8
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Cottam et al.
vided a 63% and 75% yield of 12 and 13, respectively, as white
solids. Note: Compound 13 was found by H NMR to be the
ethyl ester due to transesterification under the reaction
conditions.
showed the appearance of two aromatic signals at about 8.74
and 8.55 as doublets (J ) 2.5 Hz) for all compounds.
1
6,7-Diet h yl-1-m et h ylp t er id in e-2,4-d ion e (64). Com-
pound 43 (200 mg, 1.27 mmol) was suspended in acetonitrile
(5 mL), and 3,4-hexanedione (185 µL, 1.52 mmol) was added.
The mixture was heated at 70 °C for 15 min with minimal
product formation due to insolubility of 43. Therefore DMF
(3 mL) and water (3 mL) were added, and the temperature
was raised to 100 °C. After 90 min total reaction time the
mixture was cooled and poured into water (100 mL) and
extracted with ethyl acetate (3 × 75 mL). The organic layer
was dried over MgSO4 and evaporated to provide the colorless
Gen er a l P r oced u r e for C-Nitr osa tion of P yr im id in es.
Com p ou n d s 18-20, 27, 32, 34, 36, 38, 40, a n d 42. The
pyrimidine (15 mmol) was suspended in 1 N HCl (30 mL), and
an aqueous solution of sodium nitrite (20 mmol in 10 mL) was
added dropwise with stirring over 10 min. The suspension
went from off-white to purple almost immediately. Stirring
was continued for 1 h, the pH was adjusted to 5 with ammonia
water, and the purple solid product was collected to provide
75-90% yield after drying. The characteristic lack of the C-5
proton in the 1H NMR was evident for each compound.
Gen er a l P r oced u r e for th e Red u ction of 5-Nitr oso- to
5-Am in o p yr im id in es. Com p ou n d s 21-23, 28, a n d 43-
48. The 5-nitrosopyrimidine (15 mmol) was suspended in
water (50 mL) and heated to 80-90 °C. Sodium hydrosulfite
(45 mmol) was added with stirring in portions over 5 min. The
color quickly changed from purple to light green, and stirring
was continued for an additional 10 min. The mixture was
cooled in ice and filtered. The filtered solid was washed with
cold water, EtOH, and Et2O to provide the o-diamine in 70-
88% yield as an off-white to pale green solid.
1-n -Hexyl-3-m eth ylu r ic Acid (24). The nitrosopyrimidine
19 (270 mg, 1.06 mmol) was dissolved in ethanol (20 mL) with
warming, and palladium on carbon (75 mg, 10%) was added
under argon. Hydrogenation was performed at room temper-
ature and 15 psi for 2 h, filtered to remove catalyst, and
evaporated to dryness. The residue was combined with urea
(600 mg, 10 mmol) and heated neat on the hot plate with
stirring. The temperature reached 140 °C, which produced a
clear melt and was maintained for about 10 min with ad-
ditional urea added (1 g). Upon cooling, the melt solidified
and was dissolved in 1 N NaOH (25 mL) and boiled with
decolorizing carbon for 10 min, filtered, and acidified to pH
3-4 while hot. The resulting precipitate was collected after
cooling, washed with water, and dried to yield 160 mg (57%)
of 24 as an off-white solid: mp >290 °C dec; 1H NMR (500
MHz, DMSO-d6) δ 11.80 and 10.73 (2s, 2H, N-7 H, N-9 H),
3.78 (t, 2H, N-CH2), 3.30 (s, 3H, N-CH3, under H2O signal),
1.48 (m, 2H, 2′CH2), 1.24 (m, 6H, 3′, 4′, 5′ CH2), 0.85 (t, 3H,
CH3). Anal. C12H18N4O3.
1
crystalline product: yield 240 mg (81%); mp 218-222 °C; H
NMR (DMSO-d6) δ 11.78 (br s, 1H, NH), 3.46 (s, 3H, NCH3),
2.95 and 2.93 (2q, 4H, 2CH2 of ethyls), 1.28 and 1.23 (2t, 6H,
2CH3 of ethyls). Anal. C11H14N4O2.
Dim eth yl 3-n -Hexyl-1-m eth yl-2,4-d ioxop ter id in e-6,7-
d ica r boxyla te (66). Compound 22 (300 mg, 1.18 mmol) was
combined with dimethyl acetylenedicarboxylate (430 mg, 0.37
mL, 3 mmol) in dry DMF (5 mL), and the mixture was heated
at 180 °C (bath temperature) for 3 h. The mixture was cooled,
added to water (75 mL), extracted with EtOAc (2 × 75 mL),
dried (MgSO4), and evaporated to yield a thick oil. The crude
product was purified by silica gel flash chromatography using
2% EtOAc in CH2Cl2. Crystallization of the pure product
fraction from EtOH/H2O gave 66 in 46% yield (205 mg): mp
92-95 °C; 1H NMR (CDCl3) δ 4.12 (t, 2H, NCH2), 4.01 and
4.05 (2s, 6H, 2 COOMe), 3.72 (s, 3H, NCH3), 1.70, 1.56, 1.31,
and 0.86 (3m, 11H, 2′-6′ of hexyl group). Anal. C17H22N4O6.
1-Meth yl-6-p h en ylp ter id in e-2,4-d ion e (67). The nitroso-
pyrimidine 32 (220 mg, 1.28 mmol) was mixed thoroughly with
phenethylamine hydrochloride (1.5 g, 9.5 mmol) and heated
in an open beaker on the hot plate. After a few minutes at
about 160 °C the purple reaction mixture fused to a brown
paste. TLC indicated many products, so sulfolane (1 mL) was
added and heating was continued for 15 min. The reaction
mixture was heated in water (10 mL), then diluted to 50 mL
in water, and extracted with EtOAc (2 × 50 mL), and the
organic layer was dried over MgSO4, and then concentrated.
The residue was flash chromatographed on silica gel using 4%
MeOH in CH2Cl2: yield 75 mg (23%) of 67 as a pale yellow-
orange solid; mp >307 °C dec; 1H NMR (500 MHz, DMSO-d6)
δ 11.95 (br s, 1H, NH), 9.37 (s, 1H, C-7 H), 8.17 (m, 2H, 2′,6′
phenyl), 7.55 (m, 3H, 3′,4′,5′ phenyl), 3.51 (s, 3H, NCH3). Anal.
C13H10N4O2.
Gen er a l Meth od for Rin g Closu r e of P yr im id in es to
[1,2,5]Th ia d ia zolo[3,4-d ]p yr im id in es (Com p ou n d s 69, 70,
a n d 73). The o-diamine 23, 28, or 43 (2.3 mmol) was
suspended in dry acetonitrile (5 mL), and dry pyridine (1.5
mL) was added. Thionyl chloride (1 mL, 13.7 mmol) was added
quickly, and the mixture, which became clear and darkened,
was heated at 60 °C for 10 min. The mixture was then cooled
and poured into 1 N HCl (40 mL) with stirring. The resulting
yellow solution was extracted with ethyl acetate (3 × 40 mL),
dried over MgSO4, and evaporated to yield a pale yellow solid
which was triturated with ether (yield 65-74%).
E t h yl 4-[[2-(Met h yla m in o)b en zoyl]a m in o]b u t a n oa t e
(76). A mixture of N-methylisatoic anhydride (3.5 g, 19.8
mmol) was combined with 4-aminobutyric acid (2.5 g, 24.3
mmol) in dry DMF (50 mL) and heated at 100 °C for 2 h. TLC
indicated the reaction to be complete, and the DMF was
removed in vacuo. The residue was used directly for esteri-
fication which was accomplished by dissolving the residue in
100% ethanol (50 mL) and adding chlorotrimethylsilane (2.5
mL, 20 mmol). The mixture was heated at 65 °C for 6 h and
then evaporated to yield a brown syrup. Crude yield 87% from
isatoic anhydride. A small sample was purified for charac-
terization and biological testing by preparative TLC using 7%
MeOH in CH2Cl2. The remainder of the material was used
directly for preparation of compound 77. Anal. C14H20N2O3.
3-Meth yl-8-th iou r ic Acid (25). The pyrimidinediamine
32 (100 mg, 0.63 mmol) was combined with potassium ethyl
xanthate (810 mg, 5 mmol) and DMF (10 mL) and heated at
100 °C. The suspension became green almost immediately,
and the reaction was complete after 30 min by TLC. After a
total reaction time of 1 h, the mixture was cooled, filtered,
washed with Et2O, and dried to yield an off-white solid (310
mg) which presumably contained the unreacted potassium
ethyl xanthate and the potassium salt of the desired product.
The solid was suspended in water (5 mL) and heated to
dissolve. Glacial acetic acid was added to pH 5, and a vigorous
effervescence was noted. A white solid formed which was
filtered warm, washed with water and then ethanol, and dried
1
to yield 99 mg (79%) of the title compound: mp >320 °C; H
NMR (DMSO-d6) δ 13.40, 12.92 and 11.80 (3br s, 3H, NHs),
3.28 (s, 3H, CH3). Anal. C6H6N4O2S.
3-n -P r op ylxa n th in e (29). The pyrimidinediamine 28 (750
mg) was combined with diethoxymethyl acetate (7 mL) and
heated at 80 °C for 2 h. The mixture was evaporated to
dryness, water (5 mL) was added, and the mixture heated for
20 min to near boiling. The resulting solution was then
allowed to evaporate slowly to yield off-white crystals: yield
680 mg (86%); mp 282-284 °C (lit.15 mp 291-292 °C).
Gen er a l P r oced u r e for Rin g Closu r e of P yr im id in ed i-
a m in es to P ter id in es (49-55). The o-diamine (2 mmol) was
suspended in water (20 mL) and heated to above 70 °C before
a solution of glyoxal-sodium bisulfite addition product (10
mmol in 25 mL water) was added with stirring. The pale
green suspension slowly became light amber and clear. After
the suspension was heated for 5 min, TLC indicated reaction
was complete. The mixture was cooled, extracted with ethyl
acetate (5 × 40 mL), dried over MgSO4, and evaporated to
provide the desired product in 70 and 85% yield. 1H NMR
Eth yl 1-Meth yl-1,4-d ih yd r o-2,4-d ioxo-3(2H)-qu in a zo-
lin ebu ta n oa te (77). The residue from 76 was combined with
ethyl chloroformate (10 mL) and heated at 90 °C for 1 h. The
mixture was cooled and poured into saturated aqueous sodium
bicarbonate (50 mL) with stirring and after 10 min extracted