A flexible synthesis of C-6 and N-1 analogues of a 4-amino-1,3- dihydroimidazo[4,5-c]pyridin-2-one core

Article abstract of DOI:10.1016/j.tetlet.2011.08.119

A flexible route which enables access to derivatives of 4-amino-1,3-dihydroimidazo[4,5-c]pyridin-2-ones is described. Issues of selectivity, reaction safety, and low yields in original routes are overcome with the key improvements to the route, including

Full text of DOI:10.1016/j.tetlet.2011.08.119

Tetrahedron Letters 52 (2011) 5728–5732
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A flexible synthesis of C-6 and N-1 analogues of a
4-amino-1,3-dihydroimidazo[4,5-c]pyridin-2-one core
Duncan A. Hay a, , Fiona M. Adam a, Gerwyn Bish a, Frederick Calo a, Rachel Dixon b, M. Jonathan Fray a,
⇑
James Hitchin b, Peter Jones a, Michael Paradowski a, Gemma C. Parsons a, Katie J.W. Proctor a,
David C. Pryde a, Nicholas N. Smith a, Thien-Duc Tran a
a WorldWide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
b SRG, London Office, 16 St. Helen0s Place, London EC3A 6DF, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A flexible route which enables access to derivatives of 4-amino-1,3-dihydroimidazo[4,5-c]pyridin-2-ones
is described. Issues of selectivity, reaction safety, and low yields in original routes are overcome with the
key improvements to the route, including a Negishi cross-coupling and use of a carbamate as a protecting
group and intrinsic carbonyl source. The new route enables variation of C-6 and N-1 substituents.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 20 April 2011
Revised 1 August 2011
Accepted 19 August 2011
Available online 26 August 2011
Keywords:
TLR7
Negishi
Carbamates
Heterocycles
As part of a programme to indentify small molecule agonists of
the TLR7 receptor for antiviral applications, we recently reported
the discovery of a potent and selective lead, PF-4171455 (1,
Fig. 1)1–3 and subsequent optimisation of this lead.4 As part of this
optimisation, analogues of 1 that replaced the C-6 trifluoromethyl
and N-1 benzyl groups with heterocyclic functionality were con-
sidered attractive targets. At the time, there were no known routes
in the literature to allow flexible variation at both of these posi-
tions. Therefore, a new route was devised which utilised a cross-
coupling strategy. Issues of selectivity and low yields in our initial
routes were overcome to allow these targets to be synthesised in
an efficient and flexible manner.
Our initial strategy is exemplified by the disconnection of oxazole
target 2 (Scheme 1). The target was disconnected to the bromo-pyr-
idine intermediate 6 and commercial 2-tributylstannyloxazole (7).
In the forward direction, Stille coupling of these components should
yield intermediate 5. The nitro group could then be reduced and the
resulting product could be cyclised with a suitable carbonyl equiva-
lent, such as N,N0-carbonyldiimidazole (CDI) or triphosgene. Selec-
tive debenzylation would lead to 2.
Selective reduction of the nitro and N-oxide moieties followed by
a second nitration and rearrangement yielded 13. Diazotisation
in the presence of HCl gave 14 which was reacted with an excess
of benzylamine to yield 6. Each step in this initial sequence re-
quired great care due to the exothermic profile of many of the reac-
tion steps and the potential high energy nature of N-oxide and
nitro compounds.5
Pyridine derivative 6 was then used in the first successful syn-
thesis of the target 2, shown in Scheme 3. The Stille coupling was
carried out under microwave irradiation. Catalytic hydrogenation
over Raney Ni reduced the nitro group to yield the triaminopyri-
dine 4. CDI cyclisation gave an inseparable mixture of regioisom-
ers (in an approximate 1:1 ratio). Debenzylation of the mixture
with concentrated H2SO4 yielded the desired product 2, which
was separated from its regioisomer by preparative HPLC.6 There
were several problems with this initial route which required
NH2
4
H
N3
5 N
The synthesis of the desired pyridine coupling partner 6 is
shown in Scheme 2. 2,6-Dibromopyridine was N-oxidised using
urea hydrogen peroxide (UHP) and trifluoroacetic anhydride
(TFAA) to give 9. Nitration under forcing conditions yielded 10.
O
2
F
6
N
1
7
F
F
1
⇑
Corresponding author. Tel.: +44 1865 275677.
E-mail address: duncan.hay@ccc.ox.ac.uk (D.A. Hay).
Figure 1. PF-4171455 (1) lead molecule with atom numbering of the core.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.119

D. A. Hay et al. / Tetrahedron Letters 52 (2011) 5728–5732
5729
NHBn
H
NH2
NHBn
H
N
NH2
N
N
N
N
O
O
N
N
N
N
Bn
N
Bn
NHBn
O
O
O
3
2
4
NHBn
NHBn
NO2
NO2
N
O
N
N
SnBu3
+
N
NHBn
Br
NHBn
O
5
6
7
Scheme 1. Disconnection of a C-6 oxazole target.
Br
Br
Br
b
a
O
O
N+
N+
N
Br
Br
Br
NO2
8
9
10
Br
Br
Br
c
d
e
NO2
NH2
N
N
N
NO2
Br
Br
N
H
Br
NH2
11
12
13
Br
NHBn
f
g
NO2
Cl
NO2
N
N
Br
Br
NHBn
14
6
Scheme 2. Reagents and conditions: (a) UHP, TFAA, CH2Cl2, rt, 57%; (b) fuming HNO3, concd H2SO4, 85 °C, 93%; (c) Fe/AcOH, 30–40 °C, 90%; (d) concd HNO3, concd H2SO4, 5 °C,
quant.; (e) concd H2SO4, 50–55 °C, 83%; (f) NaNO2, concd HCl; (g) BnNH2, THF, 50 °C, 61% (over two steps).
improvement in order to synthesise more analogues. The main is-
sues were the lack of regioselectivity in the cyclisation and low
yielding debenzylation using highly corrosive concentrated
H2SO4. The low yield was partly due to losses following a difficult
HPLC separation, but there was also significant decomposition to
baseline impurities under these harsh conditions. Additional is-
sues with the route included the use of toxic organotin reagents
and by-products and moderate yield of the Stille coupling. Even
more significant was the lack of flexibility to introduce alternative
N-1 substituents. A new route was therefore devised to overcome
these challenges.
The optimised route is shown in Scheme 4. Here, a carbamate
was introduced as the amine protecting group. Importantly, this
group can act as an intrinsic carbonyl source which can subse-
quently undergo acidic cyclisation to yield the desired dihydroim-
idazo[4,5-c]pyridin-2-one cores.3,7,8 Carbamates also serve to
acidify the N–H group to which they are attached, making possible
mild base-promoted substitution at this point. Therefore, 13 was
reacted with ethyl chloroformate to give the carbamate 15. This
was then alkylated to provide appropriate N-1 functionality, in this
case 5-chloromethyl-2-methyl-pyridine was used as the alkylating
agent. Selective SNAr substitution with ammonia displaced the
bromide adjacent to the nitro group. Using a bi-phasic mixture
of concentrated ammonia solution and 2-methyltetrahydrofuran
(Me–THF) gave a near quantitative yield of the mono-displaced
product 17.
Heterocyclic zincates were considered suitable alternatives to
stannanes as they should be more reactive and the by-products
more benign.9 These were therefore prepared by C-2 deprotona-
tion of the heterocycles with n-BuLi followed by transmetallation
with ZnCl2.10 The zincates were prepared fresh and used immedi-
ately in the Negishi coupling with 17. The couplings proceeded in
moderate to good yields. The products from this step were
worked-up using an aqueous wash with dilute ammonia to re-
move zinc salts. The nitro reduction and cyclisation were carried
out in one step using acetic acid as the solvent. The nitro group
was reduced by hydrogenation over Raney Ni or Pd/C, or alterna-
tively using Zn powder. The final products were further purified
by trituration or crystallisation as required. A set of C-6 analogues
made using the optimised route is shown in Table 1. Various

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D. A. Hay et al. / Tetrahedron Letters 52 (2011) 5728–5732
NHBn
NHBn
NO2
N
NH2
N
O
N
SnBu3
N
a
N
b
NHBn
NHBn
O
O
7
5
4
NHBn
NHBn
H
H
N
N
c
N
O
O
+
N
N
N
N
N
Bn
Bn
O
O
8
3
d
NH2
NH2
H
N
H
N
N
O
+
O
N
N
N
N
N
Bn
Bn
O
O
9
2
Scheme 3. Original route. Reagents and conditions: (a) 6, Pd(PPh3)2Cl2, toluene, MW 130 °C, 2 h, 33%; (b) H2, Raney Ni, THF/MeOH, rt, quant.; (c) CDI, THF, rt, 50%; (d) concd
H2SO4, 2% (yield of 2).
Cl
Br
Br
NO2
NO2
N
N
a
.HCl
b
N
Br
NH2
NHCO2Et
Br
13
15
Br
NH2
NO2
CO2Et
NO2
CO2Et
N
d
N
c
N
Br
N
Br
17
16
N
N
NH2
NH2
H
N
NO2
e
N
N
O
CO2Et
N
Het
N
Het
N
N
Scheme 4. Optimised route. Reagents and conditions: (a) EtOCOCl, NEt3, Me–THF, 68%; (b) NaI, K2CO3, acetone, 62%; (c) 0.88 NH3, Me–THF, quant.; (d) RZnCl, Pd(PPh3)2Cl2,
THF, MW 60 °C, 33–85%; (e) various reduction/cyclisation procedures — see Table 1.
substituted oxazole, benzoxazole, and thiazole targets were
synthesised.
As previously discussed, the new route also allowed for flexibil-
ity in varying the N-1 substituent. A selection of N-1 targets is

D. A. Hay et al. / Tetrahedron Letters 52 (2011) 5728–5732
5731
Table 1
Table 2
C-6 analogues
N-1 analogues
NH2
NH2
H
N
H
N
N
N
O
O
N
N
N
HET
R
O
N
Entry N-1 Substituent (R)
Negishi yield
(%)
Reduction/cyclisation
yield (%)
Entry C-6 Substituent (Het)
Negishi yielda Reduction/cyclisation
(%)
yield (%)
1
2
75a
44b
36e
57f
N
1
85
51b
N
N
N
O
N
25b
54c
29b
F
2
72
71
48
O
F
F
N
N
3
O
3
65c
52f
N
4
O
4
5
80b
88d
17g
17g
N
53c
42b
OMe
5
66
45
N
O
N
N
6
O
N
a
b
c
Pd(PPh3)2Cl2, THF, 65 °C, 1 h.
N
Pd(PPh3)2Cl2, THF, MW 90 °C, 5 min.
Pd(PPh3)2Cl2, THF, MW 60 °C, 15 min.
Pd(PPh3)2Cl2, THF, MW 75 °C, 10 min.
7
78
41
74
63
33
34b
69d
32b
4b
d
e
S
(i) H-CubeÒ, H2 (1 bar), 10% Pd/C CatCartÒ30, AcOH (0.05 M, 1 ml/min), rt; (ii)
N
50 °C.
f
8
Zn/AcOH, rt.
(i) Raney Ni (10%), EtOH/THF (1:1); (ii) AcOH, rt.
O
g
N
9
MeO
O
N
Acknowledgements
MeO
EtO
10
11
O
Thanks to colleagues in the Pfizer Sandwich Structural and Sep-
aration Sciences who carried out HPLC separations and provided
analytical support.
N
10b
O
a
b
c
Pd(PPh3)2Cl2, THF, MW 60 °C, 15 min.
H2 (80 psi), Raney Ni, AcOH.
Zn/AcOH, rt.
Supplementary data
Supplementary data (representative experimental details) asso-
ciated with this Letter can be found, in the online version, at
doi:10.1016/j.tetlet.2011.08.119.
d
H2 (100 psi), 10% Pd/C, AcOH, rt.
shown in Table 2. In the case of entry 1, a concern was over-reduc-
tion of the pyridazine ring when reducing the nitro group. Hydro-
genation was therefore carried out in a flow apparatus so that the
reaction could be carefully monitored and stopped immediately
after the desired product had formed.
In summary, several improvements were made to the initial
route to enable flexible variation of C-6 and N-1 substituents of a
dihydroimidazo[4,5-c]pyridin-2-one core. Key amongst the
improvements was the Negishi cross-coupling and use of a carba-
mate protecting group to overcome selectivity and deprotection is-
sues, and give an acidic handle for alkylation.
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