Practical Synthesis of 2-Amino-5-fluorothiazole Hydrochloride

Abstract

The first synthesis of 2-amino-5-fluorothiazole hydrochloride is reported from 2-aminothiazole. The synthesis proceeds in 35% overall yield, involves no chromatographic purification, and has been employed to prepare multikilogram quantities of the title compound. The key fluorine-introducing step comprises the reaction of dilithiated 2-tert-butoxycarbonylaminothiazole with N-fluorobenzenesulfonimide.

Nuclear fluorination of 2,4-diarylthiazoles with Accufluor®

“…Starch paper confirmed that the Selectfluor 1 was being consumed by some mechanism, perhaps involving attack by the thiazole nitrogen [17], although no other product could be observed. A similar incomplete conversion upon reaction of 2-acetamidothiazole with Selectfluor 1 was noted by others [15]. Despite our incomplete reaction, we were able to isolate 5-fluorothiazole (8a) in 23% yield following chromatography, with the structure being confirmed by GC-MS, 1 H, 13 C, 19 F NMR, IR, and elemental analysis (vida infra).…”

“…In contrast, preparations employing direct, electrophilic fluorination, as often preferred in analogue preparation, are quite rare. For example, the only report we have been able to find involving thiazoles is the very recent fluorination of the highly activated 2-acetamidothiazole using Selectfluor 1 [15].…”

“…Considering the limited work with thiazoles, and that direct fluorination of certain heterocycles using either fluorine [16] or N-F reagents [15,17,18] is known to be difficult, or to lead to unexpected addition products [19], we have become interested in studying this ring system. Herein, we report the results of our initial work in this area, which has shown that 2,4-diarylthiazoles can be directly and selectively fluorinated at the 5-position of the thiazole, albeit in modest yield, by reaction with the N-F reagent Accufluor 1 .…”

Thiazolides as Novel Antiviral Agents. 1. Inhibition of Hepatitis B Virus Replication

“…After we had used this procedure, a report appeared confirming our result. 31 These authors, however, found that on a larger scale treatment of Boc-2-aminothiazole with two equivalents of Bu t Li, followed by addition of N -fluorobenzenesulfonimide, then acidolysis with HCl, was a more reliable route to 40 . Coupling of 40 with acetylsalicyloyl chloride followed by standard deprotection gave the 5′-F analogue 14 .…”

The [18F]2-fluoro-1,3-thiazolyl moiety—an easily-accessible structural motif for prospective molecular imaging radiotracers

“…Such 1,3-thiazoles appear susceptible to metabolism by oxidative ring opening 12. However, one report suggests that fluorination of a 1,3-thiazolyl group might lead to better resistance to metabolism in vivo 13. We hypothesized that the 2-position in 1,3-thiazoles would be an attractive site for facile incorporation of fluorine-18 from [ 18 F]fluoride ion and moreover might deliver a relatively metabolically stable [ 18 F]2-fluoro-1,3-thiazolyl structural motif.…”