Month 2018
Design, Synthesis, and Molecular Modeling of Asymmetric Tolterodine
Derivatives as Anticancer Agents
1
27.5 (ArC18,20), 127.8 (ArC ), 127.9 (ArC ), 129.4
5.66 (t, J = 7.6 Hz, 1H, CHPh), 6.76–6.78 (d, J = 8.4 Hz,
2H, ArH), 7.17–7.19 (m, 4H, ArH), 7.56 (d, J = 9.2 Hz,
2H, ArH), 8.01 (s, 1H, PhOH), 8.48 (s, 1H, COOH), 8.96
3
5
(ArC ), 143.9 (ArC ), 152.4 (ArC ), 174.5 (ArC
0
0
);
1 ,4
6
16
1
+
LC–MS (ESI): 475.5 (M+1) ; Elemental analysis C
5.48, H 7.79, N 3.25; found C 65.66, H 7.84, N 2.94.
13
6
(s, 2H, COOH); C NMR (75 MHz, CDCl ) δ ppm
3
(
S)-N,N-Diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-
2
1.20 (CH ) CH), 38.28 (CH ) , 40.12 (C3
0
0
), 45.18
3
2
2 2
phenylpropanamine-L-hydrogen tartrate (7b).
mp 220–
22°C, IR (KBr, cm ) ʋmax; 3570 m (OH), 2988w
Ar═CH), 2945w, 2707w (CH), 1697b (C═O), 1582s,
508w, 1487w (Ar–C═C), 1375 m (CN), 1265s (C–O);
(
ArCH3), 53.30 (CH ) CH), 57.25 (CH N), 61.01
3 2
2
ꢀ
1
2
(
(ArCH), 114.99 (ArC2), 125.52 (ArC19), 128.08
(
ArC18,20), 135.33 (ArC ), 148.07 (ArC ), 152.26 (ArC ),
3
5
6
1
1
56.54 (ArC ), 159.38 (ArC
0
), 165.38 (ArC3
0
), 172.29
16
1
1
H NMR (400 MHz, DMSO-d ) δ ppm 1.15 (d,
+
6
(ArC1
0
,5
0
); LC–MS (ESI): 516.6 (M+1) ; Elemental
J = 4.0 Hz, 12H, (CH ) CH), 2.17 (s, 3H, CH Ph), 2.44
3
2
3
analysis C 70.12, H 9.17, N 4.30; found C 71.10, H 9.20,
N 4.36.
(a, 2H, CH CH), 2.81 (m, 2H, (CH ) CH), 3.50 (m,
2 3 2
J = 6.4 Hz, 2H, CH N), 4.04 (s, 2H, CHOH), 4.15 (s,
2
(
R)-2-(3-(Diisopropylamino)-1-phenylpropyl)-4-
2H, CHOH), 4.32 (t, J = 7.6 Hz, 1H, CHPh), 6.73 (d,
methylphenol-2-hydroxyacetate (7e).
mp 198–200°C, IR
J = 9.2 Hz, 1H, ArH), 6.80 (d, J = 2.0, 8.0 Hz, 1H,
ArH), 7.05 (s, 1H, ArH), 7.15 (t, J = 6.8 Hz, 1H, ArH),
ꢀ1
(KBr, cm ) ʋmax; 3439s (OH), 3046w (Ar═CH), 2926w,
2
858w (CH), 1634b (C═O), 1602s, 1525w, 1476w (Ar–
7.31 (m, 4H, ArH), 8.16 (s, 1H, PhOH), 8.48 (s, 2H,
1
C═C), 1393 m (CN), 1117s (C–O); H NMR (400 MHz,
DMSO-d ) δ ppm 2.11 (d, J = 6.8 Hz, 12H, (CH ) CH),
13
COOH); C NMR (100 MHz, DMSO-d ) δ ppm 17.6,
6
6
3 2
17.5 (CH ) CH), 20.5 (ArCH ), 31.9 (CH CH), 41.0
3 2 3 2
2
.22 (s, 3H, CH Ph), 2.37–2.39 (t, J = 6.8 Hz, 2H,
3
(CH ) CH), 45.5 (CH N), 53.3 (ArCH), 72.4 (CHOH),
3 2 2
CH N), 2.80 (d, J = 6.0 Hz, 2H, CH CH), 2.89 (s, 2H,
2
2
115.2 (ArC ), 126.0 (ArC ), 127.2 (ArC ), 127.5
2 4 19
CH ), 4.01 (t, J = 7.6 Hz, 1H, CHPh), 5.03 (s, 1H,
2
(ArC18,20), 127.8 (ArC ), 127.9 (ArC ), 129.4 (ArC ),
3
5
6
CHOH), 6.63–6.65 (d, J = 8.4 Hz, 2H, ArH), 7.02–7.06
143.9 (ArC ), 152.4 (ArC ), 174.5 (ArC ); LC–MS
0 0
16
1
1 ,4
(
7
m, J = 8.4 Hz, 4H, ArH), 7.57 (d, J = 9.2 Hz, 2H, ArH),
.91 (s, 1H, PhOH), 9.08 (s, 1H, COOH); C NMR
+
(ESI): 475.5 (M+1) ; Elemental analysis C 65.48, H
13
7.79, N 3.25; found C 65.66, H 7.84, N 2.94.
(
3
75 MHz, CDCl ) δ ppm 17.21 (CH ) CH), 32.45 (CH ),
8.28 (C2 ), 45.24 (ArCH ), 53.93 (CH ) CH), 57.23
3 3 2
3
3 2
2
(
R)-2-(3-(Diisopropylamino)-1-phenylpropyl)-4-
0
methylphenol-(R)-2-hydroxysuccinate (7c). mp 209–211°C,
IR (KBr, cm ) ʋmax; 3434s (OH), 3046w (Ar═CH),
ꢀ
1
(CH N), 61.52 (ArCH), 114.70 (ArC2), 117.16
2
(
ArC ), 129.59 (ArC
), 144.79 (ArC ), 145.19
18,20 3
1
9
2924w, 2860w (CH), 1738b (C═O), 1608s, 1540w,
1
(ArC ), 153.27 (ArC ), 155.24 (ArC ), 157.51 (ArC ),
5
6
16
1
1
481w (Ar–C═C), 1310 m (CN), 1252s (C–O); H NMR
+
1
65.26 (ArC1 ); LC–MS (ESI): 400.5 (M+1) ;
0
(400 MHz, DMSO-d ) δ ppm 1.15 (d, J = 4.2 Hz, 12H,
6
Elemental analysis C 67.10, H 10.15, N 3.25; found C
8.13, H 7.28, N 4.30.
(CH ) CH), 2.17 (s, 3H, CH Ph), 2.26 (d, 2H, CH ), 2.44
3
2
3
2
6
(d, J = 6.4 Hz, 2H, CH CH), 2.81 (m, 2H, (CH ) CH),
2 3 2
(
R)-2-(3-(Diisopropylamino)-1-phenylpropyl)-4-
3
4
6
1
.50 (t, J = 6.4 Hz, 2H, CH N), 4.05 (s, 1H, CHOH),
2
methylphenol-(R)-2-hydroxypropanoate (7f).
mp 201–
03°C, IR (KBr, cm ) ʋmax; 3436s (OH), 3054w
Ar═CH), 2926w, 2859w (CH), 1633b (C═O), 1612s,
.13 (s, 1H, CHOH), 4.32 (t, J = 7.6 Hz, 1H, CHPh),
.73 (d, J = 9.2 Hz, 1H, ArH), 6.80 (d, J = 2.0, 8.0 Hz,
H, ArH), 7.05 (s, 1H, ArH), 7.15 (t, J = 6.8 Hz, 1H,
ꢀ
1
2
(
1
1
506w (Ar–C═C), 1399w (CN), 1120s (C–O); H NMR
(400 MHz, DMSO-d ) δ ppm 2.10 (d, J = 6.4 Hz,
2H, (CH ) CH), 2.27 (s, 3H, CH Ph), 2.39–2.40 (t,
ArH), 7.31 (m, 4H, ArH), 8.20 (s, 1H, PhOH), 8.42 (s,
13
6
2H, COOH); C NMR (75 MHz, DMSO-d ) δ ppm
6
1
3
2
3
14.94 (CH ) CH), 18.85 (ArCH ), 38.28 (CH ), 45.77
2
0
3
2
3
J = 5.6 Hz, 2H, CH N), 2.86 (d, J = 6.4 Hz, 2H,
2
(ArCH3), 55.30 (CH ) CH), 62.00 (CH N), 63.61
3 2 2
CH CH), 2.99 (d, J = 7.0 Hz, 3H, CHCH ), 3.01 (s,
2
3
(ArCH), 101.62 (ArC2), 105.56 (ArC19), 114.74
1
1
H, CHCH ), 4.02 (t, J = 5.6 Hz, 1H, CHPh), 5.05 (s,
H, CHOH), 6.64–6.66 (d, J = 8.8 Hz, 2H, ArH),
3
(ArC18,20), 127.94 (ArC ), 136.02 (ArC ), 146.37 (ArC ),
3
5
6
153.26 (ArC ), 158.80 (ArC ), 165.78 (ArC ); LC–
0 0
16
1
1 ,4
+
7.01–7.03 (d, J = 8.8 Hz, 4H, ArH), 7.32 (d,
J = 8.4 Hz, 2H, ArH), 9.57 (s, 1H, PhOH), 10.22 (s,
MS (ESI): 459.5 (M+1) ; Elemental analysis C 66.28, H
.23, N 3.15; found C 65.12, H 7.16, N 2.16.
7
1
3
1
H, COOH); C NMR (75 MHz, CDCl ) δ ppm
(
R)-2-(3-(Diisopropylamino)-1-phenylpropyl)-4-
3
methylphenol-2-hydroxypropane-1,2,3-tricarbo xylate (7d).
17.21 (CH ) CH), 23.48 (CH ), 32.45 (CH ), 38.28
3
2
3
2
ꢀ
1
mp 220–222°C, IR (KBr, cm ) ʋmax; 3433s (OH),
052w (Ar═CH), 2966w, 2922w, 2859w (CH), 1737b
C═O), 1603s, 1531w, 1471w (Ar–C═C), 1322 m (CN),
(C2
0
), 45.24 (ArCH3), 53.93 (CH ) CH), 57.23
3 2
3
(CH N), 61.52 (ArCH), 113.34 (ArC ), 114.70 (ArC ),
2
3
2
(
1
117.16 (ArC ), 129.59 (ArC18,20), 144.79 (ArC4),
19
1
213s (C–O); H-NMR (400 MHz, CDCl ) δ ppm 1.37
145.19 (ArC ), 154.28 (ArC ), 157.51 (ArC ), 165.26
3
5
6
16
+
(
d, J = 6.8 Hz, 12H, (CH ) CH), 2.16 (s, 3H, CH Ph),
(ArC ), 174.28 (C1
0
); LC–MS (ESI): 415.5 (M+1) ;
3
2
3
1
2
3
.30 (s, 4H, CH ), 2.42 (d, J = 6.0 Hz, 2H, CH CH),
Elemental analysis C 66.27, H 7.20, N 3.14; found C
65.10, H 7.15, N 2.13.
2
2
.99 (t, J = 6.8 Hz, 2H, CH N), 5.31 (s, 1H, CHOH),
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet