The crude wet cake was suspended in acetonitrile (235 kg) and
a small sample (2 L) retained for seeds. The product was
recrystallized by heating the suspension to 70 °C to dissolve
the solid, cooling to 65 °C and seeding with the sample from
above, and cooling to -5 °C over 18 h. The product 6 was
collected by filtration, washed with acetonitrile (2 × 20 kg)
and dried under vacuum at 60 °C for 16 h to afford 14.9 kg
(89%) as a white solid. MP: 200-202 °C. 1H NMR (DMSO-
d6) δ 1.26 (s, 12 H) 2.25 (s, 3 H) 6.72-6.82 (m, 1 H) 7.06 (dd,
J ) 11.3, 8.3 Hz, 1 H) 7.47 (d, J ) 8.5 Hz, 2 H) 7.59 (d, J )
8.5 Hz, 2 H) 7.97 (dd, J ) 7.9, 2.0 Hz, 1 H) 8.49 (d, J ) 2.5
Hz, 1 H) 9.17 (s, 1 H). 13C NMR (DMSO-d6) δ 20.9, 24.8,
83.2, 114.1 (d, J ) 19.18 Hz), 116.0, 116.7, 120.6, 122.4 (d, J
) 7.7 Hz), 126.5 (d, J ) 10.7 Hz) 133.1 (d, J ) 3.0 Hz) 135.1,
141.9, 149.8 (d, J ) 237.4 Hz), 151.4. IR (KBr) 3387, 1669,
1553, 1397, 1357, 814, 654 cm-1. MS (ESI): 371.0 m/e (M +
H). Anal. Calcd for C20H24BFN2O3: C 64.88, H 6.53, N 7.57;
found C 65.04, H 6.57, N 7.60.
1-(4-(3-Amino-1H-indazol-4-yl)phenyl)-3-(2-fluoro-5-me-
thylphenyl)urea (1). First-Generation Process. To a suspension
of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 4 (10.7
kg, 48.8 mol) in toluene (100 kg) was added 1-fluoro-5-
methylphenylisocyanate 5 (7.7 kg, 50.9 mol), and the resulting
mixture was warmed to 50 °C and stirred for 1 h. After cooling
to 25 °C, the excess isocyanate was quenched with ethanol (26
kg), and the mixture was allowed to stir for 30 min.
4-Iodo-1H-indazol-3-amine 3 (10.6 kg, 40.9 mol), sodium
carbonate (10.0 kg, 94.3 mol) and 1,1-bis (diphenylphosphino)
ferrocene palladium dichloride (400 g, 0.49 mol) were sus-
pended in the mixture from above, ethanol (75 kg) and water
(100 kg). The resulting mixture was purged of oxygen by
bubbling nitrogen through for 30 min. The reaction was heated
to reflux and stirred for 6 h. After cooling to 20 °C, EtOAc
(300 kg) and 20% NH4Cl in water (80 kg) were added, and the
mixture was stirred for 30 min and allowed to settle for 30 min,
and the bottom layer was discarded. The organic layer was
washed with 20% NH4Cl in water (160 kg) and water (100
kg) by mixing together for 30 min, settling for 30 min and
discarding the lower layers. The organic layer was then treated
with Filterol GR (15 kg) for 4 h and filtered. The organic layer
was distilled under reduced pressure (5-10 Torr) to ∼180 L.
The distillation was continued and the solvent level maintained
at 180 L with continuous addition of toluene (240 kg), during
which the product crystallized. After cooling the product slurry
to 20 °C, the product was collected by filtration, washed with
toluene (2 × 80 kg) and dried under a flow of nitrogen for 1 h.
The product wet cake was dissolved in EtOAc (400 kg) and
EtOH (175 kg), treated with Filterol GR (10 kg) for 4 h and
filtered. Concentrated HCl (7.0 kg) was added to the filtrate,
and after stirring at 20 °C for 4 h the volume was reduced to
half by vacuum distillation (5-10 Torr). The product HCl salt
was collected by filtration, washed with EtOAc (2 × 30 kg)
and dried under vacuum at 50 °C for 16 h to afford 9.3 kg
(57%) as a white solid.
with Darco G60 carbon (1.5 kg) for 4 h and then filtered. The
resulting solution was distilled under reduced pressure (5-10
Torr) to ∼300 L. The distillation was continued and the solvent
level maintained at 300 L with continuous addition of EtOH
(605 kg). The resulting suspension was heated to 70 °C to
dissolve the bulk of the material and cooled to 20 °C; the
crystallization was completed by the addition of water (375 kg).
The product was collected by filtration, washed with water (2
× 50 kg) and dried under vacuum at 70 °C for 4 h to afford
7.9 kg (46%) as a white solid.
Second-Generation Process. 4-Chloro-1H-indazol-3-amine
10 (21.6 kg, 129 mol), 1-(2-fluoro-5-methylphenyl)-3-(4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea 6 (50.0
kg, 135 mol) and K3PO4 (54.7 kg, 260 mol) were suspended
in water (165 kg) and ethanol (345 kg) which was purged of
oxygen (<100 ppm, Alpha-Omega Oxygen Analyzer, series
3000) by bubbling nitrogen through the mixture before addition
to the solids. The catalyst solution was prepared by first purging
ethanol (55 kg) to <10 ppm oxygen by bubbling with nitrogen,
then adding the ethanol to a combination of Pd(OAc)2 (580 g,
2.6 mol, 2 mol %) and 1,1′-bis(di-tert-butylphosphino)ferrocene
(1.22 kg, 2.6 mol, 2 mol %) and heating the mixture to 55 °C
for 45 min. The catalyst was then transferred to the suspension
of reactants and the reaction mixture heated to 55 °C for 1.5 h.
After cooling to 20 °C, EtOAc (1100 kg) and 20% NH4Cl in
water (170 kg) were added, and the mixture was stirred for 30
min and allowed to settle for 30 min, and the bottom layer was
discarded. The organic layer was washed with 20% NH4Cl in
water (410 kg) and water (270 kg) by mixing together for 30
min, settling for 30 min, and discarding the lower layers. The
organic layer was distilled under reduced pressure (5-10 Torr)
to ∼600 L. The distillation was continued and the solvent level
maintained at 600 L with continuous addition of toluene (820
kg), during which the product crystallized. After cooling the
product slurry to 20 °C, the product was collected by filtration,
washed with toluene (2 × 260 kg) and dried under a flow of
nitrogen for 1 h. The product wet cake was suspended in EtOAc
(1380 kg) and EtOH (300 kg), and conc. HCl (102 kg) was
added. After stirring at 20 °C for 4 h, the product HCl salt was
collected by filtration, washed with EtOAc (2 × 100 kg) and
dried under vacuum at 50 °C for 16 h to afford 49.0 kg (92%)
as a white solid.
The HCl salt was suspended in EtOAc (1200 kg) and EtOH
(525 kg) and washed with a solution of Na2HPO4 ·7H2O (46
kg) in water (1335 kg) and a solution of NaH2PO4 (23 kg) in
water (490 kg). The resulting solution of freebase was filtered
through a 0.5 µm in-line filter and treated with Filterol GR (41
kg) for 4 h. After filtration, the solution was treated with
Acticarbone CPL carbon (9 kg) for 4 h and then filtered. The
resulting solution was distilled under reduced pressure (5-10
Torr) to ∼1300 L. The distillation was continued and the solvent
level maintained at 1300 L with continuous addition of EtOH
(2720 kg). EtOH (560 kg) was added to the resulting suspension,
and it was heated to 50 °C to dissolve the bulk of the material
and cooled to 20 °C, and the crystallization was completed by
the addition of water (1280 kg). The product was collected by
filtration, washed with water (2 × 200 kg) and dried under
vacuum at 70 °C for 4 h to afford 40.9 kg (84% overall yield)
The HCl salt was suspended in EtOAc (300 kg) and EtOH
(130 kg) and washed with a solution of Na2HPO4 ·7H2O (7.5
kg) in water (225 kg) and a solution of NaH2PO4 (4.0 kg) in
water (225 kg). The resulting solution of freebase was treated
1424
•
Vol. 13, No. 6, 2009 / Organic Process Research & Development