Organic Process Research & Development 2002, 6, 847−850
Synthesis of Trifluorothymidine: Green Glycosylation Condition Using Neither
Chloroform nor Transition Metals
Hironori Komatsu* and Hideki Umetani
Mitsui Chemicals, Inc., Catalysis Science Laboratory, 580-32 Nagaura, Sodegaura-shi, Chiba 299-0265, Japan
Scheme 1. Conventional glycosylation method
Abstract:
A new green glycosylation condition useful for efficient large-
scale preparation of trifluorothymidine 1 is described. The
condition requires neither CHCl3 nor transition-metal catalysts
for â-selectivity at the anomeric C1-position, which is advanta-
geous for process development of active pharmaceutical ingre-
dients such as 1. Key features of the condition include: (1) only
an equimolar amount of trifluorothymine 2 is required, (2) the
glycosylation is performed under high concentration, (3) the
reaction is carried out at 50 °C to enhance the reaction.
Introduction
Trifluorothymidine 1 has attracted attention for decades
due to its structural analogy to natural nucleic acids such as
thymidine. Since 1 exhibits antitumor1 and antiviral activi-
ties,2 intensive investigation has been achieved for develop-
ment of medical drugs. Particularly, demands for cytomeg-
aloviral disease treatment of AIDS patients are increasing.
Conventional processes for preparing 1 involve an enzymatic
base exchange of thymidine3 and trifluoromethylation on the
5-position of 2′-deoxyuridine derivatives using CF3Cu 4 or
(CF3)2Hg.5 Those methods were not cost-effective for
industrial manufacturing because of low yield and the
expensive reagents. The best protocol has been reported by
Kawakami,6 and the key reaction is a glycosylation of chloro
sugar 4 (R ) 4-chlorobenzoyl)7 with persilylated trifluo-
rothymine 3 in the presence of ZnCl2 catalyst (Scheme 1).
However, a contamination of a significant amount of an
R-anomer 6 is a drawback. To increase the stereoselectivity,
the following points were indispensable for the reaction
condition: (1) an addition of transient metal catalyst like
ZnCl2, (2) CHCl3 solvent, and (3) large excess use of 3 (2
equiv was required for a 75:25 ratio of 5:6). To meet the
cGMP regulation standard, the residual amount of transient
metal catalysts and CHCl3 in an active pharmaceutical
ingredient should be strictly controlled at low level. For
health and environmental reasons, CHCl3 solvent should be
avoided. Additionally, usage of a stoichiometric amount of
3 is preferred for an economical process. Here we report a
new glycosylation condition useful for synthesis of 1 using
neither CHCl3 nor transition-metal catalysts.
Results and Discussion
Effects of Solvents and Additives. To avoid CHCl3,
solvent effects were examined in the presence of various
additives that were effective for the syntheses of 2′-
deoxynucleosides (Table 1). To complete the reaction, 2
equiv of 3 was used in the experiments. Kawauchi8 reported
that CuF2 had induced high â/R-selectivity even when the
stoichiometric amount of 3 was used in the glycosylation.
In the presence of excess 3, the effects of CuF2 were reduced
to show comparable selectivity with the results carried out
with no additives (entry 1). Hexamethyldisilazane (HMDS)
or triethylamine (Et3N) were effective in the synthesis of
2′-deoxyadenosine or 2′-deoxycytidine.9 However, very low
selectivity was observed in the reaction of 3 with 4. CHCl3
and 1,2,4-trichlorobenzene (1,2,4-Cl3C6H3) were acceptable
* Corresponding author. Telephone: +81-438-64-2313. Fax: +81-438-64-
(1) (a) Umeda, M.; Heidelberger, C. Cancer Res. 1968, 28, 2529. (b) Yamashita,
J.; Yasumoto, M.; Takeda, S.; Matsumoto, H.; Unemi, N J. Med. Chem.
1989, 32, 136.
(2) (a) Kaufman, H. E.; Heidelberger, C. Science 1964, 145, 585. (b) Wingard,
J. R.; Stuart, R. K.; Saral, R.; Burns, W. H. Antimicrob. Agents Chemother.
1981, 20, 286. (c) Carmine, A. A.; Brogden, R. N.; Heel, R. C.; Speight,
T. M.; Avery, G. S. Drugs 1982, 23, 329.
(3) (a) Heidelberger, C.; Parsons, D.; Remy, D. C. J. Am. Chem. Soc. 1962,
84, 3597. (b) Stout, M. G.; Hoard, D. E.; Holman, M. J.; Wu, E. S.; Siegel,
J. M. Methods Carbohydr. Chem. 1976, 7, 19.
(4) Kobayashi, Y.; Yamamoto, K.; Asai, T.; Nakano, M.; Kumadaki, I. J. Chem.
Soc., Perkin Trans. 1 1980, 2755.
(5) Schwarz, B.; Cech, D.; Reefschlaeger, J. J. Prakt. Chem. 1984, 326, 985.
(6) Kawakami, H.; Ebata, T.; Koseki, K.; Matsushita, H.; Naoi, Y.; Itoh, K.;
Mizutani, N. Heterocycles 1990, 31, 569.
(7) (a) Hoffer, M. Chem. Ber. 1960, 93, 2777. (b) Wang, Z.-X.; Duan, W.;
Wiebe, L. I.; Balzarini, J.; De Clercq, E.; Knaus, E. E. Nucleosides,
Nucleotides Nucleic Acids 2001, 20, 11.
(8) Kawauchi, N.; Fukazawa, N.; Ishibashi, H.; Otsuka, K. U.S. Patent 5,-
532,349; Chem. Abstr. 1995, 122, 291455.
(9) Kawakami, H.; Matsushita, H.; Shibagaki, M.; Naoi, Y.; Itoh, K.;
Yoshikoshi, H. Chem. Lett. 1989, 1365.
10.1021/op025555o CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/31/2002
Vol. 6, No. 6, 2002 / Organic Process Research & Development
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