Efficient formation of 4,6-disubstituted pyrrolo[2,3-d]pyrimidines: A novel route to TWS119, a glycogen synthase kinase-3β inhibitor

Article abstract of DOI:10.1016/j.tetlet.2010.05.032

A concise synthesis of 4,6-disubstituted pyrrolo[2,3-d]pyrimidines is described. The key step involves the formation of an ether or thioether linkage along with concurrent ring closure in one-pot to yield the desired product in only two steps from a common intermediate. The reaction is chemoselective to incorporate phenol, thiophenol, and thiol. This method enabled efficient production of TWS119, a glycogen synthase kinase-3β inhibitor.

Full text of DOI:10.1016/j.tetlet.2010.05.032

Tetrahedron Letters 51 (2010) 3597–3598
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Tetrahedron Letters
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Efficient formation of 4,6-disubstituted pyrrolo[2,3-d]pyrimidines: a novel
route to TWS119, a glycogen synthase kinase-3b inhibitor
*
Anand Mayasundari, Naoaki Fujii
Medicinal Chemistry Center, Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise synthesis of 4,6-disubstituted pyrrolo[2,3-d]pyrimidines is described. The key step involves the
formation of an ether or thioether linkage along with concurrent ring closure in one-pot to yield the
desired product in only two steps from a common intermediate. The reaction is chemoselective to incor-
porate phenol, thiophenol, and thiol. This method enabled efficient production of TWS119, a glycogen
synthase kinase-3b inhibitor.
Received 12 April 2010
Revised 3 May 2010
Accepted 7 May 2010
Available online 12 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Pyrrolo[2,3-d]pyrimidine is a deazapurine chemical scaffold
commonly used to create many bioactive compounds and drug can-
didates such as antifolates1 and antitumor agents.2 While numerous
examples of the 4-amino-substituted pyrrolo[2,3-d]pyrimidine are
reported, those of 4-ether or 4-thioether-substituted pyrrolo[2,3-
d]pyrimidines are rather limited.3 This is presumably due to the lack
of reliable and efficient synthetic method for the latter two. TWS119
is a glycogen synthase kinase-3b inhibitor of the 4-ether-substituted
pyrrolo[2,3-d]pyrimidine scaffold that induces neuronal differentia-
tion in pluripotent murine embryonal carcinoma and embryonic
stem cells.4 It activates the canonical Wnt pathway in cultured hepa-
tic stellate cells5 and suppresses alveolar rhabdomyosarcoma.6 Only
one patented method7 has been disclosed for the synthesis of
TWS119. However, the preparation of starting material for this
method is tedious and in low yield; key reaction step for the 4-ether
formation in this method is extremely sluggish and also in low yield;
and this method was used to produce only pyrrolo[2,3-d]pyrimi-
dines in which 6-position is substituted with an aromatic group
(Scheme S1, Supplementary data). To improve the productivity
and generality, we developed a new method for efficiently produc-
ing 4,6-disubstituted pyrrolo[2,3-d]pyrimidines including TWS119.
The first step is conventional Sonogashira coupling8 of 6-amino-
4-chloro-5-iodopyrimidine (1, prepared from commercially available
6-amino-4-chloropyrimidine in 50% yield, Scheme S2, Supplemen-
tary data) affording alkyne 3 (Scheme 1). The reaction was chemose-
lective to the 5-iodo and no bisalkynylated products were formed.
We expected that converting electron-withdrawing 4-chloro to
electron-donating 4-ether group increases the nucleophilicity of
the 6-amino group and could facilitate the cyclization forming the
fused pyrrolo moiety. Indeed, when the reaction of 3a and 3-meth-
oxy phenol was carried out at 150 °C in the presence of potassium
tert-butoxide to obtain 4-ether compound 5, we have observed that
small amount of the TWS119 precursor pyrrolo[2,3-d]pyrimidine 6
is formed (isolated mixture of 5:6 = 80:20 in 64% yield). This sug-
gests that the ether formation and cyclization can be performed in
one-pot under appropriate temperature and base. Indeed, com-
pound 6 was the major product when the reaction temperature
was 180 °C. Among tested, cesium carbonate was the most effective
base to obtain 6 as the single product in good yield (Table 1). As no
Cl
N
Cl
R
R
2a or 2b
I
N
N
PdCl2(PPh3)2
CuI, Et2NH, DMF
room-temp, 2h
NH2
N
NH2
1
3a
, 64%
R = 3-aminophenyl,
R = n-propyl, 3b, 73%
Scheme 1. Synthesis of alkynes 3a and 3b.
Table 1
Effect of base on the pyrrolo[2,3-d]pyrimidine formation
OMe MeO
NH2
MeO
+
NH2
Cl
N
O
N
O
N
HO
NH2
N
N
N
Base, DMSO
NH2
3a
180 ºC, 15 min
microwave
N
NH2
H
5
6
Entry
Base
Isolated yield% (5+6)
Ratio* (5:6)
1
2
3
4
5
6
DMAP
DBU
30
65
60
49
53
74
100:0
85:15
5:95
8:92
0:100
0:100
KOtBu
NaH
NaOH
Cs2CO3
* Corresponding author. Tel.: +1 901 595 5854; fax: +1 901 595 5715.
E-mail address: naoaki.fujii@stjude.org (N. Fujii).
*
Ratio determined by HPLC.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.032

3598
A. Mayasundari, N. Fujii / Tetrahedron Letters 51 (2010) 3597–3598
Table 2
(7, 10), thiophenol (8, 11), and thiol (9, 12) were efficiently used.
Synthesis of 4,6-disubstituted pyrrolo[2,3-d]pyrimidines
Meanwhile, alcohol, aniline, sulfonamide, malonate, acetoacetate,
and azide did not afford the desired coupling product (Fig. 1),
showing chemoselectivity of this reaction toward the building
blocks (R0-YH) for diversifying the 4-position.
Compound 6 was deprotected to afford TWS119 in 38% overall
yield from 1 (Scheme 2). NMR spectra of TWS119 obtained by this
route were identical to those of the batch obtained by the literature
method7 (Supplementary data).
R'
Y
N
Cl
R
Cs2CO3, DMSO
180 C, 15min
microwave
N
N
R' YH
4
+
R
º
N
H
N
NH2
3b
3a
or
7-12
Product
Alkyne
R0
Y
Isolated yield%
7
8
9
10
11
12
3a
3a
3a
3b
3b
3b
Phenyl
Phenyl
Cyclohexyl
Phenyl
Phenyl
O
S
S
O
S
S
77
85
64
79
87
71
In summary, we have developed a convenient method to syn-
thesize pyrrolo[2,3-d]pyrimidines in which the 4-position is
substituted by an ether or a thioether, and demonstrated this
method efficiently produces TWS119. The key steps involving the
formation of an ether or thioether linkage along with concurrent
ring closure were accomplished in single step to yield 4,6-disubsti-
tuted pyrrolo[2,3-d]pyrimidines, in only two steps from the com-
mon starting material 1.
Cyclohexyl
a)
NH2
S
OH
NH2
O
O O
Acknowledgment
CO2Me
CO2Me
b)
NaN3
This work was supported by the American Lebanese and Syrian
Associated Charities (ALSAC).
CO2Me
Figure 1. Substrates (4, R0-YH) that do not afford the objective coupled pyrrolo[2,3-
d]pyrimidines. (a) Using KOtBu or NaH instead of Cs2CO3 either did not afford the
objective product. (b) Cs2CO3 was omitted from the reaction mixture.
A. Supplementary data
Supplementary data (experimental procedures and NMR spec-
tra) associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2010.05.032.
BBr3, DCM
HO
O
NH2
6
N
º
0 C to room-temp
80%
N
H
N
References and notes
13
1. Gangjee, A.; Jain, H. D.; Queener, S. F.; Kisliuk, R. L. J. Med. Chem. 2008, 51, 4589–
4600.
2. Gangjee, A.; Kurup, S.; Ihnat, M. A.; Thorpe, J. E.; Shenoy, S. S. Bioorg. Med. Chem.
2010, in press.
Scheme 2. Synthesis of TWS119 (13).
3. CAS registration entry of query = 4-X, 6-C, 5,7-H-pyrrolo[2,3-d]pyrimidine: 1345
for X = N, 117 for X = O, 8 for X = S, on January 2010.
4. Ding, S.; Wu, T. Y.; Brinker, A.; Peters, E. C.; Hur, W.; Gray, N. S.; Schultz, P. G.
Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 7632–7637.
5. Kordes, C.; Sawitza, I.; Haussinger, D. Biochem. Biophys. Res. Commun. 2008, 367,
116–123.
6. Zeng, F. Y.; Dong, H.; Cui, J.; Liu, L.; Chen, T. Biochem. Biophys. Res. Commun. 2010,
391, 1049–1055.
7. Ding, S.; Wu, T. Y.; Gray, N. S.; Schultz, P. G. In WO2004093812A2, 2004.
8. Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis-Stuttgart
1980, 627–630.
self-condensation products of 3a (in which the aniline amino was
intermolecularly substituted to 4-position) was formed, the m-ani-
line moiety of 3a did not need to be protected. This suggests that this
one-pot reaction is chemoselective to phenol over aniline.
We also validated the general applicability of the optimized
conditions (Table 1, entry 6) for producing other pyrrolo[2,3-
d]pyrimidines (Table 2). Both aromatic (7–9) and aliphatic
substituents (10–12) can be incorporated on the 6-position. Phenol