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4143
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213; (d) Ramasamy, K.; Joshi, R. V.; Robins, R. K.; Revankar, G. R. J. Chem. Soc.,
Perkin Trans. 1 1989, 2375–2384.
aldehyde (7e) was treated with excess bromine and hydrobromic
acid/acetic acid in dichloromethane to afford the corresponding
a,a-dibromoaldehyde (8e). The dibromoaldehyde (8e) was reacted
with 2,4-diamino-6-hydroxypyrimidine (9) to afford the advanced
intermediate (10e). Ester (10e), thus obtained was hydrolyzed in
presence of an alkali to afford acid (12) and then coupled with di-
10. (a) Miwa, T.; Hitaka, T.; Akimoto, H.; Nomura, H. J. Org. Chem. 1993, 58, 1696–
1701; (b) Dave, C. G.; Shah, P. R.; Upadhyaya, S. P. Indian J. Chem. 1987, 64, 713–
715; (c) Taylor, E. C.; Patel, H. H.; Jun, J. G. J. Org. Chem. 1995, 60, 6684–6687;
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Chem. 1996, 39, 4563–4568; (g) Taylor, E. C.; Jennings, L. D.; Mao, Z.; Hu, B.; Jun,
J. G.; Zhou, P. J. Org. Chem. 1997, 62, 5392–5403; (h) Taylor, E. C.; Young, W. B. J.
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3726–3738; (j) Taylor, E. C.; Liu, B. J. Org. Chem. 2003, 68, 9938–9947; (k) Itoh,
F.; Yoshioka, Y.; Yukishige, K.; Yoshida, S.; Wajima, M.; Ootsu, K.; Akimoto, H.
Chem. Pharm. Bull. 1996, 44, 1498–1509; (l) Shih, C.; Gossett, L. S. Heterocycles
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2007, 18, 617–621; (n) McGuire, J. J.; Bergoltz, V. V.; Heitzman, K. J.; Haile, W.
H.; Russell, C. A.; Bolanowska, W. E.; Kotake, Y.; Haneda, T.; Nomura, H. Cancer
Res. 1994, 54, 2673–2679; (o) Aso, K.; Imai, Y.; Yukishige, K.; Ootsu, K.;
Akimoto, H. Chem. Pharm. Bull. 2001, 49, 1280–1287; (p) Taylor, E. C.; Liu, B.
Tetrahedron Lett. 1999, 40, 5291–5294; (q) Michael, V. V.; Kunjian, G.; Simon, D.
P. B.; Michael, R. B. Tetrahedron Lett. 2006, 47, 4149–4151; (r) Fischer, R. W.;
Misun, M. Org. Process Res. Dev. 2001, 5, 581–585.
methyl L-glutamate ester (13) in presence of coupling agent 2-
chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) to yield the corre-
sponding protected metabolite (14). The ester groups in compound
14 were hydrolyzed in presence of alkali to afford the metabolite
(15) as shown in Scheme 3.
The structures of 5-substituted 4,6-dioxo-pyrrolo[2,3-d]pyrimi-
dines (10a–10f, 12, 14 and 15) were identified by appropriate spec-
tral data.17 Thus, the structure of 10c has been elucidated by single
crystal X-ray diffraction along with other spectroscopic
techniques.18
In summary, a new, short and efficient synthetic protocol for
the synthesis of 5-substituted-4,6-dioxo-pyrrolo[2,3-d]pyrimi-
dines under mild basic conditions was established with good yields
11. Barnett, C. J.; Wilson, T. M.; Kobierski, M. E. Org. Process Res. Dev. 1999, 3, 184–
188.
12. Barnett, C. J.; Grubb, L. M. Tetrahedron Lett. 2000, 41, 9741–9745.
13. (a) Miwa, T.; Hitaka, T.; Akimoto, H.; Nomura, H. J. Med. Chem. 1991, 34, 555–
560; (b) Aso, K.; Hitaka, T.; Yukishige, K.; Ootsu, K.; Akimoto, H. Chem. Pharm.
Bull. 1995, 43, 256–261; (c) Akimoto, H.; Hitaka, T.; Miwa, T. U.S. 4,997,838,
1991.
from
a,a-dibromoaldehyde and 2,4-diamino-6-hydroxypyrimi-
dine. The methodology has been successfully applied to the syn-
thesis of a metabolite of pemetrexed. The structure of one of the
compound (10c) was elucidated by the single crystal X-ray
diffraction.
14. Woodland, J. M.; Barnett, C. J.; Dorman, D. E.; Gruber, J. M.; Shih, C.; Spangle, L.
A.; Wilson, T. M.; Ehlhardt, W. J. Drug Metab. Dispos. 1997, 25, 693–700.
15. Representative experimental procedure for the synthesis of
(8a–8f): To a solution of aldehyde (1 equiv) in dichloromethane (DCM) (20 vol)
taken into round bottomed flask, 33% hydrobromic acid in acetic acid
a,a-dibromoaldehydes
Acknowledgments
a
solution (0.1 equiv) was added. The reaction mass was cooled 0–5 °C and then
added excess bromine (5 equiv) in dichloromethane slowly at temperature less
than 10 °C. After completion of addition, temperature of the reaction mass was
raised to 25–30 °C and stirred for 5–12 h. The completion of reaction was
confirmed by TLC (Eluent: EtOAc/n-hexane, 2:8). The reaction mass was
washed with 10% aq sodium thiosulphate (2 Â 10 vol), 7% aq sodium
bicarbonate (2 Â 10 vol) and water (10 vol). The organic layer was separated
and evaporated under reduced pressure at 35–40 °C to obtain red to light
brown colored title compound (yield: 90–95%).
We thank the management of Dr. Reddys Laboratories Ltd, for
supporting this work. Cooperation from HPAI R&D and Discovery
Research colleagues is highly appreciated.
Supplementary data
16. Representative experimental procedure for the synthesis of 5-substituted-4,6-
Supplementary data associated with this article can be found, in
dioxo-pyrrolo[2,3-d]pyrimidines (10a–10f): a,a-Dibromoaldehyde (1 equiv) and
2,4-diamino-6-hydroxy pyrmidine (1 equiv) were taken into round bottomed
flask, and acetonitrile (5 vol) was then added followed by water (5 vol). After
stirring for 5 min, sodium acetate (2 equiv) was added into the reaction mass.
Then the reaction mass was stirred for 3–7 h at 40–45 °C. After monitoring the
reaction by TLC (mobile phase: MeOH/DCM, 2:8) for the absence of starting
material, the reaction mass was cooled to 25–30 °C. Filtered and washed with
1:1 acetonitrile and water mixture. The solid obtained was dried under
vacuum at 45–50 °C to obtain dark tan to light pink colored solid (yield: 74–
85%).
References and notes
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17. 2-Amino-5-methyl-5,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-4,6-dione (10a): 1H
NMR (DMSO-d6, 400 MHz): d 1.23 (d, 3H, J = 7.2 Hz), 3.20 (q, 1H, J = 7.2 Hz),
6.66 (br s, 2H, D2O exchangeable), 10.34 (br s, 1 H, D2O exchangeable), 10.48
(br s, 1H, D2O exchangeable). 13C NMR (DMSO-d6, 400 MHz): d 14.40, 38.57,
92.06, 157.09, 157.79, 163.82, 180.64. HRMS calcd for C7H9N4O2 (M+H)+:
181.0726, found: 181.0724. IR (KBr) mmax (cmÀ1): 3389, 2926, 1743, 1719,
1681, 1533, 1502, 1450, 1352, 1248, 1170, 777.
2-Amino-5-ethyl-5,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-4,6-dione (10b): 1H
NMR (DMSO-d6, 400 MHz): d 0.77 (t, 3H, J = 7.2 Hz), 1.71–1.88 (m, 2H), 3.24
(t, 1H, J = 5.6 Hz), 6.68 (br s, 2H, D2O exchangeable), 10.40 (br s, 1H, D2O
exchangeable), 10.48 (br s, 1H, D2O exchangeable). 13C NMR (DMSO-d6,
400 MHz): 9.67, 21.67, 44.77, 89.74, 157.22, 157.85, 164.59, 179.85. HRMS
calcd for C8H11N4O2 (M+H)+: 195.0882, found: 195.0881. IR (KBr) max (cmÀ1):
m
3417, 2964, 1737, 1721, 1650, 1519, 1431, 1343, 1284, 1166, 771.
2-Amino-5-propyl-5,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-4,6-dione (10c): 1H
NMR (DMSO-d6, 400 MHz): d 0.83 (t, 3H, J = 7.2 Hz), 1.20–1.35 (m, 2H), 1.63–
1.81 (m, 2H), 3.24 (t, 1H, J = 5.6 Hz), 6.65 (br s, 2H, D2O exchangeable), 10.33 (br
s, 1H, D2O exchangeable), 10.48 (br s, 1H, D2O exchangeable). 13C NMR (DMSO-
d6, 400 MHz): d 14.04, 18.58, 31.12, 43.70, 90.45, 157.15, 157.83, 164.34,
180.23. HRMS calcd for C9H13N4O2 (M+H)+: 209.1039, found: 209.1037. IR
(KBr) m
max (cmÀ1): 3404, 2958, 1715, 1659, 1524, 1431, 1349, 1274, 1165, 783.
X-ray crystallographic data for 10c: C10H16N4O3, M = 240.26, monoclinic, space
group C2/c, a = 34.30(4) Å, b = 4.994(4) Å, c = 27.38(3) Å, b = 148.791(6)°,
V = 2430(4) Å3, T = 298 K, Z = 8, Dc = 1.314 g/cmÀ1
,
l
(Mo-K
13,170 reflections measured, 2509 unique reflections, 673 observed
reflections [I > 2.0 (I)], R1_obs = 0.091, wR2_all = 0.155, Gof = 1.264.
a) = 0.7107 Å,
r
4-(2-Amino-4,6-dioxo-4,5,6,7-tetrahydro-3H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-
benzoic acid methyl ester (10d): 1H NMR (DMSO-d6, 400 MHz): d 3.14–3.25 (m,
2 H), 3.65 (t, 1H, J = 4.0 Hz), 3.80 (s, 3H), 6.63 (br s, 2H, D2O exchangeable), 7.17
(d, 2H, J = 8.4 Hz), 7.76 (d, 2H, J = 8.4 Hz), 10.35 (br s, 1H, D2O exchangeable),
10.42 (br s, 1H, D2O exchangeable). 13C NMR (DMSO-d6, 400 MHz): d 33.33,
9. (a) Kondo, T.; Ohgi, T.; Goto, T. Chem. Lett. 1983, 419–422; (b) Kondo, T.;
Okamoto, K.; Yamamoto, M.; Goto, T.; Tanaka, N. Tetrahedron 1986, 42, 199–