A convenient synthesis of trisubstituted pyrido[2,3-d]pyrimidin-7-ones

Article abstract of DOI:10.1016/S0040-4039(03)00974-2

A novel, highly efficient and scalable route for the synthesis of trisubstituted pyrido[2,3-d]pyrimidin-7-ones was developed. The target compounds were synthesized in five steps from readily available reagents in about 40% overall yield.

Full text of DOI:10.1016/S0040-4039(03)00974-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4567–4570
A convenient synthesis of trisubstituted
pyrido[2,3-d]pyrimidin-7-ones
Jiri Kasparec,a Jerry L. Adams,a Joseph Siskob and Domingos J. Silvaa,*
aMedicinal Chemistry Department, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
bSynthetic Chemistry Department, GlaxoSmithKline, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA
Received 20 March 2003; revised 16 April 2003; accepted 16 April 2003
Abstract—A novel, highly efficient and scalable route for the synthesis of trisubstituted pyrido[2,3-d]pyrimidin-7-ones was
developed. The target compounds were synthesized in five steps from readily available reagents in about 40% overall yield. © 2003
Elsevier Science Ltd. All rights reserved.
As part of our effort to design novel scaffolds for drug
discovery programs, we investigated the synthesis of
trisubstituted pyrido[2,3-d]pyrimidin-7-ones 1. Unlike
the less substituted pyridopyrimidinones previously
described by other groups,1–3 the present series of com-
pounds has three derivatization sites, allowing for the
convenient introduction of diversity around the central
cis a,b-unsaturated ester, which undergoes spontaneous
intramolecular condensation with the ortho disubsti-
tuted amine under the reaction conditions. Intermediate
3 may be prepared from the commercially available 5 in
a two-step procedure, involving a nucleophilic displace-
ment to introduce R1 (4), followed by a Suzuki cou-
pling to introduce R2 (3).
core.
Interestingly,
trisubstituted
pyrido[2,3-d]-
pyrimidin-7-ones constitute a novel structural com-
pound class, with no published description or synthesis
to the best of our knowledge.
As shown in Scheme 2, 4,6-dichloro-2-methylsulfanyl-
pyrimidine-5-carboxyaldehyde
5
was coupled to
amines (1.2–5 equiv.) at room temperature (for alkyl-
The present paper reports a novel synthetic route to
trisubstituted pyrido[2,3-d]pyrimidin-7-ones, in which
the readily available 4,6-dichloro-2-methylsulfanyl-
pyrimidine-5-carboxyaldehyde 54 is converted to the
pyrido[2,3-d]pyrimidin-7-ones in five steps in about
40% overall yield. This route allows for the stepwise
derivatization of the bicyclic core and can be easily
scaled up (>10 g scale). Experimental conditions are
presented and discussed below.
The retrosynthetic scheme for the trisubstituted
pyrido[2,3-d]pyrimidin-7-one 1 is shown in Scheme 1.
Sulfide 2 may be converted to 1 by oxidation to the
corresponding sulfone and displacement with an amine
nucleophile. The key step in our synthesis is the conver-
sion of aldehyde 3 to bicyclic intermediate 2. Such a
transformation has been previously performed employ-
ing a Horner-Emmons procedure with Still’s modifica-
tion.5,6 In this reaction, the aldehyde is converted to a
Scheme 1.
Scheme 2. Reaction conditions: (i) alkylamine, CHCl3, triethyl-
amine, 15 min, 20°C, or arylamine, CHCl3, triethylamine,
reflux, 24 h; (ii) K2CO3, Pd(Ph3)4, arylboronic acid, dioxane,
water, reflux, 16 h.
* Corresponding
author.
Tel.
+1-610-1917-6983;
e-mail:
domingos.j.silva@gsk.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00974-2

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J. Kasparec et al. / Tetrahedron Letters 44 (2003) 4567–4570
amines) or reflux (for anilines).1 In all cases studied,
only monosubstitution was observed, presumably
because the monochloro derivative 6 is not prone to
subsequent nucleophilic displacement under the reac-
tion conditions. Product 6 was easily isolated from the
reaction mixture by evaporating the solvent and recrys-
tallizing the residue. Under the reaction conditions
cited, no imine formation was observed.7
We originally envisioned performing this transforma-
tion using the Horner-Emmons reaction with Still’s
modification.5 Surprisingly, the Horner-Emmons/Still
reaction (entry I) afforded a mixture of desired pyr-
idopyrimidinone 89 and trans ester 9. Formation of the
trans isomer can be rationalized by the extreme steric
crowding around the reactive center, which may dis-
favor formation of the cis product. The ratio between 8
and 9 was found to be highly substrate dependent, and
all attempts to modify reaction conditions to afford
pure 8 failed.
Chloride 6 was coupled to aromatic boronic acids
under standard Suzuki conditions, using 1.2–1.5 equiv.
of the appropriate boronic acid, 3 equiv. of potassium
Besides affording a significant amount of undesired 9
along with 8, the Horner-Emmons/Still reaction on 7
proved difficult to scale up because of the cost of the
fluorinated phosphonate reagent and large excess of
crown ether needed (5 equiv.). Other routes for the
conversion of 7 to 8 were thus explored.
carbonate
and
catalytic
amounts
of
tetra-
kis(triphenylphosphine) palladium (3 mole%) in a 3:1
dioxane/water mixture for 24 h. Product 7 was isolated
by crystallization in very good yields (Table 1).
The conversion of aldehyde 7 to bicyclic compound 8
was investigated (Table 2). For the purposes of this
discussion, the transformations where R1 is alkyl or
aryl will be exemplified with 3-pentyl and 2-
chlorophenyl groups, respectively, since they were
found to be representative of their respective classes.
When 7 was submitted to a standard Horner-Emmons
reaction (entry II), a mixture of 8 and 9 was formed in
good yield. In the case of R1=alkyl, to our pleasant
surprise the desired 8a was heavily favored. Apparently,
under the reaction conditions, the initially formed trans
ester isomerized to the cis ester and underwent
intramolecular condensation. In the case of R1=aryl,
the major product was the trans ester 9b.
Table 1. Suzuki cross-coupling of 6 with various boronic
acids
Interestingly, 9 was quantitatively converted to 8 by
heating in toluene to 200°C (Scheme 3).10 Attempts to
reduce the required reaction temperature using catalytic
amounts of acids (TFA) or bases (DBU, NaH or
DMAP) were not successful.
R1 group in 6
R2 group, from boronic Isolated yield of
acid R2B(OH)2 7 (%)
2-Propyl
3-Pentyl
Methylcyclopropyl
Phenyl
Phenyl
2-Chlorophenyl
87
2-Chlorophenyl
2-Chlorophenyl
Phenyl
828
69
88
As an alternative to the Horner-Emmons procedure, we
envisioned that acetylation of 7 would yield 10, which
could undergo an intramolecular aldol condensation to
generate the desired 8 (Scheme 4). Indeed, when 7 was
refluxed in a 1:1 mixture of acetic anhydride and py-
ridine for 48 h the desired pyridopyrimidinone 8 was
observed (Table 1, entry III). Transient formation of
the acylated intermediate 10 was observed by LC–MS.
The reaction afforded good yields of 8 for R1=2-
2-Chlorophenyl
Phenyl
2-Chlorophenyl
93
2-Chlorophenyl
2-Chlorophenyl
85
848
Table 2. Studies of cyclization of aldehyde 7
Entry
Conditions
Reagent
Total yield
(%)
Ratio 8:9
Scheme 3. Reaction conditions: (i) toluene, sealed tube, 200°C,
quantitative.
a
b
c
I
7a
7b
7a
7b
7a
7b
88
76
78
94
10
96
45:55
70:30
85:15
5:95
Only 8
Only 8
II
III
a Horner-Emmons/Still: (CF3CH2O)2POCH2COOMe, 18-crown-6,
KHMDS, THF, −78°C, 6 h.
b Horner-Emmons: (CH3CH2O)2POCH2COOMe, NaH, THF, reflux,
2 h.
Scheme 4. Reaction conditions: (i) acetic anhydride, pyridine,
reflux, 24 h.
c Acetic anhydride, pyridine, reflux.

J. Kasparec et al. / Tetrahedron Letters 44 (2003) 4567–4570
4569
Table 3. Introduction of amine side chain
M.; Trumpp-Kallmeyer, S.; Toogood, P.; Wu, Z.; Zhang,
E. J. Med. Chem. 2000, 43, 4606–4616.
2. Klutchko, S. R.; Hamby, J. M.; Boschelli, D. H.; Wu, Z.;
Kraker, A. J.; Amar, A. M.; Hartl, B. G.; Shen, C.;
Klohs, W. D.; Steinkampf, R. W.; Driscoll, D. L.; Nel-
son, J. M.; Elliott, W. L.; Roberts, B. J.; Stoner, C. L.;
Vincent, P. W.; Dykes, D. J.; Panek, R. L.; Lu, G. H.;
Major, T. C.; Dahring, T. K.; Hallak, H.; Bradford, L.
A.; Showalter, H. D. H.; Doherty, A. M. J. Med. Chem.
1998, 41, 3276–3292.
3. Boschelli, D. H.; Wu, Z.; Klutchko, S. R.; Showalter, H.
D. H.; Hamby, J. M.; Lu, G. H.; Major, T. C.; Dahring,
T. K.; Batley, B.; Panek, R. L.; Keiser, J.; Hartl, B. G.;
Kraker, A. J.; Klohs, W. D.; Roberts, B. J.; Patmore, S.;
Elliott, W. L.; Steinkampf, R.; Bradford, L. A.; Hallak,
H.; Doherty, M. J. Med. Chem. 1998, 41, 4365–4377.
4. Aldehyde 5 is available from Maybridge but may also be
easily prepared in one step from the more readily avail-
able 4,6-dihydroxy-2-methylsulfanylpyrimidine using the
procedure described in: (a) Santilli, A. A.; Dong, H. K.;
Wander, S. K. J. Heterocyclic Chem. 1971, 8, 445–453.
For other examples of previously described pyrimidines
which could be used to assemble a heavily derivatized
bicyclic system, see: (b) Taylor, E. C.; Gillespie, P. J. Org.
Chem. 1992, 57, 5757–5761; (c) Wormstadt, F.; Brinck-
man, U.; Gutschow, M.; Eger, K. J. Heterocyclic Chem.
2000, 37, 1187–1191.
Sulfoxide used
R3 group, derived from
amine R3NH2
Isolated yield (%)
11a
11a
11b
11b
11b
11b
-CH2CH2OH
-CH2CH2NH2
-CH2CH2OH
-CH2CH2N(CH2CH3)2
1-Methylpiperidin-4-yl
-CH2CH2NH2
1a (94)
1b (78)
1c (96)
1d (92)
1e (85)
1f (82)
chlorophenyl but not for R1=3-pentyl (only 10% yield
after 48 h).
As shown above, the optimal method for the conver-
sion of 7 to 8 is highly dependent on the nature of R1,
i.e. whether R1 is alkyl or aryl. Our studies indicated
that, when R1=alkyl, 7 is cleanly converted to 8 in one
step using the Horner-Emmons reaction (Table 1, entry
II). When R1=aryl, the conversion of 7 to 8 is most
efficiently performed by reflux with acetic anhydride
and pyridine (Table 1, entry III). These procedures
have worked well for all examples of R1 used so far in
this research.
5. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24,
4405–4408.
6. Jacobsen, E. N.; Deng, L.; Furukawa, Y.; Martinez, L.
E. Tetrahedron 1994, 50, 4323–4334.
7. Under the reaction conditions, the weak base used (excess
alkylamine or aniline added) plays a key role in ensuring
that no imine is formed. When the reaction was run in
DMSO using 1 equiv. of NaH, up to 50% yield of the
corresponding imine was observed. 4-Chloro-6-(1-ethyl-
propylamino)-2-methylsulfanylpyrimidine-5-carboxalde-
1
hyde (6a): H NMR (CDCl3): l 0.92 (t, 6H, J=7.3 Hz),
As part of the final derivatization step in this synthesis,
oxidation of sulfide 8 with mCPBA afforded sulfone
11,11 which was then reacted with a wide range of
amine nucleophiles under mild conditions to afford the
desired product 112 (Table 3). The final trisubstituted
pyrido[2,3-d]pyrimidin-7-ones were easily purified by a
combination of aqueous work-up and column
chromatography.
1.50–1.74 (m, 4H), 2.52 (s, 3H), 4.22 (m, 1H), 9.21 (br s,
1H), 10.33 (s, 1H). LC MS (m/e)=274 (MH+). 4-Chloro-
6-(2-chlorophenylamino)-2-methylsulfanylpyrimidine-5-
1
carboxaldehyde (6b): H NMR (CDCl3): l 2.55 (s, 3H),
7.17 (m, 1H), 7.29 (m, 2H), 7.44 (m, 1H), 10.37 (s, 1H),
11.49 (br s, 1H). LC MS (m/e)=315 (MH+).
8. 4-(2-Chlorophenyl)-6-(1-ethylpropylamino)-2-methylsul-
fanylpyrimidine-5-carboxaldehyde (7a): 1H NMR
(CDCl3): l 0.91 (m, 6H), 1.42–1.60 (m, 4H), 2.45 (s, 3H),
4.21 (m, 1H), 7.32 (m, 4H), 8.96 (br s, 1H), 9.44 (s, 1H).
LC MS (m/e)=350.2 (MH+). 4-(2-Chlorophenyl)-6-(2-
chlorophenylamino)-2-methylsulfanylpyrimidine-5-carb-
oxaldehyde (7b): 1H NMR (CDCl3): l 2.58 (s, 3H),
7.01–7.59 (m, 7H), 8.61 (d, 1H, J=4.7 Hz), 9.65 (s, 1H),
11.48 (br s, 1H). LC MS (m/e)=390 (MH+).
Conclusion
A novel, highly efficient and scalable route to trisubsti-
tuted pyrido[2,3-d]pyrimidin-7-ones was developed.
Readily available starting material 5 was converted into
the desired pyrimidinones 1 in five steps in about 40%
overall yield.
9. 4-(2-Chlorophenyl)-8-(1-ethylpropyl)-2-methylsulfanyl-
8H-pyrido[2,3-d]pyrimidin-7-one
(8a):
1H
NMR
(CDCl3): l 0.85 (m, 6H), 2.01 (m, 2H), 2.26–2.44 (m,
2H), 2.63 (s, 3H), 5.39 (m, 0.5H), 5.75 (m, 0.5H), 6.62 (br
d, 1H, J=9.6), 7.31–7.60 (m, 5H). LC MS (m/e)=374.2
(MH+). 4-(2-Chlorophenyl)-8-(2-chlorophenyl)-2-methyl-
sulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (8b): H NMR
(CDCl3): l 1.99 (s, 3H), 6.50 (d, 1H, J=9.7 Hz), 7.11–
7.48 (m, 9H). LC MS (m/e)=414 (MH+).
References
1
1. Barvian, M.; Boschelli, D. H.; Cossrow, J.; Dobrusin, E.;
Fattaey, A.; Fritsch, A.; Fry, D.; Harvey, P.; Keller, P.;
Garrett, M.; La, F.; Leopold, W.; McNamara, D.; Quin,

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J. Kasparec et al. / Tetrahedron Letters 44 (2003) 4567–4570
10. Matyus, P.; Lowinger, L.; Wamhoff, H. Heterocycles
1985, 23, 2057–2064.
1H, J=56 Hz, J%=9.5 Hz), 7.13 (d, 1H, J=9.5 Hz), 7.42
(m, 3H), 7.54 (m, 1H). LC MS (m/e)=386 (MH+).
4-(2-Chlorophenyl)-8-(2-chlorophenyl)-2-(2-hydroxyethyl-
amino)-8H-pyrido[2,3-d]pyrimidin-7-one (1c): 1H NMR
(CDCl3): l 3.17 (m, 2H), 3.48 (m, 2H), 6.08 (br s, 1H),
6.45 (d, 1H, J=9.6 Hz), 7.26–7.67 (m, 9H). LC MS
(m/e)=427 (MH+). 4,8-Bis-(2-chlorophenyl)-2-(2-diethyl-
aminoethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (1d):
1H NMR (CDCl3): l 0.97 (m, 6H), 2.49 (s, 6H), 3.12 (m,
2H), 6.00 (br s, 1H), 7.18–7.63 (m, 9H). LC MS (m/e)=
482 (MH+). 4,8-Bis-(2-chlorophenyl)-2-(1-methylpipe-
ridin-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (1e):
1H NMR (CDCl3): l 1.42 (m, 2H), 1.79 (m, 4H), 2.25 (s,
3H), 2.75 (m, 2H), 3.15 (m, 1H), 5.33 (s, 1H), 6.39 (d, 1H,
J=9.8 Hz), 7.24–7.59 (m, 9H). LC MS (m/e)=480
(MH+). 2-(2-Aminoethylamino)-4,8-bis-(2-chlorophenyl)-
11. 4-(2-Chlorophenyl)-8-(1-ethylpropyl)-2-methanesulfonyl-
8H-pyrido[2,3-d]pyrimidin-7-one (11a): 1H NMR
(CDCl3): l 0.91 (m, 6H), 2.07 (m, 2H), 2.15 (s, 3H),
2.24–2.36 (m, 2H), 5.51 (m, 0.5H), 5.87 (m, 0.5H), 6.68
(br d, 1H, J=9.6), 7.22–7.59 (m, 5H). LC MS (m/e)=406
(MH+). 4,8-Bis-(2-chlorophenyl)-2-methanesulfonyl-8H-
1
pyrido[2,3-d]pyrimidin-7-one (11b): H NMR (CDCl3): l
3.15 (s, 3H), 6.96 (d, 1H, J=9.8 Hz), 7.26 (m, 2H),
7.51–7.80 (m, 9H). LC MS (m/e)=446 (MH+).
12. 4-(2-Chlorophenyl)-8-(1-ethylpropyl)-2-(2-hydroxyethyl-
amino)-8H-pyrido[2,3-d]pyrimidin-7-one (1a): 1H NMR
(CDCl3): l 0.75 (m, 6H), 1.98 (m, 2H), 2.05 (m, 2H), 3.40
(m, 2H), 3.59 (m, 2H), 4.71 (m, 1H), 6.09 (m, 0.5H), 6.18
(m, 0.5H), 7.04 (m, 1H), 7.50 (m, 4H), 7.89 (m, 1H). LC
MS (m/e)=387 (MH+). 2-(2-Aminoethylamino)-4-(2-
chlorophenyl) - 8 - (1 - ethylpropyl) - 8H - pyrido[2,3 - d]pyr-
imidin-7-one (1b): 1H NMR (CDCl3): l 0.83 (m, 6H),
1.99 (m, 4H), 2.44 (m, 2H), 2.98 (m, 2H), 3.59 (m, 2H),
5.35 (m, 0.5H), 5.59 (m, 0.5H), 6.01 (br s, 1H), 6.28 (dd,
1
8H-pyrido[2,3-d]pyrimidin-7-one (1f): H NMR (CDCl3):
l 2.59 (m, 2H), 3.11 (m, 2H), 5.91 (br s, 1H), 6.40 (d, 1H,
J=9.6 Hz), 7.25–7.61 (m, 9H). LC MS (m/e)=426
(MH+).