4
46
S.-X. Hua et al. / European Journal of Medicinal Chemistry 95 (2015) 435e452
(
V:V ¼ 3:1) as eluent to give compound 6e.
Yields 85.41%; 1H NMR (500 MHz, CDCl
NH), 7.33 (s, 1H), 7.29 (d, J ¼ 7.5 Hz, 1H), 7.22e7.13 (m, 2H), 5.19 (s,
H, H-12), 4.47 (t, J ¼ 7.5 Hz, 1H, H-3), 4.00e3.68 (m, 8H, H in
piperazine), 2.04 (s, 3H, eOCOCH ), 1.07 (s, 3H, CH ), 0.94 (d,
J ¼ 5.1 Hz, 3H, CH ), 0.92 (s, 3H, CH ), 0.85 (t, J ¼ 5.4 Hz, 9H, 3CH ),
); C NMR (500 MHz, CDCl ): 182.8 (eC]S), 175.9
eCONe), 171.0 (eCOOe), 141.1, 130.1, 128.3, 126.8, 125.2, 122.3,
0.9, 55.3, 48.7, 47.4, 44.5, 42.1, 39.4, 38.7, 38.2, 37.7, 36.9, 34.3, 33.8,
4.2.9. N-[3b-acetoxy-urs-12-en-28-oyl]-amino-N-(4-chlorophenyl)
piperazine-1-carbothioamide (6i)
According to the general procedure, 3b-acetoxy-urs-12-en-28-
acyl piperazine was treated with isothiocyanate, and then puri-
3
):
d
7.59e7.42 (m, 1H,
1
3
3
fied on silica gel eluted with petroleum ether/ethyl acetate
3
3
3
(V:V ¼ 3:1) as eluent to give compound 6i.
1
3
1
0
(
8
3
1
7
.70 (s, 3H, CH
3
3
d
Yields 84.14%; H NMR (500 MHz, CDCl
3
):
d
7.46 (d, J ¼ 4.4 Hz,
1H), 7.31e7.27 (m, 2H), 7.17e7.12 (m, 2H), 5.19 (s, 1H, H-12), 4.47 (t,
J ¼ 7.8 Hz, 1H, H-3), 4.00e3.69 (m, 8H, H in piperazine), 2.03 (s, 3H,
1.4, 30.3, 29.6, 28.0, 23.5, 23.3, 21.3, 21.2, 19.1, 18.1, 17.3, 16.8, 16.7,
eOCOCH
CH
(500 MHz, CDCl
38.2, 131.0, 129.1, 126.9, 125.5, 80.9, 55.3, 48.2, 47.4, 39.4, 38.1, 37.6,
3
),1.07 (s, 3H, CH
3
), 0.94 (d, J ¼ 6.1 Hz, 3H, CH
3
), 0.92 (s, 3H,
þ
13
5.5; HR-MS (m/z) (ESI): calcd for C43
78.36955; found: 778.36169.
H62BrN
3
O
3
S [Mꢂ H ]:
3
), 0.87e0.84 (m, 9H, 3CH
):
3
), 0.70 (s, 3H, CH
3
); C NMR
3
d
182.9 (eC]S), 176.9 (eCONe), 171.1 (eCOOe),
1
4.2.6. N-[3
b-acetoxy-urs-12-en-28-oyl]-amino-N-(4-bromophenyl)
36.8, 34.3, 31.9, 31.4, 30.5, 30.4, 30.3, 30.1, 29.7, 28.0, 23.5, 23.3, 22.7,
piperazine-1-carbothioamide (6f)
According to the general procedure, 3
acyl piperazine was treated with isothiocyanate, and then puri-
21.3, 21.2, 19.1, 18.1, 17.4, 16.7, 15.5; HR-MS (m/z) (ESI): calcd for
þ
b
-acetoxy-urs-12-en-28-
C
43
H62ClN
3
O
3
S [Mꢂ H ]: 734.42005; found: 734.41178.
fied on silica gel eluted with petroleum ether/ethyl acetate (V:
4.2.10. N-[3
dichlorophenyl)piperazine-1-carbothioamide (6j)
According to the general procedure, 3 -acetoxy-urs-12-en-28-
b-acetoxy-urs-12-en-28-oyl]-amino-N-(3,4-
V ¼ 3:1) as eluent to give compound 6f.
1
Yields 83.65%; H NMR (500 MHz, CDCl
3
):
d
7.67 (s, 1H, NH), 7.41
b
(
d, J ¼ 8.5 Hz, 2H), 7.08 (d, J ¼ 8.5 Hz, 2H), 5.17 (s, 1H, H-12), 4.44 (t,
J ¼ 7.8 Hz, 1H, H-3), 4.00e3.64 (m, 8H, H in piperazine), 2.02 (s, 3H,
eOCOCH ), 1.06 (s, 3H, CH ), 0.93 (s, 3H, CH ), 0.90 (s, 3H, CH ),
.85e0.81 (m, 9H, 3CH ), 0.68 (s, 3H, CH ); C NMR (500 MHz,
CDCl ): 182.6 (eC]S), 175.9 (eCONe), 171.1 (eCOOe), 138.8,
31.9, 126.0, 118.7, 80.9, 55.3, 48.7, 48.1, 47.4, 44.5, 42.1, 39.4, 38.7,
8.1, 37.6, 36.8, 34.3, 32.9, 31.4, 30.3, 29.7, 28.0, 23.5, 23.2, 21.3, 21.2,
8.1, 17.4, 16.7, 15.5; HR-MS (m/z) (ESI): calcd for C43 62BrN
acyl piperazine was treated with isothiocyanate, and then puri-
fied on silica gel eluted with petroleum ether/ethyl acetate
3
3
3
3
(V:V ¼ 3:1) as eluent to give compound 6j.
1
3
1
0
3
3
Yields 82.73%; H NMR (500 MHz, CDCl
3
):
d
7.85 (s, 1H, NH),
3
d
7.37e7.29 (m, 2H), 7.13 (dd, J ¼ 8.7, 2.4 Hz, 1H), 5.15 (s, 1H, H-12),
1
3
1
4.44 (t, J ¼ 7.7 Hz, 1H, H-3), 4.01e3.67 (m, 8H, H in piperazine), 2.02
(s, 3H, eOCOCH
CH ), 0.83 (s, 9H, 3CH
CDCl ): 182.4 (eC]S), 176.0 (eCON), 171.2 (eCOOe), 139.3, 132.4,
30.3,129.0,126.1,125.2,124.2, 80.9, 55.2, 48.7, 48.0, 47.4, 42.2, 39.4,
3
), 1.06 (s, 3H, CH
3
), 0.93 (s, 3H, CH
3
), 0.90 (s, 3H,
13
H
3
O
3
S
3
), 0.68 (s, 3H, CH ); C NMR (500 MHz,
3 3
þ
[Mꢂ H ]: 778.36955; found: 778.36210.
3
d
1
4
.2.7. N-[3 -acetoxy-urs-12-en-28-oyl]-amino-N-(2,4-
b
38.7, 38.1, 37.6, 36.8, 34.3, 32.8, 31.4, 30.3, 29.7, 28.0, 26.9, 23.5, 23.2,
DiBromophenyl)piperazine-1-carbothioamide (6g)
According to the general procedure, 3 -acetoxy-urs-12-en-28-
acyl piperazine was treated with isothiocyanate, and then puri-
21.3, 21.2, 18.1, 17.4, 16.7, 15.5; HR-MS (m/z) (ESI): calcd for
þ
b
C
43
H61Cl
2
N
3
O
3
S [Mꢂ H ]: 768.38113; found: 768.37199.
fied on silica gel eluted with petroleum ether/ethyl acetate
4.2.11. N-[3
trifluoromethylphenyl)piperazine-1-carbothioamide (6k)
According to the general procedure, 3 -acetoxy-urs-12-en-28-
acyl piperazine was treated with isothiocyanate, and then puri-
fied on silica gel eluted with petroleum ether/ethyl acetate
b-acetoxy-urs-12-en-28-oyl]-amino-N-(3-
(
V:V ¼ 3:1) as eluent to give compound 6g.
1
Yields 84.62%; H NMR (500 MHz, CDCl
3
):
d
7.72 (d, J ¼ 2.2 Hz,
b
1
H, NH), 7.67 (dd, J ¼ 8.7, 2.7 Hz, 1H), 7.43 (dd, J ¼ 8.7, 2.2 Hz, 1H),
7
(
.23 (s, 1H), 5.21 (s, 1H, H-12), 4.50e4.45 (m, 1H, H-3), 4.08e3.74
m, 8H, H in piperazine), 2.04 (s, 3H, eOCOCH ), 1.08 (s, 3H, CH ),
), 0.86 (dd, J ¼ 12.0,
); C NMR (500 MHz, CDCl ):
181.7 (eC]S), 176.0 (eCONe), 171.1 (eCOOe), 136.9, 134.9, 130.9,
27.8, 125.2, 118.9, 118.8, 80.9, 55.3, 48.7, 47.9, 47.4, 44.3, 42.1, 39.4,
8.7, 38.1, 37.6, 36.8, 34.3, 32.9, 31.4, 30.3, 29.7, 28.0, 23.5, 23.3, 21.3,
3
3
(V:V ¼ 3:1) as eluent to give compound 6k.
1
0
5
d
.95 (d, J ¼ 5.9 Hz, 3H, CH
3
), 0.92 (s, 3H, CH
3
Yields 80.91%; H NMR (500 MHz, CDCl
3
):
d
7.67 (s, 1H, NH), 7.42
13
.9 Hz, 9H, 3CH ), 0.71 (s, 3H, CH
3
3
3
(dt, J ¼ 8.4, 7.0 Hz, 4H), 5.19 (s, 1H, H-12), 4.50e4.43 (m, 1H, H-3),
4.00e3.69 (m, 8H, H in piperazine), 2.03 (s, 3H, eOCOCH ), 1.07 (s,
3H, CH ), 0.94 (s, 3H, CH ), 0.91 (s, 3H, CH
), 0.85 (t, J ¼ 5.1 Hz, 9H,
3CH ), 0.69 (s, 3H, CH ); C NMR (500 MHz, CDCl ): 182.7 (eC]
3
1
3
3
3
3
1
3
3
3
3
d
2
C
1.2, 18.1, 17.4, 16.7, 15.5; HR-MS (m/z) (ESI): calcd for
S), 176.0 (eCONe), 171.1 (eCOOe), 140.2, 131.4, 131.1, 129.4, 127.6,
124.8, 122.6, 122.0, 120.7, 80.9, 55.2, 48.2, 47.4, 44.3, 42.2, 39.4,
þ
43
H
61Br
2
N
3
O
3
S [Mꢂ H ]: 856.28002; found: 856.27097.
38.7,38.1, 37.6, 36.8, 34.3, 33.1, 32.1, 30.3, 29.6, 28.0, 23.5, 23.2, 21.3,
4
.2.8. N-[3
b
-acetoxy-urs-12-en-28-oyl]-amino-N-(3-chlorophenyl)
21.2, 18.1, 17.4, 16.7, 15.5; HR-MS (m/z) (ESI): calcd for
þ
piperazine-1-carbothioamide (6h)
C
44
H
62
F
3
N
3
O
3
S [Mꢂ H ]: 768.44643; found: 768.43730.
According to the general procedure, 3b-acetoxy-urs-12-en-28-
acyl piperazine was treated with isothiocyanate, and then puri-
fied on silica gel eluted with petroleum ether/ethyl acetate
4.2.12. N-[3
trifluoromethylphenyl)piperazine-1-carbothioamide (6l)
According to the general procedure, 3 -acetoxy-urs-12-en-28-
b-acetoxy-urs-12-en-28-oyl]-amino-N-(4-
(
V:V ¼ 3:1) as eluent to give compound 6h.
b
1
Yields 81.79%; H NMR (500 MHz, CDCl
3
):
d
7.69 (s, 1H, NH), 7.23
acyl piperazine was treated with isothiocyanate, and then puri-
(
t, J ¼ 8.0 Hz, 1H), 7.18 (d, J ¼ 1.4 Hz, 1H), 7.11 (t, J ¼ 7.6 Hz, 2H), 5.18
fied on silica gel eluted with petroleum ether/ethyl acetate
(
s, 1H, H-12), 4.46 (t, J ¼ 7.2 Hz, 1H, H-3), 3.97e3.65 (m, 8H, H in
(V:V ¼ 3:1) as eluent to give compound 6l.
1
piperazine), 2.03 (s, 3H, eOCOCH
3
), 1.06 (s, 3H, CH
3
), 0.93 (s, 3H,
), 0.69 (s, 3H, CH );
182.7 (eC]S), 176.0 (eCONe), 171.1
eCOOe), 140.9, 134.4, 129.9, 125.5, 125.2, 123.9, 122.2, 80.9, 55.3,
Yields 82.76%; H NMR (500 MHz, CDCl
3
):
d
7.90 (s, 1H, NH), 7.53
CH
3
), 0.91 (s, 3H, CH
C NMR (500 MHz, CDCl
3
), 0.86e0.82 (m, 9H, 3CH
):
3
3
(d, J ¼ 8.1 Hz, 2H), 7.30 (d, J ¼ 8.4 Hz, 2H), 5.16 (s, 1H, H-12), 4.44 (t,
1
3
3
d
J ¼ 7.7 Hz, 1H, H-3), 4.02e3.67 (m, 8H, H in piperazine), 2.02 (s, 3H,
(
eOCOCH
(s, 9H, 3CH
3
), 1.05 (s, 3H, CH
3
), 0.92 (s, 3H, CH
3
), 0.90 (s, 3H, CH ), 0.83
): d 182.5
3
13
4
2
8.3, 47.9, 47.4, 42.1, 39.4, 38.2, 38.1, 37.6, 36.8, 34.3, 32.9, 31.4, 30.3,
3
), 0.68 (s, 3H, CH
3
); C NMR (500 MHz, CDCl
3
9.7, 28.0, 23.5, 23.2, 21.3, 21.2, 18.1, 17.4, 16.7, 15.5; HR-MS (m/z)
(eC]S), 176.1 (eCONe), 171.2 (eCOOe), 143.1, 126.8, 126.5, 125.9,
125.8,125.0,123.6,122.9,120.7, 81.0, 55.2, 48.7, 48.3, 47.4, 44.4, 42.1,
39.4, 38.7, 38.1, 37.6, 36.8, 34.3, 32.9, 31.4, 30.3, 29.6, 28.0, 23.5, 23.2,
þ
(
ESI): calcd for C43
H62ClN
3
O
3
S [Mꢂ H ]: 734.42005; found:
7
34.41115.