Synthesis of new derivatives of 6-(1-adamantylmethyl)-4(3H)-pyrimidinone

Full text of DOI:10.1134/S1070428009020274

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 2, pp. 316−317. © ©Pleiades Publishing, Ltd., 2009.
Original Russian Text © ©I.A. Novakov, B.S. Orlinson, M.B. Navrotskii, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 2,
pp. 325−326.
SHORT
COMMUNICATIONS
Synthesis of New Derivatives
of 6-(1-Adamantylmethyl)-4(3H)-pyrimidinone
I. A. Novakov, B. S. Orlinson, and M. B. Navrotskii
Volgograd State Technical University, Volgograd, 400131 Russia
e-mail: thiouracil@rambler.ru
Received May 4, 2005; final version May 4, 2008
DOI: 10.1134/S1070428009020274
Many 6-(arylmethyl)-2-thiouracil derivatives are
endowed with a pronounced anti-HIV-1 activity [1]. In
this connection their analogs were synthesized, probable
anti-HIV-1 agents, new derivatives of 6-(1-adamantyl-
methyl)-4(3H)-pyrimidinone: 6-(1-adamantylmethyl)iso-
cytosine and 6-(1-adamantylmethyl)-2-thiouracil. The
synthesis was performed starting with 2-(1-adamantyl)-
acetic acid.
Under treatment with phosphorus pentachloride the
2-(1-adamantyl)acetic acid was converted into the acid
chloride that was used for acylation of 2,2-dimethyl-1,3-
dioxane-4,6-dione.After the alcoholysis of the acylation
product we obtained 3-oxoester that was converted into
the corresponding derivatives of 4(3H)- pyrimidinone by
the condensation with guanidine or thiourea in basic
medium.
O
O
O
O
O
Me
OH
Cl
Me
Me
O
O
OH
PCl5
Me
Ad
Ad
PhMe
Et N/CH Cl
O
O
3
2
2
Ad
O
i-PrOH
O
O
N
Me
O
NH
(H N) CS
NH
NH2
2
2
(H2N)2CNH
Me
O
Ad
NaOMe/MeOH
Ad
NaOMe/MeOH
N
H
S
Ad
O
Due to the low reactivity of the 2-(1-adamantyl)acetyl
chloride we failed to obtain the isopropyl 4-(1-adamantyl)-
Owing to strong shielding of the carbonyl group of the
3-oxoester with the adamantly fragment and to the
positive inductive effect of the adamantly moiety that
decreased the CH-acidity and capability to enolization of
the corresponding 3-oxoester the previously described
methods [3] failed to yield the desired derivatives of
2-thiouracil and isocytosine. However the application of
a solvent of a higher dielectric permittivity (MeOH instead
3
-oxobutanoate by the previously described method [2].
+
using Et N (pK
10.57, did not undergo quaternization
3
BH
+
with acyl halides) as the base instead of Py (pKBH 5.23,
underwent quaternization with acyl halides) and prolong-
ing the reaction time made it possible to obtain the
isopropyl 4-(1-adamantyl)-3-oxobutanoate in 62% yield.
316

SYNTHESIS OF NEW DERIVATIVES OF 6-(1-ADAMANTYLMETHYL)-4(3H)-PYRIMIDINONE
317
of EtOH) and of a larger amount of base (3 equiv instead
of 2 equiv) afforded the target derivatives of 4(3H)-
pyrimidinone in high yields. This result followed from the
increased reaction rate owing to the higher permittivity
of the medium, and also from the higher concentration of
the enolate of the initial 3-oxoester.
10.56 g (77%), mp 303–304°C (ACOH). IR spectrum
–1
(KBr), cm : 1155 (C–O), 1195 (C=S), 1550 (NH), 1660
(C=O), 2850 (CH ), 2900 (CH ), 3150 (NH), 3200
2
2
1
(NH), 3450 (NH). H NMR spectrum, ppm: 1.48–
1.64 m (12H, 6CH2), 1.91 s (3H, 3CH), 2.14 s (2H,
CH2), 5.52 s (1H, CH), 11.90 s (1H, NH), 12.26 s
(
[
(
1H, NH). Mass spectrum, m/z (I %): 276 (34.6)
M] , 149 (0.77), 135 (100), 113 (5.4), 107 (9.2), 93
rel
2
-(1-Adamantyl)acetylchloride. A mixture of
+
1
5
0.28 g (53.0 mmol) of 2-(1-adamantyl)acetic acid,
0 ml of anhydrous PhMe, and 12.15 g (58.3 mmol) of
20.8), 79 (27.7), 67 (12.2). Found, %: C 65.20; H 7.30;
+
N 10.11. M 276. C H N OS. Calculated, %: C 65.18;
15
20
2
PCl was boiled for 2 h. The solvent was removed at
5
H 17.29; N 10.14. M 276.40.
a reduced pressure. The residue was purified by
distillation in a vacuum. Yield 9.70 g (86%), bp 110–111°C
6
-(1-Adamantylmethyl)isocytosine. A mixture of
a solution of 3.29 g (60.9 mmol) of NaOMe in 30 ml
of anhydrous MeOH, 4.2 g (31.6 mmol) of guanidine
propionate, and 5.56 g (20 mmol) of isopropyl 4-(1-
adamantyl)-3-oxobutanoate was boiled for 24 h, the
solvent was distilled off, and the residue was mixed with
water (200 ml), acidified with 1 N AcOH to pH 6, and
filtered. Yield 4.41 g (85%), mp >350°C (DMSO). IR
(
2 mm Hg).
Isopropyl 4-(1-adamantyl)-3-oxobutanoate. To
a solution of 7.48 g (51.9 mmol) of 2,2-dimethyl-1,3-
dioxane-4,6-dione in 20 ml of anhydrous CH Cl at 0°C
2
2
was dropwise added while stirring within 30 min 17.5 ml
12.71 g, 125.6 mmol) of anhydrous Et N. Then at 0°C
(
3
was dropwise added while stirring within 2–2.5 h a solu-
tion of 10.70 h (50.3 mmol) of 2-(1-adamantyl)acetyl
chloride in 15 ml of anhydrous CH Cl , and then the
reaction mixture was left overnight. Afterwards it was
diluted with 25 ml of CH Cl and washed with 10% water
solution of citric acid (200 ml). The organic layer was
separated, the water layer was extracted with CH Cl
(
additionally washed with 10% water solution of citric
acid (100 ml) and with water, and dried with anhydrous
Na SO . On removing the solvent in a vacuum the residue
was mixed with anhydrous i-PrOH (100 ml) and boiled
for 3.5 h under protection from moisture. The solvent
was removed under a reduced pressure, and the residue
was distilled in a vacuum. Yield 8.69 g (62%), bp 163–
–1
spectrum (KBr), cm : 1380 (CH), 1455 (CH), 1510 (NH),
1
660 (C=O), 2900 (CH ), 3080 (NH), 3350 (NH).
2
2
2
1
H NMR spectrum, ppm: 1.53–1.67 m (12H, 6CH2),
1
.92 s (3H, 3CH), 2.04 s (2H, CH ), 5.30 s (1H, CH),
2
2
2
6.24 s (2H, NH ), 10.46 br.sC (1H, NH). Mass spectrum,
2
+
m/z (I , %): 259 (100) [M] , 243 (2.6), 216 (4.0), 202 (8.6),
rel
2
2
149 (3.3), 135 (60.3), 129 (28.5), 107 (7.9). Found, %:
2×25 ml). The combined organic solutions were
+
C 69.49; H 8.14; N 16.19. M 259. C H N O. Calculated,
1
5 21 3
%: C 69.47; H 8.16; N 16.20. M 259.35.
IR spectra were recorded on a spectrophotometer
2
4
1
Perkin-Elmer 580. H NMR spectra of compounds
obtained were registered on a spectrometer Bruker
DRX-500 at operating frequency 500.13 MHz in
DMSO-d , internal reference HMDS. Mass spectra
6
were measured on a GC-MS instrument Varian MAT-
–
1
1
65°C (1.5 mm Hg). IK spectrum (thin film), cm : 1270
111 at direct admission of the sample into the ion source,
[
(
(
C(O)OR], 1455 (CH ), 1710 (C=O), 2850 (CH ), 2900
CH ). Mass spectrum, m/z (I %): 278 (1.4) [M] , 235
1.5), 219 (1.5), 191 (1.3), 177 (5.7), 149 (3.6), 135 (100),
2
2
in electron impact mode (70 eV). The melting points
were measured on MelTemp 3.0 device, heating rate
+
2
rel
10 deg/min. The homogeneity of compounds obtained was
+
1
07 (7.1). Found, %: C 73.29; H 9.46. M 278. C H O .
17
26
3
confirmed by TLC on Sorbfil plates, spots visualization
under UV irradiation.
Calculated, %: C 73.34; H 9.41. M 278.39.
6
-(1-Adamantylmethyl)-2-thiouracil. A solution
of 16.2 g (150 mmol) of NaOMe, 7.61 g (100 mmol) of
H N) CS, and 13.9 g (50 mmol) of isopropyl 4-(1-
REFERENCES
(
2
2
adamantyl)-3-oxobutanoate in 50 ml of anhydrous MeOH
was boiled at stirring for 24 h, methanol was distilled
off in a vacuum on a steam bath, and the residue was
dissolved in 200 ml of water, and the solution was filtered.
The water filtrate was acidified to pH 3–4 with 1 N
AcOH. The separated precipitate was filtered off,
washed with water (100 ml), and dried in air. Yield
1. Mai, A., Artico, M., Sbardella, G., Massa, S., Loi, A.G.,
Tramontano, E., Scano. P., La Colla, P., J. Med. Chem. 1995,
vol. 38, p. 3258.
2
. Oikawa, Y., Sugano, K., and Yonemitsu, O., J. Org. Chem.,
978, vol. 43, p. 2087.
. Anderson, G.W., Halverstadt, I.F., Miller, W.H., and Rob-
lin, R.O.Jr., J. Am. Chem. Soc. 1945, vol. 67, p. 2197.
1
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 2 2009