(12 L) and warmed to ∼75 °C for 16-20 h or until judged
complete by HPLC. The reaction was cooled to ∼10 °C, and
the pH was adjusted to ∼8 with 3 N NaOH. The resulting solids
were filtered and washed with water (10 L). The solids were
dried at 50 °C for 16 h to yield 13 as an off-white solid (2.81
kg, 72% yield) 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1
H) 8.66 (s, 1 H) 7.72 (s, 1 H) 7.42 (s, 1 H) 7.35 (s, 1 H). HPLC
tR ) 4.09 min.
(s, 3 H) 3.59-3.64 (m, 1 H) 2.66 (m, 1 H) 2.64 (s, 1 H) 2.53
(s, 1 H) 1.76 (s, 1 H) 1.64 (s, 1 H) 1.50 (s, 1 H) 1.39 (s, 1 H)
1.24 (m, 3 H). 97:3 dr by achiral HPLC. Achiral HPLC tR’s
for each diastereomer: major ) 3.40 min, minor ) 3.52 min.
(8S)-N-Methyl-5,6,7,8-tetrahydro-8-quinolinamine, Ox-
alic Acid Salt (12 Oxalate). A slurry of sodium triacetoxy-
borohydride (2.44 kg, 11.5 mol) and 5 (2.17 kg, 7.7 mol) in
dichloromethane (21.8 L) was cooled to 5 °C. Formaldehyde
solution (37 wt % in water, 744 mL, 10 mol) was added slowly
to maintain the temperature <25 °C. The solution was stirred
for 30 min at 22 °C. The reaction was then quenched slowly
with trifluoroacetic acid (7.3 L, 95 mol). Upon completion of
the addition, the reaction was warmed up to 30 °C and stirred
for 16 h. Water (11 L) was added, and the two phases were
separated. The aqueous phase was washed with dichloromethane
(14 L), and the combined organic phases were washed with
water (2 × 5.5 L). The organic phase was discarded. The pH
of the aqueous phase was raised to 8.5-9 by the addition of 6
N NaOH and the aqueous layer extracted with dichloromethane
(3 × 13 L). The dichloromethane was exchanged for isopro-
panol by vacuum distillation to achieve a final volume of ∼7
5 L. This solution was then treated with a solution of oxalic
acid (588 g, 6.5 mol) in isopropanol (2.2 L) to induce
precipitation. After stirring for 2 h, the suspension was filtered
at 22 °C, and the solids were dried under vacuum at 22 °C to
afford 12 oxalate as a white solid (1.07 kg, 55% yield) 1H NMR
(300 MHz, DMSO-d6) δ 9.25 (br s, 1 H) 8.52 (s, 1 H) 7.69 (s,
1 H) 7.39 (s, 1 H) 4.39 (s, 1 H) 2.82 (s, 2 H) 2.65 (s, 3 H) 2.50
(s, 1 H) 2.32 (s, 1 H) 1.99 (s, 1 H) 1.80 (s, 1 H). Achiral HPLC
tR ) 1.87 min.
5-(4-Methyl-1-piperazinyl)imidazo[1,2-a]pyridine-2-car-
baldehyde, Oxalic Acid Salt (9 Oxalate). N-Methylpiperazine
(3.1 kg, 31 mol) and tetrahydrofuran (10 L) were combined
and stirred under nitrogen while cooling to -20 °C. n-Butyl
lithium (2.5 M in hexanes, 10.4 L, 26.0 mol) was added to the
reaction at a rate to maintain the temperature <-20 °C.
The contents were stirred for 15-30 min after the end of the
addition. A slurry of 13 (2.79 kg, 12.4 mol) in tetrahydrofuran
(10 L) was added at a rate to maintain the reaction temperature
<0 °C. The slurry was washed with additional tetrahydrofuran
(6 L). The reaction was stirred for 30 min and warmed to ∼-10
°C. After completion as determined by HPLC, the reaction was
quenched by the addition of 6 N HCl to achieve pH 4.0 while
maintaining the temperature <15 °C. The reaction was diluted
with heptane (14 L), and the layers were separated. The lower
(aqueous) layer was drained from the reactor, and the upper
(organic layer) was washed with 1 N HCl (2 × 1.5 L). The
combined aqueous layers were stirred at 20 °C and adjusted to
pH 9 with 4 N NaOH. The aqueous layer was extracted with
10% iPrOH/CH2Cl2 (3 × 28 L), and the combined organic
layers were washed with saturated NaHCO3 solution (14 L)
and evaporated at <25 °C to ∼8.5 L. Isopropanol (28 L) was
added, and the solution was concentrated under reduced pressure
to ∼8.5 L. Isopropanol (17 L) was added, and the reaction was
treated with a solution of oxalic acid (1.0 kg, 11.1 mol) in
isopropanol (7 L) at a rate to maintain good stirring and the
temperature between ∼25-40 °C. The reaction was stirred for
30 min, and the solids were collected and washed with
isopropanol (8.5 L). The solids were dried at 50 °C to yield 9
For (8S)-N-methyl-5,6,7,8-tetrahydro-8-quinolinamine as free
base: 1H NMR (CDCl3) δ 8.37 (d, 1H), 7.36 (d, 1H), 7.06 (dd,
1H), 3.65 (m, 1H), 2.76 (m, 2H), 2.53 (s, 3H), 2.11 (m, 1H),
1.97 (m, 1H), 1.75 (m, 2H); MS m/z 163 (M + 1).
[5-(4-Methyl-1-piperazinyl)-2-({methyl[(8S)-5,6,7,8-tet-
rahydro-8-quinolinyl]amino}methyl)imidazo[1,2-a]pyridin-
3-yl]methanol (GSK812397). A slurry of sodium triacetoxy-
borohydride (1.86 kg, 8.78 mol) and 12 oxalate (1.3 kg, 5.15
mol) in dichloromethane (13 L) was stirred at 20 °C. A solution
of 9 oxalate (2.07 kg, 6.18 mol) and triethylamine (1.25 kg,
12.4 mol) in dichloromethane (6.5 L) was added to the reaction
at a rate to maintain the temperature <30 °C. The reaction was
stirred at 20 °C for 16 h. The reaction was then quenched with
2 N NaOH to achieve pH 12 (∼13 L). Methanol (6 L) was
added to obtain a bilayer. The lower (organic) layer was
separated and the aqueous layer washed with dichloromethane
(4 × 5 L). The combined organic layers were evaporated to
minimum stir volume (∼6 L), and the solvent was exchanged
for water to achieve a final volume of 6.5 L. This solution was
maintained at 40 °C and treated with 37% aqueous formalde-
hyde (2.7 L, 35 mol). The solution was stirred at 40 °C for
24 h, and additional formaldehyde solution was added (1.35 L,
18 mol). The reaction was stirred for 72 h, cooled to 25 °C,
and treated with saturated aqueous sodium bicarbonate (5.2 L)
and dichloromethane (6.5 L). The layers were separated, and
the aqueous layer was washed with additional dichloromethane
(2 × 6.5 L). The combined organic layers were washed with
saturated aqueous sodium bicarbonate (4 L), and the organic
1
oxalate as a white solid (2.25 kg, 54% yield) H NMR (400
MHz, DMSO-d6) δ 10.01 (s, 1 H) 8.47 (s, 1 H) 7.41 (m, 2 H)
6.65 (m, 1 H) 3.34 (s, 8 H) 2.78 (s, 3 H); HPLC tR ) 2.69 min.
(8S)-N-{(1S)-1-[4-(Methyloxy)phenyl]ethyl}-5,6,7,8-tet-
rahydro-8-quinolinamine (5). A slurry of sodium triacetoxy-
borohydride (4.54 kg, 21.4 mol) in dichloromethane (22 L) was
treated with 6,7-dihydro-8(5H)-quinolinone (1.8 kg, 12.3 mol),
followed by (1S)-1-[4-(methyloxy)phenyl]ethanamine (1.8 kg,
11.9 mol). The reaction was stirred vigorously at 22 °C for 24 h.
The reaction was quenched with 1 N NaOH (27 L) to achieve
pH 8 in the aqueous layer. The phases were separated, and
the organic phase was treated with 1 N NaOH (3.5 L) to achieve
pH 11 in the aqueous layer. The phases were separated. The
dichloromethane solution was then concentrated to ∼6 L and
treated with heptane (18 L). The volume was concentrated to
9 L. Precipitation occurred upon cooling to 22 °C. The
suspension was further cooled to 0 °C and filtered. The solids
were dried at ambient temperature under vacuum with a slight
nitrogen bleed to give 5 as a light brown solid (2.18 kg, 63%).
1H NMR (400 MHz, DMSO-d6) δ 8.36 (m, 1 H) 7.44 (m, 1 H)
7.29 (m, 2 H) 7.15 (m, 1 H) 6.83 (m, 2 H) 4.00 (m, 1 H) 3.70
784
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Vol. 13, No. 4, 2009 / Organic Process Research & Development