194
HAYOTSYAN et al.
Scheme 3.
Removal of isopropyl alcohol from the filtrate gave
16.9 g (75%) of ester 2, nD20 = 1.4950. IR spectrum, ν,
1
cm–1: 1540 (ring), 1670 (C=O). H NMR spectrum, δ,
O
O
ppm (J, Hz): 1.65 br. s (1H, NH), 2.19 s (3H, 3-CH3),
2.22 s (3H, 5-CH3), 2.38 t (2H, CH2CO, J = 6.6), 2.82 t
(2H, NHCH2CH2CO, J = 6.2), 2.92 t (2H, NHCH2, J =
6.2), 3.60 s (3H, OCH3), 4.00 t (2H, CH2N, J = 6.2),
5.98 s (1H, 4-H). Found, %: C 58.88; H 8.21; N 18.10.
C11H19N3O2. Calculated, %: C 58.64; H 8.50; N 18.65.
H2N
NH2
N
N
O
HN
NH
2
+
CH3COOH
50−60oC
N
NH
O
N
H
O
O
7
6
Dimethyl 3,3′-{[2-(3,5-dimethyl-1H-pyrazol-1-yl)
ethyl]azanediyl}dipropanoate (3). Methyl acrylate,
43 g (0.5 mol), was added dropwise at 5–10°C to
13.9 g (0.1 mol) of pyrazole 1, and the mixture was left
to stand for 24 h at room temperature and then heated
for 6 h under reflux. Excess methyl acrylate was
removed to leave 30.4 g (98%) of 3 with a purity of
Scheme 4.
CO2CH3
O
CH3ONa
N
3
N
N
~97% (according to the H NMR data), nD20 = 1.4870.
1
8
1
IR spectrum, ν, cm–1: 1530 (ring), 1750 (C=O). H
By heating compound 2 with urea in glacial acetic
acid for 12 h at 50–60°C we obtained 55% of 1-[2-(3,5-
dimethyl-1H-pyrazol-1-yl)ethyl]hexahydropyrimidine-
2,4-dione (6), and cyanuric acid (7) was also isolated
as by-product (Scheme 3). Cyclization of bis-adduct 3
in the presence of sodium methoxide afforded 40% of
methyl 1-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]-4-
oxopiperidine-3-carboxylic acid (8).
NMR spectrum, δ, ppm (J, Hz): 2.18 s (3H, 3-CH3),
2.22 s (3H, 5-CH3), 2.32 t (4H, CH2CO, J = 6.9), 2.72 t
(4H, NCH2CH2CO, J = 6.9), 2.79 t (2H, 1-CH2CH2N,
J = 6.9), 3.60 s (6H, OCH3), 4.00 t (2H, 1-CH2CH2N,
J = 6.9), 6.00 s (1H, 4-H). Found, %: C 57.45; H 8.71;
N 13.20. C15H25N3O4. Calculated, %: C 57.86; H 8.09;
N 13.49.
Compound 3 was distilled under reduced pressure,
and a fraction boiling in the range from 170 to 200°C
(1 mmHg) was collected, 18 g. Crystals of 5 with mp
181°C separated from that fraction on storage. Re-
peated distillation of the filtrate gave 4.0 g of initial
pyrazole 1, bp 60°C (1 mmHg), n2D0 = 1.5030 [6] and
8.5 g of a mixture of compounds 2 and 5 at a ratio of
9:1 (1H NMR), bp 140–190°C (1 mmHg).
The structure of the newly synthesized compounds
was confirmed by IR and H NMR spectra and ele-
mental analyses.
1
Methyl 3-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl-
amino]propanoate (2) and 3-[2-(3,5-dimethyl-1H-
pyrazol-1-yl)ethylamino]propanoic acid (5). Methyl
acrylate, 25.8 g (0.3 mol), was added dropwise at 10–
20°C to 13.9 g (0.1 mol) of 2-(3,5-dimethyl-1H-pyra-
zol-1-yl)ethanamine (1), and the mixture was kept for
24 h at room temperature. Excess methyl acrylate was
removed, and the residue was distilled under reduced
pressure. A fraction boiling in the range from 150 to
160°C (1 mmHg), 15.3 g, was collected. The product
was treated with 50 mL of isopropyl alcohol left
overnight, and the precipitate of 5 was filtered off and
dried. Yield of 5 1.5 g (7.1%), mp 181°C (from
i-PrOH). IR spectrum, ν, cm–1: 1550 (ring), 1670
(C=O). 1H NMR spectrum, δ, ppm (J, Hz): 2.15 s (3H,
3-CH3), 2.21 s (3H, 5-CH3), 2.30 t (2H, CH2CO, J =
6.6), 2.74 t (2H, NHCH2CH2CO, J = 6.6), 2.91 t (2H,
NHCH2CH2N, J = 6.3), 4.08 t (2H, CH2N, J = 6.3),
4.36 m (2H, NH, COOH), 6.0 s (1H, 4-H). Found, %:
C 56.41; H 7.85; N 20.40. C10H17N3O2. Calculated, %:
C 56.85; H 8.11; N 19.89.
1-[2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]hexa-
hydropyrimidine-2,4-dione (6). A mixture of 11.3 g
(0.05 mol) of ester 2 and 12 g (0.2 mol) of urea in
15 mL of glacial acetic acid was heated for 24 h at
145–150°C. The mixture was cooled to 20°C, 10 mL
of aqueous HCl was added, and the mixture was again
heated under reflux for 8 h more. The precipitate of
cyanuric acid 7 (mp 145–148°C [8]) was filtered off,
and the filtrate was treated with a solution of sodium
carbonate until weakly alkaline reaction, extracted
with chloroform, and dried over MgSO4. The solvent
was removed, and the residue was recrystallized from
isopropyl alcohol. Yield 6.5 g (55%), mp 165–167°C.
1
IR spectrum, ν, cm–1: 1540 (ring), 1720 (C=O). H
NMR spectrum, δ, ppm (J, Hz): 2.22 s (3H, 3-CH3),
2.28 s (3H, 5-CH3), 2.35 t (2H, CH2CO, J = 6.8), 3.03 t
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 1 2016