Organic Process Research & Development
Article
CDCl3): δ 1.41−1.63 (m, 6H), 1.71−1.81 (m, 2H), 1.81−1.94
(m, 1H), 2.17−2.26 (m, 2H), 2.33 (s, 2H), 2.4 (td, J = 11.7,
2.3, 2H), 2.92 (d, J = 11.8, 2H), 3.46 (s, 1H), 3.71−3.84 (m,
4H), 3.91−4.10 (m, 4H), 4.24 (d, J = 5.9, 2H), 5.03−5.08 (m,
1H), 6.50 (d, J = 8.2, 1H), 7.00 (d, J = 8.2, 1H), 7.38 (t, J = 8.2,
1H). 13C NMR (101 MHz, CDCl3): δ 29.11, 33.10, 35.20,
36.92, 36.96, 56.15, 63.93, 67.14, 67.46, 68.27, 72.94, 74.06,
78.37, 103.17, 105.15, 131.71, 152.71, 166.02, 166.28. MP =
92.6 °C. HRMS (ESI+): calcd for (C23H32O6N2 + H)+
433.23331, found 433.23216.
6-Fluorobenzisoxazole (19). To a 500 mL RBF were
charged Potassium Hydroxide (38.9 g; 3 equiv; 0.693 mol) and
water (160 mL; 4 vol). 2,6-difluoro-N-hydroxybenzamide 26
(40.1 g, 0.231 mol) was then added and the mixture heated
with the jacket temperature set to 110 °C with stirred for 20 h.
HPLC analysis determined that no starting material remained
and the batch was cooled to 20−25 °C. The pH was then
adjusted to 1 with the addition of 4 N HCl (150 mL) where the
mixture became a thick slurry. The mixture was diluted with
water (100 mL) to aid stirring and then granulated for 2 h at
20−25 °C. The crude product was filtered and washed with
water (3 vol, 120 mL) and dried on the filter overnight. The
crude product that was 93% purity by HPLC analysis was then
reworked. The crude cake (79 g, wet) was taken up in MeOH
(7.9 vol, 320 mL) and heated to 50 °C until the solids dissolved
to a brown solution. Activated carbon (Darco G-60, 15 wt %, 6
g) and Celite (15 wt %, 6 g) were charged to the reactor and
stirred at 50 °C for 30 min and then filtered. The carbon cake
was washed with MeOH (3 vol, 120 mL). The resulting light
brown solution was concentrated to about 300 mL on rotovap
and mixture became a thick slurry. Water (200 mL) was added
resulting in a thick slurry that was granulated at room
temperature for 2 h. The product, a fine white powder was
filtered, washed with 50% MeOH/water (100 mL) and dried in
a vacuum oven at 40 °C for 16 h. The product, 6-
fluorobenzisoxazole 19 (25.0 g, 0.156 mol) was isolated in
67% yield. Additional product was recovered in a second crop
from the filtrate. 1H NMR (400 MHz, d6-DMSO at 2.50 ppm):
δ 7.09 (dd, J = 10.0, 8.0, 1H), 7.40 (d, J = 8.4, 1H), 7.61 (td, J =
8.2, 5.4, 1H), 12.69 (br, 1H). 13C NMR (101 MHz, d6-DMSO
at 39.51 ppm): δ 103.91 (d, J = 20.6), 106.78 (d, J = 4.4),
108.57 (d, J = 18.4), 132.51 (d, J = 8.1), 155.17 (d, J = 255.8),
163.44 (d, J = 7.5), 165.17 (d, J = 5.9).
PF-04995274−10 Hemicitrate Salt (27). To a 100L
reactor charged 2-propanol (73.5 L) and PF-04995274 (5.88
kg, 13.6 mol) and heated at 50 °C until all solids had dissolved.
The solution was then transferred into a spec and fiber free
200L reactor via in in-line 0.5 μm filter with a 2-propanol rinse
(29.4 L) and held at 50 °C. To the 100L reactor were charged
2-propanol (73.54 L) and PF-04995274 (5.76 kg, 13.3 mol)
and heated at 50 °C until all solids had dissolved to prepare a
second portion of the free base solution. This solution was also
filtered through the inline spec free filter into the 200L reactor.
The 100L reactor was rinsed with 2-propanol (29.4 L) and sent
into the 200L reactor via the in-line filter. The mixture was
concentrated under partial vacuum at 50 °C until a total of 118
L remained in the 200L reactor.
Methyl 2,6-Difluorobenzoate (25). To a 50 mL jacketed
reactor were charged 2,6-difluorobenzoic acid (23.00 g, 145.5
mmol), methanol (115 mL) and sulfuric acid (17.6 g, 175
mmol, 1.2 equiv). The jacket temperature was heated to 60 °C
and the reaction mixture was stirred for 40 h. The reaction was
sampled by HPLC analysis and determined to be greater than
97% complete. The reaction mixture was then concentrated
under vacuum and approximately 110 mL of methanol
distillates were collected. The resulting thin oil was cooled to
20 °C. Water (142 mL) and ethyl acetate (115 mL) were
charged to the reactor, and the product extracted into the
organic layer. The EtOAc solution was washed with a solution
of 10% sodium bicarbonate (140 mL) followed by saturated
sodium chloride (115 mL). The resulting EtOAc solution was
concentrated to thin pale oil. Isolated thin oil; methyl 2,6-
difluorobenzoate 25 (21.58 g, 125.4 mmol, 86% yield, 99.8%
1
LC purity). H NMR (400 MHz, CDCl3): δ 7.46−7.36 (m,
1H), 6.95 (t, J = 8.7, 2H), 3.95 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 161.95 (m), 159.37 (d, J = 5.9), 132.73 (t, J = 10.6),
111.95 (m), 110.95 (m) 52.71.
2,6-Difluoro-N-hydroxybenzamide (26). To a 1L
Jacketed reactor charged hydroxylamine hydrochloride (22.5
g, 1.11 equiv, 0.323 mol) and Water (100 mL) and cooled the
resulting slurry to 0−5 °C. A solution of potassium hydroxide
(63.9 g, 1.14 equiv, 0.333 mol) in Methanol (200 mL; 4 vol)
was slowly charged to the 1L reactor while maintaining a
temperature below 10 °C. Then a solution of methyl 2,6-
difluorobenzoate 25 (50.0 g, 0.292 mol) in MeOH (50 mL, 1
vol) was added to the reactor over 15 min while maintaining
the temperature below 10 °C. Additional MeOH (50 mL, 1
vol) was used to rinse the addition funnel into the reactor and
the resulting mixture was stirred at 0−5 °C for 60 min and then
heated to 20−25 °C and monitored by HPLC for consumption
of SM. After 16 h, the starting material was undetected by
HPLC analysis. The reaction mix was then distilled to remove
methanol by setting the reactor jacket temperature to 45 °C
while maintaining a pot temperature of less than 30 °C under a
vacuum of 100−200 mbar. Additional water was added (100
mL, 2 vol) and continued distillation until the batch was
reduced to about 250 mL total volume. The mixture was cooled
to 20 °C and quenched with conc HCl (37%, 85 mL, 1.75 wt
eq). A thick white slurry formed during this exothermic
addition while acidifying to pH = 1. The aqueous mixture was
extracted with EtOAc (4 × 250 mL). The combined EtOAc
layers (1L) were washed with water (250 mL, 5 vol) and dried
over Na2SO4, filtered and concentrated to an off white solid 26
To the 100 L reactor charged 2- propanol (58.8 L) and citric
acid (2.87 kg, 15.0 mol) and heated at 50 °C until all of the
solids had dissolved. Then the citric acid solution was charged
to the 200L reactor via a new 0.5 μm in-line filter over 2 h and
rinsed with 2-propanol (2 L). The resulting slurry was stirred at
50 °C for 2 h and then cooled to 20 °C over 2 h. The citrate
salt was granulated at 20 °C for 12 h and then filtered on a
Nutsche filter and washed with 2-propanol (59 L). The wet
cake was transferred to a vacuum oven and dried at 40 °C for
44 h. The isolated product, PF-04995274−10 (27) (13.86 kg,
26.22 mol) was obtained in 96% yield. 1H NMR (400 MHz, d6-
DMSO at 2.50 ppm): δ 7.54−7.48 (m, 1H), 7.12 (d, J = 8.6,
1H), 6.76 (d, J = 8.2, 1H), 5.20−5.14 (m, 1H), 4.20 (d, J = 6.2,
2H), 3.98−3.92 (m, 1H), 3.89−3.75 (m, 3H), 3.66−3.54 (m,
4H), 3.19 (d, J = 11.7, 2H), 2.65−2.50 (m, 6H), 2.26 (dtd, J =
13.8, 8.1, 5.9, 1H), 2.07−1.97 (m, 1H), 1.97−1.85 (m, 1H),
1
(44.2 g; 255 mmol; 87% yield). H NMR (400 MHz, d6-
DMSO): δ 7.25−1.10 (m, 2H), 7.6−7.45 (m, 1H), 9.46 (s,
1H), 11.21 (s, 1H). 13CNMR (101 MHz, d6-DMSO set at
39.51 ppm): δ 111.91, 112.16, 113.21, 132.21, 156.57, 157.99,
160.46 ppm. DSC (MP = 122 °C with immediate exothermic
decomposition, −965 J/g). DSC (MP = 122 °C; 133 °C onset,
−965 J/g).
H
Org. Process Res. Dev. XXXX, XXX, XXX−XXX