8) cooled to 20 °C. The filtrate was washed with CH2Cl2 (2 ×
500 mL) and concentrated under reduced pressure (55 °C, 25
mmHg). The residue was dried by suspending it in toluene (1
L) and evaporating the solvent. This was repeated with more
toluene (1 L) and MeOH (2 × 500 mL) to afford 18 (sodium/
potassium salt) as a white solid, 320.1 g (calculated to contain
139.9 g, 70%). The yield was calculated by taking an aliquot
of the solid (9.2 mg), dissolving it in D2O, and adding a known
amount of a solution of citric acid in D2O. NMR was then used
to compare the relative molar amounts of 18 and citric acid.
The weight of 18 (4.02 mg) in the aliquot was then calculated,
and from that, the weight of 18 in the crude product. 1H (400
MHz, D2O) δ 2.13 (s, 3H), 7.63 (d, J ) 8 Hz, 1H), 8.12 (d, J
) 8 Hz, 1H). LC/MS (Phenomenex Luna C18, 0.05% formic
acid/MeCN/water, 15 min gradient 5-95% MeCN, 1 mL/min)
Rt ) 3.82 min, 97% purity (UV), m/z 258, 260 (M+), 280, 282
(MNa+), remainder being starting material, m/z 228, 230 (M+).
Methyl 6-Amino-5-bromopyridine-2-carboxylate (3). Con-
centrated sulphuric acid (160 mL) was added over 30 min to
MeOH (1600 mL) with ice-bath cooling. The resulting solution
was added to crude 18 (124.9 g, calculated to contain 0.213
mol), and the resulting suspension heated under reflux for 24 h.
LCMS (Phenomenex Luna C18, 0.05% formic acid/MeCN/
water, 15 min, gradient 5-95% MeCN, 1 mL/min) showed Rt
) 5.23 min, 93% purity (uv), m/z 230, 232 (M+), remainder Rt
) 3.23 min, m/z 216, 218 (M+, 6-amino-5-bromopyridine
carboxylic acid 14. The mixture was cooled and concentrated
under reduced pressure to give a thick, white slurry, which was
poured into a mixture of water (1.5 L) and EtOAc (800 mL).
The mixture was cooled in an ice bath whilst concentrated
aqueous ammonia (250 mL) was added over 30 min with
stirring. The phases were separated and the aqueous phase
extracted with EtOAc (800 mL). The combined organic
solutions were dried (MgSO4) and concentrated under reduced
pressure. The residue (pale yellow solid, 48.3 g) was suspended
in MTBE (100 mL) for 1.5 h and the product collected by
filtration to give 3, (43.14 g, 68%; 48% from 16) as a colourless
for 15 min, and then the previously prepared solution of 2,3,5-
trichlorophenylboronic acid in THF was added over 1 h,
maintaining the temperature below 30 °C. The transfer lines
were rinsed with THF (2.8 L, 1 mL/g)), and this was added to
the mixture. The reaction mixture was then stirred under
nitrogen at 25 °C for 1 h before analysis to confirm reaction
completion. Arbocel filter aid (2.64 kg, 0.94 g/g) was added to
the reaction mixture and stirred for 45 min before filtering
through a bed of Arbocel (0.50 kg, 0.18 g/g). The filter cake
was transferred back into the reaction vessel and suspended in
THF (42 L, 15 mL/g) with stirring for 45 min and then filtered
through a bed of Arbocel (0.50 kg, 0.18 g/g). The filter cake
was then suspended in THF and filtered through Arbocel once
more using the same procedure. The transfer lines were rinsed
with THF (2.8 L, 1 mL/g) and this was added to the filter cake.
The combined filtration liquors were clarified through a ceramic
filter, and EtOAc (25.2 kg, 28.0 L, 10 mL/g) was added. The
reaction mixture was heated to distill the volume down to
approximately 28 L, and then a further charge of EtOAc (25.2
kg, 28.0 L, 10 mL/g) was made. The reaction mixture was again
heated to distill the volume down to approximately 20 L to
crystallise the product. The mixture was then cooled down to
20 °C over 3.5 h and stirred at 20 °C overnight (12 h). The
suspension was filtered, and the filter cake was washed with
EtOAc (2 × 1.4 L, 0.5 mL/g). The product was then dried under
vacuum overnight at 40 °C to give 20 as a crystalline solid
(3.08 kg, 9.29 mol, 77%). The product may be purified as
follows: 20 (3.07 kg, 9.26 mol) was added to EtOAc (15.3 L,
5 mL/g) and heated to reflux for 1 h to give a slurry. The
mixture was then cooled to 20 °C over 3.5 h and stirred at this
temperature overnight (13.5 h). The product was then filtered
and washed with EtOAc (2 × 1.5 L, 0.5 mL/g) and dried under
vacuum overnight at 40 °C to give 20 as a crystalline solid
(2.86 kg, 8.63 mol, 93% yield); the residual palladium content
1
was 257 ppm. Mp ) 197 °C (from EtOAc); H (400 MHz,
DMSO-d6) δ 3.83 (s, 3H), 6.19 (s, 2H), 7.28 (d, J ) 7.62, 1H),
7.43 (s, 1H), 7.44 (d, J ) 7.81, 1H), 7.89 (d, J ) 2.54, 1H);
13C (100 MHz, DMSO-d6) δ 52.04, 112.87, 120.72, 129.71,
130.01, 130.33, 132.27, 133.32, 138.49, 139.30, 146.11, 156.38,
165.41. HRMS m/z Found 330.9815 [M + H]+ C13H10Cl3N2O2
requires 330.9802; νmax. (neat) 3449, 3280, 3171, 2947, 1749,
1734, 1623, 1570, 1548, 1469, 1450, 1320, 1246, 1118, 1026,
827, 787 cm-1.
1
solid, mp ) 143 -145 °C. H (400 MHz, CDCl3) δ 3.95 (s,
3H), 7.36 (d, J ) 7.8 Hz, 1H), 7.78 (d, J ) 7.8 Hz, 1H). 13
C
(100 MHz, CDCl3) δ 52.9, 109.3, 116.5, 141.1, 145.3, 155.7,
165.5; m/z (ES+) 231, 233 (MH+); νmax. (neat) 3463, 3272, 3147,
3009, 1714, 1615, 1578, 1463, 1444, 1335, 1299, 1255, 1195,
1161, 1114, 1018, 839, 777, 742 cm-1; Anal. Calcd
(C7H7BrN2O2): C, 36.39; H, 3.05; N, 12.12. Actual: C, 36.22;
H, 3.03; N, 12.13.
Methyl 6-Amino-5-(2,3,5-trichlorophenyl) Pyridine-2-
carboxylate (20). THF (53.2 L, 19 mL/g) was sparged with
nitrogen at 25 °C for 15 min, and then a portion (11.1 L, 4
mL/g) was removed and used to make up a solution of 2,3,5-
trichlorophenylboronic acid (2.87 kg, 12.74 mol, 1.05 equiv)
in a separate vessel. To the remaining 42.1 L of THF was added
3 (2.80 kg, 12.12 mol) with stirring. Potassium fluoride (2.32
kg, 39.9 mol, 3.3 equiv) and water (218 mL, 12.12 mol, 1.0
equiv) were then added, and the mixture was stirred for 20 min
under nitrogen. Tris(dibenzylideneacetone)dipalladium (0.33 kg,
0.364 mol, 0.03 equiv) was then added followed by tri-tert-
butylphosphonium tetrafluoroborate (0.211 kg, 0.727 mol, 0.06
equiv). The reaction mixture was sparged with nitrogen again
N-Methyl-6-amino-5-(2,3,5-trichlorophenyl)pyridine-2-
carboxamide (1). Compound 20 (2.81 kg, 8.47 mol) was added
to THF (8.43 L, 3 mL/g) with stirring at 20 °C under nitrogen.
Methylamine (33% in EtOH, 11.2 L, 90.5 mol, 4 mL/g) was
then added over 20 min, and the reaction was stirred at 25 °C
for 5 h. The reaction mixture was transferred to a larger vessel,
and the transfer line was rinsed with THF (8.43 L, 3 mL/g)
and added to the reaction. Activated carbon (Darco KB, 2.11
kg, 0.75 g/g) was then added, and the mixture was stirred for
1.5 h. The reaction mixture was then filtered through Arbocel
filter aid (2.2 kg, 0.8 g/g), and the filter cake was washed with
THF (4.21 L, 1.5 mL/g). The reaction solution was slowly
heated to reflux to degas the methylamine. EtOH (denatured
with cyclohexane, 8.43 L, 3 mL/g) was then added, and the
solution was distilled down to a volume of approximately 11
270
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Vol. 14, No. 1, 2010 / Organic Process Research & Development