An improved and highly convergent synthesis of 4-substituted-pyrido[2,3-d]pyrimidin-7-ones

Article abstract of DOI:10.1016/j.tetlet.2006.12.064

A novel and efficient route to 4-substituted-pyrido[2,3-d]pyrimidin-7-ones is described resulting in arrays of compounds with biological interest.

Full text of DOI:10.1016/j.tetlet.2006.12.064

Tetrahedron Letters 48 (2007) 1205–1207
An improved and highly convergent synthesis of
4-substituted-pyrido[2,3-d]pyrimidin-7-ones
Hongxing Yan, Jeffrey C. Boehm, Qi Jin, Jiri Kasparec, Huijie Li, Chongjie Zhu,
Katherine L. Widdowson, James F. Callahan and Zehong Wan*
Department of Medicinal Chemistry, Respiratory and Inflammation Centre of Excellence for Drug Discovery,
GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, USA
Received 24 October 2006; revised 30 November 2006; accepted 12 December 2006
Abstract—A novel and efficient route to 4-substituted-pyrido[2,3-d]pyrimidin-7-ones is described resulting in arrays of compounds
with biological interest.
Ó 2006 Elsevier Ltd. All rights reserved.
The strategy to design organic synthetic routes in such a
way that is amenable to prepare a variety of analogues
through an array approach has been widely employed
by medicinal chemists in the pharmaceutical industry
to carry out structure activity relationship (SAR) stud-
ies.1 A recent demonstration can be found in the synthe-
sis of 2,4,8-trisubstituted pyrido[2,3-d]pyrimidin-7-ones
with general structure III (Fig. 1).2 The key features of
the synthesis include (a) conversion of aldehyde I to a
cis a,b-unsaturated ester followed by a spontaneous
intramolecular condensation to construct a bi-cyclic ring
system II, and (b) displacement of methylsulfone with
nucleophiles (e.g., amines) in the last step to afford com-
pounds III. This sequence provided an excellent route to
optimize substituents at carbon 2 (C2) of the central
scaffold. In order to further exploit this template and
to develop SAR, we sought to efficiently optimize sub-
stituents at carbon 4 (C4). Introduction of the C4 substi-
tuent as a final step would serve to increase the efficiency
of the endeavour. In this paper, we report a novel syn-
thetic route that meets these criteria and its subsequent
utilization to prepare arrays of small molecules III.
From the perspective of retrosynthetic analysis (Fig. 1),
the compounds related to IV wherein X is a leaving
group (e.g., Cl) are envisioned as key intermediates of
analogues III. Intermediates IV can be derived from V
through the selective displacement of Y with various
nucleophiles (e.g., amines). Pyridopyrimidinones with
optimal substituents at N8 (V) can be constructed from
I, a starting material used in previous syntheses.2 Con-
struction of the bi-cyclic ring system and selection of
the two leaving groups (X and Y) with different reactiv-
ity are considered critical challenges to a successful
route.
R3
R3
O
Cl
N
4
5
3N
2
6
7
1
8
N
H
N
O
N
N
S
O
N
NH
R2
O O
Cl
N
S
R1
R1
I
II
III
X
X
N
N
8
N
The synthesis commenced with investigating the forma-
tion of the pyridopyrimidinone ring system (Scheme 1).
Starting from aldehyde I, displacement with aniline 2a
(1 equiv) under similar reaction conditions as reported
previously2 afforded a mixture of 4a and 5a (1:1, 90%
combined yield). The formation of 4a suggested that
the aldehyde group was quite accessible and this could
be utilized to our advantage to furnish the desired pyri-
dopyrimidinone ring in a one pot sequence: in situ gen-
O
N
Y
O
N
N
NH
R2
R1
R1
IV
V
Figure 1. Retrosynthetic analysis.
*
Corresponding author. E-mail: Zehong_2_Wan@gsk.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.064

1206
H. Yan et al. / Tetrahedron Letters 48 (2007) 1205–1207
substrate. Instead, 3c was prepared in two steps (Method
R1
Cl
N
H
B). Displacement with 2,6-difluoroaniline 2c to form
anilinopyrimidine 6c proved quite straightforward, how-
ever, ring formation to produce 3c was problematic.
Horner–Emmons reaction under Still’s protocol3 gave
rise to an isomeric mixture (about 1:3) of 7c (Table 1,
entries 1 and 2). Intramolecular cyclization of the resultant
mixture under various reaction conditions provided only
trace amounts of 3c.4 Difficulties encountered in the
spontaneous ring closure via amide formation might
be related to the steric hinderance of 2,6-difluorophenyl
unit in the substrates. This might be avoided by amide
formation followed by spontaneous ring closure via
intramolecular aldol condensation. Acetyl chloride was
tested for the purpose (entry 3), and to our pleasure,
the desired 3c was isolated. The reaction was latter opti-
mized providing 3c in good overall yields (entries 4 and 5).
Cl
N
O
N
N
TEA, CHCl3
+
HN
S
HN
N
S
R1
R1
NH2
4
5
Cl
N
+
I
N
MeOCOCH2PO(OCH2CF3)2
TEA, THF
R1
O
O
N
S
2
a: R1=4-CF3
b: R1=2,4-di-F
c: R1=2,6-di-F
Method A
(3a, 90%; 3b, 52%)
R1
3
TEA, THF
(6c, 70%)
Method B
Ac2O / DMF
O
H
Cl
N
Cl
N
O
N
H
N
N
S
After securing the construction of pyrido[2,3-d]pyrimi-
din-7-ones, attention was directed towards the introduc-
tion of substituents at C2 (Scheme 2). Methylsulfone
was chosen initially as the leaving group due to its suc-
cess in previous syntheses.2 Starting from sulfide 3a, oxi-
dation with OxoneÒ (5 equiv, Table 2) afforded sulfone
8a (45%). Treatment of 8a with serinol 9d (1 equiv) in
DMF did not result in the selective displacement of
methylsulfone at C2. A similar result was obtained in
the reaction of 8a with amine 9e. In light of a report that
methanesulfinyl [MeS(O)–] displayed selectivity over
chlorine in the nucleophilic displacements of 2-chloro-
6-methanesulfinyl-pyridine,5 MeS(O)– was studied as
an alternative leaving group at C2.6 To this end, the oxi-
dation of 3a with m-cPBA (1.5 equiv, 10 min) provided
sulfoxide 10a in an 82% yield. Treatment of 10a with
9d, to our pleasure furnished exclusive displacement at
C2 producing 11ad. This strategy was employed to pre-
H
MeOCOCH2PO(OCH2CF3)2
N
S
R1
R1
6
7
Scheme 1.
eration of a cis a,b-unsaturated ester via the Horner–
Emmons protocol and spontaneous intramolecular
condensation and ring closure. To this end, MeOC-
OCH2PO(OCH2CF3)2, a well-established reagent for
Horner–Emmons olefination was added to the conden-
sation of aldehyde 1 with aniline 2a (Method A, Scheme
1), and remarkably furnished 3a in one step with a 90%
yield. Pyridopyrimidinone 3b was prepared in the same
way, although in a modest yield (52%) presumably due
to an increased steric hinderance of 2b. This process
failed to shed any success on 2c, an even more hindered
Table 1. Formation of pyridopyrimidinone 3c from 6c
Entry
Reaction condition
Product
Yield (%)
1
2
3
4
5
MeOCOCH2PO(OCH2CF3)2, LiCl, DIPEA, MeCN
MeOCOCH2PO(OCH2CF3)218-c-6, KHMDS, THF
AcCl, 18-c-6, K2CO3, CH2Cl2
Ac2O, microwave, 15 min, 200 °C
Ac2O/DMF (1:2), microwave, 160 °C, 30 min
7c
7c
3c
3c
3c
60a
60
13
40
50
a Mixture of cis- and trans-isomers with a ratio of 1:3 based on LC–MS and 1H NMR of crude samples presumably favouring the trans-isomer.
Cl
4
Cl
N
N
2
NH2-R2
(9d or 9e)
N
O
N
N
S
O
O
O
N
NH
R2
DMF
R1
Cl
8
R1
3
11
a: R1=4-CF3
b: R1=2,4-di-F
c: R1=2,6-di-F
NH2-R2 (9)
DMF
4
N
11ad: 45%; 11bd: 46%; 11cd: 42%
2
MeSO2Cl
60%, 2 steps
11ce
O
N
N
S
d: R2=CH(CH2OH)2
e: R2=CH2CH2NH2
11cf
O
f:R2=CH2CH2NHSO2Me
R1 10
10a: 82%; 10b: 95%; 10c: 88%
Scheme 2.

H. Yan et al. / Tetrahedron Letters 48 (2007) 1205–1207
1207
Table 2. Oxidation of sulfides 3
Substrate
Reaction condition
Product
Yield (%)
3a
3a
3a
3a
3b
3c
Oxone (5 equiv), acetone–water
Oxone (1.1 equiv), THF–water
Oxone (1.1 equiv), acetone–water
m-cPBA (1.5 equiv), CH2Cl2, 10 min
m-cPBA (1.5 equiv), CH2Cl2, 10 min
m-cPBA (1.5 equiv), CH2Cl2, 10 min
8a
45
37
40
82
95
88
8a + 10a
10a
10a
10b
10c
pare three additional compounds (11bd, 11cd and 11cf)
in moderate yields.
substituents (e.g., compounds 13 with R3 = 2-SMe–Ph,
3-SMe–Ph or 4-SMe–Ph) that pose a pronounced chal-
lenge in the previous syntheses.10 Biological evaluation
of these compounds will be reported in due course.11
With the intermediate 4-chloro-pyridopyrimidinone 11
finally in hand, the introduction of substituents at C4
via a microwave-assisted Suzuki cross-coupling7 with
boronic acids 12(g–t)8 was explored (Scheme 3) and
the results are shown in Table 3. Group R3 includes a
variety of phenyl and heterocyclic rings affording final
products 13 in good yields.9
Acknowledgements
Helpful discussions with Drs. Jeffrey K. Kerns, Michael
Palovich and Domingos J. Silva during the preparation
of this manuscript are acknowledged.
In summary, an improved synthesis that is amenable to
the facile preparation of 4-substituted-pyrido[2,3-d]pyr-
imidin-7-ones was developed. The synthesis includes
the efficient construction of the pyridopyrimidinone
template and discovery of two differentially reactive
groups [Cl vs MeS(O)–] allowing for selective substitu-
tion at C2 and C4. Fascile access to a number of ana-
logues via an array approach was demonstrated.
Noteworthily, the synthetic route provides an alterna-
tive method to prepare analogues with readily oxidizable
References and notes
1. For reviews, see: (a) Coe, D. M.; Storer, R. Annu. Rep.
Comb. Chem. Mol. Div. 1999, 2, 1; (b) Flynn, D. L. Med.
Res. Rev. 1999, 19, 408; For an example of array approach
with three points of diversity, see: (c) Wan, Z.; Boehm, J.
C.; Bower, M. J.; Kassis, S.; Lee, J. C.; Zhao, B.; Adams,
J. L. Bioorg. Med. Chem. Lett. 2003, 13, 1191.
2. Kasparec, J.; Adams, J. L.; Sisko, J.; Silva, D. J.
Tetrahedron Lett. 2003, 44, 4567.
3. (a) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24,
4405; (b) Jacobsen, E. N.; Deng, L.; Furukawa, Y.;
Martinez, L. E. Tetrahedron 1994, 50, 4323.
4. Less than 5% of 3c was identified via LC–MS when treated
under the condition of Ref. 2 (toluene, 200 °C, sealed
tube). This is most likely due to the steric hinderance in the
substrate.
Cl
R3B(OH)2
R3
12
N
N
Pd(PPh3)4, K2CO3
O
N
N
NH
R2
oC, 10 Min
150
Dioxane / water
Microwave
O
N
N
NH
R2
R1
11
R1
5. Furukawa, N.; Ogawa, S.; Kawai, T.; Oae, S. Tetrahedron
Lett. 1983, 24, 3243.
a: R1=4-CF3
d: R2=CH(CH2OH)2
f: R2=CH2CH2NHSO2Me
13
b: R1=2,4-di-F
c: R1=2,6-di-F
6. This template is apparently more closely related to 4-
chloro-2-methanesulfinyl-pyrimidine wherein chlorine
exhibited selectivity over methanesulfinyl, see: Hurst, D.
T.; Johnson, M. Heterocycles 1985, 23, 611.
Scheme 3.
7. For a review of microwave-assisted organic synthesis see:
Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225.
8. All boronic acids were purchased from commercial
sources except 12h. For the preparation of 12h, see: Dack,
K. N.; Whitlock, G. A. WO 99/29667, 1999.
9. To the solution of 11 in dioxane/water (3:1) were added 12
(1.5 equiv) and K2CO3 (3 equiv). The resultant mixture
was bubbled with argon for 5 min before Pd(PPh3)4
(0.02 equiv) was added. The reaction tube was sealed
and irradiated with a microwave reactor at 150 °C for
15 min. The mixture was concentrated under vacuo. Flash
chromatography (EtOAc/hexane) then provided com-
pound 13.
10. As shown in Ref. 2, an oxidation reaction was carried out
after the Suzuki cross-coupling and the group of –SMe
would be likely oxidized in the reaction.
11. For Representative experimental procedures and com-
pound characterization, see: Callahan, J. F.; Boehm, J.;
Wan, Z.; Yan, H. WO 06/104917, 2006.
Table 3. Yield of Suzuki cross-coupling of 11 with 12
R3
11ad
(%)
11bd
(%)
11cd
(%)
11cf
(%)
12g (2-SMe–Ph)
12h (3-SMe–Ph)
12i (4-SMe–Ph)
12j (2-OMe–Ph)
85
73
56
76
65
60
65
—
—
—
—
—
—
—
71
90
56
95
89
75
77
—
—
—
—
—
—
—
88
71
67
91
78
70
96
82
90
23
56
75
51
74
80
—
a
—
53
—
—
—
82
93
—
62
85
60
75
12k (3-OMe–Ph)
12l (4-OMe–Ph)
12m (3,4-di-F–Ph)
12n (Thiophen-2-yl)
12o (Thiophen-3-yl)
12p (Furan-2-yl)
12q (Benzofuran-2-yl)
12r (Pyridine-3-yl)
12s (Pyridine-4-yl)
12t (Benzothiophen-2-yl)
a The coupling reaction was not tested.