724
D. T. Stoelting, G. O. Mbagwu, T. Scott, M. Long, and E. L. Sharpe
Vol. 39
to cool to room temperature and 3 crystallized as a white solid
which was isolated for mp, spectral, and elemental analyses. The
physical and spectral data for this analytically pure product are
summarized in Tables 1 and 2. The remaining material in the dis-
tillation pot was extracted with ether. The ether layer was sepa-
rated, dried (magnesium sulfate), and poured through a column
of silica gel (2.5 x 13 cm) prepacked with diethyl ether.
Saturation of the aqueous extracts with sodium chloride resulted
in an oil separating out that after sitting over-night formed crys-
tals, which were isolated by vacuum filtration and rinsed with
water. The crystals were dissolved in ether and the solution was
dried (magnesium sulfate), filtered, and evaporated. The total
yield of 3 was 3.93 g, which is 60% of the 25% conversion of 1 to
3 observed by proton nmr.
methanol reaction mixture through a column of silica gel using
acetone eluant.
Acknowledgments.
The support of this research by the NIH Grant Number GM
44814 is gratefully acknowledged.
REFERENCES AND NOTES
[1a] R. A. Coburn, J. Heterocyclic Chem., 8, 881 (1971); [b] R.
A. Coburn, R. A. Carapellotti and R. A. Glennon, J. Heterocyclic
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[2a] For an excellent recent review, see: R. A. Glennon, and S. M.
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Townsend, Ed., Plenum Press, New York 1991, pp 1-23; [b] G. O.
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Magn. Reson., 21, 527 (1983); [e] G. O. Mbagwu, Diss. Abstr. Int., B42
4428 (1982); [f] R. A. Coburn and R. A. Glennon J. Heterocyclic
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(1996); [h] G. O. Mbagwu, D. K. Sen, R. Knight-Mason, K. D. Watson,
General Procedure for the Preparation of Anhydro-(8-[(2,2-
Dimethyl[1,3]dioxolan-4-yl)methyl]-5-hydroxy-7-oxothiazolo-
[3,2-a]pyrimidinium hydroxides) (5).
An intimate mixture of 1.400 mmoles of (2,2-Dimethyl-
[1,3]dioxolan-4-ylmethyl)-thiazol-2-yl-amine (3) and 1.400 to
1.470 mmoles of the appropriately substituted bis(2,4,6-
trichlorophenyl)malonate (4) was heated at 160° for 3 minutes.
After cooling the dark oil was purified on silica gel (50 g in a 2.5
cm id glass chromatography column) prepacked in chloroform
for all five derivatives except 5e, the 6-benzyl derivative, which
could be isolated by simple trituration of the crude condensation
product with diethyl ether. Elution of the column with chloroform
removed the 2,4,6-trichlorophenol by-product. When the 2,4,6-
trichlorophenol by-product had eluted as judged by TLC (50%
th
T. Scott and A. A. Adekoya, Proceedings of the 4 Joint Conference of
the American Association for Cancer Research and the Japanese Cancer
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Mason and A. Adeniji-Adele, Proceedings of the 92 Annual Meeting
of the American Association for Cancer Research, 42: 444 (2001). [j]
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G. O. Mbagwu, P. Pourquier and C. Chapey, Proceedings of the 93
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43: 370 (2002).
EtOAc/50% hexanes eluant, R = 0.40) the eluting solvent for the
f
column was switched to acetone or an acetone/chloroform mix-
ture to obtain the desired product. The product isolated in this
manner was fairly pure as judged by proton nmr. Further purifi-
cation of the chromatographed products was performed in all
cases except for the unsubstituted derivative, 5a, to get pure
solids for CHN and melting point analysis: the methyl and ethyl
derivatives, 5b and 5c, were triturated with diethyl ether to
induce crystallization from the oil; the phenyl derivative, 5d, was
recrystallized from toluene.
[3a] R. A. Coburn and R. A. Glennon, J. Pharm. Sci., 62, 1785
(1973); [b] R. A. Coburn and R. A. Glennon, J. Med. Chem., 17,
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(1981); [d] M. E. Rogers, R. A. Glennon, J. D. Smith, M. R. Boots,
N. Nanavati, E. Maconaughey, D. Aub, S. Thomas, R. G. Bass and G.
Mbagwu, J. Med. Chem., 24, 1284 (1981).
General Procedure for the Preparation of Anhydro-(8-(2,3-
Dihydroxypropyl)-5-hydroxy-7-oxothiazolo[3,2-a]pyrimidinium
Hydroxides) (6).
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Compound 5 (0.9 mmole) was dissolved in methanol (ca. 30
ml). To this solution a catalytic amount of p-toluenesulfonic acid
(5-12 mg) was added. The magnetically-stirred solution was
heated under reflux. Reaction progress was monitored by tlc
using acetone eluant. The reaction was stopped when the reactant
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Schubert, and R. G. Bass, Tetrahedron Letters, 22, 2753 (1981).
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spot at an R of ~0.7 was no longer or barely visible (typically ~2
f
hours). In general, the compounds could be easily isolated by
evaporation of the methanol and the 2,2-dimethoxypropane by-
product under reduced pressure and then trituration of the oil
with acetone, by crystallization from the cooled methanol sol-
vent, or by elution through a silica gel column using acetone as
eluant. The 6-H (6a), 6-phenyl (6d) and the 6-methyl (6b) diols
were crystallized from the reaction mixture. The 6-benzyl (6e)
diol was isolated by evaporation of the methanol mixture under
reduced pressure and then trituration of the oil with acetone. The
6-H diol (6a) was also isolated in this manner and then further
purified for mp and elemental analysis by recrystallization from
methanol. The 6-ethyl diol (6c) was purified by eluting the
[15] E. De Clercq and P. F. Torrence, J. Carbohydrates,
Nucleosides, Nucleotides, 5, 187 (1978).
[16] G. B. Elion, Adv. Enzyme. Regul., 24, 323 (1985).