Synthesis of Allocolchicine Conjugates with a Cetirizine Analog

Article abstract of DOI:10.1134/S107042801810010X

Conjugates of allocolchicine and a cetirizine analog have been synthesized as potential anti-inflammatory and anti-allergic drugs.

Full text of DOI:10.1134/S107042801810010X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 10, pp. 1498–1504. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © A.S. Zotov, E.S. Shchegravina, A.Yu. Fedorov, 2018, published in Zhurnal Organicheskoi Khimii, 2018, Vol. 54, No. 10,
pp. 1486–1492.
Synthesis of Allocolchicine Conjugates with a Cetirizine Analog
A. S. Zotova, E. S. Shchegravinaa, and A. Yu. Fedorova*
a Lobachevskii National Research State University of Nizhny Novgorod,
pr. Gagarina 23, Nizhny Novgorod, 603950 Russia
*e-mail: afnn@rambler.ru
Received May 3, 2018
Abstract—Conjugates of allocolchicine and a cetirizine analog have been synthesized as potential anti-inflam-
matory and anti-allergic drugs.
DOI: 10.1134/S107042801810010X
Allergy is one of the six most frequent pathologies
[1]. Anti-allergic medications include mainly antihis-
tamine drugs, in particular inverse agonists and neutral
antagonists of histamine H1 receptors [2–9]. Inverse
agonists bind to receptors and stabilize their inactive
conformation [10]. Neutral antagonists do not affect
the activity of basal receptors but hamper agonist
binding thereto [11]. Cetirizine (1) [12–16] is one of
the most known second-generation antihistamine drugs
and is included into the list of vitally important drugs.
One more known anti-inflammatory drug colchicine
(2) is an alkaloid isolated from Colchicum autumnale
[17], which is used for the treatment of gout and bru-
cellosis [18]; it is also capable of exhibiting multiple
anti-inflammatory effect, e.g., through neutrophil
migration inhibition [19], and direct anti-inflammatory
effect [20] via inhibition of key inflammatory signal-
ing networks known as inflammatory and pro-inflam-
matory cytokines [21].
We anticipated that colchicine–cetirizine conjugates
would exhibit enhanced anti-inflammatory activity
since these compounds affect the nidus of inflamma-
tion according to different mechanisms, so that a com-
bination of colchicine and cetirizine fragments in
a single molecule could give rise to synergistic effect
[22, 23]. Taking into account that colchicine itself pos-
sesses a significant systemic toxicity [24], we selected
less toxic allocolchicine derivatives [25–35] as compo-
nents of heterodimers 3a and 3b.
NHAc
Ph
O
N
OMe
N
Cl
O
COOH
MeO
OMe
OMe
1
2
O
O
O
MeO
MeO
( )n
Ph
NH
N
N
OMe
COOMe
Br
3a, 3b
n = 1 (a), 2 (b).
1498

SYNTHESIS OF ALLOCOLCHICINE CONJUGATES
1499
Scheme 1.
MeO
MeO
MeO
MeO
MeO
MeO
Boc
Ac
Boc
Boc2O, DMAP
Et3N, MeCN
100°C, 3.5 h
NHAc
O
N
NH
MeOH, MeONa
40°C, 1 h
OMe
OMe
OMe
O
COOMe
OMe
OMe
2
4
5
( )n
O
MeO
MeO
O
O
( )n
O
NH2
NH
COOH
Et3N, CH2Cl2
40 min
DMSO, NMM
20°C, 45 min
MeO
MeO
OMe
OMe
COOMe
COOMe
7a, 7b
6
n = 1 (a), 2 (b); NMM is N-methylmorpholine.
The colchicine fragment of conjugates 3a and 3b
was obtained from deacetylallocolcicine 6 which was
prepared in three steps starting from colchicine (2)
(Scheme 1). For this purpose, the NH group of 2 was
protected by treatment with di-tert-butyl dicarbonate
(Boc2O) [36]. Deacetylation of compound 4 thus
formed under basic conditions was accompanied by
contraction of the seven-membered tropolone ring [37]
to produce N-Boc-substituted colchicinoid 5 in 99%
yield. Removal of the Boc protection gave amine 6
which was acylated with succinic and glutaric anhy-
drides in the presence of N-methylmorpholine (NMM).
Amides 7a and 7b were isolated in 40 and 68% yield,
respectively.
(Scheme 2). In the first step, the addition of phenyl-
magnesium bromide to aldehyde 8 gave the corre-
sponding diphenylmethanol which was converted to
dibromide 9 by treatment with carbon tetrabromide
and triphenylphosphine (Appel reaction); the overall
yield of 9 starting from 8 was 72%. Compound 9
reacted with substituted piperazine 10 [39] to afford
60% of ester 11, and subsequent removal of the
methoxycarbonyl group from 11 and N-alkylation led
to cetirizine derivative 12 in 57% yield.
The colchicine (7a, 7b) and cetirizine fragments
(12) were combined by esterification according to
Yamaguchi (Scheme 3). Conjugates 3a and 3b were
obtained in 61 and 48% yield, respectively (15 and
12% over 10 steps). Study of their anti-inflammatory
and anti-allergic activity is now in progress.
The cetirizine fragment [38] was synthesized in
six steps starting from 4-bromobenzaldehyde (8)
Scheme 2.
O
N
OMe
(10)
Br
Ph
HN
CHO
a
b
Ph
N
N
Br
Br
Br
COOMe
8
9
11
Ph
c
N
N
Br
OH
12
Reagents and conditions: i: (1) PhMgBr, THF, 2 h, –30°C; (2) HCl, H2O; (3) PPh3, CBr4, CH2Cl2, 1.5 h; ii: toluene, reflux, 24 h;
iii: (1) (CH2OH)2, N2H2·H2O, KOH, 150°C, 1.5 h; (2) BrCH2CH2OH, toluene, Et3N, 100°C, 24 h.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

ZOTOV et al.
1500
Scheme 3.
O
O
O
2,4,6-Cl3C6H2COCl
Et3N, DMAP, CH2Cl2
0°C, 16 h
MeO
MeO
( )n
Ph
NH
N
N
7a, 7b
+ 12
OMe
COOMe
Br
3a, 3b
n = 1 (a), 2 (b).
was filtered off on a Schott filter, and the solvent was
removed under reduced pressure. The residue was
purified by column chromatography using petroleum
ether–ethyl acetate (12:1) as eluent. Yield of 9 1.82 g
EXPERIMENTAL
The H and 13C NMR spectra were recorded on
1
an Agilent DD2 400 spectrometer at 400 and
1
1
101 MHz, respectively; the H chemical shifts were
(77%), colorless oily material. H NMR spectrum
measured relative to the residual proton signals of the
deuterated solvents: (DMSO-d5, δ 2.50 ppm; CHCl3,
δ 7.26 ppm). Column chromatography was performed
on Silicagel 60 (70–230 mesh, Alfa Aesar). Commer-
cially available reagents (Aldrich, Alfa Aesar, Acros)
were used without additional purification. The solvents
used were purified by standard methods. Petroleum
ether was a fraction boiling at 40–65°C.
(CDCl3), δ, ppm: 6.25 s (1H), 7.51–7.27 m (9H).
13C NMR spectrum (CDCl3), δC, ppm: 63.42, 123.74,
129.15, 133.09, 133.83, 139.63, 140.50, 142.26,
143.41. Found, %: C 47.71; H 3.26. C13H10Br2. Calcu-
lated, %: C 47.89; H 3.09.
Methyl 4-[(4-bromophenyl)(phenyl)methyl]-
piperazine-1-carboxylate (11). Methyl piperazine-1-
carboxylate [39], 1.11 g (6.24 mmol), and compound
9, 2.03 g (6.24 mmol), were dissolved in toluene in
an inert atmosphere, 5.35 g (18.7 mmol) of sodium
carbonate decahydrate was added, and the mixture was
stirred for 24 h at 110°C. The solvent was removed
under reduced pressure, and the residue was purified
by column chromatography using petroleum ether–
ethyl acetate (10:1) as eluent. Yield 1.46 g (60%),
1-Bromo-4-[bromo(phenyl)methyl]benzene (9).
4-Bromobenzaldehyde (8), 1.0 g (5.4 mmol), was
dissolved in 30 mL of THF at –20°C in an inert
atmosphere, and 7.5 mL of a 1.1 M solution of phenyl-
magnesium bromide in THF was added dropwise. The
mixture was stirred for 1.5 h at –20°C, acidified with
5% aqueous HCl to pH 4, and extracted with ethyl
acetate (3×100 mL). The combined extracts were dried
over anhydrous Na2SO4, the solvent was removed
under reduced pressure, and the residue was subjected
to column chromatography using petroleum ether–
ethyl acetate (10:1) as eluent. We thus isolated 1.33 g
(94%) of 4-bromophenyl(phenyl)methanol as colorless
1
colorless oily material. H NMR spectrum (CDCl3), δ,
ppm: 2.30 s (4H), 3.44 s (4H), 3.64 s (3H), 4.19 s
(1H), 7.41–7.19 m (9H). 13C NMR spectrum (CDCl3),
δC, ppm: 43.50, 51.08, 52.08, 74.83, 120.44, 124.67,
126.20, 126.95, 128.03, 130.87, 141.07, 141.18, 155.30.
Found, %: C 58.33; H 5.54; N 7.09. C19H21BrN2O2.
Calculated, %: C 58.62; H 5.44; N 7.20.
1
oily material. H NMR spectrum (CDCl3), δ, ppm:
3.18 s (1H), 5.65 s (1H), 7.49–7.16 m (9H). 13C NMR
spectrum (CDCl3), δC, ppm: 60.60, 122.14, 127.49,
127.91, 128.07, 129.46, 133.19, 142.27, 143.43.
2-{4-[4-Bromophenyl(phenyl)methyl]piperazin-
1-yl}ethanol (12). Compound 11, 0.96 g (2.47 mmol),
potassium hydroxide, 3.73 g (66.7 mmol), and hydra-
zine hydrate, 0.6 mL (12.35 mmol), were dissolved in
25 mL of ethylene glycol, and the solution was stirred
for 1.5 h at 150°C. When the reaction was complete,
the mixture was poured into 25 mL of distilled water,
excess solid boric acid was added, sodium hydroxide
was then added to pH 8, the mixture was extracted
with tert-butyl methyl ether (3×100 mL), and the com-
bined extracts were evaporated under reduced pressure
to obtain 0.61 g (75%) of 1-[4-bromophenyl(phenyl)-
Triphenylphosphine, 5.7 g (21.7 mmol), was dis-
solved in 30 mL of methylene chloride in an inert
atmosphere, the solution was stirred for 15 min at
room temperature, and 2.9 g (8.7 mmol) of carbon
tetrabromide was added. The mixture was stirred for
5 min, and a solution of 1.9 g (7.24 mmol) of
4-bromophenyl(phenyl)methanol in 5 mL of methylene
chloride was added dropwise. The mixture was stirred
for 1.5 h, the precipitate of triphenylphosphine oxide
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

SYNTHESIS OF ALLOCOLCHICINE CONJUGATES
1501
1
methyl]piperazine as colorless oily material. H NMR
spectrum (CDCl3), δ, ppm: 2.37 s (4H), 2.90 t (4H, J =
4.6 Hz), 4.18 s (1H), 7.18 t (1H, J = 7.2 Hz), 7.41–
7.22 m (9H). 13C NMR spectrum (CDCl3), δC, ppm:
46.10, 53.08, 83.39, 120.51, 127.03, 127.79, 128.47,
129.53, 131.47, 141.73, 141.86. Found, %: C 61.91;
H 6.12; N 8.13. C17H19BrN2. Calculated, %: C 61.64;
H 5.78; N 8.46.
133.87, 134.55, 134.79, 140.85, 148.28, 150.50,
153.02, 153.14, 163.54, 170.48, 177.90.
Methyl (5S)-5-(tert-butoxycarbonylamino)-
6,7-dihydro-9,10,11-trimethoxy-5H-dibenzo[a,c][7]-
annulene-3-carboxylate (5). Solid sodium methoxide,
0.818 g (15.15 mmol), and compound 4, 1.89 g
(3.78 mmol), were dissolved in 25 mL of methanol in
an inert atmosphere, and the solution was stirred for
1 h at 40°C. When the reaction was complete, excess
sodium methoxide was neutralized with a 1 M solution
of ammonium chloride, and the mixture was extracted
with ethyl acetate (3×100 mL). The combined extracts
were dried over anhydrous sodium sulfate, the solvent
was removed under reduced pressure, and the residue
was purified by column chromatography using ethyl
acetate as eluent. Yield 1.71 g (99%), dark yellow
crystals, mp 152°C. 1H NMR spectrum (DMSO-d6), δ,
ppm: 1.31 s (9H), 1.86–1.77 m (1H), 2.03–1.94 m
(1H), 2.21–2.11 m (1H), 2.55 d.d (1H, J = 13.2,
5.9 Hz), 3.54 s (3H), 3.78 s (3H), 3.83 s (3H), 3.87 s
(3H), 4.11–4.03 m (1H), 6.76 s (1H), 7.02 d (1H, J =
10.9 Hz), 7.10 d (1H, J = 10.6 Hz), 7.21 s (1H), 7.69 d
(1H, J = 7.8 Hz). 13C NMR spectrum (DMSO-d6), δC,
ppm: 28.18, 29.25, 37.84, 56.05, 58.37, 60.69, 60.88,
78.21, 107.69, 112.18, 125.34, 130.53, 134.31, 134.46,
135.15, 140.72, 150.39, 151.11, 152.99, 154.55,
163.54, 178.05.
1-[4-Bromophenyl(phenyl)methyl]piperazine, 0.5 g
(1.5 mmol), was dissolved in 20 mL of toluene in
an inert atmosphere, 0.13 mL (1.8 mmol) of 2-bromo-
ethanol and 0.53 mL (3.75 mmol) of triethylamine
were added, and the mixture was stirred for 24 h at
100°C. When the reaction was complete, the solvent
was removed under reduced pressure, and the residue
was purified by column chromatography using petro-
leum ether–ethyl acetate–acetone (5:1:1) as eluent.
Yield of 12 0.43 g (76%), colorless oily material.
1H NMR spectrum (CDCl3), δ, ppm: 2.00 s (4H), 2.57–
2.52 m (4H), 3.59 t (2H, J = 5.4 Hz), 3.66–3.61 m
(2H), 3.79–3.76 m (1H), 4.19 s (1H), 7.41–7.24 m
(9H). 13C NMR spectrum (CDCl3), δC, ppm: 53.21,
57.75, 59.43, 59.65, 83.87, 120.74, 127.27, 127.79,
128.66, 129.54, 131.66, 141.74, 141.87. Found, %:
C 61.03; H 6.25; N 7.65. C19H23BrN2O. Calculated, %:
C 60.81; H 6.18; N 7.46.
tert-Butyl acetyl(1,2,3,10-tetramethoxy-9-oxo-
5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)carbamate
(4). Di-tert-butyl dicarbonate, 1.64 g (7.5 mmol),
N,N-dimethylpyridin-4-amine, 1.83 g (15 mmol), and
colchicine (2), 3.0 g (7.5 mmol), were dissolved in
30 mL of acetonitrile in an inert atmosphere, 1.1 mL
(7.5 mmol) of triethylamine was added, and the mix-
ture was stirred for 1 h at 100°C. An additional portion
of di-tert-butyl dicarbonate, 3.27 g (15 mmol), was
then added, and the mixture was stirred for 2.5 h.
When the reaction was complete, the solvent was
removed under reduced pressure, and the residue was
purified by column chromatography using ethyl
acetate–acetone (4:1) as eluent. Yield 2.63 g (70%),
Methyl (5S)-5-amino-6,7-dihydro-9,10,11-tri-
methoxy-5H-dibenzo[a,c][7]annulene-3-carboxylate
(6). Trifluoroacetic acid, 8 mL, was added dropwise
to a solution of 0.5 g (1.06 mmol) of compound 5 in
20 mL of methylene chloride, and the mixture was
stirred for 40 min at room temperature. Excess
trifluoroacetic acid was neutralized with NaHCO3 to
pH 8, the mixture was extracted with methylene
chloride (3×100 mL), the combined extracts were
dried over anhydrous Na2SO4, the solvent was
removed under reduced pressure, and the residue was
purified by column chromatography using methylene
chloride–methanol (10:1) as eluent. Yield 0.31 g
1
(83%), grayish yellow powder, mp 136°C. H NMR
1
yellow crystals, mp 105°C. H NMR spectrum
spectrum (DMSO-d6), δ, ppm: 0.88–0.80 m (1H),
1.49 t.d (1H, J = 9.8, 4.7 Hz), 2.14 d.d.d.d (4H, J =
24.9, 18.9, 12.6, 6.3 Hz), 3.45 d.d (1H, J = 10.5,
5.9 Hz), 3.55 s (3H), 3.76 s (3H), 3.83 s (3H), 3.86 s
(3H), 6.74 s (1H), 6.99 d (1H, J = 10.8 Hz), 7.05 d
(1H, J = 10.6 Hz), 7.64 s (1H). 13C NMR spectrum
(DMSO-d6), δC, ppm: 24.89, 40.27, 53.11, 55.84,
55.90, 60.53, 60.66, 107.34, 111.84, 125.40, 131.83,
133.76, 134.88, 135.68, 140.47, 150.15, 152.73,
153.82, 163.26, 178.20.
(DMSO-d6), δ, ppm: 1.50 d (9H, J = 6.3 Hz),
1.91 d.d.d (1H, J = 15.8, 12.4, 6.5 Hz), 2.22 s (3H),
2.34–2.25 m (1H), 2.56–2.46 m (1H), 2.69 d.d (1H, J =
13.5, 6.4 Hz), 3.54 s (3H), 3.77 s (3H), 3.83 s (3H),
3.87 s (3H), 4.90 d.d (1H, J = 12.4, 6.0 Hz), 6.77 s
(1H), 7.02 d (1H, J = 10.9 Hz), 7.11 d (1H, J =
10.7 Hz), 7.27 s (1H). 13C NMR spectrum (DMSO-d6),
δC, ppm: 27.31, 29.27, 31.83, 33.30, 55.86, 56.08,
60.68, 60.87, 84.40, 107.75, 112.19, 125.63, 131.75,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

ZOTOV et al.
1502
Amides 7a and 7b (general procedure). Compound
Esters 3a and 3b (general procedure). Colchicine
derivative 7a or 7b, 1 equiv, was dissolved in
methylene chloride in an inert atmosphere, 3 equiv of
triethylamine and 2 equiv of 2,4,6-trichlorobenzoyl
chloride (Yamaguchi reagent) were added, and the
mixture was stirred for 5 h at room temperature.
A solution of 2 equiv of compound 12 and 2 equiv of
DMAP in methylene chloride was then added, and the
mixture was stirred for 16 h at room temperature in
an inert atmosphere. The solvent was removed under
reduced pressure, and the product was isolated by
column chromatography.
6, 1 equiv, was dissolved in DMSO in an inert atmo-
sphere, 4 equiv of 4-methylmorpholine (NMM) and
1.1 equiv of succinic or glutaric anhydride were added,
and the mixture was stirred for 45 min at room tem-
perature. When the reaction was complete, the mixture
was extracted with ethyl acetate. The combined
extracts were dried over anhydrous sodium sulfate, the
solvent was removed under reduced pressure, and the
residue was purified by column chromatography using
methylene chloride–methanol (9:1) as eluent.
4-Oxo-4-{[(5S)-9,10,11-trimethoxy-3-(methoxy-
carbonyl)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-
5-yl]amino}butanoic acid (7a) was synthesized from
0.30 g (0.84 mmol) of compound 6 and 0.09 g
(0.92 mmol) of succinic anhydride in 2 mL of DMSO
in the presence of 0.37 mL (3.37 mmol) of NMM.
Methyl (5S)-5-[4-(2-{4-[4-bromophenyl(phenyl)-
methyl]piperazin-1-yl}ethoxy)-4-oxobutanamido]-
9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c][7]-
annulene-3-carboxylate (3a) was synthesized using
0.04 g (0.09 mmol) of 7a, 0.04 mL (0.26 mmol) of
triethylamine, 0.03 mL (0.17 mmol) of Yamaguchi
reagent, 0.065 g (0.17 mmol) of 12, and 0.021 g
(0.17 mmol) of DMAP. The product was purified by
column chromatography using petroleum ether–ethyl
acetate–ethanol (3.5:1:1) as eluent. Yield 0.045 g
1
Yield 0.15 g (40%), gray powder, mp 81°C. H NMR
spectrum (DMSO-d6), δ, ppm: 1.88–1.80 m (1H),
2.05–1.96 m (1H), 2.19 d.d (1H, J = 13.1, 7.2 Hz),
2.31–2.25 m (2H), 2.38–2.33 m (2H), 2.58 d.d (1H, J =
13.2, 6.1 Hz), 3.51 s (3H), 3.78 s (3H), 3.83 s (3H),
3.87 s (3H), 4.34–4.27 m (1H), 6.76 s (1H), 7.03 d
(1H, J = 10.9 Hz), 7.11 d (1H, J = 10.6 Hz), 7.16 s
(1H), 8.63 d (1H, J = 7.3 Hz). 13C NMR spectrum
(DMSO-d6), δC, ppm: 24.52, 24.64, 25.07, 35.80,
51.31, 55.90, 56.09, 60.73, 60.90, 107.76, 112.27,
125.46, 130.48, 134.27, 134.48, 135.30, 140.75,
140.97, 150.45, 150.94, 152.96, 163.53, 170.97,
178.06. Found, %: C 62.75; H 6.12; N 3.21.
C24H27NO8. Calculated, %: C 63.01; H 5.95; N 3.06.
1
(61%), viscous oily material. H NMR spectrum
(DMSO-d6), δ, ppm: 1.57 d.d (1H, J = 7.3, 4.8 Hz),
1.83 d.d (1H, J = 12.7, 7.3 Hz), 2.03–1.95 m (1H),
2.28 d.d (4H, J = 19.0, 13.4 Hz), 2.41 s (4H), 2.45 d.d
(4H, J = 7.4, 3.3 Hz), 2.72 d.d (1H, J = 7.8, 2.2 Hz),
3.50 s (3H), 3.78 s (3H), 3.82 s (3H), 3.85 s (3H),
4.04–3.99 m (2H), 4.08 t (2H, J = 5.8 Hz), 4.27 s (1H),
6.75 s (1H), 7.00 d (1H, J = 11.0 Hz), 7.09 d (1H, J =
10.7 Hz), 7.12 s (1H), 7.18 t (1H, J = 7.3 Hz), 7.29 t
(2H, J = 7.6 Hz), 7.38 d (2H, J = 2.4 Hz), 7.47 s (2H),
7.49 s (2H), 8.61 d (1H, J = 7.4 Hz). 13C NMR spec-
trum (DMSO-d6), δC, ppm: 23.75, 28.84, 40.43, 46.52,
51.36, 52.97, 55.85, 56.02, 60.24, 60.68, 61.55, 62.80,
72.28, 74.16, 85.97, 125.42, 127.09, 127.53, 128.60,
129.87, 130.01, 131.40, 134.19, 135.11, 135.74,
140.71, 142.40, 150.41, 152.91, 163.48, 164.84,
170.07, 172.11, 177.97, 184.17, 188.20, 193.01.
Found, %: C 63.07; H 6.21; N 4.92. C43H48BrN3O8.
Calculated, %: C 63.39; H 5.94; N 5.16.
4-Oxo-4-{[(5S)-9,10,11-trimethoxy-3-(methoxy-
carbonyl)-6,7-dihydro-5H-dibenzo[a,c][7]annulen-
5-yl]amino}pentanoic acid (7b) was synthesized from
0.15 g (0.42 mmol) of 6 and 0.05 g (0.46 mmol) of
glutaric anhydride in 1 mL of DMSO in the presence
of 0.19 mL (1.73 mmol) of NMM. Yield 0.13 g
1
(68%), gray powder, mp 76°C. H NMR spectrum
(DMSO-d6), δ, ppm: 1.66 d.d (2H, J = 14.6, 7.2 Hz),
1.82 d.d (1H, J = 12.0, 5.3 Hz), 2.04–1.97 m (1H),
2.16 t (4H, J = 7.5 Hz), 2.26–2.20 m (2H), 3.53 s (3H),
3.78 s (3H), 3.83 s (3H), 3.86 s (3H), 4.31 d.d (1H, J =
12.7, 5.9 Hz), 6.76 s (1H), 7.02 d (1H, J = 11.0 Hz),
7.10 d (1H, J = 8.9 Hz), 7.12 s (1H), 8.55 d (1H,
J = 7.4 Hz). 13C NMR spectrum (DMSO-d6), δC,
ppm: 21.15, 29.25, 33.09, 34.18, 34.29, 55.90, 56.09,
60.74, 60.91, 107.78, 112.19, 125.47, 130.34, 134.27,
134.47, 135.24, 140.76, 140.92, 150.48, 150.89,
152.97, 163.55, 171.11, 178.01. Found, %: C 63.41;
H 6.39; N 2.71. C25H29NO8. Calculated, %: C 63.68;
H 6.20; N 2.97.
Methyl (5S)-5-[4-(2-{4-[4-bromophenyl(phenyl)-
methyl]piperazin-1-yl}ethoxy)-4-oxopentanamido]-
9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c][7]-
annulene-3-carboxylate (3b) was synthesized using
0.03 g (0.07 mmol) of 7b, 0.03 mL (0.20 mmol) of
triethylamine, 0.02 mL (0.13 mmol) of Yamaguchi
reagent, 0.05 g (0.13 mmol) of 12, and 0.016 g
(0.13 mmol) of DMAP. The product was purified by
column chromatography using petroleum ether–ethyl
acetate–ethanol (4:1:1) as eluent. Yield 0.028 g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 10 2018

SYNTHESIS OF ALLOCOLCHICINE CONJUGATES
1503
1
12. DuBuske, L.M., Clin. Ther., 1999, vol. 21, p. 281.
(48%), viscous oily material. H NMR spectrum
(DMSO-d6), δ, ppm: 1.75–1.70 m (1H), 1.86–1.77 m
(1H), 2.04–1.95 m (1H), 2.16 t (2H, J = 7.4 Hz),
2.24 d.d (4H, J = 7.1, 4.9 Hz), 2.33–2.27 m (4H),
2.45–2.39 m (4H), 2.61–2.55 m (1H), 3.52 s (3H),
3.78 s (3H), 3.82 s (3H), 3.86 s (3H), 4.11–4.03 m
(2H), 4.26 s (1H), 4.37–4.28 m (2H), 5.75 s (1H),
6.76 s (1H), 7.01 d (1H, J = 10.7 Hz), 7.10 d (2H, J =
7.8 Hz), 7.18 t (1H, J = 7.1 Hz), 7.28 t (2H, J =
7.5 Hz), 7.38–7.36 m (2H), 7.46 d (2H, J = 2.4 Hz),
7.48 d (2H, J = 2.4 Hz), 8.54 d (1H, J = 7.4 Hz).
13C NMR spectrum (DMSO-d6), δC, ppm: 32.71,
38.43, 40.19, 43.98, 51.34, 53.12, 52.92, 54.92, 55.86,
56.03, 60.25, 60.70, 60.86, 72.28, 74.16, 87.24,
112.09, 119.77, 125.44, 127.09, 127.53, 128.60,
129.72, 129.85, 130.02, 134.21, 135.16, 140.72,
142.27, 142.41, 150.44, 150.74, 152.91, 163.50,
164.70, 170.90, 172.45, 177.94. Found, %: C 63.46;
H 6.34; N 4.78. C44H50BrN3O8. Calculated, %:
C 63.76; H 6.08; N 5.07.
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