550 J. Chin. Chem. Soc., Vol. 58, No. 4, 2011
Zaki et al.
o
to afford white needles in 78% yield, m.p. 160-162 C.
1H-NMR (CDCl3): d = 1.4 (t, J = 9 Hz, 3H, CH3), 1.85 (m,
4H, 2CH2), 2.8 (m, 4H, 2CH2), 3.2 (m, 4H, 2CH2), 3.9 (m,
4H, 2CH2), 4.3 (s, 2H, CH2 acetamide), 4.5 (q, J = 7.5 Hz,
2H, CH2) and 9.2 (s, 1H, NH) ppm. IR: n = 3200 cm-1 (NH),
2920, 2850 cm-1 (CH aliphatic), 1730 cm-1 (CO ester),
1670 cm-1 (CO amide). Anal. Calcd. for: C20H24ClN3O4S
(437.95) C, 54.85; H, 5.52; Cl, 8.10; N, 9.59; S, 7.32%.
Found: C, 55.00; H, 5.72; Cl, 8.00; N, 10.05; S, 7.22%.
Ethy-5-morpholin-4-yl-8-oxo-1,2,3,4,8,9-hexahydropyr-
imido[4¢,5¢:4,5]thieno[2,3-c]isoquinolin-10-yl sulfanyl
acetate (6)
1-Amino-5-morpholin-4-yl-6,7,8,9-tetrahydrothieno-
[2,3-c]isoquinoline (8)
Amino ester compound 1 (1.444 g, 4 mmol) was re-
fluxed with alcoholic potassium hydroxide solution (pre-
pared by dissolving 1.00 g of potassium hydroxide in 30
mL ethanol) for 1 h. then the mixture was cooled and added
to 10% HCl solution. The solid precipitate which formed
by adding HCl solution was filtered off, dried and recrys-
tallized from dioxan to afford white crystals in 96% yield,
o
m.p. 218-220 C. 1H-NMR (DMSO-d6): d = 1.8 (m, 4H,
2CH2), 2.7 (m, 4H, 2CH2), 3.1 (m, 4H, 2CH2), 3.8 (m, 4H,
2CH2), 6.3 (s, 2H, NH2) and 7.5 (s, 1H, CH thieno) ppm.
IR: n = 3520, 3350 cm-1 (NH2), 2920, 2850 cm-1 (CH
aliphatic), 1625 cm-1 (C=N). Anal. Calcd. for: C15H19N3OS
(289.40), C, 62.25; H, 6.62; N, 14.52; S, 11.08%. Found: C,
62.40; H, 6.75; N, 14.70; S, 11.30%.
A mixture of compound 5 (1.007 g, 2.3 mmol) and
potassium thiocyanate (0.22 g, 2.3 mmol) in ethanol (30
mL) was refluxed for 4 h. The solid precipitate which
formed on cold was filtered off, dried and recrystallized
from ethanol to give white crystals in 81% yield, m.p.
140-142 oC. 1H-NMR (DMSO-d6): d = 1.3 (t, J = 7.5 Hz,
3H, CH3), 1.8 (m, 4H, 2CH2), 2.7 (m, 4H, 2CH2), 3.2 (m,
4H, 2CH2), 3.85 (m, 4H, 2CH2), 4.2 (s, 2H, CH2CO), 4.5
(q, J = 7.5 Hz, 2H, CH2 ester) and 11.5 (s, 1H, NH) ppm.
IR: n = 3290 cm-1 (NH), 2920, 2830 cm-1 (CH aliphatic),
1735 cm-1 (CO ester), 1675 cm-1 (CO amide). Mass spec-
trum m/z (%): 460 (M+, 100), 429 (31.3), 403 (42.5), 92
(49.4). Anal. Calcd. For: C21H24N4O4S2 (460.58) C, 54.76;
H, 5.25; N, 12.16; S, 13.92%. Found: C, 54.50; H, 5.43; N,
12.30; S, 14.10%.
Ethyl-2-cyano-3-(5-morpholin-4-yl-6,7,8,9-tetrahydro-
thieno[2,3-c]isoquinoline-1-ylamino)acrylate (9)
A mixture of amino compound 8 (2.894 g, 0.01 mol)
and ethyl 2-cyano-3-ethoxyacrylate (1.69 g, 0.01 mol) in
ethanol (30 mL) was refluxed for 2 h. The solid precipitate
which was formed on hot during reflux was cooled, filtered
off, dried and recrystallized from ethanol-benzene mixture
o
to give brown crystals in 41% yield, m.p. 270-272 C.
1H-NMR (CDCl3): d = 1.3 (t, J = 7.5 Hz, 3H, CH3), 1.9 (m,
4H, 2CH2), 2.8 (m, 4H, 2CH2), 3.3 (m, 4H, 2CH2), 3.8 (m,
4H, 2CH2), 4.2 (q, J = 6 Hz, 2H, CH2), 7.9 (s, 1H, CH
thieno), 8.6 (s, 1H, CHacrylate) and 11.5 (s, 1H, NH) ppm.
IR: n = 3380 cm-1 (NH), 2950, 2850 cm-1 (CH aliphatic),
2210 cm-1 (CN), 1680 cm-1 (CO ester), 1620 cm-1 (C=N).
Anal. Calcd. for: C21H24N4O3S (412.51) C, 61.15; H, 5.86;
N, 13.58; S, 7.77%. Found: C, 60.95; H, 6.00; N, 13.70; S,
7.54%.
Ethyl-5-morpholin-4-yl-1-(2-phenylaminoacetylamino)-
6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-2-carboxy-
late (7)
Chloro acetylamino derivative 5 (0.438 g, 1 mmol)
and aniline (0.28 mL, 3.226 mmol) was gently refluxed for
10 minutes, then ethanol (10 mL) was added and reflux
continued for additional 2 h. The solid precipitate which
formed on hot during reflux was cooled, dried and recrys-
tallized from dioxan to give white needles in 80% yield,
m.p. 222-224 oC. 1H-NMR (CDCl3): d = 1.35 (t, J = 6 Hz,
3H, CH3), 1.8 (m, 4H, 2CH2), 2.7 (m, 4H, 2CH2), 3.25 (m,
4H, 2CH2), 3.9 (m, 4H, 2CH2), 4.05 (s, 2H, CH2 acet-
amide), 4.25 (q, J = 7.5 Hz, 2H, CH2), 6.6 (s, 1H, NH
phenylamino), 7.3-6.8 (m, 5H, ArH) and 9.2 (s, 1H, NH
acetamide) ppm. IR (cm-1): n = 3380, 3290 (2NH), 3030
(CH aromatic), 2920, 2850 (CH aliphatic), 1700 (CO es-
ter), 1670 (CO amide). Anal. Calcd. for: C26H30N4O4S
(494.62) C, 63.14; H, 6.11; N, 11.33; S, 6.48%. Found: C,
63.00; H, 6.23; N, 11.21; S, 6.66%.
5-Morpholin-4-yl-8-oxo-1,2,3,4,8,11-hexahydropyrido-
[2²,3²:4¢,5¢]thieno[2,3-c]isoquinoline-9-carbonitrile (10)
Ethyl acrylate compound 9 (0.578 gm, 1.4 mmol) was
refluxed in glacial acetic acid (20 mL) for 3 hrs. The solid
product which was formed on hot during reflux was cooled,
filtered off and recrystallized from DMF into green crystals
in 75% yield, m.p. 340-342 oC. 1H-NMR (DMSO-d6): d =
1.9 (m, 4H, 2CH2), 2.8 (m, 4H, 2CH2), 3.3 (m, 4H, 2CH2),
3.8 (m, 4H, 2CH2), 8.8 (s, 1H, CH pyridine), 11.4 (s, 1H,
NH pyridine) ppm. IR: n = 3220 cm-1 (NH), 2210 cm-1
(CN), 1635 cm-1 (C=O). Mass spectrum m/z (%): 366 (M+,
19.1), 365 (M+-1, 44.5), 347 (21.3), 334 (21.5), 321 (36.6),
316 (24.7), 308 (100). Anal. Calcd. for: C19H18N4O2S