M. A. Ameen · Novel Selective 5-HT3 Receptor Ligands
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The reaction mixture was warmed to form a clear solution. Ethyl 2-amidino-3-cyano-4,5,6,7-tetrahydrothieno[2,3-c]-
After cooling, 50% sulfuric acid was added dropwise un- pyridine-6-carboxylate (10)
til pH 2. The precipitated product was filtered off, washed
A suspension of 8 (0.61 g, 2 mmol) and ammonium hy-
with water, dried, and crystallized from ethanol as pale yel-
droxide solution (30%) (10 ml) was stirred at r. t. for 2 h.
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low crystals. Yield 82%, m.p. > 300 C – IR (KBr): ν =
3380 – 3285 (NH2, NH), 1705 (ester C=O), 1665 (C=O)
cm−1. – 1H NMR (300 MHz, [D6]-DMSO): δ = 1.20 (t, 3 H,
OCH2CH3), 2.73 (t, 2 H, 5-H), 3.64 (t, 2 H, 6-H), 4.12 (q,
2 H, OCH2CH3), 4.52 (s, 2 H, 8-H), 4.79 (br, s, 2 H, NH2),
8.35 (br, s, 1 H, NH). – 13C{H} NMR (75.5 MHz, [D6]-
DMSO): δ = 14.45 (CH3), 26.08 (C-5), 40.89 (C-6), 42.69
(C-8), 60.90 (CH2), 119.77 (C-4a), 127.95 (C-4b), 129.74
(C-8a), 151.13 (C-9a), 152.62 (C-NH2), 156.16 (C=O),
158.24 (C=O). – C12H14N4O3S (294.33): calcd. C 48.97,
H 4.79, N 19.04; found C 48.72, H 4.54, N 18.86.
The product was filtered off, washed with water and re-
crystallized from ethyl acetate/acetonitrile. Compound 10
was obtained as white needles; yield 0.51 g (91%); m. p.
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161 – 162 C – IR (KBr): ν = 3360 (NH2), 1712 (ester
C=O), 1615 (C=N) cm−1. – 1H NMR (300 MHz, [D6]-
DMSO): δ = 1.21 (t, 3 H, OCH2CH3), 2.85 (t, 2 H, 4-H),
3.65 (t, 2 H, 5-H), 4.12 (q, 2 H, OCH2CH3), 4.55 (s, 2 H,
7-H), 6.45 (br, s, 2 H, NH2), 8.35 (s, 1 H, CH). – 13C{H}
NMR (75.5 MHz, [D6]-DMSO): δ = 14.38 (CH3), 23.39
(C-4), 40.93 (C-5), 42.02 (C-7), 60.86 (CH2), 113.38 (CN),
123.99 (C-3), 129.60 (C-7a), 146.09 (C-3a), 154.55 (C=O),
159.07 (CH=N), 163.58 (C-2). – C12H14N4O2S (278.33):
calcd. C 51.78, H 5.07, N 20.13; found C 51.62, H 4.91,
N 19.98.
Ethyl 2-amino-4-oxo-5,6,7,8-tetrahydropyrido[4’,3’:4,5]-
thieno[2,3-d][1,3]thiazine-7-carboxylate (6)
A suspension of compound 5 (6.0 g, 13 mmol) in 98%
sulfuric acid (60 ml) and few drops of water was stirred at
40 – 50 ◦C for 10 h. The resultant clear solution was slowly
poured on ice-water and sodium bicarbonate (300 ml). The
precipitate was collected, washed with ethanol and dried to
give compound 6. M. p. 254 – 256 ◦C [18].
Ethyl 4-amino-3,4,5,6,7,8-hexahydropyrido[4’,3’:4,5]-
thieno[2,3-d]pyrimidine-7-carboxylate (12)
M e t h o d A
A mixture of 10 (1.0 g) and a solution of 1M alcoholic
potassium hydroxide (10 ml) was refluxed for 1 h. The re-
action mixture was acidified with 1M hydrochloric acid. The
product was collected by filtration, washed with water, dried
and recrystallized from DMF/n-hexane as colorless crystals
in 91% yield.
Ethyl 2,3-diamino-4-oxo-1,2,3,4,5,6,7,8-octahydropyrido-
[4’,3’:4,5]thieno[2,3-d]pyrimidine-7-carboxylate (7)
To a stirred suspension of 6 (0.62 g, 2 mmol) in pyridine
(10 ml), hydrazine hydrate (2.5 mmol) was added. The re-
action mixture was refluxed for 4 h. The precipitate was fil-
tered off, washed with ethanol and recrystallized from ethyl
acetate. Pale yellow needles; yield 0.54 g (87%); m. p. 297 –
M e t h o d B
Compound 8 (1.2 g, 4 mmol) in formamide (10 ml) was
refluxed for 5 h. The product that formed after cooling was
filtered off and ◦washed with ethanol. Yield 0.69 g (62%);
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m. p. 272 – 274 C. – IR (KBr): ν = 3375 (NH2), 1707 (es-
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299 C – IR (KBr): ν = 3350 – 3390 (2 NH2), 1710 (es-
ter C=O), 1618 (C=N) cm−1. – H NMR (300 MHz, [D6]-
1
ter C=O), 1685 (C=O) cm−1. – H NMR (300 MHz, [D6]-
DMSO): δ = 1.19 (t, 3 H, OCH2CH3), 2.81 (t, 2 H, 5-H),
3.68 (t, 2 H, 6-H), 4.10 (q, 2 H, OCH2CH3), 4.57 (s, 2 H,
8-H), 7.55 (br, s, 2 H, NH2), 9.12 (s, 1 H, CH). – 13C{H}
NMR (75.5 MHz, [D6]-DMSO): δ = 14.42 (CH3), 26.18
(C-5), 40.76 (C-6), 42.68 (C-8), 60.95 (CH2), 119.71 (C-4a),
127.93 (C-4b), 129.76 (C-8a), 151.14 (C-9a), 155.75 (C-2),
157.14 (C-NH2), 158.27 (C=O). – C12H14N4O2S (278.30):
calcd. C 51.78, H 5.07, N 20.13; found C 51.62, H 4.91,
N 19.98.
DMSO): δ = 1.18 (t, 3 H, OCH2CH3), 2.86 (t, 2 H, 5-H),
3.74 (t, 2 H, 6-H), 4.11 (q, 2 H, OCH2CH3), 4.61 (s, 2 H,
8-H), 4.85 (br, s, 2 H, NH2), 7.31 (br, s, 2 H, N-NH2). –
13C {H} NMR (75.5 MHz, [D6]-DMSO): δ = 14.48 (CH3),
26.18 (C-5), 40.78 (C-6), 42.71 (C-8), 60.86 (CH2), 118.98
(C-4a), 126.95 (C-4b), 129.15 (C-8a), 151.09 (C-9a), 152.52
(C-NH2), 156.07 (C=O), 158.18 (C=O). – C12H15N5O3S
(309.35): calcd. C 46.59, H 4.89, N 22.64; found C 46.42,
H 4.71, N 22.43.
[1] M. Modica, M. Santagati, A. Santagati, V. Cutuli,
N. Mangno, A. Caruso, Pharmazie 55, 500 (2000).
[2] Ho Yuh-Wen, J. Chin. Chem. Soc. 48, 1163 (2001).
[3] C. G. Dave, A. B. Shah, H. C. Shah, J. Heterocycl.
Chem. 34, 937 (1997).
[4] H. Vicueg, S. Leistner, N. Böhmen, J. Prantz, G. Wag-
ner, Pharmazie 48, 26 (1993).
[5] A. O. Abd-allah, Phosphorus, Sulfur and Silicon 178,
1115 (2003).
[6] N. Böhmen, R. Pech, Pharmazie 39, 19 (1984).
Unauthenticated
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