1 h. Product was collected by filtration, rinsed with n-heptane
(5 L), and dried at 40 °C under vacuum for 16 h to obtain 35
(1.5 kg, 81% yield) as a solid: HPLC purity >99%; 1H NMR
(400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.07 (d, J ) 5.6 Hz,
1H), 7.46 (d, J ) 8.9 Hz, 2H), 7.04 (d, J ) 9.0 Hz, 2H), 6.60
(s, 2H), 6.04 (d, J ) 5.6 Hz, 1H), 1.47 (s, 9H). 13C NMR (100
MHz, DMSO-d6) δ 169.8, 163.6, 159.9, 152.9, 146.9, 136.6,
121.9, 119.4, 95.7, 79.0, 28.1.
(d, J ) 5.3 Hz, 1H), 7.97 (s, 1H), 7.63 (d, J ) 8.5 Hz, 1H),
7.58 (d, J ) 8.5 Hz, 1H), 7.50 (d, J ) 8.8 Hz, 1H), 7.09 (d, J
) 8.8 Hz, 1H), 6.59 (s, 1H), 6.07 (d, J ) 5.7 Hz, 1H), 3.53 (s,
2H), 2.51 - 2.29 (m, 10H), 0.98 (t, J ) 7.2 Hz, 3H); 13C NMR
(125 MHz, DMSO-d6) δ 169.8, 163.7, 159.9, 152.6, 147.1,
138.8, 136.5, 131.3, 130.0, 127.6, 125.5, 122.0, 121.6, 119.8,
115.0, 95.8, 57.4, 52.8, 52.4, 51.6, 12.0. Anal. Calcd for
C25H28F3N7O2H2O: C, 56.28; H, 5.67; N, 18.38; F, 10.68.
Found: C, 56.16; H, 5.60; N, 18.36; F, 10.58. HPLC for 39S
(tR ) 8.57 min); 2 (tR ) 5.98 min): Alltech Inertsil ODS-2 5
µm C-18 150 mm × 4.6 mm, flow rate ) 1.0 mL/min, 40 °C,
gradient elution from 10:90 A:B to 65:35 A:B over 15 min; A
) acetonitrile; B ) 0.05 M NaH2PO4 (pH 2.5).
4-(4-Amino-phenoxy)pyrimidin-2-ylamine Dihydrochlo-
ride Salt (17S). To a 12-L flask equipped with a mechanical
stirrer, thermocouple, addition funnel, nitrogen inlet/outlet, and
a gas bubbler connected to 2 N NaOH solution were charged
compound 35 (700 g, 2.32 mol) and EtOAc (2.8 L). The mixture
was stirred at 25 °C for 15 min to obtain a homogeneous paste.
A solution of 6 N HCl in IPA (3 L) was charged all at once
and stirred for an additional 24 h. EtOAc (1.4 L) was added to
the slurry and stirred for an additional 30 min. Product was
collected by filtration, rinsed with EtOAc (1.4 L), and dried at
25 °C under vacuum for 16 h to obtain 17S (dihydrochloride
salt) (647 g, 100% yield) as a solid: mp 237-238 °C; HPLC
purity 99%; 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, b, 4H),
8.96 (s, b, 1H), 8.71 (s, b, 1H), 8.39 (d, J ) 7.0 Hz, 1H), 7.52
(d, J ) 8.8 Hz, 2H), 7.41 (d, J ) 8.8 Hz, 2H), 6.72 (d, J ) 7.0
Hz, 1H). Anal. Calcd for C10H12Cl1N4O: C, 43.65; H, 4.40; N,
20.23; Cl, 25.77. Found: C, 44.00; H, 4.26; N, 20.14; Cl, 25.95.
HPLC for 35 (tR ) 3.57 min); 17S (tR ) 2.28 min): Phenom-
enex Ultracarb ODS-30 5 µm C-18 250 mm × 4.6 mm, flow
rate ) 1.0 mL/min, 20 °C, isocratic, 75:25 A:B; A )
acetonitrile; B ) water.
1-[4-(2-Amino-pyrimidine-4-yloxy)phenyl]-3-[4-(4-meth-
yl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]urea (3 )
AUZ454). Aniline dihydrochloride 17S (488 g, 1.8 mol),
piperazine hydrochloride 44 (725 g, 1.7 mol), DMSO (2.4 L),
and diisopropylethylamine (725 g, 5.6 mol) were charged to a
5-L flask equipped with a mechanical stirrer, thermocouple,
heating/cooling capacity, an addition funnel, and a nitrogen inlet/
outlet. The mixture was heated to 60-65 °C, stirred for an
additional 2 h, and cooled to 50 °C. An aqueous solution of
potassium hydroxide (375 g) in water (750 mL) was added to
the mixture while maintaining the temperature between 50-57
°C. The solution was transferred to a 22-L flask equipped with
a mechanical stirrer, thermocouple, heating/cooling capacity,
addition funnel, and nitrogen inlet/outlet. Water (1 L) was added
at 50-55 °C followed by seeds. More water (6.5 L) was
charged at 50-55 °C over 1 h. The resulting slurry was cooled
to 25 °C over 1 h. Product was collected by filtration, rinsed
with water (2 L), and dried at 50 °C under vacuum (5 mmHg)
for 16 h to obtain 3 (827 g, 100% yield, HPLC assay 98%) as
a solid. To improve the purity of drug substance, 3 was
dissolved in ethanol (8.2 L, 200 proof) at 50 °C. The resulting
brown solution was filtered through a filter paper into a 22-L
flask equipped with a mechanical stirrer, thermocouple, heating/
cooling capacity, an addition funnel, and a nitrogen inlet/outlet.
The solution was heated to reflux (78 °C) and water (8.2 L)
was charged over 45 min while maintaining the temperature
between 71-75 °C. The mixture was first cooled to 60 °C over
1 h to obtain a slurry and then cooled again to 25 °C over 2 h.
Product was collected by filtration, rinsed with a mixture of
ethanol/water (2 L, 1:1 ratio), and dried at 50 °C under vacuum
(5 mmHg) for 16 h to obtain purified 3 (750 g, 91% yield) as
a solid: mp 144-147 °C; HPLC purity >99%. 1H NMR (500
MHz, DMSO-d6) δ 8.97 (s, 1H), 8.78 (s, 1H), 8.09 (d, J ) 5.7
Hz, 1H), 7.97 (s, 1H), 7.62 (d, J ) 8.9 Hz, 1H), 7.58 (d, J )
8.9 Hz, 1H), 7.50 (d, J ) 8.8 Hz, 1H), 7.09 (d, J ) 8.8 Hz,
1H), 6.60 (s, 1H), 6.07 (d, J ) 5.6 Hz, 1H), 3.53 (s, 2H),
2.51-2.30 (m, 8H), 2.15 (s, 3H); 13C NMR (125 MHz, DMSO-
d6) δ 169.8, 163.6, 159.9, 152.6, 147.1, 138.8, 136.5, 131.3,
130.0, 127.4, 125.5, 122.0, 121.6, 119.8, 115.0, 95.8, 57.4, 54.7,
52.6, 45.7. Anal. Calcd for C24H26F3N7O21.5H2O: C, 54.99; H,
5.53; N, 18.53. Found: C, 54.28; H, 5.28; N, 18.42. HPLC for
44 (tR ) 8.31 min); 3 (tR ) 5.80 min): Alltech Inertsil ODS-2
5 µm C-18 150 mm × 4.6 mm, flow rate ) 1.0 mL/min, 40
°C, gradient elution from 10:90 A:B to 65:35 A:B over 15 min;
A ) acetonitrile; B ) 0.05 M NaH2PO4 (pH 2.5).
1-[4-(2-Amino-pyrimidin-4-yloxy)phenyl]-3-[4-(4-ethyl-
piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]urea (2 )
ATH686). Piperazine hydrochloride 39S (745 g, contains 9%
THF, 1.5 mol corrected), aniline 27 (488 g, dihydrochloride
salt, 1.8 mol), DMSO (2 L), and diisopropylethylamine (693
g, 5.4 mol) were charged to a 5-L flask, equipped with a
mechanical stirrer, thermocouple, heating/cooling capacity,
addition funnel, and nitrogen inlet/outlet. The mixture was
heated to 65 °C, stirred for an additional 2 h, and then cooled
to 50 °C. An aqueous solution of potassium hydroxide (375 g)
in water (750 mL) was charged to the mixture while maintaining
the batch temperature between 48-50 °C. More water (7 L)
was charged to the resulting solution at 50-55 °C over 45 min.
The resulting slurry was cooled to 25 °C. Product was collected
by filtration, rinsed with water (2 L), and dried at 50 °C under
vacuum (5 mmHg) for 16 h to obtain 2 (769 g, 98% yield,
HPLC assay 98%) as a solid. For a higher purity of drug
substance, 2 was dissolved in ethanol (5 L, 200 proof) at 50-55
°C and filtered through a filter paper into a 22-L flask, equipped
with a mechanical stirrer, thermocouple, heating/cooling capac-
ity, addition funnel, and nitrogen inlet/outlet. The solution was
heated to reflux (78 °C, and water (2.5 L) was charged over 45
min while maintaining the temperature between 78-81 °C. The
mixture was seeded, cooled first to 70 °C over 1 h and then to
25 °C over 2 h. Solid was collected by filtration, rinsed with a
mixture of ethanol/water (2 L, 2:1 ratio), and dried at 50 °C
under vacuum (5 mmHg) for 16 h to obtain purified 2 (634 g,
1
82%) as a solid: mp 169-173 °C; HPLC assay >99%; H
NMR (500 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.78 (s, 1H), 8.09
1154
•
Vol. 12, No. 6, 2008 / Organic Process Research & Development