Facile synthesis of various nitro-substituted derivatives of Semaxinib (SU5416)

Article abstract of DOI:10.1080/00397910802044256

The synthesis of novel nitro-substituted derivatives of the tyrosine kinase inhibitor Semaxinib (SU5416) is described. The reaction of various substituted oxindoles with 3,5-dimethylpyrrol-2-carbaldehyde derivatives under Knoevenagel conditions gave an array of nitro-substituted derivatives of Semaxinib (SU5416) in high yields of 72-87%. Copyright Taylor & Francis Group, LLC.

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Facile Synthesis of Various
Nitro-Substituted Derivatives of
Semaxinib (SU5416)
a
a
a
Torsten Kniess , Manuela Kuchar & Frank Wuest
a
Institute of Radiopharmacy, Forschungszentrum
Dresden-Rossendorf , Dresden, Germany
Published online: 28 Aug 2008.
To cite this article: Torsten Kniess , Manuela Kuchar & Frank Wuest (2008) Facile
Synthesis of Various Nitro-Substituted Derivatives of Semaxinib (SU5416), Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:17, 3017-3022, DOI: 10.1080/00397910802044256
To link to this article: http://dx.doi.org/10.1080/00397910802044256
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1
Synthetic Communications , 38: 3017–3022, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802044256
Facile Synthesis of Various Nitro-Substituted
Derivatives of Semaxinib (SU5416)
Torsten Kniess, Manuela Kuchar, and Frank Wuest
Institute of Radiopharmacy, Forschungszentrum Dresden-Rossendorf,
Dresden, Germany
Abstract: The synthesis of novel nitro-substituted derivatives of the tyrosine
kinase inhibitor Semaxinib (SU5416) is described. The reaction of various substi-
tuted oxindoles with 3,5-dimethylpyrrol-2-carbaldehyde derivatives under Knoe-
venagel conditions gave an array of nitro-substituted derivatives of Semaxinib
(
SU5416) in high yields of 72–87%.
Keywords: Nitration, semaxinib, tyrosine kinase
Semaxinib (3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-indolin-2-on, SU5416)
is a potent inhibitor of signaling activity of the receptor tyrosine kinases
(RTKs) for the vascular endothelial growth factor (VEGF) and has been
investigated up to now in clinical phase II studies as anti-angiogenic
[1–4]
agent.
A broad arsenal of substituted SU5416 derivatives has been
designed and synthesized, and their potency and selectivity against RTKs
[5,6]
and VEGF was tested.
SU5416 derivatives, which are appropriately labeled with the
1
8
short-lived positron emitter F (t1=2 ¼ 109.8 min) as a bioisosteric substi-
tution for hydrogen, would allow noninvasive in vivo studies of RTKs
[
and VEGF by means of positron emission tomography (PET). The
7]
1
introduction of F into aromatic compounds is usually accomplished
8
1
8
via nucleophilic substitution of aromatic nitro compounds with [ F]flu-
[
8]
18
oride. In the course of our research efforts to prepare F-labeled
SU5416 derivatives, it became obvious that a facile synthesis of
nitro-substituted SU5416 compounds has not been reported yet. Herein,
Received November 16, 2007.
Address correspondence to Torsten Kniess, Institute of Radiopharmacy,
Forschungszentrum Dresden-Rossendorf, P.O. Box 510119, 01314 Dresden,
Germany. E-mail: kniess@fzd.de
3
017

3018
T. Kniess, M. Kuchar, and F. Wuest
we describe an approach for the facile and convenient synthesis of vari-
ous nitro-substituted SU5416 derivatives.
Commonly, Semaxinib is synthesized by a Knoevenagel conden-
sation of oxindole 1a with 3,5-dimethylpyrrol-2-carbaldehyde 2a as the
[5]
key reaction step.
Direct nitration of parent SU5416 to obtain nitro-substituted SU5416
is not feasible, because this reaction leads to the formation of a complex
mixture of different nitro-substituted isomers. Hence, we envisaged an
alternative approach consisting of (1) nitration of oxindole and pyrrol-
carbaldehyde derivatives followed by (2) Knoevenagel condensation to
afford various nitro-substituted SU5416 derivatives (Fig. 1).
Nitration is usually carried out by the reaction of oxindole 1a with
ꢀ
[9]
fuming nitric acid in concentrated sulphuric acid at 0 C. However,
application of this method afforded 5-nitro-oxindole 1c in very low yield
of 9%. Alternatively, reaction of potassium nitrate in concentrated sul-
[10]
phuric acid as described by Baeyer gave the desired 5-nitro compound
1
c in satisfactory 67% yield.
Synthesis of 3,5-dimethyl-4-nitro-pyrrol-2-carbaldehyde 2b can be
performed via two distinct synthetic routes. The first route commenced
with a nitration reaction of 2-ethoxycarbonyl-3,5-dimethyl-pyrrole in a
mixture of nitric acid and acetic acid to give ethyl-3,5-dimethyl-4-nitro-
1
H-pyrrole-2-carboxylate. Conversion of the ester into carbaldehyde 2b
was accomplished via McFadyen–Stevens reaction, which consists of
the base-catalyzed thermal decomposition of acylbenzenesulfonylhydra-
[11]
zines to aldehydes.
For this purpose, ethyl-3,5-dimethyl-4-nitro-1H-
pyrrole-2-carboxylate was reacted with benzenesulfonylhydrazide to
give the corresponding acylsulfonylhydrazine derivative, which was
ꢀ
further treated with Na CO in ethylene glycol at 160 C to afford
2
3
the desired carbaldehyde. However, application of this three-step syn-
thesis sequence gave compound 2b in only a very low total yield of
Figure 1. Synthesis of nitrosubstituted Semaxinib.

Nitro-Substituted Derivatives of Semaxinib
3019
2%. Consequently, this approach is not suitable for the synthesis of
sufficient amounts of 3,5-dimethyl-4-nitro-pyrrol-2-carbaldehyde 2b.
A second synthetic route is based on the direct nitration of the
,5-dimethylpyrrol-2-carbaldehyde 2a. However, direct nitration of 2a
3
ꢀ
in acetic anhydride and fuming nitric acid at ꢁ40 C as reported in the
[12]
literature for pyrrole-2-carbaldehyde gave a complex reaction mixture
containing various oxidized by-products. Finally we were very pleased to
find that substitution of fumic nitric acid with potassium nitrate, the
use of concentrated sulphuric acid as the solvent, and performance of
ꢀ
the reaction at ꢁ5 C gave the desired 3,5-dimethyl-4-nitro-pyrrol-2-
carbaldehyde 2b in 74% yield without formation of by-products.
The synthesis of nitro-substituted SU5416 derivatives 3b–e was
conducted through application of a Knoevenagel reaction between
carbaldehydes 2a and 2b and oxindoles 1a–c in boiling ethanol. This
procedure gave the SU 5416 derivatives 3b–e derivatives in very good
yield of 72–87%.
The submitted synthetic route represents a convenient and reliable
approach for the preparation of an array of different nitro-substituted
SU5416 derivatives 3b–e. The use of nitro-substituted compounds 3b–e
1
8
as labeling precursors for the radiolabeling with [ F]fluoride is currently
in progress.
EXPERIMENTAL
All chemicals as oxindole (2-indolinon) 1a, 5-fluoro-oxindole 1b, 3,5-
dimethylpyrrol-2-carbaldehyde 2a, potassium nitrate, and solvents were
purchased from commercial suppliers. Melting points were determined
TM
with an apparatus Galen III (Cambridge Instruments) and are uncor-
1
rected. H NMR spectra were recorded on an Inova-400 spectrometer
(Varian) at 400 MHz in DMSO-d ; chemical shifts (d) were determined
6
relative to the solvent and converted to the TMS scale. Mass spectra were
obtained on a Quattro=LC mass spectrometer (Micromass).
5
-Nitro-oxindole 1c
Oxindole 1a (1.33 g, 10 mmol) was dissolved in 13.3 g (7.26 mL) of cold
ꢀ
concentrated sulphuric acid at 0 C. After complete dissolution 1.01 g
(
10 mmol) of potassium nitrate was added portion for portion. The
ꢀ
temperature of the mixture should not exceed 5 C. After further stirring
for 30 min, the mixture was added to 200 mL of crushed ice. The precipi-
tate was collected by filtration, washed with water, and dried. The raw
product was purified by recrystallization from acetic acid (50%) to give

3020
T. Kniess, M. Kuchar, and F. Wuest
ꢀ
.2 g of 1c as an orange solid. Yield: 67%, mp 249–254 C (lit.
[7]
1
2
8
ꢀ
1
40–241 C]. H NMR d (ppm): 3.62 (s, 2H, CH ), 6.96 (d, 1H, H ),
2
7
.07 (s, 1H, H ), 8.14 (d, 1H, H ), 11.04 (s, 1H, NH). ESI-MS (ESþ):
4
6
þ
m=z 201 [M þ Na] .
3
,5-Dimethyl-4-nitro-pyrrol-2-carbaldehyde 2b
3
,5-Dimethylpyrrol-2-carbaldehyde 2a (246 mg, 2 mmol) was dissolved
in 3 mL of concentrated sulphuric acid. The temperature should be kept
ꢀ
ꢀ
at 0 C by an ice–salt mixture. The solution was cooled at ꢁ5 C, and
2
02 mg (2 mmol) of potassium nitrate were added. The mixture was
allowed to warm up to room temperature and then added to 75 mL of
crushed ice. The precipitate was separated by filtration, washed with
water, and dried. The product was obtained as 250 mg of a grey solid
ꢀ
and used without further purification. Yield: 74%, mp 220–229 C
ꢀ
[
9]
1
decomp. [Lit. 226–230 C]. H NMR d (ppm): 2.52 (s, 3H, CH ), 2.54
3
(
s, 3H, CH ), 9.72 (s, 1H, HCO), 12.87 (s, 1H, NH). ESI-MS (ES ꢁ):
3
ꢁ
m=z 167 [M ꢁ H] .
General Procedure for Knoevenagel Condensation
Oxindole 1a–c (2 mmol) and 2.4 mmol of 3,5-dimethylpyrrol-2-
carbaldehyde 2a,b were refluxed in 4 mL of ethanol with four drops of
piperidine for 4–5 h. The solvent was removed in vacuum, and the resi-
due was purified by washing with ethyl acetate or recrystallization from
dioxane.
Data
0
0
0
Compound 3b: 3-[(2 ,4 -Dimethylpyrrol-5 -yl)methylindenyl]-5-nitro-
ꢀ
1
indolin-2-one, yield: 72%, mp >280 C (decomp.). H NMR d (ppm):
.34 (s, 3H, CH ), 2.36 (s, 3H, CH ), 6.08 (s, 1H, H ), 7.03 (d, 1H,
2
0
3
3
3
H ), 7.93 (s, 1H, H ), 8.02 (d, 1H, H ), 8.76 (s, 1H, Hvinyl), 11.42
7
4
6
(
[
s, 1H, NHoxindol), 13.10 (s, 1H, NHpyrrol). ESI-MS (ESþ ): m=z 284
M þ H].
Compound 3c: 3-[(2 ,4 -Dimethylpyrrol-3 nitro-5 -yl)methylindenyl]-
0
0
0
0
1
ꢀ
indolin-2-one, yield: 84%, mp >330 C (decomp.). H NMR d (ppm):
2
H ), 7.19 (t, 1H, H ), 7.71 (s, 1H, H
.55 (s, 3H, CH ), 2.62 (s, 1H, CH ), 6.90 (d, 1H, H ), 7.02 (t, 1H,
), 7.86 (d, 1H, H ), 11.40 (s, 1H,
3
3
7
6
5
vinyl
4
NHoxindol), 14.34 (s, 1H, NHpyrrol). ESI-MS (ESþ): m=z 306 [M þ Na].

Nitro-Substituted Derivatives of Semaxinib
3021
0
0
0
0
Compound 3d: 3-[(2 ,4 -Dimethylpyrrol-3 nitro-5 -yl)methylindenyl] -
ꢀ
1
5
(
(
-fluoro-indolin-2-one, yield 87%, mp > 340 C (decomp.). H NMR d
ppm); 2.56 (s, 3H, CH ), 2.62 (s, 3H, CH ), 6.86 (dd, 1H, H ), 6.99
dt, 1H, H ), 7.80 (s, 1H, Hvinyl), 7.85 (dd, 1H, H ), 11.12 (s, 1H, NH
ox-
3
3
7
6
4
indol), 14.34 (s, 1H, NH
Compound 3e: 3-[(2 ,4 -Dimethylpyrrol-3 nitro-5 -yl)methylindenyl]-
).
pyrrol
0
0
0
ꢀ
0
1
5
-nitro-indolin-2-one, yield 76%, mp >320 C (decomp.). H NMR d
(
ppm): 2.62 (s, 3H, CH ), 2.64 (s, 3H, CH ), 7.06 (d, 1H, H ), 8.10 (d,
3
3
7
1
1
H, H ), 8.13 (s, 1H, H
6
4.36 (s, 1H, NHpyrrol).
), 8.97 (s, 1H, H ), 11.73 (s, 1H, NHoxindol),
vinyl 4
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