PAPER
Green Synthesis of a Naphthyridine Derivative
3431
2
1
5 °C for 2 h to give 5 as a white solid; yield: 258.2 g (84%); mp
06–110 °C.
Anal. Calcd for C H N O: C, 66.15; H, 7.40; N, 20.57. Found: C,
65.93; H, 7.66; N, 20.64.
1
5
20
4
HPLC Assay: >98% [Prodigy ODS-2 C , 5 mm, 150 mm × 4.6 mm,
1
8
5
-Bromo-2-(2-methylmorpholin-4-yl)[1,6]naphthyridine (3b)
flow rate = 1 mL/min, 40 °C, isocratic, A–B ( 35:65)]; 8 t = 1.9
R
A 12-L, four-necked, round-bottomed flask was charged with
CH Cl (3.7 L) and HBr (33 wt% solution in glacial AcOH, 1.24 kg,
5.05 mol). The solution was cooled to 0 °C. A solution of 11 (241
min, 5 t = 6.7 min.
R
2
2
1
H NMR (500 MHz, CDCl ): d = 7.84 (d, J = 8.2 Hz, 1 H), 7.30 (d,
3
J = 8.2 Hz, 1 H), 2.77 (s, 3 H).
g, 0.84 mol) in CH Cl (1 L) was added, causing an exotherm from
2
2
1
3
0 to 25 °C. The mixture was stirred at 25 °C for an additional 30 min
to give a slurry. The reaction was monitored by HPLC until conver-
sion was completed. The solid was collected by filtration, rinsed
with CH Cl (2 L), and air-dried for 16 h. The dried solid was dis-
C NMR (125 MHz, CDCl ): d = 162.9, 154.4, 142.3, 121.9, 116.1,
3
1
07.9, 23.5.
Anal. Calcd for C H ClN : C, 55.10; H, 3.30; Cl, 23.24; N, 18.36.
7
5
2
2
2
Found: C, 55.04; H, 3.31; Cl, 23.05; N, 18.31.
solved in a mixture of MeOH–H O (1:6, 7 L) and filtered. To the fil-
2
trate was added slowly aq sat. NH OH (28%, 360 g) at 25 °C until
pH ~9.0 was reached. The resulting slurry was cooled to 0 °C and
stirred for an additional 30 min. The solid was collected by filtra-
4
2
-Methyl-6-(2-methylmorpholin-4-yl)nicotinonitrile (10)
A 12-L, four-necked, round-bottomed flask was charged with 6-
chloro-2-methylnicotinonitrile (5; 152.6 g, 1.0 mol), (R)-(+)-2-
methylmorpholine (9) as its hydrochloride (165.1 g, 1.2 mol),
MeCN (2 L), and DIPEA (387.6 g, 3.0 mol). The mixture was heat-
ed to 80 °C and stirred for an additional 11 h. The reaction was mon-
itored by HPLC until the conversion was completed. The mixture
was cooled to 25 °C and aq 0.5 N HCl (1.4 L) was added. H O (5 L)
was added slowly at 25 °C. The resulting slurry was cooled to 0 °C
and stirred for an additional 1 h. The solid was collected by filtra-
tion, rinsed with H O (2 L), and dried in vacuo at 50 °C for 16 h to
2
obtain 3b as an off-white solid; yield: 256 g (99%); mp 139–142 °C.
HPLC Assay: >98% [Prodigy ODS-2 C , 5 mm, 150 × 4.6 mm,
18
flow rate = 1 mL/min, 40 °C, isocratic, A–B (50:50)]; 11 t = 3.33
R
min, 3b t = 5.48 min.
R
2
1
H NMR (400 MHz, CDCl ): d = 8.19 (d, J = 5.8 Hz, 1 H), 8.14 (d,
3
J = 9.4 Hz, 1 H), 7.35 (d, J = 5.8 Hz, 1 H), 6.97 (d, J = 9.4 Hz, 1 H),
4.40 (d, J = 12.9 Hz, 1 H), 4.32 (d, J = 13.1 Hz, 1 H), 4.03 (dd,
J = 11.6, 2.5 Hz, 1 H), 3.59–3.71 (m, 2 H), 3.14 (dt, J = 12.1, 2.9
Hz, 1 H), 2.79 (dd, J = 13.1, 10.2 Hz, 1 H), 1.28 (d, J = 6.3 Hz, 3 H).
13
tion, rinsed with H O (5 L), and dried in vacuo at 35 °C for 24 h to
give 10 as a white solid; yield: 206 g (95%); mp 89–92 °C.
2
HPLC Assay: >98% [Prodigy ODS-2 C , 5 mm, 150 × 4.6 mm,
flow rate = 1 mL/min, 40 °C, isocratic, A–B (50:50)]; 5 t = 3.87
min, 10 t = 5.15 min.
1
8
R
C NMR (100 MHz, CDCl ): d = 159.0, 152.6, 146.3, 143.6, 137.8,
3
R
120.3, 119.5, 111.0, 71.7, 66.3, 50.6, 44.2, 18.8.
1
H NMR (400 MHz, CDCl ): d = 7.55 (d, J = 8.8 Hz, 1 H), 6.41 (d,
+
3
HRMS: m/z [M + H] calcd for C H BrN O: 308.0398; found:
13 14 3
J = 8.8 Hz, 1 H), 4.23 (d, J = 12.9 Hz, 1 H), 4.15 (d, J = 13.1 Hz, 1
H), 3.99 (dd, J = 11.6, 3.5 Hz, 1 H), 3.55–3.67 (m, 2 H), 3.01 (dt,
J = 12.6, 3.5 Hz, 1 H), 2.66 (dd, J = 13.1, 10.6 Hz, 1 H), 2.54 (s, 3
H), 1.24 (d, J = 6.1 Hz, 3 H).
3
08.0364.
[
4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl][2-(2-methyl-
morpholin-4-yl)[1,6]naphthyridin-5-yl]amine (1)
A 12-L, four-necked, round-bottomed flask was charged with 3b
1
3
C NMR (100 MHz, CDCl ): d = 161.6, 158.7, 140.7, 118.8, 103.0,
3
(
74.0 g, 0.24 mol), 4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl-
9
5.6, 71.5, 66.2, 50.3, 43.9, 23.6, 18.8.
3
amine (2; 71.2 g, 0.264 mol), i-PrOH (2.4 L), and MeSO H (57.7
3
Anal. Calcd for C H N O: C, 66.34; H, 6.96; N, 19.34. Found: C,
6
12
15
3
g, 0.6 mol). The mixture was heated to 83 °C and stirred for an ad-
ditional 6 h. The reaction was monitored by HPLC until the conver-
5.92; H, 7.26; N, 19.49.
sion was completed. The mixture was cooled to 40 °C. H O (2.8 L),
2
2
-(2-Dimethylaminovinyl)-6-(2-methylmorpholin-4-yl)nicoti-
EtOAc (1.6 L), and sat. aq NaHCO (2.0 L) were added. The mix-
3
nonitrile (11)
ture was allowed to heat to 40 °C to give a solution. The organic
A 3-L, three-necked, round bottomed flask was charged with 10
phase was separated, washed with sat. aq NaHCO (400 mL), and
3
(169.6 g, 0.78 mol) and anhyd DMF (1.7 L). The mixture was heat-
concentrated in vacuo to remove i-PrOH. The concentrated solution
was diluted with EtOAc (2.2 L) and washed in sequence with sat. aq
ed to 150 °C. tert-Butoxybis(dimethylamino)methane (Bredereck’s
reagent, 449 g, 2.58 mol) was added in one portion. The mixture
was allowed to heat to 135 °C and stirred for an additional 1.5 h.
The reaction was monitored by HPLC until the conversion was
completed. The mixture was cooled to 25 °C and evaporated at
NaHCO (500 mL) and brine (1 L). The organic layer was concen-
3
trated in vacuo until the final volume of 1.5 L was reached. The re-
sulting solution was filtered and evaporated. The residue was
dissolved into MeOH (4.8 L) at 64 °C and stirred for an additional
7
0 °C/18 mmHg to obtain an oily residue (275 g), which solidified
3
0 min to obtain a slurry, which was cooled to 20 °C and stirred for
upon cooling. A solution of MTBE–heptane (1:1, 1.1 L) was added
to give a slurry, which was cooled to –20 °C and stirred for an ad-
ditional 30 min. The solid was collected by filtration, rinsed with a
precooled (–20 °C) solution of MTBE–heptane (1:1, 800 mL), and
dried in vacuo at 25 °C for 16 h to afford 11 as a beige solid; yield:
an additional 1 h. The solid was collected by filtration and dried in
vacuo at 60 °C for 16 h to afford 1 as an off-white solid; yield: 87.3
g (75%); mp 167–170 °C.
HPLC Assay: 99% [Prodigy ODS-2 C , 5 mm, 150 × 4.6 mm, flow
18
rate = 1 mL/min, 40 °C, isocratic, A–B (50:50)]; 3b t = 5.48 min,
1
99.3 g (89%); mp 130–133 °C.
R
2
t = 2.14 min, 1 t = 2.85 min.
R R
HPLC Assay: >98% [Prodigy ODS-2 C , 5 mm, 150 × 4.6 mm,
flow rate = 1 mL/min, 40 °C, isocratic, A–B (50:50)]; 10 t = 5.15
min, 11 t = 3.33 min.
1
8
Chiral HPLC Assay: 99% ee [Chiralcel OJ-H, 5 mm, 150 × 4.6 mm,
flow rate = 1.0 mL/min, 40 °C, isocratic, hexane–EtOH–
R
R
MeOH = 70:15:15; UV: l = 278 nm]; (R)-1 t = 16.9 min, (S)-1
1
R
H NMR (400 MHz, CDCl ): d = 7.63 (d, J = 12.4 Hz, 1 H), 7.39 (d,
3
tR = 19.4 min.
J = 8.8 Hz, 1 H), 6.12 (d, J = 8.8 Hz, 1 H), 5.36 (d, J = 12.6 Hz, 1
H), 4.13 (t, J = 15.7 Hz, 2 H), 3.97 (dd, J = 11.6, 2.5 Hz, 1 H), 3.54–
1
H NMR (400 MHz, CDCl ): d = 8.14 (s, 1 H), 8.06 (d, J = 6.0 Hz,
3
1
H), 8.01 (d, J = 9.1 Hz, 1 H), 7.87 (s, 1 H), 7.74 (s, 1 H), 7.37–7.43
3
.67 (m, 2 H), 2.98 (dd, J = 12.9, 3.5 Hz, 1 H), 2.93 (s, 6 H), 2.63
(m, 3 H), 7.22–7.31 (m, 2 H), 7.00 (d, J = 6.0 Hz, 1 H), 6.77 (d,
(
dd, J = 12.6, 10.4, Hz, 1 H), 1.22 (d, J = 6.3 Hz, 3 H).
J = 9.5 Hz, 1 H), 4.35 (d, J = 12.9 Hz, 1 H), 4.24 (d, J = 12.9 Hz, 1
H), 4.01 (d, J = 11.7 Hz, 1 H), 3.60–3.72 (m, 2 H), 3.09 (dt, J = 3.1,
1
3
C NMR (100 MHz, CDCl ): d = 160.0, 158.3, 146.6, 141.0, 120.0,
3
1
00.0, 92.3, 90.0, 71.4, 66.3, 50.5, 43.8, 40.6, 18.8.
1
2.6 Hz, 1 H), 2.74 (t, J = 10.7 Hz, 1 H), 1.28 (d, J = 6.3 Hz, 3 H).
Synthesis 2010, No. 20, 3429–3432 © Thieme Stuttgart · New York