inlet was charged 8 (40 g, 208 mmol) followed by methylene
chloride (400 mL), methanol (80 mL), and acetic acid (24.9
g, 416 mmol). The resulting solution was cooled to -20 to
(q, J ) 7 Hz, 2 H), 4.34 (q, J ) 7 Hz, 2 H), 3.79 (m, 4 H),
3.51 (s, 2 H), 2.51 (m, 4 H), 1.46 (t, J ) 7 Hz, 3 H), 1.40
1
3
(t, J ) 7 Hz, 3 H); C NMR (100 MHz, CDCl
166.1, 151.6, 140.6, 140.2, 130.8, 116.4, 95.6, 89.3, 67.3,
62.3, 60.9, 60.6, 53.9, 14.8, 14.7; Anal. Calcd for C19
IN : C, 49.73; H, 5.16; N, 5.78; found: C, 49.62; H, 5.14;
N, 5.68.
3
) δ 168.7,
-
15 °C. A 1 M iodine monochloride solution in methylene
chloride (370 g, 260 mL, 260 mmol) was added over about
0 min, keeping the temperature less than -15 °C. When
25
H -
3
2 5
O
the addition was completed, the cooling was removed and
the reaction warmed to 10-15 °C. After 1 h, the reaction
progress was monitored by GC: 1 mL of the reaction mixture
was quenched into 1 mL of 10% aqueous sodium sulfite,
and 1 mL of saturated bicarbonate was added; 5 drops of
the lower phase was diluted with 1 mL of methylene chloride,
and this was assayed by GC (injector 250 °C, initial oven
temp 125 °C, initial time ) 0, oven temp increased at 10
Ethyl 8-Iodo-6-(morpholin-4-ylmethyl)-4-oxo-1,4-di-
hydroquinoline-3-carboxylate (11). Preparation of Eaton’s
Reagent. To a 250-mL, three-neck, round-bottom flask fitted
with mechanical stirring thermocouple and nitrogen inlet,
was charged phosphorus pentoxide dimer (23.3 g, 82 mmol).
The stirring was started briefly to distribute the solids, and
the stirrer was raised above the solids in the flask. Meth-
anesulfonic acid (178 g, 120 mL, 1852 mmol) was added
and the mixture warmed to 90 °C until all the phosphorus
pentoxide dimer was dissolved. The resulting solution was
cooled to less than 30 °C.
Cyclization Reaction. To a 500-mL, three-neck, round-
bottom flask fitted with mechanical stirring, thermocouple,
and nitrogen inlet, was charged 10 (20 g, 41 mmol) followed
by Eaton’s reagent. There was an exotherm to about 47 °C.
The resulting dark-red solution was heated to 90 °C for at
least 4 h. The reaction was checked by TLC (about 0.5 mL
of reaction was quenched into 3-4 g of ice and the pH
adjusted to 7-8 by addition of 50% NaOH, 2 mL of
methylene chloride were added, and the lower layer was
spotted and eluted with 5% methanol/95% methylene
chloride). When completed, the reaction was cooled to less
than 30 °C and poured into 200 g of ice. A solution of 50%
NaOH (180 g, 2258 mmol) in 150 mL of water was slowly
added until the pH was 5-6. Methylene chloride (200 mL)
was added, and the addition of NaOH solution was resumed
until the pH was 7-8, keeping the temperature less than 30
°C (use an ice bath if needed). The phases were separated,
and the aqueous was washed with methylene chloride (1 ×
100 mL). The combined organic phases were filtered through
5 g of silica gel, and the cake was washed with 300 mL of
methylene chloride. The filtrates were concentrated on the
rotovap to about 150-mL volume. Methanol (200 mL) was
added and the solution concentrated to about 50-mL volume.
Methanol (100 mL) was added and the mixture again
concentrated to about 50-mL volume. The slurry was cooled
to 0 °C, filtered, and washed with 50 mL of methanol. The
product was dried in the vacuum oven at 50 °C overnight to
°C/min, final oven temp -275 °C, detector -275 °C, column
1
5
5 m DB-5SM). The reaction is complete when less than
% starting material remained. When the reaction was
complete, 250 mL of 10% aqueous sodium sulfite was added,
followed by a solution of 70 g of 50% NaOH in 250 mL of
water. The phases were separated, and the aqueous phase
was washed with 100 mL of methylene chloride. The
combined organic phases were washed with 100 mL of water
and concentrated on the rotovap to a thick red oil.
The crude oil was dissolved in 200 mL of ethyl acetate,
and 200 mL of Isopar C was added. The resulting mixture
was filtered through 200 g of silica gel, and the cake was
washed with 1500 mL of ethyl acetate. The organic phases
were concentrated to a dark red oil at 60 °C on the rotovap.
The oil was used as is in the next step; however, a purified
sample did eventually crystallize: mp 55.3-62.1 °C. HPLC
1
purity 87%. H NMR (400 MHz, CDCl
3
) δ 7.74 (s, 1 H),
7
4
.25 (d, J ) 8 Hz, 1 H), 6.82 (d, J ) 8 Hz, 1 H), 3.85 (m,
H), 3.51 (s, 2 H), 2.58 (m, 4 H); 13C NMR (100 MHz,
) δ 146.4, 139.9, 130.9, 129.3, 115.3, 84.3, 66.9, 62.5,
CDCl
3.8.
Diethyl 2-({[2-Iodo-4-(morpholin-4-ylmethyl)phenyl]-
3
5
amino}methylene)malonate (10). To a 1-L, three-neck,
round-bottom flask, fitted with mechanical stirring, thermo-
couple, distillation head, and nitrogen inlet was charged 9
(50 g, 157 mmol) followed by diethylethoxymethylene
malonate (37.4 g, 173 mmol) and toluene (115 mL). The
resulting mixture was heated under nitrogen with a heating
mantle with set point 120 °C. Toluene and ethanol (about
65 mL) were distilled during the heating period. When the
pot temperature reached 120 °C, the distillation slowed. The
reaction was assayed by TLC (elute with 1:1 ethyl acetate/
heptane) and was judged complete (starting material less than
provide 11.0 g (61% yield) of 11: mp 195-203 °C. HPLC
1
purity 96%. H NMR (400 MHz, DMSO-d
6
) δ 8.31 (s, 1
5%). The reaction mixture was cooled to 50 °C and vacuum
H), 7.99 (s, 1 H), 7.93 (s, 1 H), 4.06 (q, J ) 7 Hz, 2 H),
distilled to about 100 mL volume. Isopar C (200 mL) was
added and the mixture cooled to 20-25 °C, where the
mixture crystallized over ∼30 min. The resulting slurry was
stirred at 20-25 °C for 1 h, filtered, and washed with 75
mL of Isopar C. The product was dried in the vacuum oven
at 50 °C overnight, providing 65 g of 10. HPLC purity of
sample was 92%. An analytically pure sample was prepared
3.40 (m, 4 H), 3.37 (s, 2 H), 2.21 (m, 4 H), 1.11 (t, J ) 7
1
3
Hz, 3 H); C NMR (100 MHz, DMSO-d
146.1, 143.5, 138.9, 136.4, 128.1, 126.5, 110.2, 66.5, 61.3,
60.2, 53.3, 14.6; Anal. Calcd for C17 : C, 46.17;
6
) δ 173.2, 164.7,
2 4
H19IN O
H, 4.44; N, 6.35; found: C, 46.43; H, 4.37; N, 6.38.
Ethyl 2-(2-2-Hydroxyethyl)-8-(morpholin-4-ylmethyl)-
6-oxo-6H-pyrrol[3.2.1-ij]quinoline-5-carboxylate (12). 11
(985 g; 2.23 mol), CuI (42.4 g; 0.22 mol; 0.1 equiv), and
1
by recrystallization from toluene: mp 98-101 °C. H NMR
(400 MHz, CDCl
3
) δ 8.50 (d, J ) 13 Hz, 1 H), 7.89 (s, 1
Cl
2 3 2
Pd(PPh ) (15.7 g; 0.0226 mol; 0.01 equiv) were com-
H), 7.43 (d, J ) 8 Hz, 1 H), 7.23 (d, J ) 8 Hz, 1 H), 4.44
bined in a 22-L flask under nitrogen. Absolute ethanol (10
498
•
Vol. 10, No. 3, 2006 / Organic Process Research & Development