A novel approach for the synthesis of the peripheral benzodiazepine receptor ligand, PK11195

Article abstract of DOI:10.1016/j.tetlet.2007.07.203

A new synthesis of the peripheral benzodiazepine receptor ligand, PK11195 has been developed in only six-steps using a Heck-type reaction and a Suzuki coupling to effect the key transformations. The flexibility of this new approach is demonstrated by the

Full text of DOI:10.1016/j.tetlet.2007.07.203

Tetrahedron Letters 48 (2007) 7137–7139
A novel approach for the synthesis of the peripheral
benzodiazepine receptor ligand, PK11195
Louise Stevenson,a Sally L. Pimlottb and Andrew Sutherlanda,*
aWestChem, Department of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, UK
bWest of Scotland Radionuclide Dispensary, University of Glasgow and North Glasgow University Hospital NHS Trust,
Glasgow G11 6NT, UK
Received 17 July 2007; accepted 30 July 2007
Available online 2 August 2007
Abstract—A new synthesis of the peripheral benzodiazepine receptor ligand, PK11195 has been developed in only six-steps using a
Heck-type reaction and a Suzuki coupling to effect the key transformations. The flexibility of this new approach is demonstrated by
the synthesis of an iodo-analogue of PK11195 prepared from the corresponding bromide using a copper catalysed aromatic Finkel-
stein reaction.
Ó 2007 Elsevier Ltd. All rights reserved.
The peripheral benzodiazepine receptor (PBR) has been
found in high concentrations in organs such as the heart
and kidney and at a lower levels in the brain.1 The dis-
covery of this receptor has stimulated intensive research
devoted to its characterisation.2 However, despite the
wide range of pharmacological activities related to the
activation of this receptor,3 the physiological role of
PBR is still unclear. For the purpose of its characterisa-
tion a number of ligands have been developed including
benzoxazepine and benzothiazepine derivatives.4 The
first non-benzodiazepine ligand found to bind to PBR
at nanomolar concentrations was isoquinoline,
PK11195 1, which is now the most commonly used radio-
ligand for studying this receptor.1b,3,5
We now report a six-step synthesis of 1 and a bromo-
analogue using palladium mediated chemistry to effect
the key transformations. The synthesis of an iodo-ana-
logue from the corresponding bromide is also described
using a copper catalysed, aromatic halogen exchange
reaction.
O
N
N
Cl
1
Our interest in this area is focused on the single photon
emission computerised tomography (SPECT) imaging
of increased PBR expression associated with neuro-
inflammation6 and thus, we required easy access to
PK11195 1. While several elegant syntheses of 1 and
other analogues have been reported using traditional
heterocyclic chemistry to prepare the isoquinoline
ring,5,7 we required a short, flexible route, which allowed
the synthesis of not only 1 but other derivatives that
could be easily radioiodinated for SPECT imaging.
The first stage of the synthesis of PK11195 1 involved
the preparation of methyl isoquinolin-1-one-3-carboxyl-
ate 5 (Scheme 1). A number of excellent methods have
been reported for the synthesis of oxoquinoline-3-car-
boxylic acids.5,7,8 We used a one-pot procedure devel-
oped by Chattopadhyay and co-workers, which
allowed the coupling of methyl 2-iodobenzoate 2 with
amidoacrylate 3 to give 5 in 65% yield.9 The transforma-
tion is proposed to proceed via a Heck-type coupling of
2 and 3 to give presumed intermediate 4, followed by
cyclisation and loss of the N-acetyl group to give 5.9
Oxoisoquinoline 5 was brominated using phosphorus(V)
oxybromide and the resulting bromide 6 was then sub-
jected to a Suzuki reaction using 2-chlorophenylboronic
Keywords: PK11195; Peripheral benzodiazepine receptor; Isoquinoline
synthesis; Heck reaction; Suzuki reaction; Palladium catalysis.
*
Corresponding author. Tel.: +44 141 330 5936; fax: +44 141 330
4888; e-mail: andrews@chem.gla.ac.uk
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.203

7138
L. Stevenson et al. / Tetrahedron Letters 48 (2007) 7137–7139
CO2Me
CO2H
I
CO2Me
a
CO2Me
NHAc
+
a
N
N
NHAc
CO2Me
CO2Me
X
X
2
3
4
7 X= Cl
8 X= Br
9 X= Cl
10 X= Br
CO2Me
CO2Me
b
b
N
NH
O
O
Br
O
N
H
N
5
6
N
N
c
c
X
X
CO2Me
N
1 X= Cl
13 X= Br
11 X= Cl
12 X= Br
X
Scheme 2. Reagents and conditions: (a) NaOH, EtOH/H2O, 80 °C, 9
(96%), 10 (77%); (b) (COCl)2, DMF (cat.), CH2Cl2, 50 °C then sec-
butylamine in CH2Cl2, 11 (90%), 12 (60%); (c) NaH, MeI, THF, 0–
65 °C, 1 (84%), 13 (91%).
7 X= Cl
8 X= Br
Scheme 1. Reagents and conditions: (a) Pd(OAc)2, nBu4N+ClÀ,
NaHCO3, DMF, D, 65%; (b) POBr3, K2CO3, MeCN, D, 71%; (c)
Pd(PPh3)4, K3PO4, DMF, D, 2-chlorophenylboronic acid, 67% or 2-
bromophenylboronic acid, 60%.
stein reaction as described by Klapars and Buchwald.12
This procedure involves the reaction of an aromatic bro-
mide with sodium iodide and catalytic amounts of cop-
per iodide and a diamine ligand at relatively low
temperatures for this type of transformation. In our
hands, N,N-dimethylethylenediamine proved to be the
most useful ligand and gave the target iodide 14 in
63% yield after only 18 h at 130 °C (Scheme 3).13
acid,7a which gave methyl 1-(2-chlorophenyl)isoquino-
line-3-carboxylate 7 in 67% yield.
Hydrolysis of methyl ester 7 then gave the correspond-
ing carboxylic acid 9 in excellent yield (Scheme 2). Initial
attempts at completing the synthesis of 1 by directly
coupling 9 with N-methyl-sec-butylamine10 either using
a diimide coupling procedure or via the acid chloride
returned the starting materials or gave the product in
low yield. However, a stepwise approach involving for-
mation of the acid chloride and an in situ reaction with
sec-butylamine gave 11 in excellent yield. Then, N-meth-
ylation using sodium hydride and methyl iodide com-
pleted the six-step synthesis of PK11195 1 in 22%
overall yield.11
In summary, a short, flexible route for the preparation
of the PBR ligand, PK11195 1 has been developed in
three key stages involving synthesis of the isoquinoline
ring system using a Heck-type reaction, introduction
of the chlorophenyl group using a Suzuki reaction and
finally formation of the side-chain amide using an acyl-
ation/alkylation two-step strategy. This route has been
adapted for the preparation of a bromo-analogue and
this has been converted to the corresponding iodide
using a copper catalysed aromatic Finkelstein reaction.
Further studies are currently underway to transform
these compounds to radioiodinated analogues for the
SPECT imaging of inflammation in neurological disor-
ders, such as dementia and stroke.
Having established a short and direct synthesis of
PK11195, we wanted to use this approach for the prep-
aration of other analogues including an iodo-derivative
that could be used for radio-iodination and the develop-
ment of an imaging tracer. To achieve this goal, bromide
13 was prepared using exactly the same approach as
described for 1. Thus, Suzuki reaction of bromide 6 with
2-bromophenylboronic acid gave 1-(2-bromophenyl)iso-
quinoline-3-carboxylate 8 in 60% yield (Scheme 1). Sub-
sequent hydrolysis of methyl ester 8 and introduction of
the amide side-chain using the stepwise approach
described above gave bromo-analogue 13 in 42% yield
over the three steps (Scheme 2).
O
O
N
N
a
N
N
I
Br
14
13
To complete the synthesis of the target iodide, bromide
13 was subjected to a copper catalysed aromatic Finkel-
Scheme 3. Reagents and conditions: (a) CuI, NaI, N,N-dimethylethyl-
enediamine, butan-1-ol, 130 °C, 63%.

L. Stevenson et al. / Tetrahedron Letters 48 (2007) 7137–7139
7139
Oertel, W.; Banati, R. B.; Brooks, D. J. Neurobiol. Disease
2006, 21, 404–412.
Acknowledgements
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The authors gratefully acknowledge the BBSRC (stu-
dentship to L.S.), the University of Glasgow and the
Chief Scientist Office (NHS Programme Support Grant)
for financial support.
˚
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(3H, t, J 7.2 Hz, CH2CH3), 1.10–1.16 (3H, m, NCHCH3),
1.49–1.60 (2H, m, CH2CH3), 2.85 (3H, s, NCH3), 3.67–
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(CH3), 54.9 (CH), 119.5 (CH), 126.2 (C), 126.3 (CH),
127.2 (CH), 127.7 (CH), 128.7 (CH), 129.5 (CH), 130.5
(CH), 131.0 (CH), 131.4 (CH), 132.1 (C), 136.1 (C), 137.4
(C), 147.9 (C), 157.0 (C), 168.9 (C); found (EI): M+,
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DMSO-d6) 0.71 (3H, t, J 7.2 Hz, CH2CH3), 1.16–1.19 (3H,
m, NCHCH3), 1.47–1.61 (2H, m, CH2CH3), 2.86 (3H, s,
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(CI): MH+, 445.0778, C21H22ON2I requires MH+,
445.0777.
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