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COMMUNICATION
Journal Name
independently. When 43 was exposed to our optimized synthesis of a marketed drug. A detailed understanding of the
DOI: 10.1039/C6CC04259G
3 was not obtained. mechanism, preparation of new analogues of sildenafil, and
conditions, the desired compound
However, compound 43 when subjected to heating in the process development of sildenafil citrate encompassing the
presence of KHSO4 and K2SO4, the desired product was key quinazolin-4-one preparation are currently underway.
3
-
-2
obtained. This experiment suggests that HSO4 and SO4
anions, generated in situ from K2S2O8, could facilitate the
Acknowledgements
intramolecular cyclizations of amide to give quinazolinone 3.
The financial support from the SERB, New Delhi is greatly
appreciated.
O
O
K2S2O8 (3 equiv)
X
H
XH
OK
MeCN, 80 oC, 24 h
+
O
48
Notes and references
2
XH = NH
XH = CONH (0%)
XH = S (0%)
XH = O (0%)
XH = COO (0%)
(48%)
38, 44-47
XH = NH2, CONH2, SH, OH, COOH
1
2
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Sato and S. Tokita, Bioorg. Med. Chem. Lett., 2009, 19, 4075;
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O
O
KHSO4 (3 equiv)
K2SO4 (3 equiv)
K2S2O8 (3 equiv)
NH
MeCN, 80 oC, 8 h
NH2
NH
NH2
3
MeCN, 80 oC, 8 h
O
43
O
43
Scheme 6. Control experiments.
To demonstrate
laboratory concept, we prepared a marketed drug, Sildenafil
(ViagraTM).11 Sildenafil is
selective inhibitor of cyclic
a translational application of our
a
guanosine monophosphate (cGMP) specific phosphodiesterase
type 5 (PDE5) used in the treatment of male erectile
dysfunction.12
3
4
5
(a) R. Soliman, F and S. G. Soliman, Synthesis, 1979, 803; (b)
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A. K. Pearce, P. M. Searle, G. Ward and A. S. Wood, Org.
O
O
Me
Me
O
OEt
N
N
Process Res. Dev., 2000,
(a) E. Valeur and M. Bradley, Chem. Soc. Rev., 2009, 38, 606;
(b) V. R. Pattabiraman and J. W. Bode, Nature, 2011, 480
4, 17.
N
K2S2O8 (3 equiv)
MeCN, 80 oC, 8 h
OK
EtO HN
H2N
N
+
O
H2N
N
Pr
,
Pr
471; (c) C. L. Allen and J. M. J.Williams, Chem. Soc. Rev.,
2011, 40, 3405.
49
50
(81%)
51
O
Me
6
(a) J. W. Bode, R. M. Fox and K. D. Baucom, Angew. Chem.
Int. Ed., 2006, 45, 1248; (b) C. -C. Cho, J. -N. Liu, C. -H. Chien,
N
HN
EtO
O2S
1. ClSO3H, 0 o
C
N
N
J. -J. Shie, Y. -C. Chen and J. -M. Fang, J. Org. Chem., 2009, 74
,
2. N-methyl piperazine
Pr
1549; (c) J. Liu, Q. Liu, H. Yi, C. Qin, R. Bai, X. Qi, Y. Lan and A.
Lei, Angew. Chem. Int. Ed., 2014, 53, 502.
J. K. Laha, K. S. S. Tummalapalli and A. Gupta, Org. Lett.,
2014, 16, 4392.
J. K. Laha, K. S. S. Tummalapalli, A. Nair and N. Patel, J. Org.
N
N
7
8
9
Me
(65%)
52
Sildenafil
Chem., 2015, 80, 11351
.
Scheme 7. Synthesis of sildenafil.
(a) J. K. Laha, N. Dayal, R. Jain and K. Patel, J. Org. Chem.,
2014, 79, 10899; (b) J. K. Laha, N. Dayal, K. P. Jethava and D.
V. Prajapati, Org. Lett., 2015, 17, 1296; (c) J. K. Laha and N.
Dayal, Org. Lett., 2015, 17, 4742; (d) J. K. Laha, K. P. Jethava
and S. Patel, Org. Lett., 2015, 17, 5890; (e) J. K. Laha, K. S. S.
Treatment of 2-ethoxy phenylglyoxylate 49 with the
commercially available pyrrazole 50 under the optimized
conditions gave quinazolin-4-one 51 in 81% yield. In the
commercial production of the drug, quinazolin-4-one 51 is
prepared by coupling of 2-ethoxybenzoic acid and pyrrazole 50
in the presence of CDI followed by intramolecular cyclization
of the amide in the presence of t-BuOK. Distinct from the
commercial preparation, our protocol delivers the quinazolin-
4-one 51 in a single step using K2S2O8 as the only reagent in a
comparable yield. Chlorosulfonation of 51 followed by reaction
with N-methylpiperazine gave sildenafil (Scheme 7).13
Tummalapalli and K. P. Jethava, Org. Biomol. Chem. 2016, 14
2473; (f) J. K. Laha, R. A. Bhimpuria, D. Prajapati, N. Dayal
,
and S. Sharma, Chem. Commun., 2016, 52, 4329.
10 (a) Y. -M. Li, X. -H. Wei, X. -A. Li and S. -D. Yang, Chem.
Commun., 2013, 49, 11701; (b) Z. Zhang, S. Fang, Q. Liu and
G. J. Zhang, Org. Chem., 2012, 77, 7665.
11 P. J. Dunn, S. Galvinb and K. Hettenbach, Green Chem., 2004,
6
, 43.
12 N. K. Terrett, A. S. Bell, D. Brown and P. Ellis, Bioorg. Med.
Chem. Lett., 1996, , 1819.
13 A. S. Bell, D. Brown and N. K. Terrett, EP0463756A1, 1992.
6
In conclusion, the study described herein includes a
comprehensive package of new amide formation, their
unexplored intramolecular reactions to the synthesis of
diverse nitrogen heterocycles, and applications to the
4 | J. Name., 2012, 00, 1-3
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