 6b Al JasemY, Tiemann T, Gano L, Oliveira MC. J. Fluorine Chem. 2016; 185: 48
- 7 Kobayashi T, Maeda M, Komatsu H, Kojima M. Chem. Pharm. Bull. 1982; 30: 3082
- 8 Parent EE, Carlson KE, Katzenellenbogen JA. J. Org. Chem. 2007; 72: 5546
- 9 Engle KM, Pfeifer L, Pidgeon GW, Giuffredi GT, Thompson AL, Paton RS, Brown JM, Gouverneur V. Chem. Sci. 2015; 6: 5293
- 10a Jao CY, Nedelcu D, Lopez LV, Samarakoon TN, Welti R, Salic A. ChemBioChem 2015; 16: 611
- 10b Oikawa Y, Uchiyama D, Shirasawa T, Oikawa M, Ishikawa Y. Tetrahedron Lett. 2016; 57: 3949
- 11 Komatsu H, Maeda M, Kojima M. Synthesis 1977; 36
For recent reviews of fluorinated steroids, and use of their radiofluorinated derivatives in PET, see: