DESIGN, SYNTHESIS, AND CYTOTOXICITY OF SEMISYNTHETIC BETULINIC ACID
315
2
7
25
6
26
23
d.d (1H, J = 5.6 Hz, 5'-CH ), 6.28 t (1H, NH), 7.03–
ppm: 14.8 (C ), 16.1 (C ), 16.3 (C ), 16.7 (C ), 18.7
2
3
''
5''
4''
11
30
7
.07 m (2H, H , H ), 7.46–7.52 m (1H, H ), 7.96 d.d
(COOCH ), 19.4 (C ), 20.8 (C ), 21.3 (C ), 23.6
3
6
'' 13
24
2
12
15
21
(
1H, J = 1.6, 2 Hz, H ). C NMR spectrum, δ, ppm:
(C ), 24.9 (C ), 25.6 (C ), 27.8 (C ), 29.4 (C ), 30.7
2
7
25
6
26
16
22
7
4
10
1
4.9 (C ), 16.0 (C ), 16.1 (C ), 16.4 (C ), 18.1
(C ), 33.9 (C ), 34.4 (C ), 35.7 (C ), 37.1 (C ), 37.7
3
0
11
24
13
1
8
14
(COOCH ), 19.4 (C ), 20.8 (C ), 21.3 (C ), 22.6
(C ), 38.6 (C ), 40.7 (C ), 42.4 (C ), 46.7 (5'-CH ),
49.0 (C ), 50.1 (C ), 50.5 (C ), 55.3 (C ), 55.4 (C ),
80.9 (C ), 109.9 (C ), 114.6 (C ), 124.1 (C ), 132.9
(C ), 147.9 (C ), 155.1 (C ), 161.7 (C ), 167.1 (C ),
171.3 (C ), 176.7 (OCOCH ), 176.9 (CONH). ESI–
MS: m/z: 657.6 [M + H] .
3
2
5
2
3
2
12
21
15
19
18
17
9
(
C ), 25.5 (C ), 27.9 (C ), 29.0 (C ), 29.3 (C ), 29.6
1
6
22
7
10
4
3
29
1''
5''
(
C ), 30.7 (C ), 31.5 (C ), 33.6 (C ), 34.2 (C ), 35.6
1
3
1
8
14
4''
6''
2''
20
5'
(
C ), 37.1 (C ), 37.6 (C ), 42.4 (C ), 46.6 (5'-CH ),
2
1
9
18
17
9
5
3'
5
5
1
0.1 (C ), 50.5 (C ), 55.4 (C ), 55.9 (C ), 55.9 (C ),
5.9 (2''-OCH ), 81.0 (C ), 109.5 (C ), 111.6 (C ),
3
3
29
3''
+
3
1
''
5''
4''
6''
15.5 (C ), 120.5 (C ), 131.2 (C ), 132.4 (C ), 150.7
Phenyl-1,2,4-oxadiazole amide of betulinic acid
20). Yield 75%, mp 212–213°C. IR spectrum, ν, cm :
244 (C–N), 1513 (C=N), 1733 (C=O), 3374 (NH). H
NMR spectrum, δ, ppm: 0.78, 0.81, 0.83, 0.85, 0.97,
1.69, 2.03 s (3H, 24-CH , 25-CH , 26-CH , 23-CH
27-CH , 30-CH , COOCH ), 0.75–2.43 m (remaining
protons), 3.09–3.12 m (1H, H ), 4.44 t (1H, H ), 4.59
d (1H, J = 0.4 Hz, H ), 4.63 d.d (1H, J = 5.6 Hz,
5'-CH ), 4.73 d (1H, J = 1.6 Hz, H ), 4.76 d.d (1H,
J = 5.6 Hz, 5'-CH ), 6.26 t (1H, NH), 7.44–7.51 m
2
0
2''
5'
3'
(
(
[
C ), 158.1 (C ), 166.7 (C ), 171.0 (C ), 175.4
OCOCH ), 176.5 (CONH). ESI–MS: m/z: 708.5
M + Na].
–1
(
1
3
1
2
-Benzyloxyphenyl-1,2,4-oxadiazole amide of
3
3
3
,
3
betulinic acid (18). Yield 60%, mp 203–204°C. IR
3
3
3
–
1
19
3
spectrum, ν, cm : 1251 (C–N), 1574 (C=N), 1721
1
29α
(
C=O), 3464 (NH). H NMR spectrum, δ, ppm: 0.76,
2
9β
0
2
2
4
.78, 0.81, 0.83, 0.97, 1.67, 2.06 s (3H, 24-CH , 25-CH ,
3
3
2
6-CH , 23-CH , 27-CH , 30-CH , COOCH ), 1.17–
3
3
3
3
3
2
5''
1
9
3''
4''
.08 m (remaining protons), 3.12–3.15 m (1H, H ),
.46 t (1H, H ), 4.57 d.d (1H, J = 0.4 Hz, H ), 4.65
(3H, H , H and H ), 8.04 d.d (2H, J = 1. 6 Hz, J =
3
29α
2''
6'' 13
27
1.2 Hz, H , H ). C NMR spectrum, δ, ppm: 14.6 (C ),
2
5
6
26
d.d (1H, J = 5.6 Hz, 5'-CH ), 4.67 d (1H, J = 1.6 Hz,
16.0 (C ), 16.1 (C ), 16.4 (C ), 18.1 (COOCH ), 19.4
2
3
2
2
9β
11
30
24
23
H
), 4.73 d.d (1H, J = 5.6 Hz, 5'-CH ), 5.18 s (2H,
OCH ), 6.26 t (1H, NH), 7.03–7.07 m (2H, H , H ),
.42–7.51 m (5H, H , H to H ), 7.94 d.d (1H, J =
.6, 2.0 Hz, H ). C NMR spectrum, δ, ppm: 14.9 (C ),
(C ), 20.8 (C ), 21.3 (C ), 23.6 (C ), 25.5 (C ), 26.9
2
3
''
5''
12
15
21
16
22
(C ), 27.9 (C ), 29.4 (C ), 29.7 (C ), 30.7 (C ),
33.6 (C ), 34.2 (C ), 35.7 (C ), 37.7 (C ), 38.2 (C ),
2
4
''
2'''
6'''
7
4
10
13
1
7
1
1
(
(
3
3
(
8
(
6
'' 13
27
8
14
19
38.3 (C ), 40.7 (C ), 42.5 (5'-CH ), 46.6 (C ), 50.1
2
2
5
6
26
18
17
9
5
3
6.0 (C ), 16.1 (C ), 16.4 (C ), 18.1 (COOCH ), 19.4
(C ), 50.5 (C ), 55.4 (C ), 55.9 (C ), 80.9 (C ), 109.5
3
2
3
0
11
24
23
29
1''
2''
6''
3''
5''
C ), 20.8 (C ), 21.3 (C ), 22.6 (C ), 25.5 (C ), 27.9
(C ), 126.5 (C ), 127.4 (C , C ), 128.8 (C , C ),
131.2 (C ), 150.6 (C ), 168.2 (C ), 171.0 (C ), 176.7
(COOCH ), 176.7 (CONH). ESI–MS: m/z: 656.7
1
2
21
15
16
22
4''
20
5'
3'
C ), 29.0 (C ), 29.3 (C ), 29.6 (C ), 30.7 (C ),
7
10
4
13
1
1.5 (C ), 33.6 (C ), 34.2 (C ), 35.6 (C ), 37.1 (C ),
7.6 (C ), 42.4 (C ), 46.6 (5'-CH ), 50.1 (C ), 50.5
C ), 55.4 (C ), 55.9 (C ), 55.9 (C ), 71.1 (2''-OCH ),
1.0 (C ), 109.5 (C ), 111.6 (C ), 115.5 (C ), 120.5
3
8
14
19
+
2
[M + H] .
1
8
17
9
5
2
Benzyl-1,2,4-oxadiazole amide of betulinic acid
21). Yield 70%, mp 226–227°C. IR spectrum, ν, cm :
242 (C–N), 1511 (C=N), 1732 (C=O), 3376 (NH). H
NMR spectrum, δ, ppm: 0.83, 0.85, 0.88, 0.95, 0.96,
.6, 2.04 s (3H, 24-CH , 25-CH , 26-CH , 23-CH , 27-
CH , 30-CH , COOCH ), 0.85–2.43 m (remaining protons),
3.12–3.15 m (1H, H ), 4.04 d (2H, J = 2.0 Hz,
1''-CH ), 4.44 t (1H, H ), 4.57 d.d (1H, J = 0.4 Hz,
H ), 4.64 d.d (1H, J = 5.6 Hz, 5'-CH ), 4.72 d (1H,
3
29
3''
1''
–1
(
1
5
''
4'''
3'''
5'''
2'''
6'''
C ), 127.6 (C ), 128.9 (C , C ), 127.1 (C , C ),
1
4
''
6''
1'''
20
1
(
(
31.2 (C ), 132.4 (C ), 136.7 (C ), 150.7 (C ), 158.1
2
''
5'
3'
C ), 166.7 (C ), 171.0 (C ), 175.4 (OCOCH ), 176.5
3
1
+
3
3
3
3
CONH). ESI–MS: m/z: 762.5 [M + H] .
3
3
3
1
9
3
-Pyridine-1,2,4-oxadiazole amide of betulinic
3
acid (19). Yield 55%, mp 203–204°C. IR spectrum, ν,
2
–
1
29α
cm : 1257 (C–N), 1576 (C=N), 1737 (C=O), 3316
2
1
29β
(
NH). H NMR spectrum, δ, ppm: 0.75, 0.78, 0.81,
J = 1.6 Hz, H ), 4.78 d.d (1H, J = 5.6 Hz, 5'-CH ),
2
6.17 t (1H, NH), 7.27–7.32 m (4H, H to H ).
NMR spectrum, δ, ppm: 14.6 (C ), 16.0 (C ), 16.2
2
''
6''
13
0
2
.83, 0.97, 1.67, 2.03 s (3H, 24-CH , 25-CH , 26-CH ,
C
3
3
3
2
7
25
3-CH , 27-CH , 30-CH , COOCH ), 1.17–2.39 m
3
3
3
3
1
9
6
26
30
(
(
remaining protons), 3.11–3.14 m (1H, H ), 4.43 t
1H, H ), 4.57 d.d (1H, J = 0.4 Hz, H ), 4.68 d.d (1H,
(C ), 16.4 (C ), 18.2 (COOCH ), 19.4 (C ), 20.9
3
3
29α
11
23
24
2
12
(C ), 21.2 (C ), 23.7 (C ), 24.9 (C ), 25.6 (C ), 27.9
2
9β
15
21
16
22
J = 5.6 Hz, 5'-CH ), 4.69 d (1H, J = 1.6 Hz, H ), 4.75
(C ), 29.3 (C ), 30.7 (C ), 32.2 (C ), 33.9 (1''-CH ),
2
2
1
7
4
10
13
d.d (1H, J = 5.6 Hz, 5'-CH ), 6.34 t (1H, NH), 7.57–
34.3 (C ), 35.6 (C ), 37.1 (C ), 38.0 (C ), 38.4 (C ),
2
5
''
4''
8
14
19
7
(
.61 m (1H, H ), 8.42-8.47 m (1H, H ), 8.7–8.73 m
40.7 (C ), 42.4 (C ), 46.6 (5'-CH ), 49.1 (C ), 50.0
2
6
''
2''
13
18
17
9
5
3
1H, H ), 9.24 m (1H, H ). C NMR spectrum, δ,
(C ), 50.5 (C ), 55.4 (C ), 55.8 (C ), 81.0 (C ), 109.5
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 88 No. 2 2018