H.-W. Xu et al. / Steroids 75 (2010) 419–423
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Table 1
Compounds synthesized.
(1H, s), 3.82–3.77 (3H, m), 3.53 (2H, m), 3.30 (1H, d, J = 8.0 Hz), 3.25
(2H, m), 3.0 (2H, br) 2.27 (1H, m, H-17), 0.92 (3H, s, CH3-19), 0.78
(3H, s, CH3-18); 13C NMR (100.6 MHz, CDCl3, TMS): ı 169.9, 165.1,
150.9, 135.1, 134.5, 130.3, 129.8, 128.7, 128.6, 116.4, 109.5, 98.3,
98.2, 95.4, 86.6, 82.5, 82.2, 75.8, 72.7, 72.5, 69.5, 68.2, 68.0, 66.4,
66.3, 55.4, 42.1, 41.5, 37.8, 17.1, 36.7, 36.2, 35.0, 32.9, 32.6, 30.7,
30.2, 29.8, 29.5, 26.6, 26.4, 23.5, 18.1, 8.7; HR-MS mz−1: [M+Na]+
Comps.
R1
Comps.
R1
Comps.
R1
2a
2b
2c
Furoyl
Ph
p-FPh
2e
2f
2g
p-ClPh
o-ClPh
m-ClPh
2i
2j
2k
m-MeOPh
2,4,5-Trimeoph
benZo[1,3]dioxole-
5-methanyl
2d
m-BrPh
2h
p-MeOPh
2l
CH=C(CH3)CH2CH2
CH=C(CH3)2
925.4111(calculated 925.4117), calculated for C48H67ClNaO14
.
1.2.8. 21-p-Methoxylbenzylidene digoxin (2h)
Yield 93%; m.p. 156.5–157.8 ◦C; IR 3455, 2932, 2880, 1737,
1604, 1511, 1449, 1406, 1379, 1302, 1255, 1175, 1128, 1061, 1014,
82.1, 81.8, 73.9, 72.8, 69.25, 67.8, 67.6, 67.2, 66.4, 66.3, 55.9, 41.1,
40.6, 38.6, 38.5, 38.1, 34.9, 31.8, 30.3, 30.1, 29.7, 29.2, 26.6, 26.2,
23.8, 18.5, 18.2, 9.6; HR-MS mz−1: [M+Na]+ 935.4416 (calculated
954, 868, 829 cm−1 1H NMR (400 MHz, CDCl3, TMS): 7.75 (2H,
;
935.4405), calculated for C49H68NaO16
.
d, J = 8.4 Hz, Ar-H), 6.89 (2H, d, J = 8.6 Hz, Ar-H), 6.6 (1H, s, H-24),
6.15 (1H, s, H-22), 4.85–4.92 (4H, m),4.24 (2H, br), 4.11 (1H, s),
4.02 (1H,s), 3.84 (3H, s, OCH3), 3.75–3.82 (3H, m), 3.49 (2H, m),
3.2–3.15 (4H, m), 0.92 (3H, s, CH3-19), 0.78 (3H, s, CH3-18); 13C
NMR (100.6 MHz, CDCl3, TMS): ı 170.8, 165.2, 160.1, 148.7, 132.5,
126.2, 114.6, 114.2, 111.3, 98.3, 98.2, 95.4, 86.5, 82.5, 82.1, 75.8,
72.6, 72.5, 69.5, 68.2, 67.9, 66.4, 66.3, 53.4, 55.3, 42.1, 41.5, 37.8,
37.1, 36.7, 36.2, 34.9, 32.8, 32.6, 29.7, 29.5, 26.6, 26.4, 23.5, 21.6,
18.1, 8.7; HR-MS mz−1: [M+Na]+921.4631 (calculated 921.4613),
1.3.1. 21-(3,7-Dimethyl-2,6-octanedieneylidene)-digoxin (2l)
Yield 94%; m.p.: 159.7–160.4 ◦C; IR 3453, 2966, 2933, 2880,
1734, 1635, 1578, 1449, 1405, 1378, 1316, 1273, 1164, 1128,
1068, 955, 869 cm−1 1H NMR (400 MHz, CDCl3, TMS): 6.63 (1H,
;
d, J = 11.2 Hz, H-24), 6.40 (1H, d, J = 10.4 Hz, C = C-CH2), 6.08 (1H, s,
H-22), 5.01 (1H, s, CH2–CH=C–C), 4.90–4.75 (3H, m, 3 × H-1ꢀ), 4.25
(2H, br), 4.11 (1H, s), 4.02 (1H, s), 3.73–3.77 (6H, m), 3.44–3.47 (2H,
m), 3.22–3.29 (5H, m), 3.10 (2H, br), 0.92 (3H, s, CH3-19), 0.75 (3H,
s, CH3-18); 13C NMR (100.6 MHz, CDCl3, TMS): ı 170.5, 163.7, 149.1,
147.8, 123.7, 118.6, 115.0, 109.3, 98.3, 98.2, 95.4, 86.5, 82.5, 82.1,
72.6, 72.4, 69.5, 68.2, 68.0, 67.9, 66.4, 66.3, 57.0, 55.2, 42.0, 41.5,
40.1, 37.8, 37.1, 36.6, 36.2, 34.9, 32.8, 32.5, 31.5, 30.2, 28.9, 26.5,
25.7, 23.5, 21.6, 18.3, 18.1, 17.6, 17.1, 8.7; HR-MS mz−1: [M+Na]+
calculated for C49H70NaO15
.
1.2.9. 21-m-Methoxylbenzylidene digoxin (2i)
Yield 90%; m.p. 171.6–172.5 ◦C; IR 3466, 2933, 2880, 1739, 1597,
1487, 1450, 1405, 1379, 1305, 1247, 1164, 1129, 1067, 1014, 654,
869, 754 cm−1 1H NMR (400 MHz, CDCl3, TMS):ı 8.20 (1H, d,
;
937.5287 (calculated. 937.5290), calculated for C51H78NaO14
.
J = 8.0 Hz, Ar-H), 7.30 (2H, m, Ar-H), 7.10 (1H, s, H-24), 6.86 (1H,
d, J = 8.0 Hz, Ar-H), 6.19 (1H, s, H-22), 4.91–4.84 (3H, m, 3 × H-
1ꢀ), 4.24 (3H, s), 4.12 (1H, s), 4.03 (1H, s), 3.85 (3H, s, OCH3),
3.82–3.77 (4H, m), 3.57 (2H, m), 3.29–3.19 (4H, m), 2.27 (1H, m),
0.91 (3H, s, CH3-19), 0.78 (3H, s, CH3-18); 13C NMR (100.6 MHz,
CDCl3, TMS): ı 170.7, 165.5, 157.6, 150.0, 131.5, 130.2, 122.2, 121.0,
115.2, 110.5, 105.0, 98.2, 98.1, 95.3, 86.5, 82.4, 82.0, 75.6, 72.5, 72.4,
69.4, 68.2, 68.0, 67.9, 66.3, 66.2, 55.8, 55.5, 41.9, 41.4, 37.7, 37.0,
36.6, 36.1, 34.9, 32.8, 32.5, 29.4, 26.5, 26.4, 23.4, 21.6, 18.1, 8.7; HR-
MS mz−1: [M+Na]+ 921.4631 calculated 921.4613), calculated for
1.3.2. 21,21-Dihydroxymethyl (4)
m.p.: 184.3–185.5 ◦C; IR:3435, 2934, 2880, 1736, 1630, 1450,
1405, 1378, 1165, 1129, 1067, 1014, 869 cm−1 1H NMR(400 Hz,
;
CDCl3): 5.87 (1H, s, H-22), 5.0 (1H, br), 4.81 (1H, br), 4.70–4.64
(3H, m), 4.55 (2H, br), 4.2 (1H, br), 4.15 (1H, br), 3.90 (4H,s,
2 × CH2OH), 3.78 (2H, s), 3.73 (2H, s), 3.49-3.62 (5H, m), 3.01 (2H,
d, J = 9.2 Hz), 2.89 (1H, br). 2.01 (1H, m), 0.72 (3H, s, CH3-19), 0.54
(3H, s, CH3-18); 13C NMR (100 Hz, CDCl3) 179.04, 173.29, 119.02,
99.34, 99.25, 95.54, 94.31, 84.52, 82.16, 81.9, 74.1, 72.89, 72.31,
70.09, 69.26, 67.82, 67.71, 67.23, 66.51, 66.36, 62.48, 59.43, 58.98,
55.71, 44.21,38.69, 38.53, 38.16, 36.54, 34.89, 32.96, 31.81, 30.21,
29.7, 26.7, 26.23, 21.7, 18.60, 18.26, 10.32; HR-MS mz−1: [M+H]+
C49H70NaO15.
1.2.10. 21-(2,4,5-Trimethoxyl benzylidene)-digoxin (2j)
Yield 91%; m.p. 162.2–163.9 ◦C; IR 3447, 2933, 2884, 1740, 1638,
1578, 1506, 1451, 1420, 1380, 1332, 1268, 1164, 1128, 1068, 1012,
863.4398 (calculated 863.4405), calculated for C43H68NaO16
.
869 cm−1 1H NMR (400 MHz, CDCl3, TMS): ı 7.25 (1H, s, Ar-H),
;
7.02 (1H, s, Ar-H), 6.5 (1H, s, H-24), 6.17 (1H, s, H-22), 4.87 (3H, m),
4.22 (2H, s), 4.09 (1H, s), 4.01 (1H, br), 3.87 (9H, od), 3.87–3.77 (3H,
m), 3.65 (1H, s), 3.48 (2H, m), 3.28–3.17 (4H, m), 0.90 (3H, s, CH3-
19), 0.76 (3H, s, CH3-18); 13C NMR (100.6 MHz, CDCl3, TMS): ı 170,
165, 153, 149, 138, 138.3, 128.9, 115, 111.1, 107.9, 98.2, 95.3, 86.5,
82.5, 82.1, 76.7, 75.9, 72.6, 72.4, 69.5, 68.2, 68.0, 66.4, 66.3, 60.9,
56.2, 55.4, 42.1, 41.4, 37.7, 37.0, 36.6, 36.2, 34.9, 32.6, 29.7, 26.5,
26.4, 23.5, 18.1, 8.7; HR-MS mz−1: [M+Na]+ 981.4858 (calculated
2. Results and discussion
The compound 21-alkylidene digoxin (2) was prepared by the
reaction of digoxin with aldehyde in methanol in the presence of
Na2CO3. Without strong base and functional protection, the reac-
tion can proceed smoothly in refluxing (Scheme 1). Using this
procedure, a series of 21-aromaticidene digoxin analogues (Table 1)
were obtained with good yields in most cases. In the above reaction,
aromatic aldehyde showed good reaction activity, but the reaction
could not take place between the ketone or alkyl aldehyde and
digoxin under the same conditions; this can be rationalised taking
into consideration the electronic and steric factors.
981.4824), calculated for C51H74NaO17
.
1.3. 21-(1,3-Benzodioxol-5-ylmethylidene)-digoxin (2k)
Yield 86%; m.p. 152.5–153.7 ◦C; IR 3462, 2933, 2880, 1742, 1645,
1472, 1449, 1405, 1380, 1317, 1274, 1229, 1163, 1128, 1068, 1015,
953, 869 cm−1; 1H NMR (400 MHz, DMSO, TMS): ı 7.29 (1H, s, Ar-H),
7.12 (1H, d, J = 8.0 Hz, Ar-H), 7.02(1H, d, J = 8.0 Hz„ Ar-H), 6.69 (1H, s,
H-24), 6.13 (1H, s, H-22), 6.09 (2H, s,O-CH2-O), 5.0 (1H,br, OH). 4.8
(3H, ot, 3 × H-1ꢀ), 4.25 (2H, br, OH), 4.04 (2H, s), 3.91 (1H, s), 3.84
(1H, d, J = 2.4 Hz), 3.7–3.63(5H, m), 3.13 (3H, d, J = 9.2 Hz), 2.99 (1H,
d), 2.23 (1H, m), 0.84 (3H, s, CH3-19), 0.63 (3H, s, CH3-18); 13C NMR
(100.6 MHz, DMSO, TMS): ı 169.5, 166.6, 152.9, 148.7, 148.1, 131.7,
128.8, 127.5, 125.9, 114.1, 109.2, 109.0, 10.1, 99.2, 99.1, 95.5, 85.1,
6–12 h.
21-Methylidene digoxin (3) was designed by the reaction of
digoxin with paraformaldehyde in the same condition. However,
21-dihydroxymethanyl digoxin (4) was obtained with a yield of 80%
(Scheme 2). Namely, an addition reaction was carried out between
digoxin and two formaldehyde molecules, and the dehydration
reaction was inhibited.
Reagent and conditions: paraformaldehyde, Na2CO3, methanol,
reflux, 6 h.