Synthesis of fluoro-containing pyrimidinones from hexafluoroacetone(ethoxycarbonylimine)

Article abstract of DOI:10.1007/s11172-005-0439-5

Cyclocondensation of hexafluoroacetone(ethoxycarbonylimine) with various 1,3-C,N-bisnucleophiles afforded novel bis(trifluoromethyl)pyrimidinones, including fused ones, in preparative yields.

Full text of DOI:10.1007/s11172-005-0439-5

1518
Russian Chemical Bulletin, International Edition, Vol. 54, No. 6, pp. 1518—1522, June, 2005
Synthesis of fluoroꢀcontaining pyrimidinones
from hexaf luoroacetone(ethoxycarbonylimine)
V. B. Sokolovꢀ and A. Yu. Aksinenko
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (095) 785 7024. Eꢀmail: alaks@ipac.ac.ru
Cyclocondensation of hexafluoroacetone(ethoxycarbonylimine) with various 1,3ꢀC,Nꢀbisꢀ
nucleophiles afforded novel bis(trifluoromethyl)pyrimidinones, including fused ones, in preꢀ
parative yields.
Key words: hexafluoroacetone(ethoxycarbonylimine), 1,3ꢀC,Nꢀbisnucleophiles, pyrimiꢀ
dineꢀ2,4ꢀdiones, pyrimido[4,5ꢀd]pyrimidineꢀ2,4,7ꢀtriones, 4,6,7,8ꢀtetrahydropyrimidineꢀ2,6ꢀ
diones, pyrimido[4,5ꢀd]pyrimidineꢀ2,5ꢀdiones, heterocyclization, organofluorine compounds.
Scheme 1
Alkoxycarbonylimines of hexafluoroacetone, as well
as its acylimines, are starting materials for the synthesis of
various heterocyclic compounds containing geminal
trifluoromethyl groups. These are used as heterodienes
and dienophiles in cycloaddition reactions with Nꢀcyano
amines,1 nitriles,2 phosphorus(III) acid derivatives,3,4 and
cyclopentadiene2 and as 1,3ꢀbiselectrophilic reagents in
cyclocondensation reactions with 1,3ꢀbisnucleophiles.5,6
In the present work, we obtained a number of novel
2,2ꢀbis(trifluoromethyl)pyrimidinones by cyclocondensaꢀ
tion of 1,3ꢀC,Nꢀbisnucleophiles with readily available
hexafluoroacetone(ethoxycarbonylimine). Some substiꢀ
tuted pyrimidinones were reported to exhibit various
types of biological (e.g., antimicrobial7 and antiviral8) acꢀ
tivity and to be inhibitors of serine proteases.9 All this
makes it topical to search for routes to compounds of
this class.
In this reaction, we used 6ꢀaminouracil, 6ꢀaminothioꢀ
uracil, Nꢀsubstituted 3ꢀaminocyclohexenones, 3ꢀaminoꢀ
crotononitrile, and 6ꢀaminopyrimidinones as bisnucleoꢀ
philic reagents.
It was found that hexafluoroacetone(ethoxycarbonylꢀ
imine) (1), like its benzoylimine,5 exothermically reacts
at 20 °C with N,Nꢀdimethylꢀ6ꢀaminouracil (2a) to give
C(5)ꢀalkyl derivative 3. This product was converted into
dihydropyrimidopyrimidinetrione 4a by heating in DMF
(1 h, 90 °C) in the presence of catalytic amounts of Et3N
(Scheme 1).
The cyclocondensation of imine 1 with 6ꢀaminouracils
2b—e, 6ꢀaminothiouracils 5a—d, 3ꢀaminocyclohexenones
6a—g, 3ꢀaminocrotononitrile (7), and 6ꢀaminopyrimiꢀ
dinones 8a,b (equimolar amounts of the reagents were
mixed in DMF at 20 °C; after the exothermic reaction
was completed, the mixture was heated at 90—100 °C for
5 h in the presence of catalytic amounts of Et3N; no
intermediate adducts were isolated) yielded pyrimidiꢀ
nones 4b—e, 9a—d, 10a—g, 11, and 12a,b, respectively
(Scheme 2).
Pyrimidinones 4 and 9—12 were obtained in 69—88%
yields as crystalline solids. Their compositions and strucꢀ
tures were confirmed by elemental analysis and NMR
spectroscopy. The 1H and 19F NMR spectra contain charꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1474—1478, June, 2005.
1066ꢀ5285/05/5406ꢀ1518 © 2005 Springer Science+Business Media, Inc.

Fluoroꢀcontaining pyrimidinones
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 6, June, 2005
1519
Scheme 2
2,4: R = Me (b), Ph (c), 4ꢀMeC6H4 (d), CH2Ph (e); 5, 9: R = Ph (a), 4ꢀMeC6H4 (b), 4ꢀFC6H4 (c), CH2CH2Ph (d);
6, 10: R = Bu (a), 4ꢀFC6H4 (b), 3ꢀClC6H4 (c), CH2Ph (d), CH2CH2Ph (e), 2ꢀClC6H4CH2 (f), (furanꢀ2ꢀyl)methyl (g);
8, 12: X = Ph (a), CO2Et (b)
acteristic signals at δ 9.0—12.0 for NH protons and at
δ 2.8—6.4 for geminal CF3 groups.
Thus, the cyclocondensation reactions of hexafluoroꢀ
acetone(ethoxycarbonylimine) with enamines allowed the
preparation of various novel (including fused) 2,2ꢀbis(triꢀ
fluoromethyl)pyrimidinones.
The structure of pyrimidopyrimidinedione 9c was adꢀ
ditionally confirmed by chemical transformations. For
instance, keeping of equimolar amounts of compound 9c,
triethylamine, and benzyl chloride or ethyl chloroacetate
in DMF at 20 °C for 12 h gave pyrimidopyrimidinediones
12a,b (see Scheme 2). Compounds 12a,b were also obꢀ
tained independently via Sꢀalkylation of aminothiouracil
5c with activated chlorides XCH2Cl (X = Ph and CO2Et)
followed by cyclocondensation of the resulting aminoꢀ
pyrimidinones 8a,b with imine 1 into compounds 12a,b
(Scheme 3).
Experimental
1
H and 19F NMR spectra were recorded on a Bruker
DXP 200 spectrometer. Melting points were determined in glass
capillaries. Hexafluoroacetone(ethoxycarbonylimine) (1) was
prepared according to a known procedure.10 The starting
6ꢀaminouracils 2,11 6ꢀaminothiouracils 5,11 and 3ꢀaminoꢀ
cyclohexenones 6 12 were prepared according to available proꢀ
cedures. 3ꢀAminocrotononitrile (Aldrich) was used as purchased.
6ꢀAminoꢀ5ꢀ(2ꢀethoxycarbonylaminoꢀ1,1,1,3,3,3ꢀhexafluoroꢀ
propanꢀ2ꢀyl)ꢀ1,3ꢀdimethylꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ2,4ꢀ
dione (3). A mixture of imine 1 (2.37 g, 0.01 mol) and aminouracil
2a (1.55 g, 0.01 mol) in DMF (10 mL) was stirred at 20 °C for
1 h and poured into water (50 mL). The precipitate that formed
was filtered off and recrystallized from benzene to give comꢀ
pound 3 (3.15 g, 80%), m.p. 199—201 °C. Found (%): C, 36.58;
Scheme 3
X = Ph, CO2Et

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Russ.Chem.Bull., Int.Ed., Vol. 54, No. 6, June, 2005
Sokolov and Aksinenko
H, 3.47; N, 14.11. C12H14F6N4O4. Calculated (%): C, 36.74;
H, 3.60; N, 14.28. 1H NMR (DMSOꢀd6), δ: 1.22 (t, 3 H, CMe,
J = 7.1 Hz); 3.16, 3.32 (both s, 3 H each, NMe); 4.08 (q, 2 H,
CH2O, J = 7.1 Hz); 6.66 (s, 2 H, NH2); 8.04 (s, 1 H, NH).
19F NMR (DMSOꢀd6), δ: 5.29, 17.76 (both s, 1 : 1).
1,3ꢀDimethylꢀ5,5ꢀbis(trifluoromethyl)ꢀ5,8ꢀdihydroꢀ1H,6Hꢀ
pyrimido[4,5ꢀd]pyrimidineꢀ2,4,7ꢀtrione (4a). A. Triethylamine
(0.2 mL) was added to a solution of compound 3 (3.92 g, 0.01 mol)
in DMF (10 mL). The reaction mixture was heated at 90—100 °C
for 5 h, cooled, and poured into water (50 mL). The precipitate
that formed was filtered off and recrystallized from 50% EtOH to
give compound 4a (3.22 g, 86%), m.p. 291—293 °C. Found (%):
C, 34.51; H, 2.15; N, 16.11. C10H8F6N4O3. Calculated (%):
C, 34.69; H, 2.33; N, 16.18. 1H NMR (DMSOꢀd6), δ: 3.21, 3.42
(both s, 3 H each, NMe); 8.95, 10.62 (both s, 1 H each, NH).
19F NMR (DMSOꢀd6), δ: 5.41 (s).
heated at 90—100 °C for 5 h, cooled, and poured into water
(50 mL). The precipitate that formed was filtered off and recrysꢀ
tallized from 50% EtOH to give compound 4a (3.11 g, 83%).
1ꢀMethylꢀ5,5ꢀbis(trifluoromethyl)ꢀ5,8ꢀdihydroꢀ1H,6Hꢀpyriꢀ
mido[4,5ꢀd]pyrimidineꢀ2,4,7ꢀtrione (4b), 1ꢀphenylꢀ5,5ꢀbis(triꢀ
fluoromethyl)ꢀ5,8ꢀdihydroꢀ1H,6Hꢀpyrimido[4,5ꢀd]pyrimidineꢀ
2,4,7ꢀtrione (4c), 1ꢀ(4ꢀmethylphenyl)ꢀ5,5ꢀbis(trifluoromethyl)ꢀ
5,8ꢀdihydroꢀ1H,6Hꢀpyrimido[4,5ꢀd]pyrimidineꢀ2,4,7ꢀtrione
(4d), 1ꢀbenzylꢀ5,5ꢀbis(trifluoromethyl)ꢀ5,8ꢀdihydroꢀ1H,6Hꢀ
pyrimido[4,5ꢀd]pyrimidineꢀ2,4,7ꢀtrione (4e), 8ꢀphenylꢀ7ꢀthioxoꢀ
4,4ꢀbis(trifluoromethyl)ꢀ4,6,7,8ꢀtetrahydroꢀ1H,3Hꢀpyrimiꢀ
do[4,5ꢀd]pyrimidineꢀ2,5ꢀdione (9a), 8ꢀ(4ꢀmethylphenyl)ꢀ7ꢀ
thioxoꢀ4,4ꢀbis(trifluoromethyl)ꢀ4,6,7,8ꢀtetrahydroꢀ1H,3Hꢀpyriꢀ
mido[4,5ꢀd]pyrimidineꢀ2,5ꢀdione (9b), 8ꢀ(4ꢀfluorophenyl)ꢀ7ꢀ
thioxoꢀ4,4ꢀbis(trifluoromethyl)ꢀ4,6,7,8ꢀtetrahydroꢀ1H,3Hꢀpyriꢀ
mido[4,5ꢀd]pyrimidineꢀ2,5ꢀdione (9c), 8ꢀphenethylꢀ7ꢀthioxoꢀ
4,4ꢀbis(trifluoromethyl)ꢀ4,6,7,8ꢀtetrahydroꢀ1H,3Hꢀpyrimiꢀ
do[4,5ꢀd]pyrimidineꢀ2,5ꢀdione (9d), 1ꢀbutylꢀ7,7ꢀdimethylꢀ4,4ꢀ
bis(trifluoromethyl)ꢀ4,6,7,8ꢀtetrahydroꢀ1H,3Hꢀquinazolineꢀ2,5ꢀ
B. A mixture of imine 1 (2.37 g, 0.01 mol) and aminouracil
2a (1.55 g, 0.01 mol) in DMF (10 mL) was stirred at 20 °C for
1 h and Et3N (0.2 mL) was added. The reaction mixture was
Table 1. Yields, melting points, and elemental analysis data for compounds 4b—e,
9a—d, 10a—g, and 11
Comꢀ
pound
Yield
(%)
M.p.
/°C
Found
Calculated
Molecular
formula
(%)
C
H
N
4b
72
82
78
76
75
71
69
82
75
71
69
82
77
70
79
88
315—317
260—262
316—318
324—326
312—314
246—248
287—289
256—258
218—220
279—291
215—217
225—227
218—220
241—242
283—285
301—303
32.38
32.54
42.48
42.65
44.01
44.16
44.31
44.13
40.82
40.98
42.28
42.46
39.41
39.26
43.66
43.84
49.61
49.74
50.77
50.95
49.21
49.05
54.11
54.29
55.12
55.30
50.01
50.18
49.72
49.76
35.33
35.18
1.67
1.82
2.18
2.05
2.63
2.47
2.31
2.47
1.84
1.97
2.21
2.38
1.48
1.65
2.59
2.76
5.07
5.22
3.39
3.56
3.27
3.43
4.45
4.32
4.47
4.64
3.59
3.77
3.79
3.93
1.69
1.85
16.69
16.87
14.39
14.21
13.89
13.72
13.86
13.72
13.81
13.66
13.38
13.20
12.91
13.08
12.93
12.78
7.17
7.25
6.72
6.60
6.21
6.36
6.81
6.66
6.27
C9H6F6N4O3
4c
C14H8F6N4O3
C15H10F6N4O3
C15H10F6N4O3
C14H8F6N4O2S
C15H10F6N4O2S
C14H7F7N4O2S
C16H12F6N4O2S
C16H20F6N2O2
C18H15F7N2O2
C18H15ClF6N2O2
C19H18F6N2O2
C20H20F6N2O2
C18H15ClF6N2O2
C17H16F6N2O3
C8H5F6N3O
4d
4e
9a
9b
9c
9d
10a
10b
10c
10d
10e
10f
10g
11
6.45
6.33
6.16
6.67
6.83
15.22
15.38

Fluoroꢀcontaining pyrimidinones
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 6, June, 2005
1521
dione (10a), 1ꢀ(4ꢀfluorophenyl)ꢀ7,7ꢀdimethylꢀ4,4ꢀbis(trifluoroꢀ
methyl)ꢀ4,6,7,8ꢀtetrahydroꢀ1H,3Hꢀquinazolineꢀ2,5ꢀdione (10b),
1ꢀ(3ꢀchlorophenyl)ꢀ7,7ꢀdimethylꢀ4,4ꢀbis(trifluoromethyl)ꢀ
4,6,7,8ꢀtetrahydroꢀ1H,3Hꢀquinazolineꢀ2,5ꢀdione (10c), 1ꢀbenꢀ
zylꢀ7,7ꢀdimethylꢀ4,4ꢀbis(trifluoromethyl)ꢀ4,6,7,8ꢀtetrahydroꢀ
1H,3Hꢀquinazolineꢀ2,5ꢀdione (10d), 7,7ꢀdimethylꢀ1ꢀphenethylꢀ
4,4ꢀbis(trifluoromethyl)ꢀ4,6,7,8ꢀtetrahydroꢀ1H,3Hꢀquinazolineꢀ
2,5ꢀdione (10e), 1ꢀ(2ꢀchlorobenzyl)ꢀ7,7ꢀdimethylꢀ4,4ꢀbis(triꢀ
fluoromethyl)ꢀ4,6,7,8ꢀtetrahydroꢀ1H,3Hꢀquinazolineꢀ2,5ꢀdione
(10f), 1ꢀfurfurylꢀ7,7ꢀdimethylꢀ4,4ꢀbis(trifluoromethyl)ꢀ4,6,7,8ꢀ
tetrahydroꢀ1H,3Hꢀquinazolineꢀ2,5ꢀdione (10g), and 6ꢀmethylꢀ
2ꢀoxoꢀ4,4ꢀbis(trifluoromethyl)ꢀ1,2,3,4ꢀtetrahydropyrimidineꢀ5ꢀ
carbonitrile (11) were obtained from imine 1 (0.01 mol) and the
corresponding enamines (0.01 mol) as described for pyrimidiꢀ
none 4a. The yields, melting points, and spectroscopic characꢀ
teristics of compounds 4b—e, 9a—d, 10a—g, and 11 are given in
Tables 1 and 2.
6ꢀAminoꢀ2ꢀbenzylsulfanylꢀ1ꢀ(4ꢀfluorophenyl)ꢀ1,4ꢀdihydroꢀ
pyrimidinꢀ4ꢀone (8a). A mixture of 6ꢀaminothiouracil 5c (2.37 g,
0.01 mol), benzyl chloride (1.27 g, 0.01 mol), and Et3N (1.01 g,
0.01 mol) in DMF (20 mL) was kept at 20 °C for 12 h and
poured into water (50 mL). The precipitate that formed was
filtered off and recrystallized from 50% EtOH to give compound
8a (2.6 g, 80%), m.p. 187—189 °C. Found (%): C, 62.21; H, 4.17;
N, 12.97. C17H14FN3OS. Calculated (%): C, 62.37; H, 4.31;
N, 12.84. 1H NMR (DMSOꢀd6), δ: 4.25 (s, 2 H, CH2); 5.07 (s,
1 H, CH); 5.95 (s, 2 H, NH2); 7.31 (m, 7 H, H arom.); 7.45 (m,
2 H, H arom.). 19F NMR (DMSOꢀd6), δ: –30.92 (m).
Ethyl {[6ꢀaminoꢀ1ꢀ(4ꢀfluorophenyl)ꢀ4ꢀoxoꢀ1,4ꢀdihydropyriꢀ
midinꢀ2ꢀyl]sulfanyl}acetate (8b) was obtained analogously
from aminothiouracil 5c (0.01 mol) and ethyl chloroacetate
(0.01 mol). The yield of compound 8b was 2.4 g (74%),
m.p. 208—210 °C. Found (%): C, 52.13; H, 4.18; N, 12.85.
C
14H14FN3O3S. Calculated (%): C, 52.00; H, 4.36; N, 13.00.
1H NMR (DMSOꢀd6), δ: 1.25 (t, 3 H, Me, J = 7.2 Hz); 3.82 (s,
2 H, CH2); 4.14 (q, 2 H, CH2, J = 7.2 Hz); 5.07 (s, 1 H, CH);
6.05 (s, 2 H, NH2); 7.36, 7.52 (both m, 2 H each, H arom.).
19F NMR (DMSOꢀd6), δ: –31.62 (m).
7ꢀBenzylsulfanylꢀ8ꢀ(4ꢀfluorophenyl)ꢀ4,4ꢀbis(trifluoromethyl)ꢀ
1,2,3,4,5,8ꢀhexahydropyrimido[4,5ꢀd]pyrimidineꢀ2,5ꢀdione
(12a). A. A mixture of imine 1 (2.37 g, 0.01 mol), pyrimidinone
8a (3.27 g, 0.01 mol), and Et3N (0.2 mL) in DMF (10 mL) was
heated at 90—100 °C for 5 h, cooled, and poured into water
(50 mL). The precipitate that formed was filtered off and recrysꢀ
tallized from 50% EtOH to give compound 12a (4.2 g, 81%),
m.p. 220—222 °C. Found (%): C, 48.49; H, 2,68; N, 10.65.
C
21H13F7N4O2S. Calculated (%): C, 48.65; H, 2.53; N, 10.81.
1H NMR (DMSOꢀd6), δ: 4.28 (s, 2 H, CH2); 7.37 (m, 8 H,
7 H arom. + NH); 7.68 (m, 2 H, H arom.); 8.73 (s, 1 H, NH).
19F NMR (DMSOꢀd6), δ: 5.75 (s, 6 F); –30.09 (m, 1 F).
Table 2. 1H and 19F NMR spectra of compounds 4b—e, 9a—d, 10a—g, and 11 (in DMSOꢀd6)
Comꢀ
pound
δ (J/Hz)
1H
19F
4b
4c
4d
3.38 (s, 3 Н, Ме); 8.98, 10.57, 11.28 (all s, 1 H each, NH)
5.49 (s)
5.40 (s)
5.44 (s)
7.29 (m, 2 Н, H arom.); 7.51 (m, 3 Н, H arom.); 8.86, 9.37, 11.40 (all s, 1 H each, NH)
2.42 (s, 3 Н, Ме); 7.18, 7.29 (both d, 2 H each, H arom., J = 8.1);
8.78, 9.05, 11.32 (all s, 1 H each, NH)
4e
5.33 (s, 2 Н, CH2); 7.17 (d, 2 Н, H arom., J = 7.8); 7.25 (t, 1 Н, H arom., J = 7.8);
7.33 (t, 2 Н, H arom., J = 7.8); 8.78, 9.05, 11.32 (all s, 1 H each, NH)
7.41—7.64 (m, 5 Н, H arom.); 9.12, 9.67, 12.96 (all s, 1 H each, NH)
2.46 (s, 3 Н, Ме); 7.18, 7.21 (both d, 2 H each, H arom., J = 8.0);
7.38 (s, 1 Н, NH); 9.05, 12.75 (both br.s, 1 H each, NH)
5.31 (s)
9a
9b
6.27 (s)
6.44 (s)
9c
7.31 (m, 3 Н, H arom. + NH); 7.38 (m, 2 Н, H arom.); 8.97 (s, 1 Н, NH);
12.76 (br.s, 1 Н, NH)
3.05, 4.97 (both m, 2 H each, CH2); 7.14—7.44 (m, 5 Н, H arom.); 9.11, 10.97, 12.67
(all s, 1 H each, NH)
5.50 (s, 6 F);
–33.35 (m, 1 F)
6.25 (s)
9d
10a
10b
10c
10d
10e
10f
10g
11
0.96 (t, 3 Н, Ме, J = 7.6); 1.06 (s, 6 Н, 2 Ме); 1.28—1.61 (m, 4 Н, 2 CH2);
2.21, 2.58 (both s, 2 H each, CH2 ring); 3.73 (m, 2 Н, NCH2); 8.71 (s, 1 Н, NH)
0.98 (s, 6 Н, 2 Ме); 2.18, 2.23 (both s, 2 H each, CH2); 7.14—7.32 (m, 4 Н, H arom.);
9.04 (s, 1 Н, NH)
6.11 (s)
5.78 (s, 6 F);
–33.91 (m, 1 F)
6.12 (s)
1.05 (s, 6 Н, 2 Ме); 2.14, 2.25 (both s, 2 H each, CH2); 7.22 (m, 1 Н, H arom.);
7.34 (s, 1 Н, H arom.); 7.51—7.62 (m, 2 Н, H arom.); 9.21 (s, 1 Н, NH)
0.94 (s, 6 Н, 2 Ме); 2.23, 2.55 (both m, 2 H each, CH2); 5.11 (s, 2 Н, NCH2);
7.17 (d, 2 Н, H arom., J = 8.1); 7.33 (m, 3 Н, H arom.); 9.04 (s, 1 Н, NH)
0.93 (s, 6 Н, 2 Ме); 2.11, 2.22 (both s, 2 H each, CH2); 2.83 (m, 2 Н, NCH2CH2);
3.94 (m, 2 Н, NCH2); 7.20—7.31 (m, 5 Н, H arom.); 8.79 (s, 1 Н, NH)
0.92 (s, 6 Н, 2 Ме); 2.12, 2.41 (both s, 2 H each, CH2); 5.03 (s, 2 Н, NCH2);
6.96 (t, 1 Н, H arom., J = 7.8); 7.27, 7.42 (both m, 2 H each, H arom.); 9.15 (s, 1 Н, NH)
1.07 (s, 6 Н, 2 Ме); 2.27, 2.76 (both m, 2 H each, CH2); 5.05 (s, 2 Н, NCH2);
6.24, 6.37, 7.44 (all s, 1 H each, H arom.); 8.89 (s, 1 Н, NH)
6.38 (s)
6.30 (s)
6.22 (s)
6.18 (s)
2.82 (s)
2.18 (s, 3 H, Me); 9.12, 10.62 (both s, 1 H each, NH)

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Russ.Chem.Bull., Int.Ed., Vol. 54, No. 6, June, 2005
Sokolov and Aksinenko
B. A mixture of pyrimidopyrimidinedione 9c (4.28 g,
0.01 mol), benzyl chloride (1.27 g, 0.01 mol), and Et3N (1.01 g,
0.01 mol) in DMF (20 mL) was kept at 20 °C for 12 h and
poured into water (50 mL). The precipitate that formed was
filtered off and recrystallized from 50% EtOH to give compound
12a (3.9 g, 75%), m.p. 220—222 °C.
4. V. B. Sokolov, A. Yu. Aksinenko, O. V. Korenchenko, and
I. V. Martynov, Izv. Akad. Nauk SSSR, Ser. Khim., 1989,
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Akad. Nauk, Ser. Khim., 2001, 1064 [Russ. Chem. Bull., Int.
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Khim., 2003, 2053 [Russ. Chem. Bull., Int. Ed., 2003,
52, 2167].
7. M. Brands, Y. C. Grande, R. Endermann, R. Gahlmann,
J. Krüger, and S. Raddatz, Bioorg. Med. Chem. Lett., 2003,
13, 2641.
Ethyl {[1ꢀ(4ꢀfluorophenyl)ꢀ4,7ꢀdioxoꢀ5,5ꢀbis(trifluoromeꢀ
thyl)ꢀ1,4,5,6,7,8ꢀhexahydropyrimido[4,5ꢀd]pyrimidinꢀ2ꢀyl]sulfaꢀ
nyl}acetate (12b). A. Ester 12b was obtained analogously from
imine 1 (0.01 mol) and pyrimidinone 8b (0.01 mol). The yield of
compound 12b was 4.0 g (78%), m.p. 254—256 °C. Found (%):
C, 42.21; H, 2.38; N, 10.76. C18H13F7N4O4S. Calculated (%):
1
C, 42.03; H, 2.55; N, 10.89. H NMR (DMSOꢀd6), δ: 1.22 (t,
3 H, Me, J = 7.6 Hz); 3.92 (s, 2 H, CH2); 4.16 (q, 2 H, CH2O,
J = 7.6 Hz); 7.49, 7.75 (both m, 2 H each, H arom.); 9.01 (s,
1 H, NH); 10.04 (br.s, 1 H, NH). 19F NMR (DMSOꢀd6), δ:
5.73 (s, 6 F); –30.08 (m, 1 F).
B. Ester 12b was obtained from pyrimidopyrimidinedione 9c
(0.01 mol) and ethyl chloroacetate (0.01 mol) as described for
compound 12a. The yield of compound 12b was 3.8 g (74%),
m.p. 254—256 °C.
8. R. Salidino, M. C. Panti, E. Mincone, C. Cristini,
T. Palamara, P. Savini, S. Marini, and M. Botta, Bioorg.
Med. Chem. Lett., 1998, 8, 1833.
9. F. Akahoshi, A. Ashimori, T. Yshimura, T. Imada,
M. Nakajiama, N. Mitsutomi, S. Kuwahara, T. Ohtsuka,
C. Fukaya, M. Miyazaki, and N. Nakamura, Bioorg. Med.
Chem., 2001, 9, 301.
10. O. V. Korenchenko, V. B. Sokolov, A. Yu. Aksinenko, and
I. V. Martynov, Izv. Akad. Nauk SSSR, Ser. Khim., 1990,
373 [Bull. Acad. Sci. USSR, Div. Chem. Sci., 1990, 39, 313
(Engl. Transl.)].
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Received February 10, 2005;
in revised form April 11, 2005