m, multiplet), number of protons, coupling constant(s) in
hertz. Mass spectra were recorded with a Finnagan LCQ
mass spectrometer. All new compounds were characterized
by full spectroscopic and analytical data, and yields refer to
spectroscopically homogeneous materials. Microanalyses
were performed by the Abbott Analytical Department.
4,5-Dibromo-2-(3,4-difluorophenyl)-2H-pyridazin-3-
one (5). To a 3 L flask equipped with a mechanical stirrer,
thermometer, an additional funnel, and a reflux condenser
under nitrogen was added 3,4-difluroanilline (4) (32.0 g),
followed by 480 mL of 12% HBr at -5 °C with a cooling
bath. A NaNO2 solution (18.0 g in 180 mL H2O) was added
slowly over 30 min keeping the reaction temperature < 0
°C. After the addition was complete, the light brown solution
was stirred for 30 min at -10 °C to -5 °C. A solution of
SnCl2 (112.0 g of SnCl2 dissolved in 480 mL of 24% HBr)
was slowly added at -10 °C to -5 °C over 1 h. The reaction
mixture was stirred at -10 °C to -5 °C. After 1 h, HPLC
analysis indicated the reaction was complete. Mucobromic
acid6 (64.0 g) was added all at once as a solid. The resulting
mixture was heated to reflux until less than 1 area % of
hydrazine remained. The mixture was allowed to cool slowly
to room temperature overnight, whereupon the product
precipitated out of solution. The product was isolated by
filtration and washed with water. The solid was dried to
constant weight at 50 °C with a N2 bleed. The yield of
product 5 was 62.6 g (68.9% yield). Mp: 187-190 °C.
mately 12%. The solution assayed for 8.3 kg (78% of theory)
of compound 6. The product is typically 88-91 HPLC area%
and is contaminated with 4-9% regioisomer and 2-6% bis-
ether. Spectral data: 1H NMR (CDCl3/300 MHz): δ 7.94
(s, 1H), 7.51 (ddd, J ) 3.7, 2.3, 0.9 Hz, 1H), 7.37 (m, 1H),
7.28 (m, 1H), 4.75 (t, J ) 6.6 Hz, 2H), 2.50 (bs, 1H), 2.03
(t, J ) 6.6 Hz, 2H), 1.32 (s, 6H). MS m/e 390 (M + H)+.
Anal. Calcd for C15H15BrF2N2O3: C,46.29; H, 3.88; N, 7.20.
Found C, 46.35; H, 3.89; N, 7.11.
2-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-
5-(methylsulfanylphenyl)-2H-pyridazin-3-one (7). A ni-
trogen purged reaction vessel was charged with 4-(methylthio)-
phenylboronic9 acid (4.2 kg), palladium(II) acetate (46 g),
triphenylphosphine (108 g), potassium tribasic phosphate (4.4
kg), and potassium dibasic phosphate (7.2 kg). The mixture
was evacuated and purged (nitrogen/vacuum) 3 times. The
alkoxylated bromide 6 in IPA solution (40.1 kg) was added.
The mixture was agitated and purged (nitrogen/vacuum) 4
times. The mixture was heated to 70-75 °C for 3.5 h until
<0.6 A% starting material remained as monitored by HPLC
analysis. After the reaction mixture was cooled to 25 ( 5
°C, distilled water (40 kg) and EtOAc (80.1 kg) were added.
The solution was stirred for 30 min, and the aqueous layer
was removed. The organic layer was washed with 10%
aqueous potassium phosphate (2 × 80.2 kg), 5% aqueous
NaHCO3 (80.2 kg), and saturated aqueous NaCl (80 kg). The
solvent was distilled at 50 °C to a volume of 40 L, and
EtOAc (80.5 kg) was added after the reaction mixture cooled
to 30 °C and a GC sample was taken. The reaction mixture
was distilled again at 50 °C under vacuum to 40 L. This
procedure was repeated until the GC analysis of the amount
of IPA in the EtOAc solvent was less than 3%. Heptane (42.5
kg) was added, and a sample was taken for GC analysis.
Additional heptane or EtOAc was then added to adjust the
heptane/EtOAc ratio determined by GC to approximately 2:1.
Silica gel (3 kg) was added, and the mixture was heated to
70 °C for 30 min. While hot, the mixture was filtered through
a cartridge filter. The filtrate was distilled under vacuum at
35 °C to a volume of approximately 70 L. A GC sample
was taken, and the ratio of solvents was determined. Based
on this analysis, EtOAc and heptane were added to give a
ratio of approximately 1:4 and an overall volume of 120 L
of solvent. The solution was heated to 70 °C for 30 min,
and then the solution was allowed to cool at a rate of 5 °C
per hour to 5 °C. The solid was not filtered until the
supernatant level was less than 10 mg/mL. After 10 h at 5
°C, the supernatant level was 7.1 mg/mL. The solid was
filtered and washed with cold 6:1 heptane/EtOAc (25 kg)
and heptane (40 kg). The wetcake was dried at 45-50 °C
in a vacuum oven with a nitrogen purge to yield 6.75 kg
(76%) of product having a potency of 98.4%. An additional
0.832 kg (9.4%) of product was recovered from the walls of
the reactor having a potency of 98%. The overall weight
adjusted yield of recovered, isolated product 7 was 84%. The
palladium content of the crystallized product was 50 mcg/g.
Analysis of the mother liquors showed another 0.977 kg
(11%) of product giving a HPLC yield of 95% for this
1
Spectral data: H NMR (CDCl3/300 MHz): δ 7.94 (s, 1H),
7.52 (ddd, J ) 3.7, 2.3, 0.9 Hz, 1H), 7.42-7.39 (m, 1H),
7.32-7.22 (m, 1H). MS m/e 367 (M + H)+. Anal. Calcd
for C10H4Br2F2N2O: C,32.82; H, 1.10; N, 7.65. Found: C,
32.71; H, 1.10; N, 7.74.
5-Bromo-2-(3,4-difluorophenyl)-4-(3-hydroxy-3-meth-
ylbutoxy)-2H-pyridazin-3-one (6). Into a reactor was
charged 3-methyl-1,3-butanediol (3.43 kg, 32.98 mol) and
THF (45 kg). The resulting solution was cooled to -20 °C
and was charged with a 1 M solution of NaHMDS in THF
(29.9 kg, 33.1 mol). Into a different reactor was charged with
4,5-dibromo-pyridazine-6-one (5) (10.5 kg @ 95% potency
or 9.98 kg, 27.26 mol) and THF (245 kg). The resulting
mixture was cooled to -20 °C, and the previously prepared
alkoxide/THF solution was charged at such a rate as to
maintain an internal temperature < -8 °C. The mixture was
stirred at -20 °C until less than 1 area% dibromide remains.
The reaction mixture was quenched by transferring the
reaction mixture into a reactor containing precooled 13%
NH4Cl (316 kg), while maintaining an internal temperature
of <25 °C. The pH of the quenched reaction mixture was
adjusted to 3 with 3 M HCl (typically 22 kg). The biphasic
reaction was allowed to settle for typically 30 min. The
bottom layer was discarded. The organic layer was filtered
into another reactor to remove any emulsionary solids. The
filter was washed with EtOAc (245 kg). The filtrates were
combined and washed twice with 200 kg of water. The
organic extract was concentrated to minimum volume, and
the solvent was switched to IPA by chasing twice with IPA
(65 kg). The reaction mixture was concentrated to a final
volume such that the product concentration was approxi-
1
reaction. Spectral data: H (CDCl3) δ 7.96 (s, 1H), 7.61 (m,
516
•
Vol. 10, No. 3, 2006 / Organic Process Research & Development