Improved synthesis of the thiophenol precursor N-(4-chloro-3-mercaptophenyl)picolinamide for making the mGluR4 PET ligands

• Published in: Tetrahedron Vol. 75; no. 29; pp. 3917 - 3922
• Main Authors: Wang, Junfeng, Shoup, Timothy M., Brownell, Anna-Liisa, Zhang, Zhaoda
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 19.07.2019; Elsevier
• Subjects: biomarkers; brain; chemical reactions; chemical structure; Chemistry; Chemistry, Organic; drugs; dyskinesia; ligands; mGluR4 PAM; mGluR4 PET ligand; monkeys; N-(3-mercaptophenyl)picolinamide derivatives; organic compounds; Physical Sciences; Science & Technology; The thiol protection; therapeutics; N-(3-mercaptophenyl)picolinamide derivatives; mGluR4 PAM; The thiol protection; mGluR4 PET ligand; POSITIVE ALLOSTERIC MODULATOR; RADIOLIGAND; RECEPTOR; GROUP-III; DISCOVERY; RODENT MODELS; POTENT; RADIOSYNTHESIS; DERIVATIVES; PARKINSONS-DISEASE
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2019.06.010

Recently [11C]mG4P012 (previously [11C]KALB012 and presently named as [11C]PXT012253 by Prexton Therapeutics) had been used as a biomarker during the preclinical development of a potential therapeutic drug, PXT0002331 (an mGluR4 PAM), for PD and l-dopa-induced dyskinesia. [11C]mG4P012 was shown to be a promising PET radioligand for mGluR4 in the monkey brain and for further development in human subjects. However, the previously reported multi-step synthesis of the thiophenol precursor suffered from low yields and difficult workup procedures. To support the translational research of [11C]mG4P012 and the other potential applications, we have developed a new route for synthesis of the thiophenol precursor and optimized the reaction conditions. The synthesis of N-(4-chloro-3-mercaptophenyl)picolinamide from 1-chloro-4-nitrobenzene has been greatly improved from 8% to 52% total yield with easy handling and in gram scales. [Display omitted]