A new synthetic methodology for tiazofurin

Article abstract of DOI:10.1081/NCN-100002548

A new synthesis of tiazofurin is described from 2,3-O-isopropylidene-5-O-benzoyl-β-D-ribofuranosyl cyanide.

Full text of DOI:10.1081/NCN-100002548

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A NEW SYNTHETIC METHODOLOGY FOR TIAZOFURIN
a
a
Kanda S. Ramasamy & Johnson Y. N. Lau
a
ICN Pharmaceuticals, Inc. , 3300 Hyland Avenue, Costa Mesa, California, 92626, U.S.A.
Published online: 07 Feb 2007.
To cite this article: Kanda S. Ramasamy & Johnson Y. N. Lau (2001) A NEW SYNTHETIC METHODOLOGY FOR TIAZOFURIN,
Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 1329-1331, DOI: 10.1081/NCN-100002548
To link to this article: http://dx.doi.org/10.1081/NCN-100002548
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 1329–1331 (2001)
A NEW SYNTHETIC METHODOLOGY FOR
TIAZOFURIN
∗
Kanda S. Ramasamy and Johnson Y. N. Lau
ICN Pharmaceuticals, Inc., 3300 Hyland Avenue, Costa Mesa,
California 92626
ABSTRACT
A new synthesis of tiazofurin is described from 2,3-O-isopropylidene-5-
O-benzoyl-β-D-ribofuranosyl cyanide.
Tiazofurin (1) [1, 2-(β-D-ribofuranosyl)thiazole-4-carboxamide)] attracted
considerable attention because of its significant activity against both human lym-
phoid (2), and lung tumor cell lines (3), and murine-implanted human ovarian
cancers (4). The biological effects also include its efficacy in the treatment of
acute myeloid leukemia (5). In addition, recent studies of tiazofurin have gener-
ated even more interest as a possible treatment for patients with chronic myeloid
leukemia(CML)inblastcrisis(6). Tiazofurinshowsactivitybyinhibitionofinosine
monophosphate dehydrogenase (IMPDH), by forming the corresponding NAD-like
tiazofurin adenine dinucleotide (TAD), which induces the shutdown of guanine
nucleotide synthesis (7).
Several methods are known in the literature (8–14) for the synthesis of tiazofu-
rin. But, most of them suffer from low yield, give a mixture of products (2 & 3) and
utilize hydrogen sulfide gas, which is environmentally unsafe on large-scale pro-
duction. The biological importance of tiazofurin and the problems associated with
thereportedmethodsencouragedustodiscoveranewsyntheticmethodologyforthe
preparation of tiazofurin. In this communication, we describe a new method for the
synthesis of tiazofurin, which eliminates the use of H S gas and the by-products.
2
∗
Corresponding author.
1
329
Copyright ꢀC 2001 by Marcel Dekker, Inc.
www.dekker.com

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1
330
RAMASAMY AND LAU
Figure 1.
The synthetic route for tiazofurin is shown in Scheme 1. We elected to use the
known 1-cyano-2,3-O-isopropylidene-5-O-benzoyl-β-D-ribofuranose (4) (15) as
our starting material. Reaction of 4 with cysteine ethyl ester hydrochloride in the
presence of triethylamine at room temperature gave readily thiazoline intermedi-
1
ate 5 in 90% yield. H NMR spectrum of 5 showed the presence of a thiazoline
methylene group at δ3.61 and a methine proton at δ5.08 which are characteristic of
2
ꢀ
-thiazolines (16). Oxidation of 5 with activated MnO (17) in benzene afforded a
2
clean product 6. Observation of the NMR spectrum of 6 indicated the absence of the
methylene and the methine protons of the thiazoline ring and the presence of a vinyl
Scheme 1. Reagents and conditions: i) Cysteine ethyl ester HCl/TEA; ii) MnO
iii) 90%TFA; iv) NH /MeOH.
2
/Benzene;
3

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SYNTHETIC METHODOLOGY FOR TIAZOFURIN
1331
proton, whichaccountedforthedehydrogenationof5. Exposureof6to90%TFAfor
ꢁ
1
h at room temperature gave ethyl 2-(5 -O-benzoyl-β-D-ribofuranosyl)thiazole-
4-carboxylate (7) in 98% yield. Finally, treatment of 7 with methanolic ammonia
at room temperature for 12 h afforded tiazofurin in 90% yield.
There are several merits to the present method. First, it avoided the use of toxic
mercuric salt and hydrogen sulfide, which are environmentally unsafe. Secondly,
the formation of the side products 2 and 3 were eliminated, and the yield of tiazo-
furin is substantially improved over previous methods. Third, the present method
does not require column chromatographic purification, thereby reducing the cost of
production of the drug. Fourth, the same methodology could be used to construct
other five membered C-nucleosides by replacing sulfur in 1 with heteroatoms such
as oxygen, selenium or nitrogen. The synthesis of other such C-nucleosides are in
progress and their results will be reported elsewhere.
In summary, we have developed a safe, convenient and higher yielding new
methodology for the synthesis of the important antitumor agent tiazofurin.
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