acid (3:2:0.1) or DMF (the R values are not given because the final products, in contrast with the starting materials, form
f
1
elongated bands in the chromatograms), H NMR (Table 1), and elemental analysis.
The purity of the starting materials was monitored using TLC and systems CHCl and CHCl —ethylacetate (3:1).
3
3
The starting N-substituted barbituric and 2-thiobarbituric acids (5a and b, 7b-j, and 7i-r) were prepared by the
literature method [12] from diethylmalonate and the corresponding urea and thiourea derivatives.
4-Methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-methylenedioxy-[4,5-g]isoquinolin-5-ol (1). Cotarnine chloride
monohydrate (pharm., 27.1 g, 0.1 mole) was dissolved in water (100 mL), stirred, treated with aqueous KOH (10%, 0.11 mole),
and held at 15oC for 6 h. The precipitate was filtered off, washed with water, and dried in a vacuum desiccator at 45oC over
KOH to give 1, 18.9 g (80%), mp 130-132oC (lit. 130oC [3]).
5-(4-Methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-methylenedioxy-[4,5-g]isoquinolinyl-1)1,3-dimethylbarbituric
(5-dihydrocotarnyl-1,3-dimethylbarbituric) acid (3). Method A. A mixture of 2 (1.56 g, 0.01 mole) and dry cotarnine (1,
2.36 g, 0.01 mole) was treated with CHCl (20 mL), heated to dissolve the solids, and boiled for another 2 min. The hot solution
3
was filtered through filter paper to remove solids. The resulting solution was kept for one day at room temperature. The
precipitate was separated, washed with CHCl and CCl , and dried in a vacuum desiccator to give 3, 3.45 g, as colorless needle-
3
4
like crystals.
5-(4-Methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-methylenedioxy-[4,5-g]isoquinolinyl-1)1-methylbarbituric (5-
dihydrocotarnyl-1-methylbarbituric) acid (8b). This was prepared by method A from cotarnine (1) and 1-methylbarbituric
acid (7b).
5-(4-Methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-methylenedioxy-[4,5-g]isoquinolinyl-1)1,3-dimethyl-2-
thiobarbituric (5-dihydrocotarnyl-1,3-dimethyl-2-thiobarbituric) acid (6a). Method B. 1,3-Dimethyl-2-thiobarbituric acid
(5a, 1.72 g, 0.01 mole) and cotarnine (1, 2.59 g, 0.011 mole) were dissolved in anhydrous methanol (20 mL) and filtered
through filter paper to remove solids. The resulting solution was kept for 3 h at 40 C and for 1-3 days at room temperature.
The crystalline precipitate was separated, washed with methanol, and dried in a vacuum desiccator to give 6a, 3.17 g.
5-(4-Methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-methylenedioxy-[4,5-g]isoquinolinyl-1)1,3-diethyl-2-
thiobarbituric (5-dihydrocotarnyl-1,3-diethyl-2-thiobarbituric) acid (6b) was prepared by methods A and B from cotarnine
(1) and 1,3-diethyl-2-thiobarbituric acid (5b).
5-(4-Methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-methylenedioxy-[4,5-g]isoquinolinyl-1)1-benzylbarbituric (5-
dihydrocotarnyl-1-benzylbarbituric) acid (8c), 5-(4-methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-methylenedioxy-[4,5-
g]isoquinolinyl-1)1-phenylbarbituric (5-dihydrocotarnyl-1-phenylbarbituric) acid (8d), 5-(4-methoxy-6-methyl-5,6,7,8-
tetrahydro-2H-1,3-methylenedioxy-[4,5-g]isoquinolinyl-1)1-p-fluorophenylbarbituric
(5-dihydrocotranyl-1-p-
fluorophenylbarbituric) acid (8e), 5-(4-methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-methylenedioxy-[4,5-g]isoquinolinyl-
1)1-p-chlorophenylbarbituric (5-dihydrocotarnyl-1-p-chlorophenylbarbituric) acid (8f), 5-(4-methoxy-6-methyl-5,6,7,8-
tetrahydro-2H-1,3-methylenedioxy-[4,5-g]isoquinolinyl-1)1-p-bromophenylbarbituric
(5-dihydrocotarnyl-1-p-
bromophenylbarbituric) acid (8g), 5-(4-methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-methylenedioxy-[4,5-g]isoquinolinyl-
1)1-p-methylphenylbarbituric (5-dihydrocotarnyl-1-p-methylphenylbarbituric) acid (8h), 5-(4-methoxy-6-methyl-5,6,7,8-
tetrahydro-2H-1,3-methylenedioxy-[4,5-g]isoquinolinyl-1)1-p-methoxyphenylbarbituric
methoxyphenylbarbituric) acid (8j), 5-(4-methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-methylenedioxy-[4,5-
g]isoquinolinyl-1)1-methyl-2-thiobarbituric (5-dihydrocotarnyl-1-methyl-2-thiobarbituric) acid (8i), 5-(4-methoxy-6-
methyl-5,6,7,8-tetrahydro-2H-1,3-methylenedioxy-[4,5-g]isoquinolinyl-1)1-cyclohexyl-2-thiobarbituric (5-
dihydrocotranyl-1-cyclohexyl-2-thiobarbituric) acid (8l), 5-(4-methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-
(5-dihydrocotarnyl-1-p-
methylenedioxy-[4,5-g]isoquinolinyl-1)1-phenyl-2-thiobarbituric (5-dihydrocotarnyl-1-phenyl-2-thiobarbituric) acid (8m),
5-(4-methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-methylenedioxy-[4,5-g]isoquinolinyl-1)1-p-fluorophenyl-2-thiobarbituric
(5-dihydrocotarnyl-1-p-fluorophenyl-2-thiobarbituric) acid (8n), 5-(4-methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-
methylenedioxy-[4,5-g]isoquinolinyl-1)1-p-chlorophenyl-2-thiobarbituric
(5-dihydrocotarnyl-1-p-chlorophenyl-2-
thiobarbituric) acid (8o), 5-(4-methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-methylenedioxy-[4,5-g]isoquinolinyl-1)1-p-
methylphenyl-2-thiobarbituric (5-dihydrocotarnyl-1-p-methylphenyl-2-thiobarbituric) acid (8p), 5-(4-methoxy-6-methyl-
5,6,7,8-tetrahydro-2H-1,3-methylenedioxy-[4,5-g]isoquinolinyl-1)1-p-methoxyphenyl-2-thiobarbituric (5-dihydrocotarnyl-
1-p-methoxyphenyl-2-thiobarbituric) acid (8q), and 5-(4-methoxy-6-methyl-5,6,7,8-tetrahydro-2H-1,3-methylenedioxy-
[4,5-g]isoquinolinyl-1)1,3-diphenyl-2-thiobarbituric (5-dihydrocotarnyl-1,3-diphenyl-2-thiobarbituric) acid (8r) were
prepared by method B from cotarnine (1) and the corresponding derivatives of barbituric (7c-j) or 2-thiobarbituric
549