Organic Process Research & Development 2006, 10, 346−348
Technical Notes
Practical Synthesis of 2-Amino-5-fluorothiazole Hydrochloride
Paul H. Briner,† Matthew C. T. Fyfe,*,† Pierre Martin,‡ P. John Murray,† Fre´de´ric Naud,‡ and Martin J. Procter†
Prosidion Limited, Watlington Road, Oxford OX4 6LT, U.K., and SolVias AG, Klybeckstrasse 191,
Postfach, CH-4002, Basel, Switzerland
Abstract:
Previously,1 we synthesized the hydrochloride salt of 3 from
the trifluoroacetamide 2a. This amide was made by quench-
ing the dilithio species, formed by treating 5-bromo-2-
trifluoroacetamidothiazole (1a) with 2.2 equiv of n-BuLi,
with N-fluorobenzenesulfonimide (NFSi),6 as delineated by
Route a in Table 1. By employing this approach, 10.9 g of
3‚HCl was isolated from 50.0 g of bromide 1a. However,
this route required a difficult chromatographic separation
following the fluorination step and was unreliable, especially
when carried out on a larger scale. Here, we report a
substantially improved route for the synthesis of 3‚HCl that
does not rely on column chromatography and allows its
preparation on a multikilogram scale.
Initial attempts to prepare 3, or a suitable precursor, via
a number of routes either failed or had limited success. These
routes included the Balz-Schiemann fluorodediazoniation7
of 2-acetamido-5-aminothiazole8 and the direct formation of
the 2-amino-5-fluorothiazole ring system9 via the condensa-
tion of chlorofluoroacetaldehyde hydrate10 with thiourea by
a process analogous to that employed previously for the
synthesis of 2-amino-5-chlorothiazole.11 Nucleophilic aro-
matic substitution reactions of fluoride12 with 2-amino-13 or
2-acetamidothiazoles14 bearing a leaving group at the 5-posi-
tion were also not useful.
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.
Recently, we discovered a range of novel glucokinase
activators, bearing a 2-aminothiazole moiety, that are po-
tential medicaments for Type 2 Diabetes.1 It proved necessary
to site a fluorine atom2 on the 5-position of the thiazole ring
system in these compounds to restrict oxidative ring-opening
metabolism,3 a phenomenon that could lead to toxicity in
vivo. Thus, we required a practical preparation of amides of
2-amino-5-fluorothiazole (3, Table 1). Surprisingly, little
information is available on this “simple” organic molecule
in the chemical literature. In the late 1970s, 3 was described4
in the patent literature as a building block for a number of
herbicides. Nonetheless, the compound’s synthesis was not
outlined, nor were any characterization data reported. More
recently, it was stated5 that the trifluoroacetate salt of 3 had
been prepared by deprotection of 2-tert-butoxycarbon-
ylamino-5-fluorothiazole (2c) with TFA. However, details
of the characterization of 3‚TFA, as well as the synthetic
procedure employed to prepare 2c, were not furnished.
A partially successful route involved the fluorination of
2-acetamidothiazole (1b) by 1-fluoro-4-chloromethyl-1,4-
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) [F-TEDA,
Selectfluor]15 followed by amide hydrolysis (Route b, Table
1). On a small scale (1.5 mmol 1b), the key fluorination
step worked in moderate yield (48%). However, on a larger
scale (35.2 mmol 1b), the isolated yield was much lower
(7%) and the maximum conversion of 2-acetamidothiazole
that could be obtained was only 60%, as ascertained by both
* To whom correspondence should be addressed. E-mail: mfyfe@
prosidion.com. Fax: +44 (0)1865 871 279.
† Prosidion Limited.
‡ Solvias AG.
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C. M.; Schofield, K. L.; Shah, V. K.; Yasuda, K. PCT Int. Appl. WO 2004/
072031, 26 August 2004; Chem. Abstr. 2004, 141, 225496. (b) Fyfe, M.
C. T.; Gardner, L. S.; Nawano, M.; Procter, M. J.; Williams, G. M.; Witter,
D.; Yasuda, K.; Rasamison, C. M.; Castelhano, A. PCT Int. Appl. WO
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Vol. 10, No. 2, 2006 / Organic Process Research & Development
10.1021/op0502194 CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/10/2006