Iida et al.
vacuum distillation. Water (800 mL) was added to the suspen-
sion, followed by aging at 22 °C for 2 h. The batch was filtered,
and the solids washed with water (2 × 80 mL) and dried at 45
°C to afford 2a (40.8 g, 33% yield). 1H NMR (400 MHz, DMSO-
d6): δ 12.35 (br s, 1H), 9.06 (d, J ) 1.0 Hz, 1H), 8.87 (d, J )
5.0 Hz, 1H), 7.84 (dd, J ) 1.0, 5.0 Hz, 1H), 2.68-2.74 (m, 1H),
1.90-2.11 (m, 6H), 1.76-1.85 (m, 2H). 13C NMR (100.6 MHz,
DMSO-d6): 175.9, 167.9, 150.6, 147.5, 144.9, 133.1, 119.1, 87.2,
38.1, 33.1, 23.9. Anal. Calcd for C13H13NO4: C, 63.15; H, 5.30;
N, 5.67. Found: C, 63.34; H, 5.19; N, 5.65. Mp: 240.5-243.5
°C.31
cis-1′-Oxospiro[1,3′-cyclohexane(1′H)-furo[3,4-c]pyri-
dine]-4-carboxylic Acid Chloride Hydrochloride (16b).
Acid 2b (1.0 g, 4.0 mmol) was combined with oxalyl chloride
(4 mL), DMF (50 µL), and THF (4 mL) and the mixture heated
to 65 °C for 7 h. On cooling to room temperature, the slurry
was filtered, and the flask and cake were washed with THF
(2 × 5 mL). The wet cake was stirred with THF (10 mL) at
room temperature for 10 min and filtered. The solid was dried
in vacuo at 30 °C for 2 h to provide 0.96 g of product 16b as a
colorless powder (79%). 1H NMR (400 MHz, DMSO-d6): δ 9.33
(s, 1H), 8.96 (d, J ) 5.3 Hz, 1H), 8.05 (d, J ) 5.3 Hz, 1H), 2.44
(dt, J ) 12.5, 3.5 Hz, 1H), 2.23 (td, J ) 12.5, 3.5 Hz, 2H), 1.97
(dd, 2H), 1.80 (d, 2H), 1.68 (qd, 2H). 13C (100.6 MHz, DMSO-
d6): δ 176.1, 166.8, 148.5, 147.6, 142.3, 135.4, 120.4, 86.6, 40.5,
34.0, 24.8.
1-(2-Fluorophenyl)-1H-pyrazole-3-amine Tosylate (3a).
To a suspension of 2-fluorophenylhydrazine hydrochloride (4a)
(50 g, 307 mmol; JEMCO, Inc.) in EtOH (300 mL) was added
20 wt % NaOEt in EtOH (293 g, 861 mmol; Nihon Soda).
Ethoxyacrylonitrile (5) (53.8 g, 554 mmol; Degussa) was then
added at ambient temperature. The reaction mixture was
heated to 82 °C and aged for 20 h. The reaction mixture was
cooled to 20 °C, followed by addition of water (250 mL) and 6
N HCl to adjust the pH to 2.9-3.1. The resulting aq EtOH
solution was stirred at 20 °C for 2 h. After treatment with 5
N NaOH and adjusting the solution to pH 6.5-8.0, the reaction
mixture was concentrated to ca. 600 mL, and IpAc (750 mL)
was added. The layers were separated, and the organic layer
was washed with 10% aq NaCl (200 mL). Activated carbon
(Sirasagi P, 1.8 g) was added to the resulting solution at 22
°C. After 2 h, the activated carbon was removed by filtration
through Celite, and the bed was washed with IpAc (1 × 200
mL). The combined organic layers were concentrated to ca. 460
mL.
Compound 2b (free base). 1H NMR (400 MHz, DMSO-
d6): δ 9.12 (d, J ) 0.7 Hz, 1H), 8.86 (d, J ) 5.0 Hz, 1H), 7.83
(dd, J ) 0.7, 5.0 Hz, 1H), 2.43-2.50 (m, 1H), 2.20 (td, J ) 4.0
Hz, 2H), 2.02-1.93 (m, 2H), 1.81-1.64 (m, 4H). 13C NMR
(100.6 MHz, DMSO-d6): δ 176.1, 167.6, 150.0, 147.6, 144.5,
132.8, 118.7, 86.2, 40.5, 34.2, 24.8. Mp: >260 °C.
(b) Via the Ketene-Mediated Isomerization of 2a and
2b. A mixture of spirolactone acids 2a/2b (800 g, 3.23 mol;
55% 2b/45% 2a) obtained from the previously described
metalation reaction (vida supra) was charged to a 50-L vessel
containing THF (17.6 L). The slurry was treated with DMF
(260 mL, 3.2 mol) and then at 22 °C with POCl3 (350 mL, 3.7
mol) over 10 min to form the acid chloride. The solution was
warmed to 40 °C over 45 min, aged for 2 h, and then cooled to
24 °C. In a separate 12-L flask was sequentially added THF
(3.3 L), TMEDA (1.7 L, 11.3 mol), tert-butyl alcohol (465 mL,
4.9 mol), and LiCl (143 g, 3.3 mol). After aging at 25 °C for 1
h, the resulting solution was added to the acid chloride at 24-
30 °C over 25 min and aged for 19 h at 35-39 °C. The reaction
mixture was cooled to 0 °C and quenched by adding 33% aq
H2SO4 (4.2 L) slowly over 20 min, during which time the
internal temperature rose to 22 °C. The resulting solution was
heated to 50 °C for 3 h and then cooled to 22 °C and the pH
adjusted to 2.4 with 6 N NaOH (7.0 kg). The organic layer
was separated, washed with aq HCl/NaCl (pH 2.5, 2 × 8 L),
and azeotropically dried via a constant volume distillation at
atmospheric pressure until the KF was <0.3%. The solution
of spirolactones 2a/2b was cooled to 22 °C, and concentrated
HCl (60 mL) was slowly added to the solution. The resulting
slurry was aged at 25 °C for 3 h, and the precipitate (2b‚HCl)
removed via filtration and washed with THF (1 × 1 L). The
filtrate containing trans-spirolactone acid 2a was concentrated
to 6.5 L in vacuo (internal temp ) 38-42 °C), and the resulting
slurry cooled to 22 °C over 1 h and aged for 1 h. Heptane (6 L)
was added over 2 h and the slurry was cooled to 0 °C and aged
for 20 h, followed by vacuum filtration. The product cake was
rinsed with THF-heptane (2/3, 2 × 600 mL) and dried in
vacuo at 45 °C to provide 2a (445 g, 97.8% purity). NMR values
were identical to previously reported values (vida supra).
trans-1′-Oxospiro[1,3′-cyclohexane(1′H)-furo[3,4-c]pyr-
idine]-4-carboxylic Acid Chloride Hydrochloride (16a).
Acid 2a (2.1 g, 8.50 mmol) was combined with THF (18 mL)
and DMAC (3 mL) at 35 °C for 10 min and then the mixture
cooled to 2 °C, followed by the dropwise addition of thionyl
chloride (0.78 mL, 10.7 mmol). The solution was aged at 2 °C
for 1 h, warmed to room temperature, aged for 1 h, and then
cooled to 2 °C for 30 min prior to isolation by filtration. The
cake was washed with THF (1 × 7 mL) and hexanes (1 × 7
mL) followed by drying in vacuo at room temperature to a
constant weight (2.44 g, 77%). Compound 16a exists as a 1:1
A solution of TsOH‚H2O (27.1 g 142.2 mmol) in EtOH (67
mL) was added to the pyrazole solution over 3 h, followed by
IpAc (53 mL) over 1 h at 22 °C. The mixture was stirred at 22
°C for 14 h, cooled to 0 °C, aged for 2 h, and filtered. The cake
was washed with EtOH-IpAc (1:9, 84 mL) and IpAc (84 mL)
1
and then dried in vacuo at 30 °C to give 3a (66.5 g, 62%). H
NMR (400 MHz, DMSO-d6): δ 9.68 (br s, 3H), 8.24 (dd, J )
2.0, 2.0 Hz, 1H), 7.72 (dd, J ) 8.0, 8.0 Hz, 1H), 7.51-7.42 (m,
4H), 7.37 (dd, J ) 7.6, 7.6 Hz, 1H), 7.12 (d, J ) 8.0 Hz, 2H),
6.44 (d, J ) 2.3 Hz, 1H), 2.28 (s, 3H). 13C NMR (125.7 MHz,
DMSO-d6): δ 153.57 (d, J ) 248.8 Hz), 145.23, 144.59, 137.93,
134.16 (d, J ) 7.2 Hz), 129.12 (d, J ) 7.9 Hz), 128.14, 127.3
(d, J ) 9.6 Hz), 125.5, 125.47 (d, J ) 5.4 Hz), 124.7, 117.1 (d,
J ) 19.9 Hz), 101.0, 20.8. Anal. Calcd for C22H19FN4O3S: C,
55.00; H, 4.62; N, 12.03. Found: C, 55.13; H, 4.51; N, 12.00.
Mp: 142-145 °C.
1-(2-Fluorophenyl)-1H-pyrazole-3-amine Hydrochlo-
ride (3b). An ethanolic solution (24 mL) of free base 3 (5.87
assay g, 33 mmol) was treated with 4N HCl/EtOAc (9.1 mL,
36.4 mmol) over 30 min at 22 °C. The resulting slurry was
aged at 22 °C for 1 h, followed by the addition of EtOAc (132
mL) over 2 h. The slurry was aged at 22 °C for 13 h and
filtered. The cake was washed with EtOAc (1 × 25 mL) and
dried in vacuo to give 3b (6.4 g, 91% recovery). 13C NMR data
(100.6 MHz, DMSO-d6): δ 153.9 (d, J ) 249 Hz), 144.2, 134.4,
129.5 (d, J ) 7.9 Hz), 127.6 (d, J ) 9.7 Hz), 125.1, 117.5 (d,
J ) 19.9 Hz), 101.7. Anal. Calcd for C9H9ClFN3: C, 50.60; H,
4.25; N, 19.67. Found: C, 50.45; H, 4.01; N, 19.57. Mp: 146-
149 °C.
trans-N-[1-(2-Fluorphenyl)-1H-pyrazol-3-yl]-1′-oxospi-
ro[cyclohexane-1,3′(1′H)-furo[3,4-c]pyridine]-4-carboxa-
mide (1). Dimethylacetamide (DMAC; 5.65 L) was charged
to a nitrogen-purged flask, followed by acid 2a (712 g, 2.85
mol) at 22 °C. The solution was cooled to -14 °C and treated
with thionyl chloride (357 g, 3.0 mol) over 30 min. The internal
temperature did not exceed -10 °C during the addition. The
solution was aged at -10 °C for 10 min and then treated over
1 h at -11 ((3) °C with a previously prepared solution of
1
THF solvate. H NMR (400 MHz, DMSO-d6): δ 9.24 (d, J )
0.8 Hz, 1H), 8.94 (d, J ) 5.2 Hz, 1H), 8.03 (dd, J ) 0.8, 5.2 Hz,
1H), 3.58 (m, 4H), 2.70 (m, 1H), 2.12-2.10 (m, 4H), 1.97-1.87
(m, 2H), 1.84-1.76 (m, 2 H), 1.74 (m, 4H). 13C NMR (100.6
MHz, DMSO-d6): 175.6, 167.2, 148.3, 148.2, 142.9, 135.5,
120.6, 87.5, 67.4, 32.8, 25.5, 23.7 (italicized NMR peaks are
from THF).
(31) XPRD and DSC indicate that 2a exists as a mixture of two
distinct crystals forms, thus explaining the 3 °C melting point range.
DSC: form I-endotherm peak at 245.0 °C; form II-endotherm peak at
247.4 °C.
9228 J. Org. Chem., Vol. 70, No. 23, 2005