Design and development of arrayable syntheses to accelerate SAR studies of pyridopyrimidinone and pyrimidopyrimidinone

Article abstract of DOI:10.1016/j.tetlet.2008.11.014

Chemoselectivity of chlorine versus methylthio (-SCH₃), methylsulfinyl (-SOCH₃), or methylsulfonyl [-S(O)₂CH₃] in either functionalization or substitution of pyridopyrimidinone and pyrimidopyrimidinone was studi

Full text of DOI:10.1016/j.tetlet.2008.11.014

Tetrahedron Letters 50 (2009) 370–372
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Design and development of arrayable syntheses to accelerate SAR
studies of pyridopyrimidinone and pyrimidopyrimidinone
*
Zehong Wan , Hongxing Yan, Ralph F. Hall, Xichen Lin, Stefano Livia, Tomasz Respondek,
Katherine L. Widdowson, Chongjie Zhu, James F. Callahan
Department of Medicinal Chemistry, Respiratory Centre of Excellence for Drug Discovery, Research and Development, GlaxoSmithKline Pharmaceuticals,
709 Swedeland Road, King of Prussia, PA 19406, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Chemoselectivity of chlorine versus methylthio (–SCH3), methylsulfinyl (–SOCH3), or methylsulfonyl
[–S(O)2CH3] in either functionalization or substitution of pyridopyrimidinone and pyrimidopyrimidinone
was studied. Utilization to prepare final targets for accelerated SAR studies via two-dimensional array
syntheses has been demonstrated in both systems.
Received 23 October 2008
Revised 3 November 2008
Accepted 5 November 2008
Available online 8 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Heterocyclic small molecules have been extensively explored
by the pharmaceutical industry for the treatment of various health
problems.1 Most of the time very intense synthetic efforts have
been involved in order to establish structure–activity relationships
(SARs). This process is quite time-consuming, and adds signifi-
cantly to the cycle-time for drug discovery. Accelerated SAR studies
have thus played an important role to progress lead identification
and optimization programs in a timely and competitive manner.2
Therefore, synthesis allowing structural diversity introduced later
in a sequence if not in the last step is ideally sought. This has been
considered very challenging when there are two or more points of
diversity to be studied. Selection of chemically reactive substitu-
ents (e.g., leaving groups) with different reaction preferences is
envisioned critical for the success of these studies.3
stituents (e.g., amines) at C2.4 A second generation synthetic route
was later developed to optimize substituents at C4 on the basis of
chemoselectivity displayed by 4-chlorine versus 2-methylsulfinyl
(–SOCH3).5 The pyrimidopyrimidinone (II), a template with a struc-
ture similar to I, has been studied by GlaxoSmithKline and others
to identify compounds that display anti-inflammatory activity.6,7
We are interested in developing synthetic strategies that can be
utilized to optimize substituents at C2 and C4 in both systems, ide-
ally starting from a common intermediate. From the perspective of
retrosynthetic analysis, identification of two leaving groups (LG2
and LG4) with different reaction preferences has been considered
vital for success. Chlorine and methylthio (–SCH3) have been cho-
sen due to the early success achieved in I. This Letter reports our
research of the relative reactivity of LG2 (–SCH3, –SOCH3, and
–SO2CH3) versus LG4 (–Cl) in both templates (III and IV). Final
development of arrayable syntheses leading toward I and II is also
described.
Our success in this area has been recently realized in pyrido-
pyrimidinone system (I, Fig. 1), whose SAR was initially explored
through a stepwise synthesis allowing rapid optimization of sub-
Compounds in this Letter were prepared from 4,6-dichloro-2-
(methylthio)-5-pyrimidinecarbaldehyde 1 (Scheme 1).8 Nucleo-
philic displacement with 2,6-difluoroaniline afforded 2. Amide
formation followed by intramolecular condensation under the
assistance of microwave irradiation provided 3. Oxidation to the
methyl sulfoxide 4 or the methyl sulfone 5 was achieved by con-
trolling the amount of oxidant (e.g., m-CPBA) used. The pyrimido-
pyrimidinone ring was also prepared from 1. Oxime formation
followed by dehydration with SOCl2 provided the pyrimidine
nitrile 6. Displacement with 2,6-difluoroaniline, reduction of the
nitrile to a benzylamine, and ring construction with carbonyl
diimidazole then furnished compound 8. Oxidation of the sulfide
to sulfoxide 9 or sulfone 10 was accomplished once again by
manipulating the amount of m-CPBA.
R4
LG4
Z
N
4
Z
N
2
O
Cl
N
R2'
O
F
N
N
F
N
O
F
N
N
F
LG2
H
N
R2
Cl
S
I: Z = CH
II: Z = NH
III: Z = CH
IV: Z = NH
Figure 1. Retrosynthetic analysis.
* Corresponding author. Present address: Department of Medicinal Chemistry,
GSK R&D China, 898 Halei Road Pudong, Shanghai 20 1203, China. Tel.: +86 21
61590719; mobile: +86 13918783790.
With the six substrates 3–5 and 8–10 available, we were ready
to investigate the chemoselectivity of 2-SMe, 2-SOMe, and 2-
S(O)2Me relative to 4-Cl in the two tri-substituted pyrimidinones
E-mail address: Zehong.2.Wan@gsk.com (Z. Wan).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.014

Z. Wan et al. / Tetrahedron Letters 50 (2009) 370–372
371
Table 2
Cl
4
Ac2O, DMF
O
Cl
O
Cl
Microwave
Results of nucleophilic displacement at C2
160 oC, 0.5 h
2,6-di-F-aniline
N
H
N
H
N
2
TEA, 55 o
70%
S
C
50%
N
Cl
O
F
S(O)n
N
N
F
HN
N
F
S
Cl
N
HN
NH2(CH2)2N(CH3)2
TEA, CH2Cl2
Cl
F
1
Z
N
4
Z
N
2
Z
N
2
(1) NH2-OH.HCl
HOAc, 50-70 oC
80%
r.t., 12 hr
O
F
N
N
F
S(O)n
O
F
N
N
F
S(O)n
mCPBA
mCPBA
5
n=2
3
4
n=1
O
F
N
N
F
NH
n=0
87%
85%
(2) SOCl2, 93%
N
Cl
4
Cl
Cl
(1) BH .THF
3
Substrate
N
N
VII
2,6-di-F-aniline
VIII
(2) CDI, CH Cl
2
2
HN
N
N
N
DMF, 50 oC, 90%
2
81%, 2 steps
Sub
Z
n
VII:VIIIa
Yield
O
F
S(O)n
Cl
N
S
N
N
F
HN
N
F
S
F
3
4
5
8
9
CH
CH
CH
NH
NH
NH
0
1
2
0
1
2
VII only
VIII only
1:2
81% VII
75% VIII
—
19% VII
85% VIII
—
6
7
mCPBA
88%
mCPBA
VII onlyb
VIII only
1:1.5
8
9
n=1
10
n=2 80%
n=0
10
Scheme 1.
a
Product ratios are based on LC–MS measurement of the crude mixture.
About 70% of 8 was recovered.
b
I and II. Reactions that were studied were the Suzuki cross-cou-
pling at C4 and the nucleophilic displacement at C2 with amines.
Standard experimental conditions have been adapted for the pur-
pose of demonstrating application with more of general interests.
Palladium-catalyzed [e.g., 0.05 equiv Pd(PPh3)4] cross-coupling
with a phenyl boronic acid [1.2 equiv PhB(OH)2] in the presence
of K2CO3 (3 equiv) under microwave irradiation (150 °C, 15 min)
was investigated first (Table 1).9 The best selectivity has been dem-
onstrated between the 4-Cl and the 2-SMe in both heterocycles,
and very good yield of the desired product V has been achieved.
Both 2-SOMe and 2-S(O)2Me are labile enough to hydrolyze under
the reaction conditions with a notable amount of compound VI
being formed.
Nucleophilic displacement with amines (e.g., 1 equiv NH2CH2-
CH2N(CH3)2) in the presence of triethyl amine (3 equiv) was stud-
ied (rt, 12 h) next (Table 2).10 The best selectivity over 4-Cl was
achieved by the 2-SOCH3 substituent, and the desired compound
VIII has been isolated with a very good yield in both templates.
Limited selectivity has been displayed between the 2-S(O)2Me
and the 4-Cl, and approximate equal amounts of VII and VIII were
formed. The 4-Cl is more reactive than the 2-SMe, and displace-
ment at C4 (VII) was the major reaction in both systems. The reac-
tion preferences of 4-Cl observed in the two fused pyrimidines are
different from a simple pyrimidine system, where excellent selec-
tivity has been achieved between a 4-Cl and a 2-SMe, 2-S(O)Me
and 2-S(O)2Me substituent.11
After 2-SMe/4-Cl and 2-SOMe/4-Cl have been identified as the
best combinations for Suzuki coupling at C4 and substitution at
C2, respectively, attention was directed toward developing array-
able syntheses in both systems. Starting from 3 (Strategy A,
Scheme 2), Suzuki cross-coupling afforded the sulfide 11. Oxida-
tion to a mixture of sulfone/sulfoxide, followed by nucleophilic dis-
placement then afforded the target 12.12 Rapid optimization of
substituents (e.g., amines) at C2 have been achieved through this
strategy. On the other hand, rapid optimization at C4 has been
accomplished via Strategy B. Oxidation of 3 to the sulfoxide fol-
lowed by displacement with an amine then furnished compound
13, which is a key intermediate for rapid optimization of substitu-
ents at C4 as exemplified by a Suzuki cross-coupling reaction
affording 12. Similarly, both strategies have been readily expanded
to pyrimidopyrimidinone system (Scheme 3) furnishing the
desired product 1513 in an arrayable fashion.
In summary, advanced pyrimidinone templates with 2-SCH3
and 4-Cl have been prepared from a common intermediate 1.
Arrayable syntheses allowing rapid and facile access to various
substituents at either C2 or C4 have been developed for both
systems.
Table 1
Results of Suzuki cross-coupling at C4
PhB(OH)2, K2CO3
Pd(PPh3)4, Microwave
150 oC, 15 min
Cl
mCPBA, 93%
NH2(CH2)2N(CH3)2, 88%
PhB(OH)2, K2CO3
N
Z
4
N
Pd(PPh3
)
Z
N
4
83%
2
Strategy A
Z
N
O
F
N
N
F
S
O
F
N
N
F
S(O)n
Microwave
O
F
N
F
S(O)n
N
Cl
150 oC,15 min
O
F
N
N
F
OH
4
N
2
N
11
O
F
N
N
F
S
Substrate
N
V
VI
O
F
N
N
F
N
H
Cl
Sub
Z
n
V:VIa
Yield
3
N
12
3
4
5
8
9
CH
CH
CH
NH
NH
NH
0
1
2
0
1
2
V only
1:4
1:17
V only
VI only
1:27
83% V
—
79% VI
87% V
64% VI
78% VI
N
O
F
N
N
F
N
150 oC, 15 min
mCPBA, 87%
Strategy B
H
PhB(OH)2, K2CO3
NH2(CH2)2N(CH3)2
75%
Pd(PPh3)4, Microwave
81%
13
10
a
Product ratios are based on LC–MS measurement of the crude mixture.
Scheme 2.

372
Z. Wan et al. / Tetrahedron Letters 50 (2009) 370–372
8. Compounds 1 and 6 could be prepared according to the procedure published
by: Santilli, A. A.; Dong, H. K.; Wander, S. K. J. Heterocycl. Chem. 1971, 8, 445.
9. A solution of the substrate (0.27 mmol, 1 equiv) and PhB(OH)2 (1.2 equiv) in
dioxane–water (3:1, 4 mL) was mixed with K2CO3 (3 equiv). The resultant
mixture was bubbled with N2 for 5 min before Pd(PPh3)4 (0.05 equiv) was
added. The reaction vessel was sealed and irradiated using microwave
irradiation at 150 °C for 15 min. Solids in the mixture were filtered off, and
the relative percentage of components in this crude solution was measured
with LC–MS. Separation via reverse phase HPLC where applicable then
provided the product. 8-(2,6-Difluorophenyl)-2-(methylthio)-4-phenylpyrido-
[2,3-d]pyrimidin-7(8H)-one (V, Z = CH, n = 0): 1H NMR (400 MHz, DMSO): d 2.3
(s, 3H), 6.8 (d, 1H, J = 12 Hz), 7.4–7.8 (m, 8H), 8.1 (d, 1H, J = 12 Hz). LC–MS
(m/e) = 382 (MH+). 8-(2,6-Difluorophenyl)-2-hydroxy-4-phenylpyrido[2,3-d]-
pyrimidin-7(8H)-one (VI, Z = CH): 1H NMR (400 MHz, DMSO): d 6.4 (d, 2H,
J = 8 Hz), 7.4–7.7 (m, 9H). LC–MS (m/e) = 352 (MH+). 1-(2,6-Difluorophenyl)-
7-(methylthio)-5-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (V,
Z = NH, n = 0): 1H NMR (400 MHz, DMSO): d 2.1 (s, 3H), 4.5 (s, 2H), 7.3–7.7
(m, 8H), 8.0 (s, 1H). LC–MS (m/e) = 385 (MH+). 1-(2,6-Difluorophenyl)-
7-hydroxy-5-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (VI, Z =
NH): 1H NMR (400 MHz, DMSO): d 4.2 (s, 2H), 7.3–7.6 (m, 8H), 8.0 (s, 1H).
LC–MS (m/e) = 355 (MH+).
10. A solution of the substrate (0.2 mmol) in CH2Cl2 (3 mL) was mixed with
triethylamine (3 equiv) and N,N-dimethyl-1,2-ethanediamine (1 equiv). The
resultant solution was stirred at room temperature for about 12 h. Percentage
of components in this crude solution was measured with LC–MS. Separation
via reverse phase HPLC where applicable then provided the product.
8-(2,6-Difluorophenyl)-4-{[2-(dimethylamino)ethyl]amino}-2-(methylthio)-
pyrido[2,3-d]pyrimidin-7(8H)-one (VII, Z = CH, n = 0): 1H NMR (400 MHz,
DMSO): d 2.2 (s, 3H), 2.5 (s, 6H), 3.3 (t, 2H, J = 8 Hz), 4.0 (t, 2H, J = 8 Hz), 6.5
(d, 1H, J = 12 Hz), 7.3–7.7 (m, 3H), 8.3 (d, 1H, J = 12 Hz). 8.5 (br s, 1H). LC–MS
(m/e) = 392 (MH+). 4-Chloro-8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)-
ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one (VIII, Z = CH): 1H NMR
PhB(OH)2, K2CO3
Pd(PPh3)4, Microwave
150 oC, 15 min
mCPBA
NH2(CH2)2N(CH3)2
HN
N
87%
77%
Strategy A
O
N
N
F
S
Cl
F
HN
N
4
2
HN
N
14
O
N
N
F
S
N
F
O
F
N
N
F
N
H
Cl
HN
N
8
15
N
O
N
N
F
N
150 oC, 15 min
Strategy B
mCPBA, 88%
H
F
PhB(OH)2, K2CO3
NH2(CH2)2N(CH3)2
85%
Pd(PPh3)4, Microwave
92%
16
Scheme 3.
Acknowledgment
The authors wish to thank Dr. Mike Palovich for helpful discus-
sions during the preparation of this Letter.
(400 MHz, MeOD):
(m, 2H), 6.6 (d, 1H, J = 12 Hz), 7.2–7.6 (m, 3H), 8.1 (d, 1H, J = 12 Hz). LC–MS
(m/e) = 380 (MH+). 1-(2,6-Difluorophenyl)-5-{[2-(dimethylamino)ethyl]-
amino}-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (VII,
Z = NH, n = 0): 1H NMR (400 MHz, DMSO): d 2.1 (s, 3H), 2.5 (s, 6H), 3.2 (m,
2H), 3.8 (m, 2H), 4.6 (s, 2H), 7.2 (m, 2H), 7.5 (m, 1H), 7.9 (br s, 1H), 8.3 (br s,
1H). LC–MS (m/e) = 395 (MH+).
d
2.8 (s, 3H), 2.9 (s, 3H), 3.3 (m, 2H), 4.0
References and notes
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J. L. Bioorg. Med. Chem. Lett. 2003, 13, 1191; (b) Yan, H.; Kerns, J. K.; Jin, Q.; Zhu,
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11. Hurst, D. T.; Johnson, M. Heterocycles 1985, 23, 611.
12. 8-(2,6-Difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-4-phenylpyrido[2,3-d]-
pyrimidin-7(8H)-one (12): 1H NMR (400 MHz, MeOD): d 2.6 (br s, 3H), 2.9 (br s,
3H), 3.3 (br s, 2H), 4.0 (br s, 2H), 6.5 (d, 2H, J = 8 Hz), 7.2–7.8 (m, 8H), 8.0 (d, 2H,
J = 8 Hz). LC–MS (m/e) = 422 (MH+).
13. 1-(2,6-Difluorophenyl)-7-{[2-(dimethylamino)ethyl]amino}-5-phenyl-3,4-dihydro-
pyrimido[4,5-d]pyrimidin-2(1H)-one (15): 1H NMR (400 MHz, MeOD): d 2.8 (s,
6H), 3.2 (br s, 2H), 3.6 (br s, 2H), 4.5 (s, 2H), 7.2–7.7 (m, 8H). LC–MS (m/e) = 425
(MH+).
6. Boehm, J. C.; Adams, J. L., et al. GlaxoSmithKline, Unpublished results.
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