SYNTHESIS OF NEW COMBRETASTATIN Aꢀ4 ANALOGUES
75
ture of ketone (IIIa) (326 mg, 1 mmol) and morphoꢀ 49.13 (C16, C16'), 50.21 (C16, C16'), 56.46 (12,14ꢀ
line (170 mg, 2 mmol) in toluene (10 mL) was boiled OCH3), 61.09 (13ꢀOCH3), 93.29 (C2), 105.26 (C11,
for 10 h and evaporated in vacuo. The product was C15), 124.30 (C6, C8), 128.52 (C5, C9), 136.75
crystallized from benzene. Compound (VIIa) was (C10), 141.06 (C13), 145.53 (C4), 147.72 (C7), 152.94
obtained in a yield of 70% (290 mg) as a mixture of two (C12, C14), 159.73 (C3), 186.01 (C1). МСꢀВР: found,
isomers (
E
/
Z
, 7 : 3), mp 153–155
°
C
.
m/z 412.1626 [M
]+. C22H24N2O6; calculated, M =
412.1629. IR spectrum: 1622 (C=O).
E
isomer. 1H NMR: 3.23 (4H, m, H16, H16'), 3.73
(4H, m, H17, H17'), 3.80 (3H, s, 7ꢀOCH3), 3.85 (6H,
s, 12,14ꢀOCH3 av), 3.87 (3H, s, 13ꢀOCH3), 5.87 (1H,
s, H2), 6.89 (2H, m, J1 0.3, J2 2.2, J3 8.5, H6, H8),
Interaction of 3ꢀ(4ꢀnitrophenyl)ꢀ1ꢀ(3,4,5ꢀtriꢀ
methoxyphenyl)propꢀ2ꢀinꢀ1ꢀone (Ib) with piperidine.
The mixture of ketone (IIIb) (170 mg, 0.5 mmol) and
piperidine (85 mg, 1 mmol) in toluene (5 mL) was
boiled for 3 h (TLC control). 3ꢀHydroxyꢀ3ꢀ(4ꢀ3ꢀ(4ꢀ
nitrophenyl)ꢀ1ꢀ(3,4,5ꢀtrimethoxyphenyl)propꢀ2ꢀinꢀ
1ꢀone (VIII) was isolated as in the previous procedure.
3ꢀHydroxyꢀ3ꢀ(4ꢀnitrophenyl)ꢀ1ꢀ(3,4,5ꢀtrimethoxyꢀ
phenyl)propꢀ2ꢀenꢀ1ꢀone (VIII) was prepared in a yield
of 33% (60 mg), mp 202–204°C (benzene–hexane).
For spectral characteristics see above.
7.09 (2H, s, H11, H15), 7.19 (2H, m, J1 0.3, J2 2.8, J3
8.5, H5, H9). 13C NMR (CDCl3): 48.67 (C16, C16'),
55.41 (7ꢀOCH3), 56.47 (12,14ꢀOCH3), 61.08 (13ꢀ
OCH3), 66.83 (C17, C17'), 97.29 (C2), 105.54 (C11,
C15), 114.34 (C6, C8), 128.10 (C4), 130.47 (C5, C9),
136.88 (C10), 141.07 (C13), 152.92 (C12, C14),
160.63 (C7), 165.00 (C3), 188.56 (C1).
Z
isomer. 1H NMR: 3.39 (4H, m, H16, H16'), 3.83
(4H, m, H17, H17'), 3.84 (3H, s, 7ꢀOCH3), 3.84 (6H,
s, 12,14ꢀOCH3 av), 3.86 (3H, s, 13ꢀOCH3), 5.61 (1H,
s, H2), 6.92 (2H, m, J1 0.3, J2 2.1, J3 8.5, H6, H8),
(E)ꢀ3ꢀ(4ꢀNitrophenyl)ꢀ3ꢀ(piperidineꢀ1ꢀyl)ꢀ1ꢀ(3,4,5ꢀ
trimethoxyphenyl)propꢀ2ꢀenꢀ1ꢀone (VIb) was preꢀ
pared in a yield of 47% (100 mg) with mp 137–139°C
7.14 (2H, s, H11, H15), 7.42 (2H, m, J1 0.3, J2 2.6, J3
1
(benzene). H NMR: 1.63 (4H, m, H17, H19), 1.69
8.5, H5, H9). 13C NMR: 52.44 (C16, C16'), 55.68 (7ꢀ
OCH3), 56.39 (12,14ꢀOCH3), 61.11 (13ꢀOCH3),
67.62 (C17, C17'), 97.68 (C2), 105.25 (C11, C15),
114.14 (C6, C8), 130.68 (C4), 131.59 (C5, C9),
136.90 (C10), 140.81 (C13), 153.06 (C12, C14),
161.72 (C7), 164.54 (C3), 184.74 (C1).
(2H, m, H18), 3.23 (4H, m, H16, H20), 3.85 (9H, s,
12,13,14ꢀOCH3), 6.00 (1H, s, H2), 7.07 (2H, m, J1
0.3, J2 1.9, J3 8.5, H5, H9), 7.43 (2H, s, H11, H15),
8.27 (2H, m, J1 0.3, J2 2.4, J
3 8.5, H6, H8). 13C NMR:
24.37 (C18), 25.94 (C17, C19), 49.52 (C16, C20),
56.52 (12,14ꢀOCH3), 61.10 (13ꢀOCH3), 95.46 (C2),
105.35 (C11, C15), 124.19 (C6, C8), 129.46 (C5, C9),
136.56 (C10), 141.30 (C13), 144.72 (C4), 148.09
(C7), 153.03 (C12, C14), 162.29 (C3), 187.34 (C1).
Found, %: C 64.62; H 5.90; N 6.46. C23H26N2O6. Calꢀ
culated, %: C 64.78; H 6.15; N 6.57. IR spectrum:
1625 (C=O).
MCꢀBP: found,
m/z 413.1833 [M ;
]+. C23H27NO6
calculated, M = 413.1830. IR spectrum: 1627 (C=O).
Interaction of 3ꢀ(4ꢀnitrophenyl)ꢀ1ꢀ(3,4,5ꢀtrimethoꢀ
xyphenyl)propꢀ2ꢀinꢀ1ꢀon (IIIb) with pyrrolidine. The
mixture of ketone (IIIb) [7] (170 mg, 0.5 mmol) and
pyrrolidine (70 mg, 1 mmol) in benzene (10 mL) was
boiled for 2 h. After the completion of the reaction
(TLC control), the solvent was removed in vacuo.
3ꢀHydroxyꢀ3ꢀ(4ꢀnitrophenyl)ꢀ1ꢀ(3,4,5ꢀtrimethoxꢀ
yphenyl)propꢀ2ꢀenꢀ1ꢀone (VIII) was isolated by colꢀ
umn chromatography (toluene, tolueneꢀethylacetate,
(E)ꢀ3ꢀ(4ꢀNitrophenyl)ꢀ3ꢀmorpholinoꢀ1ꢀ(3,4,5ꢀtriꢀ
methoxyphenyl)propꢀ2ꢀenꢀ1ꢀone (VIIb). The mixture
of ketone (IIIb) (341 mg, 1 mmol) and morpholine
(174 mg, 2 mmol) in toluene (10 mL) was boiled for
5 h. After the completion of the reaction, the solvent
was removed in vacuum, and the product (VIIb) was
crystallized from benzene with a yield of 85% (365 mg),
ethylacetate) in a yield of 22% (40 mg), mp 203–
1
205°C
(benzeneꢀhexane). H NMR: 3.93 (3H, s,
mp 195–197°C
. 1H NMR: 3.19 (4H, m, H16, H16'),
OCH3), 3.95 (6H, s, 2OCH3), 6.78 (1H, s), 7.23 (2H,
s), 8.11 (2H, d, 8.8, ArH), 8.32 (2H, d, 8.8, ArH),
3.74 (4H, m, H17, H17'), 3.85 (9H, s, 12,13,14ꢀ
OCH3), 6.03 (1H, s, H2), 7.07 (2H, s, H11, H15),
J
J
13
16.74 (OH, s, 1H). C NMR: 56.33, 60.95, 93.97,
104.89, 123.77, 127.85, 130.41, 140.70, 142.69,
7.44 (2H, m, J1 0.4, J2 1.8, J3 8.4, H5, H9), 8.26 (2H,
13
m, J1 0.4, J2 2.5, J3 8.4, H6, H8). C NMR: 48.36
(C16, C16'), 56.51 (12,14ꢀOCH3), 61.11 (13ꢀOCH3),
66.51 (C17, C17'), 97.34 (C2), 105.50 (C11, C15),
124.24 (C6, C8), 129.72 (C5, C9), 135.87 (C10),
141.68 (C13), 143.70 (C4), 148.21 (C7), 153.08 (C12,
149.71, 153.22, 180.19, 187.98. МCꢀВР: found,
359.1000 [
]+. C18H17NO7; calculated, M = 359.0999.
IR spectrum,
,cm–1: 1591 (C=О); 3425 (OH).
)ꢀ3ꢀ(4ꢀNitrophenyl)ꢀ3ꢀ(pyrrolidineꢀ1ꢀyl)ꢀ1ꢀ(3,4,5ꢀ
trimethoxyphenyl)propꢀ2ꢀenꢀ1ꢀone (Vb) was syntheꢀ
sized with a yield of 58% (120 mg), mp 185–186.5
m/z
M
ν
(E
C14), 162.10 (C3), 187.67 (C1). МCꢀВР: found,
428.1578 [
]+. C22H24N2O7; calculated, M =
428.1574. IR spectrum: 1639 (C=O).
Histamine inflammation. We used in the experiꢀ
m/z
°
C
1
M
(benzene). H NMR: 1.88 (2H, br.m, H17, H17'),
2.08 (2H, br.m, H17, H17'), 3.03 (2H, br.m, H16,
H16'), 3.49 (2H, br.m, H16, H16'), 3.84 (9H, s,
12,13,14ꢀOCH3 av), 5.80 (1H, s, H2), 7.09 (2H, s, ment 72 outbred mice, i.e., males (nine groups of eight
H11, H15), 7.44 (2H, m, J1 0.4, J2 1.8, J3 8.4, H5, animals) with mass of 25–30 g. The studied comꢀ
H9), 8.28 (2H, m, J1 0.4, J2 2.5, J3 8.4, H6, H8). pounds were administrated intraperitoneally as a susꢀ
13C NMR: 25.17 (C17, C17'), 25.66 (C17, C17'), pension in distilled water with addition of emulsifier
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 41
No. 1
2015