Synthesis of a 5-alkoxypyrido[3,4-d]pyrimidin-4(3H)-one derivative via directed ortho-metallation of a pyridine analogue

Article abstract of DOI:10.1016/j.tetlet.2004.03.087

The synthetic strategy towards a 5-alkoxypyrido[3,4-d]pyrimidin-4(3H)-one is described, utilizing palladium catalyzed amination of a bromopyridine, and subsequent directed ortho-metallation/carboxylation as the key steps.

Full text of DOI:10.1016/j.tetlet.2004.03.087

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3733–3735
Synthesis of a 5-alkoxypyrido[3,4-d]pyrimidin-4(3H)-one derivative
via directed ortho-metallation of a pyridine analogue
*
Allan P. Dishington, Paul D. Johnson and Jason G. Kettle
AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, England SK10 4TG, UK
Received 23 January 2004; revised 9 March 2004; accepted 16 March 2004
Abstract—The synthetic strategy towards a 5-alkoxypyrido[3,4-d]pyrimidin-4(3H)-one is described, utilizing palladium catalyzed
amination of a bromopyridine, and subsequent directed ortho-metallation/carboxylation as the key steps.
Ó 2004 Published by Elsevier Ltd.
As part of an ongoing research programme, we sought
to investigate the structure–activity relationships around
a series of 5-alkoxyquinazolin-4(3H)-one derivatives as
exemplified by 1. These compounds were readily acces-
We envisaged that the pyrido[3,4-d]pyrimidin-4(3H)-one
core 3 could be efficiently assembled in a manner anal-
ogous to the quinazolin-4(3H)-one ring system.
9–16
Thus, the C-2 and N-3 atoms would be introduced as a
formamide equivalent into a suitably substituted amino
isonicotinic acid 4, itself prepared by a directed ortho-
metallation/carboxylation strategy applied to the amino
N
sible to us via nucleophilic aromatic substitution (S Ar)
of commercially available 5-fluoroquinazolin-4(3H)-
one, with alkoxide nucleophiles formed in situ by
sodium hydride deprotonation of the appropriate alco-
hols. As part of these studies we became interested in the
effects of substitution of nitrogen into the ring at C-7, to
give the 5-alkoxypyrido[3,4-d]pyrimidin-4(3H)-one as
exemplified by 2. Despite extensive interest in the pyr-
ido[3,4-d]pyrimidin-4(3H)-one core from the medicinal
17
pyridine 5. This should be accessible by a palladium-
catalyzed amination of a bromopyridine 6. Commer-
cially available dibromopyridine 7 would be utilized as
starting material (Scheme 1).
The sequence commenced with the treatment of 3,5-
dibromopyridine 7 with sodium methoxide (1.5 equiv/
DMF/40 °C/20 h) to give the methoxypyridine derivative
8 in 72% yield (Scheme 2). Palladium-catalyzed amina-
tion of 8 with tert-butyl carbamate, following the
1
–8
and synthetic chemistry communities,
aware of any routes available that give this specific
mono)substitution pattern. Herein we report our pre-
we are not
(
liminary findings on the synthesis of this ring system.
N
OR
OR
O
O
N
OR
O
N
CO H
2
NH
NH
N
N
N
X
NH
NH
2
2
1
2
X = CH
X = N
3
4
5
OR
Br
N
N
Br
Br
6
7
Keywords: Amination; DoM; Pyridopyrimidine.
*
Corresponding author. Tel.: +44-(0)1625-518269; fax: +44-(0)1625-
13910; e-mail: allan.dishington@astrazeneca.com
Scheme 1. Retrosynthetic strategy for assembly of the 5-alkoxypyr-
idopyrimidinone core.
5
0
040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.03.087

3734
A. P. Dishington et al. / Tetrahedron Letters 45 (2004) 3733–3735
O
H N
O
2
O
Br
O
Pd dba
Xantphos /
/
2
3
i) n-BuLi
NaOMe / DMF /
0 oC / 72%
O
4
Cs CO
/
3
ii) ClCO Et
2
2
N
N
N
59%
dioxane /
N
H
9
O
Br
Br
91%
7
8
O
O
NH
O
O
.
AcOH
CO R
2
CO R
2
H
NH2
O
TFA / Et SiH
NH
3
N
N
o
EtOH / 100 C /
20h / ~78% over
N
N
H
O
NH2
N
2
steps
1
0a R = H
11a R = H
11b R = Et
12
1
0b R = Et
Scheme 2. Synthesis of the pyridopyrimidinone core.
1
8
procedure described by Yin and Buchwald (Pd
Xantphos/Cs CO
2
2
dba
3
/
treatment of the methyl ether 12 with magnesium bro-
mide (1 equiv) in pyridine at reflux for 2 h. An aqueous
work-up afforded the hydroxypyridine derivative 13 in
75% yield. Protection of the pyrimidinone portion as an
N-pivaloyloxymethylamide by sequential treatment with
sodium hydride (1.1 equiv) in DMF, followed by
N-pivaloyloxymethyl chloride (POM-Cl) (1.2 equiv)
provided the substrate 14 required for a Mitsunobu
reaction in only 50% yield. Attempts to improve on this
yield were unrewarded. This alcohol was partnered with
4-hydroxy-N-methylpiperidine (1.25 equiv) under Mits-
unobu conditions (di-tert-butyl azodicarboxylate
(DTAD), PPh , CH Cl ) to afford the crude ether 15.
3
/dioxane/90 °C/48 h) gave the carba-
mate 9 in 91% yield on a multi-gram scale. Gratifyingly,
early attempts to introduce a carboxylate function at
position C-4 of the pyridine, by metallation with n-but-
yllithium and quenching with solid carbon dioxide were
19
successful. However, the subsequent cyclization of the
deprotected amino acid 11a with formamidine acetate to
give the pyrido[3,4-d]pyrimidin-4(3H)-one 12 proved
problematic due to the insolubility of the starting
material. This problem was circumvented by metallation
of the pyridine 9 with n-butyllithium (2.5 equiv/
78 ! 10 °C/THF) and quenching with ethyl chloro-
formate (1 equiv/ꢀ78 °C) to give the ethyl ester 10b in
9% overall yield. Removal of the protecting group with
trifluoroacetic acid provided the amino ester 11b. The
improved solubility of this material in ethanol under
reflux ensured an efficient cyclization with formamidine
acetate to afford the pyrido[3,4-d]pyrimidin-4(3H)-one
12, which precipitated from the reaction mixture in 78%
yield from the carbamate 10b.
ꢀ
3
2
2
This was stirred in 7 N ammonia in methanol for 24 h to
give, after silica-gel chromatography, the 5-alkoxypyr-
ido[3,4-d]pyrimidin-4(3H)-one 2 in 48% yield over two
steps.
5
In conclusion we have described the first synthesis of the
5-alkoxypyrido[3,4-d]pyrimidin-4(3H)-one ring system
in nine steps from commercially available starting
material in 5% overall yield. It is anticipated that further
molecular complexity can be introduced at C-4 via a
chlorination-displacement strategy, and that a diverse
set of alcohols be coupled to the C-5 hydroxy group.
With the bicyclic core now assembled, the pendant
4
-hydroxy-N-methylpiperidine could be attached
Scheme 3). The 5-hydroxy function was revealed by
(
OH
O
N
i) NaH / DMF
ii) POM-Cl /
OH
O
N
O
O
O
N
MgBr
pyridine / 75%
2
50%
NH
N
O
NH
N
N
N
N
1
2
13
14
N
N
NH3 / MeOH (7N) /
8% over 2 steps
OH
O
O
O
O
O
N
4
PPh3 / DTAD /
DCM
N
O
NH
N
N
N
1
5
2
Scheme 3. Introduction of the N-methylpiperidin-4-yloxy side-chain.

A. P. Dishington et al. / Tetrahedron Letters 45 (2004) 3733–3735
3735
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