Synthetic Approaches to the Bifunctional Chelators for Radio nuclides Based on Pyridine-Containing Azacrown Compounds

Article abstract of DOI:10.1055/s-0039-1691540

Synthetic ways to introduce functional groups (CO ₂ Me, CO ₂ H, OCH ₂ CO ₂ H, OCH ₂ C≡CH, CH ₂ OH, CH ₂ Cl, CH ₂ N ₃) into the pyridine ring of pyridine-containing azacrown compounds are described. These groups were introduced at position-4 of the pyridine ring, while keeping the macrocyclic carboxylate groups available for metal chelation. The derivatives were obtained by macrocyclization reaction of 4-substituted, trimethyl pyridine-2,4,6-tricarboxylate or by modification of methyl ester group in pyridine fragment of macrocycles. Obtained derivatives can be applied for preparing radiotherapeutic agents by conjugation to different vector biomolecules for targeted drug delivery to cancer cells without damaging healthy tissue.

Full text of DOI:10.1055/s-0039-1691540

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–I
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A. D. Zubenko et al.
Paper
Synthesis
Synthetic Approaches to the Bifunctional Chelators for Radio-
nuclides Based On Pyridine-Containing Azacrown Compounds
Anastasia D. Zubenko*a
Anna A. Shchukinaa,b
Olga A. Fedorovaa,b
0
0
0
0-
0
0
0
3-4
7
0
7-3
8
7
5
bifunctional
chelator
R
-COOMe
-COOH
-CH2OH
= -CH2Cl
-CH2N3
O
O
N
a A. N. Nesmeyanov Institute of Organoelement Compounds of
Russian Academy of Sciences, Vavilova St. 28,
119991 Moscow, Russian Federation
b D. I. Mendeleev University of Chemical Technology of Russia,
Miusskaya Sq. 9, 125047 Moscow, Russian Federation
nastya.mutasova@yandex.ru
R
metal-based
radiopharmaceuticals
NH
HN
N
-CH2COOH
-OCH2C CH
N
N
COOt-Bu
t-BuOOC
COOt-Bu
Received: 11.10.2019
Accepted after revision: 03.12.2019
Published online: 16.12.2019
DOTA
(1,4,7,10-tetraazacyclododecane-1,4,7,10-
tetraacetic acid) (Figure 1) is one of the current ‘gold stan-
dards’ for a number of isotopes, including 111In, 177Lu, 86/90Y,
225Ac, and 44/47Sc, and it is likely the most commonly used
chelator to this day.5,21 But it inconveniently requires elevat-
ed temperatures for radiolabeling with essentially all radio-
metals.22–24 DTPA (diethylenetriaminepentaacetic acid)
(Figure 1) is one of the oldest and most pervasive acyclic
chelators used in radiochemistry, and like most acyclic che-
lators it can be radiolabeled with many radiometal ions at
room temperature in a matter of minutes.25 As a first gener-
ation radiometal chelator, it suffers from stability issues in
DOI: 10.1055/s-0039-1691540; Art ID: ss-2019-t0574-op
Abstract Synthetic ways to introduce functional groups (CO2Me,
CO2H, OCH2CO2H, OCH2C≡CH, CH2OH, CH2Cl, CH2N3) into the pyridine
ring of pyridine-containing azacrown compounds are described. These
groups were introduced at position-4 of the pyridine ring, while keep-
ing the macrocyclic carboxylate groups available for metal chelation.
The derivatives were obtained by macrocyclization reaction of 4-substi-
tuted, trimethyl pyridine-2,4,6-tricarboxylate or by modification of
methyl ester group in pyridine fragment of macrocycles. Obtained de-
rivatives can be applied for preparing radiotherapeutic agents by conju-
gation to different vector biomolecules for targeted drug delivery to
cancer cells without damaging healthy tissue.
Key words bifunctional chelators, azacrown compounds, macro-
cyclization, radiopharmaceuticals, bioconjugation
COOH
N
HOOC
HOOC
N
N
COOH
COOH
Nuclear medicine is a powerful tool with the ability to
both image disease and subsequently treat the diseased
state without harming the surrounding healthy tissue.1–4
Ligands that are typically used to construct radiopharma-
ceuticals are bifunctional chelators (BFCs), which are sim-
ply chelators with reactive functional groups that can be
covalently coupled to targeting vectors (e.g., peptides,
nucleotides, antibodies, nanoparticles).5–10
BFCs serve as linkers between the radionuclide and tar-
geting biomolecule and therefore play a crucial role in the
success of targeted radionuclide therapy. The BFC is expect-
ed to impart high in vivo stability to the radiolabeled bio-
molecule translating to minimum radiation dose to non-
target organs. The choice of BFC is therefore governed by
the thermodynamic and kinetic stability of the radiometal
complexes.6,11–14 Fast room temperature radiolabeling be-
comes an important property when working with BFC-
conjugates of heat sensitive molecules such as antibodies
and their derivatives, or when working with short half-life
isotopes such as 212/213Bi, 68Ga, 44Sc, and 62Cu.15–20
DTPA
O
O
HOOC
HOOC
COOH
N
N
N
N
N
NH
N
HN
N
HOOC
COOH
COOH
N
DOTA
COOH
L
R
N
-COOMe
-COOH
-CH2OH
-CH2Cl
-CH2N3
-CH2COOH
O
O
R
=
R
NH
N
HN
N
-OCH2C CH
HOOC
COOH
N
R
R
O
BFC-L
Figure 1 Structures of DTPA, DOTA, L, and bifunctional derivatives of L
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
A. D. Zubenko et al.
Paper
Synthesis
vivo with many radiometal ions and is universally not as
stable as the macrocycles, making its use obsolete in recent
years.26–28
propargyl, chloride, or azide functions to be eventually
used for conjugation and leave the carboxylate groups of
macrocyclic moiety available for metal chelation.
In our earlier studies, the synthesis of the new deriva-
tives of pyridine containing azacrown compounds and their
complex formation with heavy metal ions have been re-
ported.29,30 The rigid structure of pyridine-2,6-dicarboxam-
ide fragment provides fast kinetics of complex formation,
the introduction of additional coordination groups im-
proves the binding properties of macrocycles. These chela-
tors have also been tested as chelating agent for radionu-
clides.
Scheme 1 demonstrates the synthesis of a pyridine con-
taining azacrown ethers 3a,b with a methyl ester substitu-
ent in the 4-position of the pyridine ring. The aromatic es-
ter was chosen because it can be easily transformed into a
carboxylic acid, an amide, an alcohol, or into other com-
pounds in good yields under mild conditions. Moreover,
methyl ester can be selectively cleaved in the presence of
tert-butyl esters using alkaline conditions of hydrolysis.
Me
COOH
Ligand L (Figure 1) possessing three acetate pendant
arms forms the most stable complex with Bi3+ (lgK = 21)
through the studied ligands. The complex L·Bi3+ is stable
even in 100 times volume excess of fetal serum during at
least 3 hours. The complex L·Bi3+ demonstrates fast clear-
ance in vivo.31 The results of in vitro serum stability and in
vivo biodistribution studies suggest that the novel ligand L
can be promising as BFC for the preparation of radiophar-
maceutical with short half-life 213Bi. Thus, it is essential to
have in hand a family of L derivatives with different reactive
functions in order to allow covalent coupling of the free li-
gand or its metal complexes to bioactive molecules, biomol-
ecules, macromolecules, or nanosystems.
a)
b)
Me
N
Me
HOOC
N
COOH
COOMe
COOMe
O
O
N
c)
NH
NH
HN
d)
MeOOC
N
COOMe
HN
H
N
1, 40%
n
2a, n = 0, 62%
2b, n = 1, 59%
COOH
COOMe
There are several possible approaches to the conjuga-
tion of chelator to a targeting moiety. The most common
conjugation strategy is to substitute one acetate donor.26,32
This strategy has been used for a long time in the field of
DOTA bioconjugates.33–38 However, in some cases, this ap-
proach can affect the denticity of the ligand, the overall
charge of the complex and may decrease in vitro and in vivo
stabilities of the resulting metal complexes.39 Three other
approaches can be exploited, which do not affect on the co-
ordination ability of macrocyclic moiety. In the presented
approaches in Figure 1, the functional group can be at-
tached to (i) one of the pyridine carbon,40–42 (ii) one of the
carbons of the ethylene group of the macrocyclic chelator
backbone,43–47 and (iii) one of the -positions to the carbox-
ylic groups.32,40,48–51 In our research, the 4-position of the
pyridine ring was chosen for modification due to big syn-
thetic facilities in obtaining the acyclic pyridine precursors.
Also, we assumed that in this case the functional group
should be sufficiently far away from the coordination cage
to limit any interference with the coordination cage.
Synthetic methodology for building the skeletal back-
bone of pyridine-azacrown compound is the double amida-
tion reaction29,52–54 with high efficiency in the crucial mac-
rocyclization step. Herein, we wish to demonstrate that this
approach provides an easy access to new BFCs. Also, in this
paper we suggest the ways for the further modification of
the substituted pyridine ring in pyridine-azacrown ethers
without destruction of macrocyclic unit. The BFCs, de-
scribed in this report, display ester, carboxylic acid, alcohol,
O
O
O
O
N
N
e)
NH
N
HN
NH
HN
N
N
N
N
N
COOt-Bu
COOt-Bu
t-BuOOC
COOt-Bu
t-BuOOC
n
COOt-Bu
3a, n = 0, 80%
3b, n = 1, 77%
4, 67%
Scheme 1 Reagents and conditions: (a) CrO3, H2SO4, 80 °C; (b) 1) SOCl2,
reflux, 2) MeOH, reflux; (c) triethylenetetramine, MeOH, RT (2a), tetra-
ethylenepentamine, MeOH, RT (2b); (d) tert-butyl bromoacetate, K2CO3,
MeCN, reflux; (e) 1 M NaOH, MeOH, RT
The trimethyl pyridine-2,4,6-tricarboxylate (1) was pre-
pared from commercial 2,4,6-collidine in three steps ac-
cording to the reported procedure53 (Scheme 1): an oxida-
tion by chromium oxide in sulfuric acid to pyridine-2,4,6-
tricarboxylic acid, which was then transferred to the corre-
sponding trimethyl ester 1 through the stage of the forma-
tion of acid chloride by action of thionyl chloride (overall
yield is 40%).
The macrocyclization reaction between ester 1 and
polyamines was carried out similarly to the synthesis of the
unfunctionalized pyridine-azacrown compounds without
use of any template agents and high-dilution technique. We
used triethylenetetramine or tetraethylenepentamine to
prepare 15- and 18-membered azacrown compounds in
good overall yields (yields of 2a and 2b are 62% and 59% re-
spectively).
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

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A. D. Zubenko et al.
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Synthesis
It should be noted that the presence of additional ester
groups in the 4-position of the pyridine ring did not have a
noticeable negative effect on the process of macrocycliza-
tion if the yields of 2a,b are compared with those of analo-
gous unsubstituted pyridine containing azamacrocyclic
compounds described earlier.29 We propose that the pyri-
dine nitrogen atom affects the formation of the macrocycle
due to the formation of hydrogen bonds with polyamine. In
any case, this does not exclude the possibility of side reac-
tions occurring in the ester group located in the 4-position
of the pyridine ring.
At the next stage, chelating groups were introduced into
the macrocycle structure by alkylation of N-atoms with
tert-butyl bromoacetate in acetonitrile. Hydrolysis of meth-
yl ester was carried out selectively in methanol solution of 1
M NaOH at room temperature, since tert-butyl and amide
groups were not affected under such conditions (yield 67%).
It is known that spacing between the radiometal chelate
and the targeting vector affects the pharmacodynamics, af-
finity, and mode of excretion of the bioconjugate.55 For ob-
taining the chelators with longer distance between macro-
cycle and COOH groups, the synthesis presented in Scheme
2 is proposed. Chelidamic acid was used as the starting
compound, from which diester 5 was obtained with 86%
yield.56 The dimethyl chelidamate (5) in solution exists in
two tautomeric forms (NH and OH), while the alkylation
with tert-butyl bromoacetate quantitatively proceeds at the
oxygen atom to form compound 6.57
Macrocyclization gives azacrown compound 7 in 44%
yield, the following hydrolysis of tert-butyl ester in boiling
water without the addition of acid as catalyst results in 8 in
high yield (Scheme 2). This convenient way to remove tert-
butyl protection group was developed by us earlier,30,58 it
avoids the use of ion-exchange resin or other difficult
methods for the purification of the target product. At the fi-
nal stage, the chelating groups are introduced to obtain a bi-
functional derivative 9 in 73% yield.
In order to prepare a bifunctional derivative available
for a click chemistry approach, in particular for the 1,3-di-
polar Huisgen cycloaddition between alkyne and azide
functions,59–63 we envisioned a synthetic way to a propargyl
derivative 12 (Scheme 3). It includes alkylation of dimethyl
chelidamate (5) with propargyl bromide resulting in 10,64
following macrocyclization giving 11 and alkylation with
chelating tert-butyl acetate groups (Scheme 3).
O
O
a)
b)
COOMe
N
MeOOC
N
H
5
COOMe
MeOOC
10, 98%
O
N
O
N
O
O
O
O
c)
NH
HN
NH
HN
HN
N
N
COOt-Bu
NH
H
N
O
O
N
t-BuOOC
a)
b)
COOt-Bu
12, 90%
11, 30%
HOOC
N
H
COOH
MeOOC
N
H
COOMe
COOt-Bu
O
Scheme 3 Reagents and conditions: (a) propargyl bromide, K2CO3,
MeCN, reflux; (b) tetraethylenepentamine, MeOH, RT; (c) tert-butyl
bromoacetate, K2CO3, MeCN, reflux.
5, 86%
O
O
COOt-Bu
O
The alcohol group is of great practical interest, since it
can be easily modified by replacing it with a halide and
azide groups, which can be used for covalent binding of a
chelator to various molecules.17,65,66
N
c)
d)
NH
HN
MeOOC
COOMe
N
NH
HN
6, 100%
H
N
To introduce the hydroxymethyl group at the 4-position
of the pyridine ring, in accordance with the literature meth-
od,67 dimethyl 2,6-pyridinedicarboxylate (13) prepared
from the corresponding acid68 was oxidized using Fenton’s
reagent [Н2О2, Fe(ClO4)2] in methanol in the presence of
perchloric acid (Scheme 4). In this case, methanol plays the
role of both a solvent and a reagent. After macrocyclization
of the precursor 14 with polyamines and the introduction
of chelating groups by alkylation with tert-butyl bromoace-
tate, the hydroxyl group of 15a,b was replaced by chloride
through the reaction with thionyl chloride. At the last stage,
the obtained crude chloride products 17a,b were reacted
with sodium azide in acetonitrile to give the targeted azide
derivatives 18a,b in 60% and 57% yield, respectively.
7, 44%
COOH
O
N
O
COOH
O
O
O
O
N
N
e)
NH
N
HN
NH
HN
N
COOt-Bu
NH
HN
H
N
t-BuOOC
COOt-Bu
8, 96%
9, 73%
Scheme 2 Reagents and conditions: (a) 1) SOCl2, reflux, 2) MeOH, re-
flux; (b) tert-butyl bromoacetate, K2CO3, MeCN, reflux; (c) tetraethyl-
enepentamine, MeOH, RT; (d) H2O, reflux; (e) tert-butyl bromoacetate,
K2CO3, MeCN, reflux.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

D
A. D. Zubenko et al.
Paper
Synthesis
yields in the crucial macrocyclization step and suitable
overall yields. Thanks to their free CO2Me, CO2H, C≡CH, OH,
Cl, or N3 groups, all the novel derivatives may undergo cou-
pling reactions with a wide range of biological vectors to
create bioconjugates capable of targeted drug delivery to
cancer cells without damaging healthy tissue. The creation
of the effective chelators for short half-life radionuclides is
an extremely urgent task. Therefore, the obtained bifunc-
tional derivatives have good prospects for practical applica-
tion in the field of radiopharmaceuticals, since in vitro and
in vivo studies of L have shown advantages over known an-
alogues. Therefore, in the future, we plan to develop the
synthesis of conjugates from the obtained BFCs of L with
biomolecules and study their properties, in particular ra-
dionuclide labeling with 213Bi, thermodynamic and kinetic
stability, as well as biodistribution. In conclusion, it should
be emphasized that the described approach to the synthesis
of BFCs based on 15- and 18-membered pyridine-azacrown
compounds can be considered as promising for preparing
other macrocycles containing pyridine ring, since it was
shown that the presence of various functional groups in 4-
position of the pyridine ring does not interfere the macro-
cyclization reaction resulting in the desired derivatives.
This greatly expands the possibilities of using this approach
in the future.
OH
a)
b)
MeOOC
N
COOMe
MeOOC
N
COOMe
14, 51%
13
OH
OH
O
O
O
O
N
N
c)
d)
NH
HN
NH
HN
NH
HN
N
N
H
N
N
COOt-Bu
n
t-BuOOC
n
15a, n = 0, 56%
15b, n = 1, 49%
COOt-Bu
16a, n = 0, 72%
16b, n = 1, 65%
Cl
N3
O
O
O
O
N
N
e)
NH
N
HN
NH
N
HN
N
N
N
N
COOt-Bu
t-BuOOC
t-BuOOC
COOt-Bu
COOt-Bu
n
n
COOt-Bu
18a, n = 0, 60%
18b, n = 1, 57%
17a, n = 0
17b, n = 1
Scheme 4 Reagents and conditions: (a) MeOH, H2O2, Fe(ClO4)2, HClO4,
H2O; (b) triethylenetetramine, MeOH, RT (15a), tetraethylenepentam-
ine, MeOH, RT (15b); (c) tert-butyl bromoacetate, K2CO3, MeCN, reflux;
(d) SOCl2, CHCl3, RT; (e) NaN3, NEt3, MeCN, reflux.
All commercially available reagents were used without further purifi-
cation. The progress of reactions was followed with TLC using silica
gel (Macherey-Nagel, Alurgam Xtra Sil G/UV254, 0.20 mm silica gel 60)
and Al2O3 (Merck, 60 F254, neutral). Trimethyl pyridine-2,4,6-tricar-
boxylate (1),53 dimethyl chelidamate (5),56 dimethyl 4-(2-tert-butoxy-
2-oxoethoxy)pyridine-2,6-dicarboxylate (6),57 dimethyl 4-(prop-2-
ynyloxy)pyridine-2,6-dicarboxylate (10),64 dimethyl 2,6-pyridinedi-
carboxylate (13),68 and dimethyl 4-(hydroxymethyl)pyridine-2,6-di-
carboxylate (14)67 were synthesized following the literature proce-
dures.
In current research, we demonstrated that selective re-
duction of the methyl ester group with NaBH4 is possible in
the presence of the amide groups in macrocycle 2a (Scheme
5). Thus, the reduction of 2a with NaBH4 in methanol gave
hydroxyl derivative 15a in high yield (80%). Besides, reac-
tion of the ester derivative 2a with an excess (9 equiv) of
neat propargylamine yielded the derivative 19.
1H and 13C NMR spectra were recorded at 25 °C on Bruker Avance 400,
Bruker Avance 500, and Bruker Avance 600 MHz spectrometers.
Chemical shifts for 1H and 13C are reported in parts per million () rel-
ative to deuterated solvent as an internal reference (CDCl3 1H  = 7.27
H
O
N
OH
COOMe
1
and 13C  = 77.00; D2O  = 4.75; CD3CN H  = 1.94; DMSO-d6 1H  =
2.50 and 13C  = 39.51). Coupling constants (J) are given in hertz (Hz).
Spectral assignments were based in part on the two-dimensional
NMR experiments (1H COSY, HSQC, and HMBC). Numbering of hydro-
gen and carbon nuclei used to describe the 1H and 13C NMR spectra is
given in the Supporting Information. Electrospray ionization mass
spectrometry (ESI-MS) analyses were performed using a Finnigan
LCQ Advantage mass spectrometer equipped with an octopole ion-
trap mass-analyzer, an MS Surveyor pump, a Surveyor auto sampler, a
Schmidlin-Lab nitrogen generator (Germany), and Finnigan X-Calibur
1.3 software for data collecting and processing. Direct infusion of the
sample solution was used. Positive electrospray ionization was
achieved using an ionization voltage at 4.5 kV at a temperature of
200 °C. Electrospray full scan spectra in the range m/z 100–2000 were
obtained by infusion at 0.05 mL·min–1 of 50 M aqueous solutions of
the compounds. Melting points were determined on a Mel-temp II ap-
paratus in open capillary tubes. IR spectra were recorded from KBr
O
O
O
O
O
O
N
N
N
b)
a)
NH
HN
NH
HN
NH
HN
NH HN
NH HN
NH HN
15a, 80%
2a
19, 69%
Scheme 5 Reagents and conditions: (a) NaBH4, MeOH, RT; (b) propar-
gylamine, RT.
In conclusion, we have reported the synthesis of a series
of bifunctional derivatives of pyridine-azacrown com-
pounds bearing a free reactive functional group at the 4-po-
sition of the pyridine ring. The synthetic methodology de-
veloped herein provides a simple route to BFCs in high
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

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A. D. Zubenko et al.
Paper
Synthesis
pellets on Magna IR (Nicolet) and Tensor 37 (Bruker) Fourier spec-
trometers. Elemental analyses were carried out on a Carlo Erba 1108
elemental analyzer.
Compound 3b
Compound 3b was obtained analogously to 3a by using of 2b (350 mg,
0.92 mmol), tert-butyl bromoacetate (404 L, 2.77 mmol), and K2CO3
(766 mg, 5.55 mmol) in MeCN (30 mL). The crude product obtained
by concentration of the combined organic extracts was purified by
column chromatography (Al2O3, EtOAc/EtOH 50:1). The product was
obtained as а yellow oil; yield: 513 mg (77%).
1H NMR (400.13 MHz, CDCl3):  = 1.33 (s, 9 H, Н16), 1.41 (s, 18 H,
Н12), 2.78 (br s, 4 H, Н8), 2.82 (br s, 8 H, Н6,7), 3.26 (s, 2 H, H13), 3.35
(s, 4 H, H9), 3.55 (br s, 4 H, H5), 3.99 (s, 3 H, H18), 8.84 (s, 2 Н, Н2).
13C NMR (100.61 MHz, CDCl3):  = 28.1 (С-16), 28.1 (С-12), 37.0 (С-5),
51.6 (С-7), 52.0 (С-6), 52.9 (С-18), 53.5 (С-9), 54.3 (С-13), 54.6 (С-8),
80.8 (С-15), 81.2 (С-11), 123.9 (С-2), 140.4 (С-1), 150.3 (С-3), 162.9
(С-4), 164.7 (С-17), 170.7 (С-14), 171.2 (С-10).
MS (ESI): m/z [M + H]+ calcd for C35H56N6O10 + H+: 721.4; found:
721.4; m/z [M + Na]+ calcd for C35H56N6O10 + Na+: 743.4; found: 743.2.
Compound 2a
Compound 2a was prepared according to a modified procedure.29
A
solution of triethylenetetramine (289 mg, 1.97 mmol) in MeOH (50
mL) was quickly added to a solution of triester 1 (500 mg, 1.97 mmol)
in MeOH (100 mL) at RT. The mixture was stirred for 7 days and then
the solvent was evaporated in vacuum. The crude product was recrys-
tallized from MeCN to give 2a as a beige solid; yield: 411 mg (62%);
mp 205 °С (dec.).
1H NMR (600.22 MHz, CDCl3):  = 2.84 (s, 4 H, Н7), 2.95 (t, J = 5.7 Hz, 4
H, H6), 3.50 (q, J = 5.7 Hz, 4 H, H5), 3.99 (s, 3 H, Н9), 8.74 (s, 2 Н, Н2),
9.11 (br s, 2 Н, NH).
13C NMR (150.93 MHz, CDCl3):  = 39.0 (С-5), 47.5 (С-6), 49.7 (С-7),
52.9 (С-9), 123.2 (С-2), 141.1 (С-1), 149.8 (С-3), 162.1 (С-4), 164.5 (С-
8).
MS (ESI): m/z [M + H]+ calcd for С15Н21N5O4 + H+: 336.2; found: 336.4.
Anal. Calcd for C35H56N6O10: C, 58.32; H, 7.83; N, 11.66. Found: C,
58.29; H, 7.85; N, 11.65.
Anal. Calcd for С15Н21N5O4·Н2О: C, 53.33; H, 6.29; N, 13.33. Found: C,
Compound 4
53.33; H, 6.51; N, 12.98.
A solution of 1 М NaOH in MeOH (350 L) was added to a solution of
compound 3b (250 mg, 0.35 mmol) in MeOH (8 mL) and the mixture
was stirred at RT for 24 h. At first H2O (10 mL) and then aq 0.2 M HCl
(1.75 mL) were added to the mixture, and product was extracted with
CHCl3. The product 4 was purified by column chromatography (SiO2,
CHCl3/EtOH 1:1) and obtained as a white solid; yield: 164 mg (67%);
mp 152–154 °С.
Compound 2b
Compound 2b was obtained analogously to 2a by using of triester 1
(500 mg, 1.97 mmol) and tetraethylenepentamine (374 mg, 1.97
mmol) in MeOH (150 mL). The crude product was recrystallized from
MeCN to give 2b as a beige solid; yield: 441 mg (59%); mp 204–207
°С.
1H NMR (600.22 MHz, CDCl3):  = 2.76 (t, J = 4.6 Hz, 4 H, Н8), 2.88 (t,
J = 4.6 Hz, 4 H, H7), 2.92 (t, J = 5.0 Hz, 4 H, H6), 3.65 (q, J = 5.0 Hz, 4 H,
H5), 4.01 (s, 3 H, Н10), 8.43 (br s, 2 Н, NH), 8.90 (s, 2 Н, Н2).
IR (KBr): 3351 (NH), 2978–2862 (СН2), 1730 (С=О, COOtBu), 1675
(amide I), 1532 (amide II), 1155 cm–1 (С–О, COOtBu).
1H NMR (500.13 MHz, CDCl3):  = 1.15 (s, 9 H, Н16), 1.39 (s, 18 H,
Н12), 2.74–3.56 (br s, 16 H, Н5,6,7,8), 2.94 (s, 2 H, Н13), 3.26 (s, 4 H,
H9), 8.85 (s, 2 Н, Н2), 9.67 (br s, 2 Н, NH).
13C NMR (125.76 MHz, CDCl3):  = 27.6 (С-16), 28.1 (С-12), 36.9 (С-5),
49.1 (С-6), 50.6 (С-9), 52.0 (С-7), 53.7 (С-8), 56.1 (С-13), 81.4 (С-11),
82.5 (С-15), 124.2 (С-2), 146.7 (С-1), 149.8 (С-3), 164.1 (С-4), 168.2
(С-17), 169.7 (С-10), 170.2 (С-14).
MS (ESI): m/z [M + H]+ calcd for C34H54N6O10 + H+: 707.4; found:
707.3; m/z [M + Na]+ calcd for C34H54N6O10 + Na+: 729.4; found: 729.3;
m/z [M + K]+ calcd for C34H54N6O10 + K+: 745.1; found: 745.3.
13C NMR (150.93 MHz, CDCl3):  = 38.8 (С-5), 49.1 (С-6, С-7), 49.9 (С-
8), 53.0 (С-10), 124.5 (С-2), 140.5 (С-1), 150.4 (С-3), 162.7 (С-4), 164.6
(С-9).
MS (ESI): m/z [M + H]+ calcd for C17H26N6O4 + H+: 379.2; found: 379.6.
Anal. Calcd for C17H26N6O4: C, 53.96; H, 6.93; N, 22.21. Found: C,
53.82; H, 7.08; N, 22.31.
Compound 3a
Anal. Calcd for C34H54N6O10·H2O: C, 56.34; H, 7.79; N, 11.59. Found: C,
56.19; H, 7.51; N, 11.38.
A solution of tert-butyl bromoacetate (174 L, 1.19 mmol) in MeCN
(10 mL) was added to a mixture of 2a (200 mg, 0.60 mmol) and K2CO3
(329 mg, 2.39 mmol) in MeCN (20 mL) and refluxed for 20 h. The sol-
vent was evaporated under vacuum and the residue was dissolved in
H2O and extracted with CHCl3. The crude product obtained by con-
centration of the combined organic extracts was purified by column
chromatography (Al2O3, EtOAc). The product was obtained as а yellow
oil; yield: 269 mg (80%).
1H NMR (400.13 MHz, CDCl3):  = 1.38 (s, 18 H, Н13), 2.90 (s, 4 H, Н7),
3.01 (t, J = 5.7 Hz, 4 H, Н6), 3.25 (s, 4 H, H10), 3.50 (q, J = 5.1 Hz, 4 H,
H5), 3.99 (s, 3 H, H9), 8.75 (s, 2 H, Н2), 9.10 (br s, 2 Н, NH).
Compound 7
Compound 7 was obtained analogously to 2a by using of 6 (500 mg,
1.54 mmol) and tetraethylenepentamine (291 mg, 1.54 mmol) in
MeOH (150 mL). The product was purified by column chromatogra-
phy (Al2O3, CH2Cl2/MeOH 10:1) and obtained as a yellow oil; yield:
305 mg (44%).
1H NMR (400.13 MHz, CDCl3):  = 1.48 (s, 9 Н, Н12), 2.82 (br s, 4 Н,
Н8), 2.89 (br s, 8 Н, Н6,7), 3.63 (br s, 4 Н, Н5), 4.68 (s, 2 Н, Н9), 7.80 (s,
2 Н, Н2), 8.74 (br s, 2 Н, NH).
13C NMR (100.61 MHz, CDCl3):  = 28.2 (С-13), 36.5 (С-5), 51.3 (С-6),
52.7 (С-10), 52.9 (С-9), 53.7 (С-7), 81.3 (С-12), 123.1 (С-2), 140.9 (С-
1), 149.5 (С-3), 162.5 (С-4), 164.5 (С-8), 170.2 (С-11).
1H NMR (400.13 MHz, D2O):  = 1.4 (s, 9 Н, Н12), 2.79 (br s, 12 Н,
Н6,7,8), 3.48 (br s, 4 Н, Н5), 4.69 (s, 2 Н, Н9), 7.42 (s, 2 Н, Н2).
MS (ESI): m/z [M + H]+ calcd for C27H41N5O8 + H+: 564.3; found: 564.3.
13C NMR (100.61 MHz, D2O):  = 27.2 (С-12), 38.6 (С-5), 46.5 (С-6),
46.7 (С-7), 47.1 (С-8), 65.7 (С-9), 84.9 (С-11), 110.8 (С-2), 150.0 (С-3),
164.6 (С-4), 166.4 (С-10), 168.7 (С-1).
Anal. Calcd for C27H41N5O8: C, 57.53; H, 7.33; N, 12.43. Found: C,
57.48; H, 7.38; N, 12.35.
MS (ESI): m/z [M + H]+ calcd for С21Н34N6O5 + H+: 451.3; found: 451.3.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

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A. D. Zubenko et al.
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Synthesis
Anal. Calcd for С21Н34N6O5: C, 55.98; H, 7.61; N, 18.65. Found: C,
Compound 12
55.97; H, 7.63; N, 18.63.
Compound 12 was obtained analogously to 3a by using of 11 (100 mg,
0.27 mmol), tert-butyl bromoacetate (117 L, 0.80 mmol), and K2CO3
(221 mg, 1.60 mmol) in MeCN (15 mL). The product was obtained as a
yellow oil; yield: 172 mg (90%).
Compound 8
H2O (15 mL) was added to the crown compound 7 (200 mg, 0.44
mmol), and the mixture was refluxed for 12 h. The solution was
washed with CHCl3 and the aqueous layer was separated and concen-
trated under vacuum. The product was obtained as a beige solid;
yield: 168 mg (96%); mp 285 °С (dec.).
1H NMR (400.13 MHz, D2O):  = 2.92 (br s, 4 Н, Н8), 3.03 (br s, 4 Н,
Н7), 3.06 (br s, 4 Н, Н6), 3.63 (br s, 4 Н, Н5), 4.68 (s, 2 Н, Н9), 7.26 (s, 2
Н, Н2).
IR (KBr): 3368 (NH), 2125 (C≡C), 1738 (C=O), 1678 (amide I), 1530
cm–1 (amide II).
1H NMR (400.13 MHz, CDCl3):  = 1.35 (s, 9 H, H19), 1.43 (s, 18 H,
H15), 2.58 (t, J = 2.54 Hz, 1 H, H11), 2.79 (br s, 4 H, H8), 2.83 (br s, 8 H,
H6,7), 3.27 (s, 2 H, H16), 3.36 (s, 4 H, H12), 3.54 (br s, 4 H, H5), 4.85 (d,
J = 2.54 Hz, 2 H, H9), 7.90 (s, 2 H, H2), 8.82 (s, 2 H, NH).
13C NMR (100.61 MHz, CDCl3):  = 28.1 (C-19), 28.1 (C-15), 35.9 (C-5),
51.6 (C-9), 51.9 (C-7), 53.4 (C-6), 54.4 (C-16), 54.6 (C-12), 56.1 (C-8),
77.2 (C-11), 80.7 (C-10), 81.1 (C-14,18), 111.0 (C-2), 151.1 (C-3), 163.4
(C-4), 166.1 (C-1), 170.8 (C-17), 171.2 (C-13).
13C NMR (100.61 MHz, D2O):  = 36.2 (С-5), 45.3 (С-8), 48.4 (С-6), 48.5
(С-7), 67.3 (С-9), 111.0 (С-2), 149.2 (С-3), 164.4 (С-4), 167.5 (С-1),
176.1 (С-10).
MS (ESI): m/z [M + H]+ calcd for С17Н26N6O5 + H+: 395.2; found: 395.2.
MS (ESI): m/z [M + H]+ calcd for С36Н56N6O9 + H+: 717.4; found: 717.7;
m/z [M + Na]+ calcd for С36Н56N6O9 + Na+: 739.4; found: 739.3.
Anal. Calcd for С17Н26N6O5·2H2O: C, 47.43; H, 7.02; N, 19.52. Found: C,
47.39; H, 7.05; N, 19.50.
Anal. Calcd for С36Н56N6O9: C, 60.32; H, 7.87; N, 11.72. Found: C,
60.33; H, 7.91; N, 11.68.
Compound 9
Compound 15a
Compound 9 was obtained analogously to 3a by using of 8 (100 mg,
0.25 mmol), tert-butyl bromoacetate (111 L, 0.76 mmol) and K2CO3
(210 mg, 1.52 mmol) in MeCN (15 mL). The product was obtained as a
yellow oil; yield: 136 mg (73%).
1H NMR (400.13 MHz, CDCl3):  = 1.43 (s, 18 Н, Н14), 1.48 (s, 9 Н,
Н18), 2.80 (br s, 4 Н, Н8), 2.84 (br s, 8 Н, Н6,7), 3.27 (s, 2 Н, Н15), 3.36
(s, 4 Н, Н11), 3.54 (br s, 4 Н, Н5), 4.63 (s, 2 Н, Н9), 7.84 (s, 2 Н, Н2),
8.78 (br s, 2 Н, NH).
13C NMR (100.61 MHz, CDCl3):  = 27.9 (С-18), 28.2 (С-14), 37.8 (С-5),
49.2 (С-6), 50.5 (С-11), 52.0 (С-7), 53.7 (С-8), 56.1 (С-15), 63.7 (С-9),
81.4 (С-13), 82.6 (С-17), 110.7 (С-2), 151.9 (С-3), 164.7 (С-4), 168.9
(С-1), 169.7 (С-12), 170.5 (С-16), 171.0 (С-10).
Method A: Compound 15a was obtained anlogous to 2a by using of 14
(500 mg, 2.22 mmol) and triethylenetetramine (325 mg, 2.22 mmol)
in MeOH (150 mL). The product was isolated as a beige solid; yield:
683 mg (56%).
Method B: NaBH4 (14 mg, 0.36 mmol) was added to solution of 2a
(100 mg, 0.30 mmol) in anhyd MeOH (10 mL), and the mixture was
refluxed for 5 h. H2O was added to the mixture and the product was
extracted with CHCl3. Compound 15a was obtained by concentration
of the combined organic extracts as a beige solid; yield: 73 mg (80%);
mp 225–228 °С.
1H NMR (400.13 MHz, CDCl3):  = 2.88 (s, 4 H, Н7), 2.97 (t, J = 5.4 Hz, 4
H, H6), 3.51 (q, J = 5.4 Hz, 4 H, H5), 4.85 (s, 2 H, Н8), 8.19 (s, 2 Н, Н2),
9.02 (br s, 2 Н, NH).
MS (ESI): m/z [M + H]+ calcd for С35Н56N6O11 + H+: 737.4; found: 737.4.
Anal. Calcd for С35Н56N6O11·H2O: C, 55.69; H, 7.74; N, 11.13. Found: C,
55.76; H, 7.80; N, 11.10.
13C NMR (100.61 MHz, CDCl3):  = 39.0 (С-5), 47.4 (С-6), 49.5 (С-7),
63.4 (С-8), 121.1 (С-2), 148.6 (С-3), 154.8 (С-1), 163.1 (С-4).
MS (ESI): m/z [M + H]+ calcd for С14Н21N5O3 + H+: 308.2; found: 308.1.
Compound 11
Compound 11 was obtained analogously to 2a by using of 10 (500 mg,
2.01 mmol) and tetraethylenepentamine (380 mg, 2.01 mmol) in
MeOH (150 mL). The product was purified by column chromatogra-
phy (Al2O3, CH2Cl2/EtOH 10:1) to afford 11 as a white solid; yield: 225
mg (30%); mp 156–159 °С.
1H NMR (400.13 MHz, CDCl3):  = 2.61 (t, J = 2.3 Hz, 1 Н, Н11), 3.07 (br
s, 8 Н, Н7,8), 3.14 (br s, 4 Н, Н6), 3.65 (br s, 4 Н, Н5), 4.85 (d, J = 2.3 Hz,
2 Н, Н9), 7.82 (s, 2 Н, Н2), 9.51 (br s, 2 Н, NH).
Anal. Calcd for С14Н21N5O3·H2O: C, 51.68; H, 7.13; N, 21.52. Found: C,
51.64; H, 7.16; N, 21.50.
Compound 15b
Compound 15b was obtained analogously to 2a by using 14 (500 mg,
2.22 mmol) and tetraethylenepentamine (420 mg, 2.22 mmol) in
MeOH (150 mL). The product was obtained as a yellow oil; yield: 436
mg (49%).
1H NMR (400.13 MHz, D2O):  = 2.67 (br s, 9 Н, Н7,8,11), 2.76 (br s, 4
Н, Н6), 3.47 (br s, 4 Н, Н5), 4.72 (s, 2 Н, Н9), 7.36 (s, 2 Н, Н2).
13C NMR (100.61 MHz, D2O):  = 38.8 (С-5), 47.1 (С-6), 47.2 (С-7), 47.5
(С-8), 56.6 (С-9), 76.4 (С-10,11), 110.9 (С-2), 149.8 (С-3), 164.6 (С-4),
166.1 (С-1).
1H NMR (400.13 MHz, CDCl3):  = 2.77 (m, 4 H, H8), 2.87 (m, 8 H,
H6,7), 3.34 (br s, 4 H, H5), 4.74 (s, 2 H, Н9), 8.18 (s, 2 Н, Н2), 8.32 (br s,
2 Н, NH).
13C NMR (100.61 MHz, CDCl3):  = 38.7 (С-5), 48.7 (С-6), 48.7 (С-7),
49.2 (С-8), 62.5 (С-9), 122.0 (С-2), 148.7 (С-3), 155.0 (С-1), 163.5 (С-
MS (ESI): m/z [M + H]+ calcd for С18Н26N6O3 + H+: 375.2; found: 375.2.
4).
MS (ESI): m/z [M + H]+ calcd for С16Н26N6O3 + H+: 351.2; found: 351.3.
Anal. Calcd for С18Н26N6O3·H2O: C, 55.09; H, 7.19; N, 21.41. Found: C,
55.11; H, 7.23; N, 21.40.
Anal. Calcd for С16Н26N6O3·H2O: C, 52.16; H, 7.66; N, 22.81. Found: C,
52.20; H, 7.71; N, 22.83.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

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A. D. Zubenko et al.
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Synthesis
Compound 16a
Compound 18b
Compound 16a was obtained analogously to 3a by using of 15a (300
mg, 0.98 mmol), tert-butyl bromoacetate (285 L, 1.95 mmol), and
K2CO3 (539 mg, 3.91 mmol) in MeCN (30 mL). The product was puri-
fied by column chromatography (Al2O3, EtOAc/EtOH 25:1) to give a
light-yellow oil; yield: 377 mg (72%).
1H NMR (400.13 MHz, CDCl3):  = 1.38 (s, 18 H, Н12), 2.91 (s, 4 H, Н7),
3.01 (t, J = 5.4, 5.7 Hz, 4 H, Н6), 3.25 (s, 4 H, H9), 3.47 (q, J = 5.1 Hz, 4 H,
H5), 4.84 (s, 2 H, H8), 8.26 (s, 2 H, Н2), 9.08 (br s, 2 Н, NH).
13C NMR (100.61 MHz, CDCl3):  = 28.0 (С-12), 36.4 (С-5), 51.2 (С-6),
52.6 (С-9), 53.5 (С-7), 63.1 (С-8), 81.3 (С-11), 121.2 (С-2), 148.2 (С-3),
151.2 (С-1), 163.6 (С-4), 170.2 (С-10).
MS (ESI): m/z [M + H]+ calcd for С26Н41N5O7 + H+: 536.3; found: 536.1;
m/z [M + Na]+ calcd for С26Н41N5O7 + Na+: 558.3; found: 558.1.
Compound 18b was obtained analogously to 18a by using of 16b (200
mg, 0.29 mmol), SOCl2 (1 mL) in CHCl3 (10 mL), NaN3 (281 mg, 4.33
mmol), and NEt3 (321 L, 2.31 mmol) in MeCN (25 mL). The product
18b was obtained as a yellow oil; yield: 118 mg (57%).
IR (KBr): 3370 (NH), 2106 (N3), 1730 (C=O), 1674 (amide I), 1532 cm–1
(amide II).
1H NMR (400.13 MHz, CDCl3):  = 1.35 (s, 9 Н, Н17), 1.43 (s, 18 H,
Н13), 2.81 (br s, 4 H, Н8), 2.85 (br s, 8 H, Н6,7), 3.28 (s, 2 H, H14), 3.36
(s, 4 H, H10), 3.57 (br s, 4 H, H5), 4.55 (s, 2 H, H9), 8.29 (s, 2 Н, Н2),
8.88 (br s, 2 Н, NH).
13C NMR (100.61 MHz, CDCl3):  = 28.0 (С-17), 28.2 (С-13), 36.9 (С-5),
47.8 (С-9), 51.5 (С-7), 52.8 (С-6), 53.3 (С-10), 54.2 (С-14), 56.2 (С-8),
81.2 (С-16), 81.4 (С-12), 123.1 (С-2), 149.8 (С-3), 151.7 (С-1), 163.5
(С-4), 170.6 (С-15), 171.2 (С-11).
Anal. Calcd for С26Н41N5O7: C, 58.30; H, 7.72; N, 13.07. Found: C,
58.28; H, 7.78; N, 13.05.
MS (ESI): m/z [M + H]+ calcd for С34Н55N9O8 + H+: 718.4; found: 718.3.
Anal. Calcd for С34Н55N9O8: C, 56.89; H, 7.72; N, 17.83. Found: C,
56.96; H, 7.80; N, 17.79.
Compound 16b
Compound 16b was obtained analogously to 3a by using of 15b (300
mg, 0.86 mmol), tert-butyl bromoacetate (374 L, 2.57 mmol), and
K2CO3 (709 mg, 5.14 mmol) in MeCN (40 mL). The product was puri-
fied by column chromatography (Al2O3, EtOAc/EtOH 25:1) and ob-
tained as a light-yellow oil; yield: 386 mg (65%).
1H NMR (400.13 MHz, CDCl3):  = 1.34 (s, 9 Н, Н17), 1.42 (s, 18 H,
Н13), 2.79–2.86 (m, 12 H, Н6,7,8), 3.25 (s, 2 H, H14), 3.36 (s, 4 H,
H10), 3.54 (br s, 4 H, H5), 4.85 (s, 2 H, H9), 8.37 (s, 2 Н, Н2), 8.90 (br s,
2 Н, NH).
13C NMR (100.61 MHz, CDCl3):  = 28.0 (С-17), 28.1 (С-13), 36.9 (С-5),
51.6 (С-7), 51.8 (С-6), 53.4 (С-10), 54.4 (С-14), 54.6 (С-8), 63.2 (С-9),
80.8 (С-16), 81.2 (С-12), 122.1 (С-2), 149.0 (С-3), 154.2 (С-1), 164.0
(С-4), 170.8 (С-15), 171.2 (С-11).
Compound 19
Crown compound 2a (115 mg, 0.34 mmol) was dissolved in propar-
gylamine (200 L), and the mixture was stirred at RT for 6 days. Then
MeCN was added to the mixture and the formed precipitate was col-
lected by filtration and dried to afford the product 19 as a beige solid;
yield: 85 mg (69%); mp 280 °С (dec.).
1H NMR (400.13 MHz, CD3CN):  = 2.50 (t, J = 2.5 Hz, 1 H, H11), 2.75
(s, 4 H, Н7), 2.87 (t, J = 5.7 Hz, 4 H, H6), 3.38 (q, J = 5.7 Hz, 4 H, H5),
4.15–4.17 (m, 2 H, H9), 8.47 (s, 2 Н, Н2), 9.19 (br s, 2 Н, NH).
1H NMR (400.13 MHz, DMSO-d6):  = 2.7 (s, 4 H, Н7), 2.81 (t, J = 5.1
Hz, 4 H, H6), 3.16 (t, J = 2.2, 2.5 Hz, 1 H, H11), 3.35 (q, J = 5.1 Hz, 4 H,
H5), 4.10 (q, J = 2.2, 2.5 Hz, 2 H, H9), 8.54 (s, 2 Н, Н2), 9.28 (t, J = 4.1,
4.5 Hz, 2 Н, NH), 9.28 (t, J = 5.1 Hz, 1 Н, NH).
MS (ESI): m/z [M + H]+ calcd for С34Н56N6O9 + H+: 693.4; found: 693.2.
Anal. Calcd for С34Н56N6O9: C, 58.94; H, 8.15; N, 12.13. Found: C,
58.90; H, 8.18; N, 12.10.
13C NMR (100.61 MHz, DMSO-d6):  = 29.0 (С-9), 38.7 (С-5), 47.2 (С-
6), 49.1 (С-7), 73.4 (С-11), 80.6 (С-10), 121.1 (С-2), 144.6 (С-1), 149.8
(С-3), 162.1 (С-8), 163.4 (С-4).
MS (ESI): m/z [M + H]+ calcd for C17H22N6O3 + H+: 359.2; found: 359.2.
Compound 18a
SOCl2 (0.5 mL) was added to a solution of 16a (50 mg, 0.09 mmol) in
CHCl3 (5 mL), and the mixture was stirred at RT for 4 h. The solvent
was evaporated under vacuum to yield the chloride 17a. NaN3 (9 mg,
0.14 mmol) was added to a solution of 17a in MeCN (5 mL) and NEt3
(100 L, 0.72 mmol) was added dropwise to the mixture. The reaction
mixture was refluxed for 18 h and concentrated under vacuum. The
residue was dissolved in H2O and extracted with CHCl3. After concen-
tration of the combined organic extracts, the product 18a was ob-
tained as a yellow oil; yield: 31 mg (60%).
Anal. Calcd for C17H22N6O3·MeOH: C, 55.37; H, 6.71; N, 21.52. Found:
C, 55.87; H, 6.52; N, 21.54.
Funding Information
The work was supported by Russian Science Foundation (grant No 16-
13-10226). The characterization of the products was performed with
the financial support from the Ministry of Science and Higher Educa-
tion of the Russian Federation using the equipment of Center for mo-
1H NMR (400.13 MHz, CDCl3):  = 1.41 (s, 18 H, Н12), 2.93 (s, 4 H, Н7),
3.03 (t, J = 5.2 Hz, 4 H, Н6), 3.27 (s, 4 H, H9), 3.51 (q, J = 5.2 Hz, 4 H,
H5), 4.57 (s, 2 H, H8), 8.21 (s, 2 Н, Н2), 9.12 (br s, 2 Н, NH).
lecular composition studies of INEOS RAS.
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e
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13C NMR (100.61 MHz, CDCl3):  = 27.8 (С-12), 36.5 (С-5), 47.7 (С-8),
50.9 (С-6), 52.5 (С-9), 53.6 (С-7), 81.3 (С-11), 123.2 (С-2), 149.9 (С-3),
152.0 (С-1), 163.4 (С-4), 170.9 (С-10).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691540.
MS (ESI): m/z [M + H]+ calcd for С26Н40N8O6 + H+: 561.3; found: 561.2.
S
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Anal. Calcd for С26Н40N8O6: C, 55.70; H, 7.19; N, 19.99. Found: C,
55.75; H, 7.15; N, 19.98.
References
(1) Bourgeois, M.; Bailly, C.; Frindel, M.; Guerard, F.; Chérel, M.;
Faivre-Chauvet, A.; Bodet-Milin, C. Expert Opin. Biol. Ther. 2017,
17, 813.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

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A. D. Zubenko et al.
Paper
Synthesis
(2) Cai, Z.; Anderson, C. J. J. Labelled Compd. Radiopharm. 2014, 57,
224.
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