Organic Process Research & Development
Article
the product as a yellow solid. Yield: 4.6 g (90%). Purity (LC-
2-Methoxyquinoline-6-carboxylic Acid (14). 6-Iodo-2-me-
thoxyquinoline (12) (5.7 g, 1.0 equiv) was dissolved in THF
(50 mL). Isopropylmagnesium chloride (11 mL of a 2 M
solution in THF, 1.05 equiv) was added drowise at 0 °C. CO2
gas was added via cannula at −20 °C. 20% aqueous citric acid
solution (60 mL) was added to the reaction mixture. The
mixture was extracted with TBME (2 × 150 mL). The
combined organic layers were washed with H2O (50 mL) and
concentrated to dryness under reduced pressure. The residue
was dissolved in 2 M aqueous NaOH (80 mL) and extracted
with TBME (100 mL). The organic layer was discarded. The
aqueous layer was treated with 32% aqueous HCl (25 mL) at 0
°C and extracted with TBME (300 mL). The organic layer was
washed with H2O (100 mL) and concentrated to dryness on a
rotary evaporator to afford the product as a bright yellow solid.
Yield: 3.9 g (96%). Purity (LC-MS): 100% (210 nm), tR 0.75
MS): 100% (210 nm), tR 0.56 min; [M + 1]+ = 257, mp 290 °C
1
(DSC); H NMR (D6-DMSO) δ: 12.73 (d, 1 H), 8.33 (d, J =
1.8 Hz, 1 H), 8.13 (d, J = 9.3 Hz, 1 H), 7.97 (dd, J1 = 8.7 Hz, J2
= 1.9 Hz, 1 H), 7.53 (d, J = 8.7 Hz, 1 H), 7.29 (d, J = 9.3 Hz, 1
H), 3.77 (m, 4 H), 1.65−1.67 (m, 2 H), 1.58−1.60 (m, 4 H),
13C NMR (D6-DMSO) δ: 167.9, 158.3, 150.6, 138.8, 130.7,
129.6, 126.1, 123.8, 121.8, 111.1, 45.8, 25.9, 24.8.
N-Isopropyl-2-(piperidin-1-yl)quinoline-6-carboxamide
(11). A solution of 2-(piperidin-1-yl)quinoline-6-carboxylic acid
(10) (2.0 g, 1.0 equiv), triethylamine (1.6 g, 2.0 equiv), 50%
T3P solution in CH2Cl2 (5.5 g, 1.1 equiv), and isopropylamine
(0.51 g, 1.1 equiv) in CH2Cl2 (20 mL) was stirred for 16 h at
22 °C. The reaction mixture was extracted with 1 M aqueous
HCl (50 mL) and H2O (2 × 25 mL). The combined aqueous
layers were treated with 32% aqueous NaOH (20 mL) and
extracted with CH2Cl2 (50 mL, 2 × 25 mL). The combined
organic layers were washed with H2O (2 × 20 mL) and
concentrated to dryness under reduced pressure to afford the
product as a beige solid. Yield: 2.0 g (85%). Purity (LC-MS):
100% (210 nm), tR 0.62 min; [M + 1]+ = 298, mp 193 °C
(DSC); 1H NMR (CDCl) δ: 8.07 (d, J = 2.0 Hz, 1 H), 7.90 (d,
J = 9.2 Hz, 1 H), 7.84 (dd, J1 = 2.1 Hz, J2 = 8.7 Hz, 1 H), 7.67
(d, J = 8.7 Hz, 1 H), 7.03 (d, J = 9.2 Hz, 1 H), 6.02 (d, J = 7.3
Hz, 1 H), 4.35 (m, 1 H), 3.77−3.79 (m, 4 H), 1.70−1.72 (m, 6
H), 1.31 (d, J = 6.6 Hz, 6 H), 13C NMR (CDCl3) δ: 166.6,
158.1, 149.9, 137.9, 127.8, 127.0, 127.0, 126.4, 121.8, 110.4,
46.1, 41.9, 25.9, 24.8, 23.0.
1
min; [M + 1]+ = 204, mp 215 °C (DSC); H NMR (D6-
DMSO) δ: 12.99−13.13 (m, 1 H), 8.57 (d, J = 1.7 Hz, 1 H),
8.42 (d, J = 8.9 Hz, 1 H), 8.15 (dd, J1 = 8.7 Hz, J2 = 1.9 Hz, 1
H), 7.84 (d, J = 8.7 Hz, 1 H), 7.11 (d, J = 8.9 Hz, 1 H), 4.03 (s,
3 H), 13C NMR (D6-DMSO) δ: 167.6, 163.9, 148.8, 140.9,
130.9, 129.9, 127.4, 126.8, 124.6, 114.3, 54.0.
2-Methoxyquinolin-6-yl)boronic Acid (15). 6-Iodo-2-me-
thoxyquinoline (12) (5.7 g, 1.0 equiv) was dissolved in THF
(50 mL). Isopropylmagnesium chloride (11 mL of a 2 M
solution in THF, 1.05 equiv) was added dropwise at 0 °C.
Trimethyl borate (4.2 g, 2.0 equiv) in THF (10 mL) was added
at 0 °C. HCl (2 M aqueous, 25 mL) was added, and the
mixture was extracted with iPrOAc (2 × 100 mL). The organic
layer was washed with H2O (2 × 25 mL) and concentrated to
dryness to yield a yellow solid (3.1 g). The solid was dissolved
in 2 N aqueous NaOH (100 mL), and the resulting solution
was washed with iPrOAc (2 × 25 mL). The water phase was
cooled to 0 °C, and 32% aqueous HCl (25 mL) was added. The
resulting suspension was extracted with iPrOAc (2 × 100 mL).
The combined organic layers were washed with H2O (2 × 25
mL) and concentrated to dryness under reduced pressure to
afford the product as a bright yellow solid. Yield: 2.2 g (54%).
Purity (LC-MS): 98.2% (210 nm), tR 0.60 min; [M + 1]+ =
6-Iodo-2-methoxyquinoline (12). 2-Chloro-6-iodoquinoline
5 (51.0 g, 1.0 equiv) was dissolved in toluene (400 mL) and
heated to 80 °C. 25% NaOMe solution in MeOH (122 g, 3.0
equiv) was added to the solution, and the suspension was
stirred for 1 h at 80 °C. The reaction mixture was cooled to 0
°C, and 32% aqueous HCl solution (70 mL) and H2O (160
mL) were added. The organic layer was separated, washed with
H2O (160 mL), and concentrated to dryness on a rotary
evaporator to yield a brown solid (50 g, 97%). The crude
product was dissolved in CH2Cl2 (400 mL) and filtered over
silica gel (50 g). The silica gel was rinsed with CH2Cl2 (200
mL). The combined filtrates were concentrated to dryness to
obtain a yellow solid. Yield: 45.0 g (88%). Purity (LC-MS):
96.9% (210 nm); tR 1.01 min, [M + 1]+ = 286; mp 87 °C
1
204; H NMR (D6-DMSO) δ: 8.31 (s, 1 H), 8.23 (d, J = 8.8
Hz, 1 H), 8.18 (s, 2 H), 8.04 (d, J = 8.3 Hz, 1 H), 7.73 (d, J =
8.3 Hz, 1 H), 7.01 (d, J = 8.8 Hz, 1 H), 4.00 (s, 3 H), 13C NMR
(D6-DMSO) δ: 162.8, 147.6, 140.3, 135.3, 135.2, 129.8−130.9
(m), 126.0, 124.6, 113.2, 53.7.
1
(DSC); H NMR (D6-DMSO) δ: 8.32 (d, J = 1.4 Hz, 1 H),
8.18 (d, J = 8.9 Hz, 1 H), 7.90 (dd, J1 = 8.7 Hz, J2 = 1.6 Hz, 1
H), 7.56 (d, J = 8.7 Hz, 1 H), 7.04 (d, J = 8.9 Hz, 1 H), 3.98 (s,
3 H), 13C NMR (D6-DMSO) δ: 162.8, 145.5, 138.8, 138.4,
136.6, 129.3, 127.4, 114.3, 89.3, 53.8.
2-Chloro-1-(2-methoxyquinolin-6-yl)ethan-1-one (16). 6-
Iodo-2-methoxyquinoline 12 (5.7 g, 1.0 equiv) was dissolved in
THF (50 mL). Isopropylmagnesium chloride (11 mL of a 2 M
solution in THF, 1.05 equiv) was added dropwise at 0 °C. 2-
Chloro-N-methoxy-N-methylacetamide (4.3 g, 1.6 equiv) in
THF (10 mL) was added at −20 °C. The mixture was warmed
to 22 °C and stirred at this temperature overnight. HCl (2 M
aqueous, 25 mL) was added, and the mixture was extracted
with iPrOAc (2 × 100 mL). The organic layers were combined
and washed with H2O (2 × 50 mL) and concentrated to
dryness under reduced pressure. The crude product was
slurried in MeOH (50 mL) to afford a bright yellow solid.
Yield: 3.8 g (81%). Purity (LC-MS): 100% (210 nm), tR 0.92
2-Methoxyquinoline-6-carbaldehyde (13). 6-Iodo-2-me-
thoxyquinoline (12) (5.7 g, 1.0 equiv) was dissolved in THF
(50 mL). Isopropylmagnesium chloride (11 mL of a 2 M
solution in THF, 1.05 equiv) was added dropwise at 0 °C.
DMF (1.5 mL, 1.1 equiv) was added at −20 °C. HCl (2 M
aqueous, 25 mL) was added, and the mixture was extracted
with iPrOAc (2 × 100 mL). The organic layer was washed with
H2O (2 × 25 mL) and concentrated to dryness under reduced
pressure to afford the product as a bright yellow solid. Yield: 3.5
g (93%). Purity (LC-MS): 98% (210 nm), tR 0.84 min; [M +
1]+ = 188, mp 110 °C (DSC); 1H NMR (D6-DMSO) δ: 10.12
(s, 1 H), 8.54 (d, J = 1.8 Hz, 1 H), 8.46 (d, J = 8.9 Hz, 1 H),
8.09 (dd, J1 = 8.6 Hz, J2 = 1.9 Hz, 1 H), 7.91 (d, J = 8.6 Hz, 1
H), 7.16 (d, J = 8.9 Hz, 1 H), 4.04 (s, 3 H), 13C NMR (D6-
DMSO) δ: 192.7, 164.4, 149.9, 141.1, 133.7, 132.6, 128.2,
127.8, 124.9, 114.7, 54.1.
1
min; [M + 1]+ = 236, mp 148 °C (DSC); H NMR (D6-
DMSO) δ: 8.66 (d, J = 1.9 Hz, 1 H), 8.40 (d, J = 8.9 Hz, 1 H),
8.17 (dd, J1 = 2.0 Hz, J2 = 8.8 Hz, 1 H), 7.88 (d, J = 8.8 Hz, 1
H), 7.15 (d, J = 8.9 Hz, 1 H), 5.30 (s, 2 H), 4.04 (s, 3 H), 13
C
NMR (D6-DMSO) δ: 191.4, 164.3, 149.3, 141.1, 130.7, 130.4,
128.6, 127.7, 124.6, 114.7, 54.1, 48.1.
G
Org. Process Res. Dev. XXXX, XXX, XXX−XXX