Synthesis of novel N2-adamantyl derivatives of 2-amino-6-methyl-4(3H)-pyrimidinone as potential activators of tumor necrosis factor (TNF) release

Article abstract of DOI:10.1007/s10593-006-0243-7

A method has been developed for the synthesis of N²-adamantyl-2- amino-6-methyl-4(3H)-pyrimidinones based on the reaction of (adamant-1-yl) alkylamine with 2-(ethylsulfanyl)-6-methyl-4(3H)-pyrimidinone which can lead to the corresponding derivatives in which the exocyclic nitrogen atom and the adamantyl radical are separated by a hydrocarbon fragment.

Full text of DOI:10.1007/s10593-006-0243-7

Chemistry of Heterocyclic Compounds, Vol. 42, No. 10, 2006
SYNTHESIS OF NOVEL N2-ADAMANTYL
DERIVATIVES OF 2-AMINO-6-METHYL-
4(3H)-PYRIMIDINONE AS POTENTIAL ACTIVATORS
OF TUMOR NECROSIS FACTOR (TNF) RELEASE
I. A. Novakov, B. S. Orlinson, R. V. Brunilin, M. B. Nawrozkij, E. N. Savel'ev,
and G. A. Novikova
A method has been developed for the synthesis of N2-adamantyl-2-amino-6-methyl-4(3H)-pyrimidinones
based on the reaction of (adamant-1-yl)alkylamine with 2-(ethylsulfanyl)-6-methyl-4(3H)-pyrimidinone
which can lead to the corresponding derivatives in which the exocyclic nitrogen atom and the adamantyl
radical are separated by a hydrocarbon fragment.
Keywords: (adamant-1-yl)alkylamines, 2-(adamant-1-yl)alkylamino-6-methyl-4(3H)-pyrimidinones,
2-(ethylsulfanyl)- 6-methyl-4(3H)-pyrimidinone, aminolysis.
2-(1-Adamantylamino)-substituted hetarenes show interest as inducers of the release of tumor necrosis
factor [1]. Hence they can be considered as potential agents for the immunotherapy of malignant tumors. As was
shown by a group of Polish investigators the most active are the corresponding 6-methylpyrimidine [2] and
6-methylpyridine [3] derivatives, some of which have reached preclinical stage investigation. Hence the
synthesis and study of novel members of this series of substances is a current goal.
The preparation of these compounds by the reaction of aminohetarenes with 1-adamantanol in the
presence of trifluoroacetic acid (needed to generate the adamantyl cation in situ) has been reported [1, 2].
However this method does not permit the synthesis of the corresponding adamantyl derivatives in which the
adamantane ring and the amino group are separated by a hydrocarbon fragment.
O
O
EtOCH2CH2OH
NH
NH
NHR
RNH2
+
–EtSH
Me
N
S
Me
N
1a–e
3a–e
Me
2
1, 3 a R = 1-AdCH2, b R = 1-AdCH(Et), c R = 1-Ad(CH)Ph, d R = 1-AdCH2CH2,
e R = 1-AdCH2CH(Me)
__________________________________________________________________________________________
Volgograd State Technical University, Volgograd 400131, Russia; e-mail: thiouracil@rambler.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1541-1544, October, 2006. Original
article submitted May 19, 2005.
0009-3122/06/4210-1331©2006 Springer Science+Business Media, Inc.
1331

With the aim of synthesizing adamantyl-substituted aminohetarenes we have studied the reaction of a
series of adamantane-containing amines 1a-e with 2-(ethylsulfanyl)-6-methyl-4(3H)-pyrimidinone (2) (prepared
as in [4]) and we have shown that the corresponding 2-[(1-adamantyl)alkyl]-6-methyl-4(3H)-pyrimidinones 3a-e
are formed.
The reactions were carried out by refluxing components 1 and 2 in 2-ethoxyethanol medium. The latter
was used in view of its high dielectric permittivity, boiling point, and ability specifically to solvate the transition
states of a series of ionic reactions.
We have shown that, while in the case of adamantylalkylamines 1a-e the yield of the target compounds
reaches 37-82%, for 4-(1-adamantyl)aniline the target compound could not be prepared, evidently connected
with the markedly lower basicity and nucleophilicity of this amine when compared with the rest.
At the same time, for aliphatic amines the maximum yield is observed in cases where the amino group
and the adamantane fragment were separated by a two-carbon bridge (amines 1d,e) whereas in the
1-adamantylmethylamine derivatives 1a,b the yield of the corresponding pyrimidinones 3a,b was much lower.
This can also be explained by the fact that the basicity of amine 1d (pKa of the conjugated acid 16.84 [5]) is
greater than the amine 1e (16.41). The basicities of amines 1a and 1b (pKa of the conjugated acid 16.22 [5] and
16.00 respectively) are lower than amines 1d,e. One exception is the amine 1c in which the greater yield of the
target derivative 3c is explained by the much lower solubility and related loss upon purification.
We propose that the reaction has the character of a solvolytic fission of the starting 2. This is indirectly
confirmed by the fact that an iminothioether element is present in its chemical structure which governs its ability
to undergo nucleophilic attack at the C(2) atom of the pyrimidine heterocycle. Such a hypothetical mechanism is
indirectly confirmed by literature data for the nucleophilic substitution of the methoxy group in 2-methoxy-
4(3H)-pyrimidinones in the presence of potassium alkoxide in the corresponding anhydrous alcohol medium [6-
8]. The higher reactivity of thio analogs of these materials evidently determines their susceptibility to solvolytic
fission by amines, having a lower basicity and nucleophilicity when compared with potassium alkoxide.
This proposal for the reaction mechanism is also confirmed by the fact that, if carried out in the absence
of solvent (aiding the dissociation of the amine and pyrimidinone 2) a sharp lowering of the yield of the target
derivatives 3 is seen and a marked tarring of the reaction mixture occurs. Similarly, lowering of the yield of the
target products occurs when changing 2-ethoxyethanol for 1,2-dimethoxyethane (a lower boiling solvent with a
lower dielectric permittivity).
EXPERIMENTAL
1H NMR spectra were recorded on a Varian Mercury 300B (300 MHz) instrument with HMDS
(δ 0.05 ppm) as internal standard. Melting points were determined on a MelTemp 3.0 instrument at a heating rate
of 10°C/min. The basicities of the amines 1b,c,e were determined by potentiometric titration using a reported
method [5].
2-[1-(1-Adamantyl)propyl]amino-6-methyl-4(3H)-pyrimidinone (3b). A mixture of the pyrimidinone
2 (2 g, 11.7 mmol), amine 1b (4.5 g, 23.6 mmol) and EtOCH2CH2OH (10 ml) was refluxed for 6 days, solvent
was distilled off under vacuum, and the residue was divided between CHCl3 (120 ml) and a 10% aqueous
solution of citric acid (pH 4). The organic phase was separated, washed with water (3 × 50 ml) and NaHCO3
solution (50 ml), dried over Na2SO4, and evaporated under reduced pressure. The residue was chromatographed
on a Merck Kieselgel 60 silica gel (40-60 µm, 40 g) using C6H14–AcMe–EtOH (12:3:1) as eluent. The eluates
containing the target material were combined and evaporated in a vacuum and the residue was crystallized twice
1
from C6H14. Yield 1.3 g (37%); mp 217-219°C (C6H14). H NMR spectrum (CCl4), δ, ppm (J, Hz): 0.86 (3H, t,
J = 7.3, CH3); 1.13-1.24 (2H, m, CH2); 1.56 (6H, s, CH2 (adamantane)); 1.62 (6H, s, CH2 (adamantane)); 1.94
1332

(3H, s, CH (adamantane)); 2.05 (3H, s, CH3); 3.66 (1H, t, J = 9.8, CH); 5.27 (1H, s, 5-CH); 7.02 (1H, d, J = 9.2,
N(2)H); 10.81 (1H, s, N(3)H). Found, %: C 72.20; H 9.00; N 13.67. C18H27N3O. Calculated, %: C 71.72; H 9.03;
N 13.94.
2-(1-Adamantylmethyl)amino-6-methyl-4(3H)-pyrimidinone (3a) was prepared similarly to
compound 3b from amine 1a and pyrimidinone 2 (duration of refluxing 3 days). Yield 46%; mp 244-246°C
(EtOH). 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 1.40 (6H, d, J = 9.8, CH2 (adamantane)); 1.65-1.49 (6H,
m, CH2 (adamantane)); 1.90-1.95 (6H, m, CH3, CH (adamantane)); 2.94 (2H, s, CH2); 5.32 (1H, d, J = 9.8, 5-
CH); 6.27 (1H, s, N(2)H); 10.22 (1H, d, N(3)H). Found, %: C 70.50; H 8.47; N 15.01. C16H23N3O. Calculated, %:
C 70.30; H 8.48; N 15.37.
2-[(1-Adamantyl)(phenyl)methyl]amino-6-methyl-4(3H)-pyrimidinone (3c) was prepared from
1
amine 1c and pyrimidine 2 similarly to 3b. Yield 64%; mp 297-299°C, decomp. (DMSO–water). H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 1.34-1.45 (6H, m, CH2 (adamantane)); 1.50-1.57 (6H, m, CH2
(adamantane)); 1.86 (3H, s, CH (adamantane)); 1.89 (3H, s, CH3); 4.65 (1H, d, J = 9.4, CH); 5.34 (1H, s, 5-CH);
7.11-7.28 (6H, m, C6H5, N(2)H); 10.23 (1H, br. s, N(3)H). Found, %: C 76.00; H 7.80; N 11.84. C22H27N3O.
Calculated, %: C 75.61; H 7.79; N 12.02.
2-[2-(1-Adamantyl)ethyl]amino-6-methyl-4(3H)-pyrimidinone (3d) was prepared from amine 1d and
the pyrimidinone 2 similarly to compound 3b (duration of refluxing 3 days). Yield 82%; mp 185-187°C,
1
decomp. (EtOH). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 1.23 (2H, t, J = 7.9, CH2); 1.45 (6H, s, CH2
(adamantane)); 1.60 (6H, dd, J1 = 12.2, J2 = 8.6, CH2 (adamantane)); 1.88 (3H, s, CH (adamantane)); 1.97 (3H,
s, CH3); 3.19 (2H, br. s, CH2); 5.35 (1H, s, 5-CH); 6.25 (1H, s, N(2)H); 10.37 (1H, br. s, N(3)H). Found, %:
C 70.88; H 8.75; N 14.55. C17H25N3O. Calculated, %: C 71.04; H 8.77; N 14.62.
2-[1-(1-Adamantyl)-2-propyl]amino-6-methyl-4(3H)-pyrimidinone (3e) was prepared from amine 1e
and pyrimidinone 2 similarly to compound 3b (duration of refluxing 4 days). Yield 52%; mp 209-211°C (EtOH).
1H NMR spectrum (CCl4), δ, ppm (J, Hz): 1.13 (3H, d, J = 6.11, CH3); 1.21-1.39 (2H, m, CH2); 1.50-1.65 (12H,
m, CH2 (adamantane)); 1.90 (3H, s, CH (adamantane)); 2.12 (3H, s, CH3); 4.13 (1H, br. s, CH); 5.39 (1H, s, 5-
CH); 6.80 (1H, d, J = 6.7, N(2)H); 10.82 (1H, br. s, N(3)H). Found, %: C 72.00; H 9.03; N 13.89. C18H27N3O.
Calculated, %: C 71.72; H 9.03, N 13.94.
REFERENCES
1.
J. K. Mauri, W. Lasek, A. Gorska, T. Switaj, M. Wamil, I. Mlynarczuk, and Z. Kazimierczuk,
Anticancer Drug Des., 16, 73 (2001).
2.
3.
Z. Kazimierczuk, A. Gorska, T. Switaj, and W. Lasek, Bioorg. Med. Chem.. Lett., 11, 1197 (2001).
W. Lasek, T. Switaj, J. Sienko, M. Kasprzycka, G. Basak, M. Miklaszewicz, M. Maj, D. Nowis,
T. Grzela, J. Golab, I. Mlynarczuk, A. Jalili, B. Kaminska, M. Dziembowska, K. Czajkowski,
M. Nowaczyk, A. Gorska, and Z. Kazimierczuk, Cancer Chemother. Pharmacol., 50, 213 (2002).
I. A. Novakov, B. S. Orlinson, and M. B. Nawrozky, Russian Federation Patent 2238269,
http://v3.espacenet.com/textdoc?DB=EPODOC&IDX=RU2238269&F=0.
B. A. Korolev, A. P. Khardin, S. S. Radchenko, I. A. Novakov, and B. S. Orlinson, Zh. Org. Khim., 14,
1632 (1978).
M. Botta, M. Artico, S. Massa, A. Gambacorta, M. E. Marongiu, A. Pani, and P. La Colla, Eur. J. Med.
Chem., 27, 251 (1992).
M. Artico, S. Massa, A. Mai, M. E. Marongiu, G. Piras, E. Tramontano, and P. La Colla, Antiviral
Chem. Chemother., 4, 361 (1993).
4.
5.
6.
7.
8.
S. Massa, A. Mai, M. Artico, G. Sbardella, E. Tramontano, A. G. Loi, P. Scano, and P. La Colla,
Antiviral Chem. Chemother., 6, 1 (1995).
1333