6
-(1-Butyl-4-nitro-2-propylimidazol-5-yl)thiopurine (1b) [8], 6-(1-Methyl-5-nitroimidazol-4-yl)-
thiopurine (1c) [9], and 6-(2-Ethyl-5-nitro-1-propylimidazol-4-yl)thiopurine (1d) [9] were obtained using
the methods referred to.
9
-Substituted Derivatives of 6-(4-Nitroimidazol-5-yl)thiopurines (2a-s) and 6-(5-Nitroimidazol-4-
yl)thiopurines (2t,u). (General Method). A. Finely ground anhydrous potassium carbonate (0.011 mol) was
added to a solution of the 6-(nitroimidazolyl)thiopurine 1a-d (0.01 mol) in anhydrous DMF (40-50 ml), and
this was followed by the alkyl halide (methyl iodide, ethyl iodide, isopropyl bromide, isobutyl bromide)
(
0.02 mol) or the aralkyl halide (benzyl chloride, 4-chlorobenzyl chloride, phenethyl bromide),
ethylenechlorohydrin, bromoacetaldehyde diethyl acetal, α-bromo ketone (bromoacetone, phenacyl bromide,
-methoxyphenacyl bromide, 4-bromophenacyl bromide), or bromoacetic acid (or its ethyl ester)
0.011-0.015 mol). The reaction mixture was stirred: at 40°C for 9 h (for preparation of compound 2p), at 70°C
for 7 h (2r), 9 h (2t,u), 10 h (2i,m), 15 h (2a), or 17 h (2k), or at 80°C for 10 h (2c,d,g,j,l,n,s), 15 h (2e,f), or
7 h (2b). At the end of the heating period the reaction product was poured into water (150-200 ml) and the
precipitated solid was filtered off, washed on the filter with sodium hydroxide solution (1 N, 3-4 times, each
0-15 ml), with water to neutral reaction of the water wash, and then dried to give compounds 2a-g,i-m,p,r-u.
4
(
1
1
Compounds 2a,b,e-g,i,j,s were separated by distillation of the DMF in vacuo and subsequent treatment of the
residue as described above. Acid 2n was separated after distillation of DMF in vacuo. The residue was
dissolved in water, the solution treated with activated carbon, filtered, acidified, and then treated with formic
acid to pH 5. The precipitated solid (according to TLC containing an admixture of the starting compound 1a)
was filtered, suspended in water, sodium bicarbonate (1.43 g) added, the solution filtered from the residual 1a,
acidified with formic acid to pH 5, and the residue was filtered off, washed with water, and dried to give the
acid 2n in 41% yield.
B. A mixture of compound 1a, b (0.01 mol), finely ground anhydrous potassium carbonate (0.01 mol),
and the methyl or ethyl benzenesulfonate (0.011 mol) in anhydrous DMF (40 ml) was stirred at 80-82°C for
1
0 h, cooled, poured into water (200 ml), and treated as above as reported in method A to give compounds 2p,q.
The yield of compound 2p was 77%. A sample, mixed with a sample prepared as in method A (yield 72%), did
not show a depressed melting point and their IR spectra were identical.
Compounds 2a-u are high melting yellow, light yellow, or colorless (compound 2l) crystalline materials
which are insoluble in water (except 2n, o) and difficultly soluble in the majority of organic solvents.
9
-Formylmethyl-6-(1-methyl-4-nitroimidazol-5-yl)thiopurine (2h). A suspension of the acetal 2g
(
1.46 g, 0.005 mol) in 36% HCl (10 ml) was stirred for 2 h at 18-20°C, during which time the starting material
dissolved fully. The solution was diluted with water (20 ml) and 25% aqueous ammonia was added with ice
cooling and stirring to pH 5. The separate solid was filtered, washed with water, and dried to give the aldehyde
2
h (0.8 g).
9
-Carboxymethyl-6-(1-methyl-4-nitroimidazol-5-yl)thiopurine (2n). A suspension of the ester 2m
(
3.36 g, 0.01 mol) and NaOH solution (1N, 10 ml, 0.01 mol) was refluxed for 30 min, during which time the
starting material dissolved fully. The solution was heated with activated carbon, filtered, the filtrate acidified
with formic acid to pH 4, and the precipitate was filtered, washed with water, and dried to give compound 2n
(
2.3 g, 70%); mp 225-226°C (water). A sample, mixed with a sample prepared as in method A, did not show a
depressed melting point and their IR spectra were identical.
Sodium Salt of 9-Carboxymethyl-6-(1-methyl-4-nitroimidazol-5-yl)thiopurine (2o). Obtained by
reaction of equimolar amounts of the acid 2n and NaHCO in water with subsequent precipitation from the
aqueous solution using acetone.
3
9
-Carboxymethylhypoxanthine (3). A suspension of compound 2p (9.07 g, 0.025 mol) in 18% HCl
(
90 ml) was refluxed for 2 h. The solution formed was treated by heating with activated carbon and then filtered.
The filtrate was carefully neutralized with a 20% solution of NaOH with cooling and stirring to pH 2-3. The
precipitated solid was filtered off, washed with water and then acetone, and dried to give compound 3 (2.7 g,
5
-1
6%); mp 263-266°C (decomp., precipitated with HCl from the basic solution). IR spectrum, ν, cm : 1680,
6
13