928
K. A. Memoli
Vol 44
sodium carbonate, 25 mL of saturated aqueous sodium chloride,
dried over anhydrous magnesium sulfate, filtered and evaporated
to dryness to provide 3 as a yellow liquid (11.2 g) which was used
as such in the next step. H NMR (300 MHz, CDCl3) ꢀ 3.95 (s,
3H), 5.10 (s, 2H), 7.35 (dd, 1H), 8.3 (d, 1H), 8.75 (d, 1H).
g), m.p. 109-111 °C. 1H NMR (300 MHz, CDCl3) ꢀ 5.25 (s, 2H),
5.60 (s, 2H), 6.25 (m, 1H), 6.95 (d, 1H), 7.20 (dd, 1H), 7.40 (m,
6H), 8.25 (m, 2H), 9.10 (s, 1H), 9.40 (s, 1H).
1
Conversion of 5 to 5,11-Dihydro-6H-pyrido[3,2-e]pyrrolo-
[1,2-a][1,4]diazepine (2). A stirred mixture of 5 (1.0 g), 10%
palladium on carbon (10 mg), anhydrous magnesium sulfate (10
mg) and 5 drops of acetic acid in ethyl acetate (10 mL) was
hydrogenated at atmospheric pressure until H2 uptake ceased.
The reaction mixture was then filtered through Celite and the
solvent removed in vacuo. The crude product was a yellow
crystalline solid weighing 0.53 g, which was purified by
chromatography on silica gel, eluting with a solvent gradient of
5-30 % ethyl acetate/petroleum ether, to provide the title product
as a yellow crystalline solid, m.p. 171- 172 °C. Calcd. for
C11H11N3: C, 71.33; H, 5.99; N, 22.59. Found: C, 71.09; H, 6.10;
Conversion of 3 to Methyl 2-[(2-formyl-1H-pyrrol-1-yl)-
methyl]nicotinate (4). To a suspension of sodium hydride (50
% in oil, 5.8 g, .12 mol) in dry DMF (25 mL) was added slowly
under nitrogen a solution of pyrrole 2-carboxaldehyde (10.5 g,
0.11 mol) in 25 mL of DMF and the reaction mixture was stirred
at room temperature for 30 minutes. The reaction was then
cooled to 5 °C and 3 (11.2 g) was added slowly, the temperature
being maintained at or below 20 °C. After the addition was
complete, the reaction was stirred at room temperature for 30
minutes, evaporated to dryness, and the residue dissolved in
ethyl acetate (250 mL). This solution was washed with water (3
X 25 mL) and dried over anhydrous magnesium sulfate. The
solvent was then removed in vacuo leaving a crystalline solid
(23.4 g) which was purified by chromatography on silica gel
eluting with a solvent gradient of 5-50 % ethyl acetate/petroleum
ether to provide 4 as a tan crystalline solid (13.75 g), m.p. 91-93
1
N, 22.95. H NMR (300 MHz, CDCl3): ꢀ 4.10 (b, 1H), 4.45 (s,
2H), 5.40 (s, 2H), 6.05 (s, 2H), 6.75 (m, 2H), 6.95 (dd, 1H), 7.85
(d, 1H).
REFERENCES
1
°C. H NMR (300 MHz, CDCl3): ꢀ 4.00 (s, 3H), 6.00 (s, 2H),
6.30 (m, 1H), 7.00 (m, 1H), 7.05 (m, 1H), 7.25 (dd, 1H), 8.25 (d,
1H), 8.60 (d, 1H), 9.45 (s, 1H).
[1] Present Address: The Orchard Apt. 139F, Cranbury, N. J.
[2] Artico, M.; De Martino, G.; Giuliano, R.; Massa, S.;
Filacchioni, G. Farmaco, Ed. Sci. 1969, 24(3), 276-84.
Conversion of
4 to Benzyl 2-[(2-formyl-1H-pyrrol-1-
yl)methyl]pyridin-3-ylcarbamate (5). To a stirred solution of 4
(13.65 g, 55.9 mmol) in methanol (50 mL) was added sodium
hydroxide (2.2 g, 55.9 mmol). The reaction mixture was
refluxed under nitrogen for 2 hours and the solvent was removed
in vacuo. The five grams of the sodium salt so obtained were
suspended in a mixture of benzyl alcohol (20 mL) and benzene
(30 mL). Diphenylphosphoryl azide (6.54 g, 1.2 equiv.) was
added and the reaction was slowly heated to reflux. After
refluxing for 1 hour, the reaction was cooled and washed with
water, dried over anhydrous magnesium sulfate, filtered and
evaporated to dryness to provide 5 as a tan crystalline solid (4.4
[3] (a) Artico, M. Boll. Chim. Farm. 1980, 119(8), 455-68 and
119(9), 505-20. (b) Albright, J. D.; Reich, M. F.; Delos Santos, E. G.;
Dusza, J. P.; Sum, F.; Venkatesan, A. M.; Coupet, J.; Chan, P. S.; Ru,
X.; Mazandarani, H.; Bailey, T. J. Med. Chem. 1998, 41(14), 2442-2444.
[4] 5,11-Dihydro-6H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine.
[5] (a) Jeromin G. E.; Orth W.; Rapp B.; Weiss W. Chem. Ber.
1987, 120, 649. (b) Sato Y.; Sakane K.; Tabuchi S.; Mitsui H.; Katsumi
I.; Satoh Y. WO 96-04254.
[6] Kamikawa T.; Hanaoka Y.; Saito K.; Yamagiwa Y.;
Fukuhara K.; Kubo I. Bioorganic & Medicinal Chemistry 1996, 4(8),
1317.