HETEROCYCLES, Vol. 87, No. 12, 2013
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around 600 g DMF was recovered. The residuum was dissolved in CH Cl (1.5 kg) and washed with
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2
water (1 kg × 3). The CH Cl solution was stirred rapidly with 10% aq. HCl solution (600 g) at rt for 4 h.
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2
The organic layer was separated, washed with water (1 kg × 2), 5% aq. NaHCO (1 kg × 2) respectively,
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dried over anhydrous Na SO . The solvent was recovered to give crude 14 (146 g) as a yellow-brown
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4
solid, which was purified by recrystallization from 85% MeOH/H O (290 g) one time to give the pure 14
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1
(
110 g, 69%) as a grey needle. mp 101 ~ 103 ºC (ref., 101 ~ 102 ºC). H NMR (300 Hz, CDCl ): δ 4.13
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(s, 3H), 6.04 (s, 2H), 6.59 (d, 1H, J = 8.1 Hz), 7.47 (d, 1H, J = 8.1 Hz), 10.22 (s, 1H). ESI-MS (m/z):
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03.0 (M + Na), 383.0 (2M + Na).
4-Methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-8-ol (18). A mixture of
compound 14 (90.0 g, 0.5 mol) and 15 (55.2 g, 0.53 mol) in anhydrous MeOH (500 g) was stirred at rt for
h before it was cooled to 0 ~ 10 ºC. NaBH (11.5 g, 0.3 mol) was added portionwise into the reaction
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4
mixture over 1 h to keep the reaction temperature below 20 ºC. The reaction solution was stirred for
another 30 min at rt. The volatile materials were removed and the residuum was dissolved in CH Cl (1
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2
kg), washed with water (1 kg × 3). The solvent was recovered to give 2,2-dimethoxy-N-((4-methoxy-
benzo[d][1,3]dioxol-5-yl)methyl)ethanamine 16 (135 g) as a faint yellow oil.
A mixture of compound 16 (135 g, 0.5 mol) and 37% aq. HCHO solution (61 g, 0.75 mol) in MeOH (600
g) was stirred at rt for 1 h before it was cooled to 0 ~ 10 ºC. NaBH (15.0 g, 0.4 mol) was added
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portionwise into the reaction mixture over 1 h to keep the reaction temperature below 20 ºC. The reaction
solution was stirred for another 1 h at rt. The volatile materials were removed and the residuum was
dissolved in CH Cl (1 kg), washed with water (1 kg × 3). The solvent was recovered to give
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2
2
,2-dimethoxy-N-((4-methoxybenzo[d][1,3]dioxol-5-yl)methyl)-N-methylethanamine 17 (142 g) as a
faint yellow oil.
Compound 17 (142 g, 0.5 mol) was mixed with 20% aq. HCl (600 g) and stirred at rt for 24 h. 50% aq.
NaOH solution was then added slowly into the reaction mixture to adjust the solution pH 10 ~ 11, and
keep the solution temperature below 40 ºC. The resulting brown-yellow solid was collected by suction
filtration, washed by water (100 g × 3), and dried at 50 ºC to give the crude 18 (114 g) as a tan solid,
which was purified by recrystallization from 90% EtOH/H O (230 g) to give pure 18 (91.2 g, 77%) as a
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white solid. mp 151 ~ 153 ºC (ref., 153 ~ 154 ºC). H NMR (300 Hz, CDCl ): δ 2.45 (s, 3H), 2.87-3.11
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(m, 3H), 3.71 (m, 1H), 3.99 (s, 3H), 4.46 (m, 1H), 5.89 (s, 2H), 6.59 (s, 1H). ESI-MS (m/z): 238.0 (M +
H), 497.0 (2M + Na).
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-Methoxy-6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinoline (19). NaHB (15.1 g, 0.4 mol)
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was added portionwise into a stirred solution of compound 18 (71.2 g, 0.3 mol) and TFA (137 g, 1.2 mol)