Microwave assisted synthesis of multiple labelled SR244870 a compound related to ferroquine (SSR97193)

Full text of DOI:10.1002/jlcr.1208

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 477–479.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1208
Short Research Article
Microwave assisted synthesis of multiple labelled SR244870, a
compound related to ferroquine (SSR97193)y
TENZEELA ILYAS2, POLLY DAVIES1, ALAN MCNEILL2 and DAVID IAN SMITH2
1University of Hull, Hull, HU6 7RX, UK
2Sanofi-aventis research, Isotope Chemistry and Metabolite Synthesis Department, Alnwick Research Centre, Willowburn Avenue, Alnwick,
Northumberland NE66 2JH, UK
Received 4 October 2006; Revised 27 November 2006; Accepted 28 November 2006
Keywords: 4-amino-7-chloroquinoline; ferroquine; hydrogen-deuterium exchange; microwave assisted synthesis
Introduction
In order to support our bioanalysis studies in this
area, a synthesis of a multiply stable labelled derivative
of 4-amino-7-chloroquinoline (SR244870) was re-
quired. We were able to develop a route to a comp-
ound containing an additional four mass units,
[2H3,15N]SR244870 3. All labels were incorporated by
the use of microwave-assisted reactions.
Malaria is caused by four species of protozoan para-
sites of the genus Plasmodium infecting human red
blood cells. Of the different species, the Plasmodium
falciparum parasite can cause death from cerebral
infection, and one of the leading anti-malarial drugs
is chloroquine 1. However, increasing parasite resis-
tance to the quinoline-based drugs has seen a gradual
growth in deaths caused by the disease1 and thus the
investigation into a more potent and effective drug. One
such compound is ferroquine (SSR97193) 2, which is
presently in development at sanofi-aventis.
2H
15NH2
2H
Cl
N
H
N
2H
3
Cl
N
N
Results and discussion
1
The overall synthesis (Scheme 1) was based upon our
previous synthesis of [quinoline-3-14C]SSR97193, re-
cently reported by Taylor.2 Following the reaction
conditions therein, [2H3]4,7-dichloroquinoline could be
derived from [2,4,5,6-2H4]3-chloroaniline and Meldrums
H
N
N
Cl
Fe
N
acid.
Although [2,4,6-2H3]3-chloroaniline is commerci-
ally available it was rapidly synthesized from
3-chloroaniline via acid-catalysed H/2H exchange,
enhanced under microwave conditions.
2
*Correspondence to: Tenzeela Ilyas, Sanofi-aventis research, Isotope
Chemistry and Metabolite Synthesis Department, Alnwick Research
Centre, Willowburn Avenue, Alnwick, Northumberland NE66 2JH, UK.
E-mail: tenzeela.ilyas@sanofi-aventis.com
yProceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
It was found that microwave irradiation at 1508C and
150 psi was sufficient for complete exchange at the
acidic positions. A natural progression of this was the
incorporation of a deuterium atom at the 5-position to
Copyright # 2007 John Wiley & Sons, Ltd.

478 T. ILYAS ET AL.
2H
OMe
OMe
80 C, 3 hrs
2H
Cl
2H
O
RT, 16 hrs
O
O
O
O
O
O
MeO
2H
O
O
O
°
O
O
2H
2H
N
H
2H
H
OMe
Cl
NH2
2H
4
Ph2O
reflux
H
2H
O
2H
Cl
N
H
2H 15N
2H
Cl
2H
2H
POCl3
reflux
15NH4OH
microwave
N
H
Cl
Cl
N
2H
2H
2H
Scheme 1
The standard conditions of acetic acid in an equal
ratio to deuterated water in order to increase the acidity
of the mixture and aid dissolution were not necessary
for our purposes. The aniline substrate was soluble
in deuterated water as the deuteriochloride salt
but additional deuterium chloride (2HCl) was required
to adequately lower the pH. Trials conducted varying
2H
2H
2H
2H
Cl
2H
2H2O, 2HCl
5 mol%K 2PtCl4
microwave
180oC,150 psi, 2 hrs
Cl
NH2
NH2
2H
2H
the amount of 2HCl with
a constant 5 mol% of
Figure 1
potassium tetrachloroplatinate, indicated that 1.1 eq.
of 2HCl was the optimum amount for the meta H/2H
exchange of [2H3]-3-chloroaniline, (see Table 1).
These results reinforced Garnett’s findings that
changes in pH significantly affected the relative rates
of exchange.
Table
1 The ratio of residual hydrogens determined by
1HNMR at position 5 in comparison to positions 2, 4 and 6
2HCla
Time (min)b
2c
4c
5c
6c
0
40
40
40
40
40
1d
1
1
1
1d
1
1
1
6
3.5
3.5
2.8
12.5
1d
1
1
1
0.2
0.6
1.1
2.0
Further optimization, resulted in the equilibrium
amount of residual hydrogens at position 5 being
brought in line with positions 2, 4 and 6.
1
1
1
The per-deuterated 3-chloroaniline 4 was thus taken
through to [2H3]4,7-dichloroquinoline to enable la-
belled trials of the amination step to be conducted.
The conventional method of passing ammonia gas over
the substrate in phenol was not viewed as being
practical for [15N]ammonia so the employment of other
aminating reagents was explored. [15N]Potassium ptha-
limide proved too unreactive even under microwave
conditions. However, amination was found to proceed
smoothly with [15N]ammonium chloride in pyridine
under microwave conditions to give the amine in a 49%
yield. Unfortunately, none of the 15N-label was found to
be incorporated into the amine produced. It is postu-
lated that a variation of the Chichibabin reaction,
which involves the attack of alkali metals with pyridine,
a The number of equivalents of deuterium chloride to sub-
strate.
b The irradiation time at 1858C and 150 psi.
c The hydrogen/deuterium exchange position on the sub-
strate.
d These values are defined as the equilibrium amount of
residual hydrogens.
afford the fully deuterated [2,4,5,6-2H4]3-chloroaniline
4. This was achieved with the aid of a catalyst,
platinum tetrachloroplatinate, via the homogenous
H/2H exchange reaction reported by Garnett,3 accel-
erated by microwave irradiation, (see Figure 1).
[2,4,5,6-2H4]3-chloroaniline was obtained with a yield
of 60% and >97% deuterium incorporation.
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 477–479
DOI: 10.1002.jlcr

MICROWAVE ASSISTED SYNTHESIS OF MULTIPLE LABELLED SR244870 479
Figure 2
had taken place. In this case reaction between the
amine and pyridine, followed by attack on the labelled
4,7-dichloroquinoline, produced exclusively the 14N-
product.4
exchange was observed in reaction with 7-chloro-4-
hydroxyquinoline.
Conclusion
The desired incorporation was achieved with the use
of [15N]ammonium hydroxide solution (see Figure 2).
However, the necessity to conduct the reaction at
high temperature and pressure over a relatively long
period of time in the microwave, led to the formation
of the desired amine 3 in only 49% yield. Some
hydrolysis product 5 and base-induced loss of deuter-
ium from the 8-position were also observed. This has
prompted the exploration of other methods of amine
incorporation.
Success of H/2H exchange on 3-chloroaniline led
us to attempt direct deuteration of the 4-amino-7-
chloroquinoline, in order to remove the need for
synthesis. Unfortunately, deuterium exchange was
only observed at the 3-position of the molecule.
Attempts to promote H/2H exchange in commercially
available 4,7-dichloroquinoline exclusively afforded the
hydrolysis product, 7-chloro-4-hydroxyquinoline, with
only partial exchange at the 3, 6 and 8 positions. No
A route to [2H3,15N]SR244870 3 was developed in which
the stable isotopes were derived from readily available
2H2O and ammonium-15N-hydroxide. Microwave en-
hanced H/2H exchange promoted rapid access to the
key intermediate [2H4]3-chloroaniline. The use of micro-
wave conditions in the amination step enabled the
successful incorporation of all the labels by microwave-
assisted reactions.
REFERENCES
1. Biot C, Glorian G, Maciejewski LA, Brocard JS,
Domarle O, Blampian G, Millet P, Georges AJ,
Abessolo H, Dive D, Lebibi J. J Med Chem 1997;
40: 3715–3718.
2. McNeill A, Murrell V, Taylor K. J Label Compd
Radiopharm 2004; 47: 1019–1027.
3. Garnett JL. Catalysis Rev 1971; 5: 229–267.
4. Konig W. J Prakt Chem 1911; 83(1): 406–418.
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 477–479
DOI: 10.1002.jlcr