148
N. V. Kolotova et al.
1658 (C2=O); 1H NMR spectrum in DMSO-d6 (d, ppm): 1.45
(s, 3H, CH3), 2.89, 3.27 (dd, 2H, AB-system J2 18.0 Hz,
CH2), 7.02 (d, 1H, C9H, for notations see Scheme 1), 7.81 (d,
1H, C8H), 8.70 (s, 1H, C6H); C10H9BrN2O3; m.w., 285.10.
Compound Ic. The first crystallization yields 2.0 g of a
mixture of IIIa (III: R1 = CH3, R2 = H) and Ic: m.p.,
206 – 207°C (with decomp.); IR spectrum (nmax, cm – 1):
3328 (COOH), 3142 (NH), 1678 (COOH, C=C), 1637
(COamide). Compound IIIa probably occurs in a 2-imide form,
as evidenced by the relatively low frequency of the NH
(amidine group) stretching vibrations in the IR spectrum and
by the absence of a signal due to the amide proton in the re-
gion above 8 ppm. We failed to isolate product IIIa in pure
form because repeated crystallization is accompanied by
heterocyclization with the formation of pyridopyrimidine Ic.
1H NMR spectrum of IIIa + Ic in DMSO-d6 (d, ppm):
1.42 (s, 3H, C4-CH3, Ic, 59%), 1.89 (s, 3H, –CH=C–CH3,
tate – ether (1 : 1 : 1) system; the spots on the plates were de-
tected by exposure to iodine vapor. The yields, physicoche-
mical characteristics, and spectral parameters of
pyrido[1,2-a]pyrimidines (Ia – Ic) and amide IVa are pre-
sented with comments in the description of synthesis below.
The data for compounds IV – VII are summarized in Table 1.
The data of elemental analysis coincide with the values ob-
tained by analytical calculations according to the empirical
formulas.
4-Methyl-2-oxo-3,4-dihydropyrido[1,2-a]pyrimidine-
4-carboxylic acids (Ia – Ic). To a solution of 10 mmole of
2-aminopyridine, 2-amino-5-bromopyridine, or 2-amino-4-
picoline in 40 – 50 ml of ethyl acetate was added with stir-
ring a solution of citraconic anhydride (1.12 g, 10 mmole) in
30 ml of ethyl acetate and the mixture was allowed to stand
at room temperature for 2 – 3 h. The precipitated product
was separated by filtration and multiply recrystallized (until
reaching the desired purity) from a 70% (compound Ia) or
96% (Ib and Ic) aqueous ethanol solution.
IIIa, 41%), 2.25 (s, 3H, 4¢-CH3, IIIa), 2.38 (s, 3H, C8–CH3,
Ic), 2.97, 3.24 (dd, 2H, CH2, AB-system J2 19.0 Hz, Ic), 6.02
(s, 1H, CH, IIIa), 6.56, 6.58, 6.80, 6.83, 7.00, 7.79, 8.33
(group of signals, 7H, 2C5H3N, NH, Ic + IIIa).
Compound Ia. Yield, 1.80 g (82%); m.p., 233 – 234°C
(with decomp.); IR spectrum (nmax, cm – 1): 1758 (COOH),
1650 (C2=O); 1H NMR spectrum in DMSO-d6 (d, ppm): 1.40
(s, 3H, CH3), 2.92, 3.21 (dd, 2H, AB-system J2 18.0 Hz,
CH2), 6.81 (t, 1H, C7H, for notations see Scheme 1), 7.07 (d,
1H, C9H), 7.75 (t, 1H, C8H), 8.32 (d, 1H, C6H); mass spec-
trum m/z (Irel, %; only peaks with Irel > 5% are listed):
206(40) [M]+, 189(5) [M–OH]+, 188 [M–H2O]+, 162(16)
[M–CO2]+, 161(100) [M–CO2–H]+, 160(28) [M–CO2–2H]+,
133(6) [M–CO2–H–CO]+, 132(23) [M–CO2–2H–CO]+,
131(21), 121(57), 120(27), 94(31) [C5H4N–NH2]+, 92(12),
79(8), 78(54), 69(9), 68(15), 67(18); C10H10N2O3; m.w.,
206.20.
Triple recrystallization (repeated synthesis) yields pure
Ic: yield, 1.75 g (80%); m.p., 211 – 212°C (with decomp.);
1
IR spectrum (nmax, cm – 1): 1755 (COOH), 1652 (C2=O); H
NMR spectrum in DMSO-d6 (d, ppm): 1.42 (s, 3H, C4-CH3),
2.38 (s, 3H, C8-CH3), 2.97, 3.24 (dd, 2H, AB-system, J2
19.0 Hz, CH2), 6.83 (d, 1H, C7H, for notations see Scheme
1), 7.00 (t, 1H, C9H), 8.33 (d, 1H, C6H); mass spectrum m/z
(Irel, %; only peaks with Irel > 5% are listed): 220(24) [M]+,
203(5) [M–OH]+, 202(32) [M–H2O]+, 176(19) [M–CO2]+,
175(97) [M–CO2–H]+, 174(23) [M–CO2–2H]+, 161(10)
[M–CO2–CH3]+, 160(5) [M–CO2–H–CH3]+, 147(10)
[M–CO2–H–CO]+, 146(28) [M–CO2–2H–CO]+, 145(17),
135(62), 134(29), 131(11), 120(5), 119(6), 108(12),
Compound Ib. Yield, 2.10 g (74%); m.p., 199 – 200°C
(with decomp.); IR spectrum (nmax, cm – 1): 1760 (COOH),
TABLE 1. Physicochemical Characteristics of 2-Pyridylamides and 2-Pyrimidylamides of Dicarboxylic Acids (IV – VII)
M.p., °C
Com- Yield,
pound
Empirical
formula
1H NMR spectrum (DMSO-d6): d, ppm*
(with
%
decomp.)
IVa
83
132 – 133 C9H8N2O3
161 – 162 C8H7N3O3
122 – 123 C9H9N3O3
142 – 143 C9H10N2O3
148 – 149 C8H9N3O3
6.14 (s, 2H, CH=CH), 6.58 – 8.05 (m, 4H, C5H4N), 8.82 (bs, 1H, NH)
IVb
V
93
88
80
62
70
65
84
82
86
91
6.25 (s, 2H, CH=CH), 6.59 (t, 1H, Hb in C4H3N2), 8.25 (d, 2H, Ha), 8.30 (s, 1H, NH)
1.98 (s, 3H, CH3), 5.88 (s, 1H, CH=), 6.55 (t, 1H, Hb in C4H3N2), 8.28 (d, 2H, Ha), 9.28 (bs, 1H, NH)
2.35 (s, 4H, CH2–CH2), 6.25 – 8.45 (m, 4H, C5H4N), 10.52 (bs, 1H, NH)
VIa*
VIb
VIIa
VIIb
VIIc
VIId
VIIe
VIIf
2.42 (s, 4H, CH2–CH2), 6.53 (t, 1H, Hb in C4H3N2), 8.30 (d, 2H, Ha), 8.45 (bs, 1H, NH)
226 – 227 C13H10N2O3 6.55 – 8.88 (m, 8H, C6H4, C5H4N), 10.88 (bs, 1H, NH)
132 – 133 C14H12N2O3 2.08 (s, 3H, CH3), 6.08 – 8.55 (m, 7H, C6H4, C5H3N), 10.85 (bs, 1H, NH)
161 – 162 C13H9N3O5
6.68 – 8.95 (m, 8H, C6H3, C5H4N, NH)
172 – 173 C13H6Cl4N2O3 6.48 – 9.00 (m, 4H, C5H4N), 11.30 (bs, 1H, NH)
125 – 126 C12H9N3O3
177 – 178 C12H8N4O5
6.58 (t, 1H, Hb in C4H3N2), 6.72 – 8.05 (m, 4H, C6H4), 8.23 (d, 2H, Ha), 8.42 (bs, 1H, NH)
6.68 (t, 1H, Hb in C4H3N2), 8.28 (d, 2H, Ha), 7.78 – 8.62 (m, 3H, C6H3), 9.05 (bs, 1H, NH),
12.18 (bs, 1H, COOH)
*
See Scheme 2 for Ha and Hb proton localization.