Organic Process Research & Development
ARTICLE
dissolved in water (85 L), and then acid 23 (2.5 kg; 4.38 mol) and
20 wt % Pd(OH)2/C (50% water wet; 250 g) were added and
were rinsed into the vessel with water (4 L). The mixture was
hydrogenated at 60 °C and 8.3 bar hydrogen pressure until
hydrogen uptake ceased (90 min). The mixture was cooled to
20 °C and placed under nitrogen. Arbocel (2.5 kg) was added,
followed by a water wash (10 L), and the mixture was stirred at
20 °C for 40 min. The slurry was then filtered through a Gauthier
filter, washing with water (20 L). The aqueous solution was
concentrated under vacuum (∼100 mbar) at 50 °C to a volume
of 11 L, and then a vacuum distill and replace operation was
performed at 50 °C with acetonitrile until all water had been
removed (maintaining ∼11 L volume, around 20 L acetonitrile
used). The mixture was cooled to 20 °C over 2 h and was then
granulated for 16 h. The solid was isolated by filtration, washing
with acetonitrile (4.6 L) and was dried at 40 °C under vacuum to
(2H, ddd, J = 10.2, 8.4, 2.2 Hz), 6.83 (3H, m), 4.44 (1H, dd, J =
7.6, 4.9 Hz), 4.32 (2H, d, J = 5.9 Hz), 3.46 (3H, s), 3.45ꢀ3.20
(1H, br. s), 2.91 (1H, s), 2.65 (2H, m), 2.56 (2H, s), 0.93 (3H, s),
0.91 (3H, s). 13C NMR (100 MHz, DMSO-d6) δ: 170.2, 157.1,
149.7, 140.2, 139.9, 138.4, 135.7, 135.4, 131.1, 130.8, 128.7,
128.4, 127.6, 127.5, 126.5, 125.2, 124.7, 124.4, 124.2, 124.0,
123.8, 115.7, 115.1, 72.0, 52.7, 50.2, 46.3, 42.5, 42.2, 26.6, 26.4.
LCMS: found m/z 618.27 [M + H]+. Anal. Calcd For
C34H39N3O6S: C, 66.10; H, 6.36; N, 6.80; S, 5.19. Found: C,
65.53; H, 6.29; N, 6.54; S, 5.12.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: pieter.de.koning@pfizer.com.
1
give sodium salt 24a as a light brown solid (1.38 kg; 69%). H
NMR (400 MHz, DMSO-d6) δ: 7.14 (1H, d, J = 2.2 Hz), 7.08
(2H, m), 6.98 (1H, br. s), 6.87 (2H, m), 6.75 (1H, d, J = 8.2 Hz),
4.41 (1H, dd, J = 7.6, 4.7 Hz), 3.25 (2H, s), 2.81 (3H, s),
2.70ꢀ2.59 (2H, m), 2.55 (2H, s), 0.93 (3H, s), 0.92 (3H, s). 13C
NMR (100 MHz, DMSO-d6) δ: 174.5, 150.1, 138.1, 137.6,
134.7, 131.2, 127.4, 127.0, 126.8, 122.0, 114.8, 72.2, 52.6, 50.2,
46.4, 45.0, 26.7, 26.5. LCMS: found m/z 437.21 [M + H]+.
N-[(40-Hydroxybiphenyl-3-yl)methyl]-2-[3-(2-{[(2R)-2-hydro-
xy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl]-
amino}-2-methylpropyl)phenyl]acetamide, 8. A slurry of so-
’ ACKNOWLEDGMENT
We thank Watcharee Cooper, Isabelle LeMaitre, and Guy
Matthews for analytical support; Dave Clifford, Matt Morland,
and John Williams for large scale support; and Stuart Field, Steve
Fussell, Ben Mathews and Neal Sach for reaction and purification
screening.
’ REFERENCES
dium salt 24a (1.6 kg; 3.49 mol) and hydrochloride salt 6 HCl
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3
(905 g; 3.84 mol) in pyridine (12.8 L) was stirred at 25 °C for
30 min, and then 1-(dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (803 g; 4.19 mol) was added in one portion. The
resulting mixture was stirred at 25 °C for 12 h, at which point
HPLC analysis indicated complete conversion. The mixture was
distilled under reduced pressure at 40ꢀ50 °C down to a volume of
8 L. A distill and replace procedure with ethanol under reduced
pressure at 40ꢀ50 °C was then used to remove the pyridine (target
NMT 5% pyridine remaining), giving a final volume of 8 L. The
vacuum was released, and demineralized water (17.6 L) was added
at a constant rate over 1 h, maintaining the temperature at 45ꢀ
50 °C. The resulting suspension was cooled to 20 °C over 2 h and
was stirred at 20 °C for 12 h. The solid was isolated by filtration,
washing with a 1:1 mixture of ethanol and water (2 ꢁ 3.2 L), and
dried under suction for 1 h. The filter cake was dried under vacuum
at 40 °C for 24 h to give crude 8 (1.73 kg, 2.8 mol, 80%).
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acetone (40.7 L) and water (5.1 L), and the mixture was heated
to reflux to give a solution. The hot solution was filtered through
a 1.2 μm filter, washing with acetone (5 L). The filtered solution
was concentrated to 20 L by distillation and then cooled to 20 °C
over 4 h. The resulting slurry was granulated for 16 h, then the
solid was isolated by filtration, washing twice with a mixture of
filtered acetone (1.9 L) and filtered water (0.64 L). After being
blown dry for 30 min, the damp cake was recharged to the vessel,
and a mixture of filtered methanol (8.1 L) and filtered water
(0.45 L) was added. The slurry was refluxed for 3 h, then cooled
to 20 °C over 4 h, and then granulated for 16 h. The solid was
isolated by filtration, washing twice with a mixture of filtered
methanol (1.0 L) and filtered water (90 mL), and then tray dried
at 40 °C under vacuum to give 8 (576 g; 45%) as an off-white
solid. Mp 198 °C; 1H NMR (400 MHz, DMSO-d6) δ: 8.53 (1H,
t, J = 5.9 Hz), 7.41 (4H, m), 7.32 (1H, t, J = 7.6 Hz), 7.20 (1H,
m), 7.17 (1H, d, J = 7.4 Hz), 7.13 (2H, m), 7.09 (1H, m), 7.01
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dx.doi.org/10.1021/op2001904 |Org. Process Res. Dev. 2011, 15, 1247–1255