Solid-phase synthesis of pyrido[2,3-d]pyrimidin-7-ones

Article abstract of DOI:10.1016/j.tetlet.2005.10.030

A novel solid-phase method for the synthesis of 4-methyl-pyrido[2,3-d] pyrimidin-7-one compounds with two diversity points is described. The polymer supported methylsulfonyl derivatives A₃, achieved by coupling compound G with different resin-bound amines A₁ followed by oxidation with MCPBA, are substituted with several amines R₁R₂NH. Final cleavage affords 126 compounds having formula H in good yield and purity.

Full text of DOI:10.1016/j.tetlet.2005.10.030

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8749–8752
Solid-phase synthesis of pyrido[2,3-d]pyrimidin-7-ones
Mauro Angiolini, Domenico Fusar Bassini, Markus Gude and Maria Menichincheri*
Discovery Oncology, Nerviano Medical Sciences, viale Pasteur 10, 20014 Nerviano, Italy
Received 28 September 2005; revised 10 October 2005; accepted 11 October 2005
Available online 25 October 2005
Abstract—A novel solid-phase method for the synthesis of 4-methyl-pyrido[2,3-d]pyrimidin-7-one compounds with two diversity
points is described. The polymer supported methylsulfonyl derivatives A3, achieved by coupling compound G with different
resin-bound amines A1 followed by oxidation with MCPBA, are substituted with several amines R1R2NH. Final cleavage affords
126 compounds having formula H in good yield and purity.
ꢀ 2005 Elsevier Ltd. All rights reserved.
In drug discovery combinatorial chemistry based on
pharmacophoric scaffolds is a promising approach
towards new bioactive entities. In this respect, pyrido-
[2,3-d]pyrimidin-7-ones having structure 1 represent an
attractive heterocyclic class due to their biological effects
in particular as kinase inhibitors (Fig. 1).1–6
the aim to synthesize a 4-methyl-pyrido[2,3-d]pyrimidin-
7-one based library with two diversity points, one at
position 2 and the other at para position of the phenyl
ring present on the scaffold.
The retrosynthetic route is reported in Scheme 1 where
the aryl amidic moiety is first introduced with the use
of a solid supported amine A1. The amine at position
2 is derived from a nucleophilic displacement of a meth-
ylsulfone. The final compounds of general formula 2 are
easily released from the resin under acidic conditions
with trifluoroacetic acid (Scheme 1).
Thus, in the effort to identify new active compounds we
envisaged the opportunity to design a chemical library
of potential biological interest based on structure 2
(Fig. 1). As for our knowledge, solid-phase expansion
of such heterocyclic series is scarcely documented in
the literature. So we undertook a synthetic study for
the development of a solid supported methodology with
As the first step a synthetic route to 4-methyl-pyrido-
[2,3-d]pyrimidin-7-one scaffold D, a key intermediate
both for solution and solid-phase methods, was devel-
oped according to Scheme 2. Thus condensation be-
tween the commercially available diethyl ethylidene
malonate A with S-methyl-isothiourea followed by oxi-
dation with NBS smoothly affords compound B. Treat-
ment of B with POCl3 and nucleophilic aromatic
substitution at position 6 with tert-butyl-4-aminobenzo-
ate gives the pyrimidine derivative C in good yield.
Selective reduction of the ethyl ester C followed by oxi-
dation with MnO2 affords the aldehyde, which in turn
undergoes Horner–Emmons olefination and final intra-
molecular cyclization gives scaffold D. This route is amen-
able to large scale synthesis (20g). Oxidation of D with
MCPBA gives the methylsulfone moiety, which provides
the template for investigating the solution-phase nucleo-
philic substitution at position 2 with different amines.7
CH3
R'
N
N
R1
N
N
N
O
R''
N
N
N
R
O
H
R2
1
O
NH
R3
2
Figure 1.
Keywords: Pyrido[2,3-d]pyrimidin-7-one; Solid-phase; Formyl resin;
Scaffold; Library.
*
Corresponding author. Tel.: +39 0331 581928; fax: +39 0331
581757; e-mail: maria.menichincheri@nervianoms.com
Present address: Actelion AG, Allschwil, Switzerland.
A model case is reported in Scheme 2 where a 2.5-fold
excess of N-phenylpiperazine is refluxed in dioxane with
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.030

8750
M. Angiolini et al. / Tetrahedron Letters 46 (2005) 8749–8752
CH3
CH3
N
CH3
N
CH3
N
N
N
N
R1R2NH
R3NH-CH2
H+
N
R
R1
1N
R2
N
N
O
N
O
N
MeO2S
N
O
H
N
G
O
MeS
R2
A1
O
N
O
N
O
N
O
Cl
R3
R3
R3
2
Scheme 1.
CH3
N
O
O
N
O
O
O
i, ii
N
O
iii,iv
S
NH
O
O
S
N
H
O
A
B
O
OtBu
C
N
CH3
CH3
CH3
N
N
N
v, vi, vii, viii
N
N
O
ix, x
xi, xii, xiii
N
N
N
O
S
N
N
O
N
Ph
N
Ph
O
N
Ph
O
OtBu
H
O
OtBu
D
E
F
Scheme 2. Reagents and conditions: (i) S-methyl isothiourea, TEA, anhydrous ethanol, reflux, 3 h, 55%; (ii) anhydrous K2CO3, benzoyl peroxide,
NBS, anhydrous dioxane, 90 ꢁC, 3 h, 92%; (iii) POCl3, reflux, 2 h, 50%; (iv) tert-butyl 4-aminobenzoate (2 equiv), DIPEA, dioxane, reflux, 72 h, 81%;
(v) NaBH4, anhydrous ethanol, 45 ꢁC, 4 h, 82%; (vi) MnO2, CH2Cl2, rt, overnight, 70%; (vii) Ph3PCHCOOEt, anhydrous THF, reflux, 2.5 h, 94%;
(viii) DIPEA/DBU (10:1 v/v), reflux, 30 h, 71%; (ix) MCPBA, CH2Cl2, rt, 1.5 h, 87%; (x) 4-phenylpiperazine (2.5 equiv), dioxane, reflux, 0.5 h, 87%;
(xi) TFA, CH2Cl2, rt, 8 h, 95%; (xii) oxalyl chloride, anhydrous DMF, CH2Cl2, rt, 2 h, 95%; (xiii) benzylamine, TEA, CH2Cl2, rt, 78%.
the sulfone for half an hour to give compound E in good
yield. These conditions proved to be optimal not only
for primary and secondary aliphatic amines but also
the less reactive aromatic amines such as ethyl para-ami-
nobenzoate. Finally E is readily converted into the cor-
responding acid chloride and coupled with benzyl amine
to afford F. The reaction sequence depicted in Scheme 2
involves a reverse addition order of amine R1R2NH and
R3NH2 on the scaffold with respect to the solid-phase.
of the polymer-supported intermediate A2 with MCPBA
affords sulfone A3, which is then subjected to aromatic
substitution at 60 ꢁC in THF using 6 equiv of different
amines R1R2NH. Final release of intermediate A4 from
the solid support under acidic conditions with trifluro-
acetic acid completes the preparation of the library.
Thus 16 different amines were selected for nucleophilic
substitution at position 2 of the scaffold A3 bearing nine
diverse residues R3. This achieves 126 final compounds
having general formula H, with overall yields ranging
from 50% to 80% and good purity. All the compounds
The solid-phase route is reported in Scheme 3 where the
intermediate D previously described is converted in
good yield into the corresponding chloride G after
deprotection with trifluoroacetic acid and activation
with oxalyl chloride. Then the intermediate G is coupled
to the resin-bound amine A1, prepared by reductive
amination with NaBH(AcO)3 of the selected amines
R3NH2 (see Table 1 both for residues R3 and for
R1R2N) condensed with a formyl resin [4-(4-formyl-3-
methoxyphenoxy)butyrylaminomethyl resin]. Oxidation
1
were characterized by HPLC-MS and H NMR tech-
nique. A representative selection of 10different final
compounds is reported in Table 1 with their HPLC-
MS purity and yields.8,9
In conclusion we have developed a useful methodology
to prepare in a scalable way a pyrido[2,3-d]pyrimidin-
7-one scaffold and to build on solid-phase a library of
126 compounds with double diversity.

M. Angiolini et al. / Tetrahedron Letters 46 (2005) 8749–8752
8751
OHC
R3NH2
+
vii
HN
R3
CH3
N
CH3
N
CH3
N
N
N
N
iii
i, ii
S
N
O
S
N
O
S
N
O
A1
O
N
O
OtBu
O
Cl
G
R3
D
A2
CH3
N
CH3
CH3
N
N
N
N
iv
v
vi
R1
R1
N
N
O
H
N
N
N
N
O
O
SO2
R2
R2
O
N
O
N
O
N
R3
R3
R3
A3
A4
H
Scheme 3. Reagents and conditions: (i) TFA, CH2Cl2, rt, 2 h, 95%; (ii) oxalyl chloride, anhydrous DMF, CH2Cl2, rt, 2 h, 95%; (iii) A1 (R3NH-Y-
Pol), CH2Cl2, TEA (10equiv), rt, overnight; (iv) MCPBA, CH 2Cl2, rt, 1.5 h; (v) R1R2NH 6 equiv, TEA 6 equiv, THF, 60 ꢁC, 1 h; (vi) TFA/CH2Cl2
(50%, v/v), rt, 1.25 h; (vii) R3NH2, THF/CH2Cl2 (4:1, v/v), AcOH, NaBH(OAc)3, rt, overnight.
Table 1. Pyrido[2,3-d]pyrimidin-7-ones H produced via Scheme 3
Product
R1R2N
R3
Yield (%)a
5090
Purity (%)b
N
*
H1
N
N
*
N
*
OMe
OMe
NH
H2
H3
H4
55
80
90
*
*
*
N
74
H
N
*
O
6062
O
N
*
H5
H6
78
65
90
80
HN
N
*
*
H
N
*
Ph
*
*
HO
COOH
H7
H8
6070
57
N
*
*
*
N
O
90
H
N
N
CH3(CH2)7
H9
67
75
54
90
*
*
OMe
OMe
H
N
O
*
H10
*
a Four-step overall yields from G.
b All the crude products purities are calculated by HPLC-MS at k = 254 nm.

8752
M. Angiolini et al. / Tetrahedron Letters 46 (2005) 8749–8752
methoxyphenoxy)butyrylaminomethyl resin (AMEBA
resin) (500 mg, 0.40 mmol, loading 0.59 mmol/g, 100–200
mesh, 1% DVB, Novabiochem) in 5 ml of THF/DCM
(4:1, v/v) benzylamine (260 ll, 2.40mmol) and AcOH
(135 ll, 2.40mmol) were added. Shaking continued for
15 min, then NaBH(AcO)3 (250mg, 1.20mmol) was added
and shaking was continued over-night at room tempera-
ture. The completion of the reaction was confirmed by
disappearance of the formyl signal via solid-phase NMR
technique. The resin was washed with MeOH (2 · 1 min),
DMF (2 · 1 min), DCM (1 · 1 min), MeOH (1 · 1 min)
and DCM (3 · 1 min). The resin was dried at 30 ꢁC at
10Torr for 2 h.
Polymer supported N-benzyl-4-[4-methyl-7-oxo-2-methyl-
sulfanyl-7H-pyrido[2,3-d]pyrimidin-8-yl]benzamide A2: To
a suspension of polymer supported benzylamine A1 (0.40
mmol) in 15 ml of DCM and TEA (0.82 ml, 5.9 mmol),
4-[4-methyl-7-oxo-2-methylsulfanyl-7H-pyrido[2,3-d]pyrimi-
din-8-yl]benzoyl chloride was added and the mixture
was shaken over-night at room temperature. This was
then filtered and the resin was washed in the following
order: DMF (3 · 1 min), DCM/MeOH (1:1, v/v, 3 · 1 min),
DCM (3 · 1 min), MeOH (1 · 1 min) and DCM (3 ·
1 min). The resin so achieved was dried for 2 h at 10Torr
and 30 ꢁC.
Polymer supported N-benzyl-4[4-methyl-7-oxo-2-methyl-
sulfonyl-7H-pyrido[2,3-d]pyrimidin-8-yl]benzamide A3: The
resin A2 (ca. 45 mg, 0.0214 mmol) was suspended in 1 ml of
DCM and treated for 1.5 h with MCPBA (14.3 mg,
0.064 mmol) at room temperature. The resin A3 was then
washed with dioxane (2 · 1 min) and DCM (2 · 1 min).
Polymer supported N-benzyl-4-[4-methyl-7-oxo-2-(1-piper-
azinyl)-7H-pyrido[2,3-d]pyrimidin-8-yl]benzamide A4: To a
mixture of resin A3 in 1 ml of THF and TEA (14 mg,
0.13 mmol) was added the respective amine (0.13 mmol)
and shaking was continued for 1 h at 60 ꢁC. The resin A4
was then washed with THF (2 · 1 min), DMF (3 · 1 min)
and DCM (3 · 1 min).
Release of product H1 from the resin A4: Resin A4 was
treated with a mixture of TFA/DCM (1 ml, 50% v/v) for
75 min. The resin was filtered, washed with DCM
(1 · 1 min) and the combined organic layers were evapo-
rated yielding compound H1. 1H NMR (400 MHz, DMSO-
d6): d 9.18 (t, 1H), 8.34 (d, 2H), 8.03 (m, 3H), 7.47 (m, 7H),
6.62 (t, 1H), 6.36 (d, 1H), 4.51 (d, 2H), 3.62 (m, 4H), 3.33
(m, 4H), 2.58 (s, 3H); LC/MS (ESI): m/z 647 (M+H).
To the best of our knowledge, this represents the
first combinatorial expansion on this versatile scaffold
reported in the literature.
References and notes
1. VanderWel, S. N.; Harvey, P. J.; McNamara, D. J.; Repine,
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Kraker, A. J.; Amar, A. M.; Hartl, B. G.; Shen, C.; Klohs,
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`
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CHIMIA 2003, 57, 229–236.
9. Typical procedure for solid-phase: Synthesis of N-benzyl-
4-[4-methyl-7-oxo-2-(4-pyrimidin-2-yl-piperazin-1-yl)-7H-
pyrido[2,3-d]pyrimidin-8-yl]benzamide (compound H1).
Preparation of polymer supported benzylamine A1 by
reductive amination: To a suspension of 4-(4-formyl-3-