Journal of Medicinal Chemistry
Article
at rt for an additional 1 h. The mixture was then diluted with H2O (50
mL) and extracted with EtOAc (3 × 50 mL). The combined organic
extracts were washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The resulting crude residue was
chromatographed over silica gel (0−10% CH3OH in CH2Cl2) to give
ethyl 3-(4-(3,5-dimethyl-1H-pyrazol-4-yl)piperazin-1-yl)-4-iodoben-
zoate (25) as a brown oil, which was carried forward as is without
further purification (0.200 g, 53%, crude).
Step E. To a solution of ethyl 3-(4-(3,5-dimethyl-1H-pyrazol-4-
yl)piperazin-1-yl)-4-iodobenzoate (25, 0.200 g, 0.44 mmol) in EtOH
(4 mL), THF (4 mL) and H2O (2 mL) was added anhydrous LiOH
(0.105 g, 4.38 mmol). The reaction mixture was stirred at rt for 3 h and
concentrated under reduced pressure. The resulting aqueous mixture
was diluted with H2O (10 mL) and acidified with 2 N HCl to pH 3. The
mixture was extracted with EtOAc (3 × 50 mL), and the combined
organic extracts were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The resulting crude residue was
chromatographed over silica gel (0−10% CH3OH in CH2Cl2) to give 3-
(4-(3,5-dimethyl-1H-pyrazol-4-yl)piperazin-1-yl)-4-iodobenzoic acid
(26) as an off-white solid (80.0 mg, 43%): 1H NMR (acetone-d6, 400
MHz) δ 7.95 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H),
3.12−3.10 (m, 4H), 3.03−2.98 (m, 4H), 2.11 (s, 6H); ESI MS m/z 427
[M + H]+.
3-((3aR,6aS)-5-(3,5-Dimethyl-1H-pyrazol-4-yl)hexahydropyrrolo-
[3,4-c]pyrrol-2(1H)-yl)-4-fluorobenzoic Acid (32). Step A. A mixture
of tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbox-
ylate (27, 1.0 g, 4.71 mmol) and methyl 3-bromo-4-fluorobenzoate (1.0
g, 4.29 mmol) in anhydrous 1,4-dioxane (50 mL) was degassed with N2
for 5 min. Cs2CO3 (4.17 g, 12.8 mmol), X-Phos (0.240 g, 0.503 mmol),
and Pd2(dba)3·CHCl3 (0.248 g, 0.240 mmol) were then added, and the
mixture was stirred in a sealed tube at 110 °C for 16 h. The mixture was
allowed to cool to rt and then concentrated under reduced pressure.
The resulting residue was chromatographed over silica gel (0−30%
EtOAc in hexanes) to give tert-butyl (3aR,6aS)-5-(2-fluoro-5-
(methoxycarbonyl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-
carboxylate (28) as a brown oil (0.400 g, 26%): 1H NMR (400 MHz,
acetone-d6) δ 7.37−7.35 (m, 2H), 7.14−7.08 (m, 1H), 3.88 (s, 3H),
3.61 (brs, 4H), 3.36−3.29 (m, 4H), 3.03 (brs, 2H), 1.38 (s, 9H); ESI
MS m/z 365 [M + H]+.
Step B. To a 0 °C cooled solution of tert-butyl (3aR,6aS)-5-(2-fluoro-
5-(methoxycarbonyl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-
carboxylate (28, 0.390 g, 1.07 mmol) in CH2Cl2 (30 mL) was added
TFA (5.0 mL, 65.33 mmol), and the resulting solution was stirred at rt
for 3 h while gradually warming to rt. The mixture was then
concentrated under reduced pressure and diluted with H2O (30 mL),
basified with saturated aqueous NaHCO3 solution (50 mL), and
extracted with EtOAc (3 × 50 mL). The combined organic extracts
were washed with brine (50 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude material was triturated
with Et2O and filtered to give pure methyl 4-fluoro-3-((3aR,6aS)-
hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzoate (29) as a brown
solid (0.220 mg, 78%, crude): ESI MS m/z 265 [M + H]+.
Step D. To a solution of methyl 3-((3aR,6aS)-5-(3,5-dimethyl-1H-
pyrazol-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-fluoroben-
zoate (31, 60.0 mg, 0.16 mmol) in CH3OH (4 mL), THF (4 mL), and
H2O (2 mL) was added anhydrous LiOH (20.0 mg, 0.84 mmol). The
reaction mixture was stirred at rt for 3 h and concentrated under
reduced pressure. The aqueous layer was then diluted with H2O (30
mL) and neutralized to approximately pH = 7 with 2 N aqueous HCl
(monitored with Hydrion pH paper). The aqueous mixture was
extracted with EtOAc (3 × 50 mL), and the combined organic solution
was washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The crude residue was chromatographed over silica
gel (0−10% CH3OH in CH2Cl2) to give 3-((3aR,6aS)-5-(3,5-dimethyl-
1H-pyrazol-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-fluoro-
benzoic acid (32) as an amorphous off-white solid (4.8 mg, 8.7%): 1H
NMR (400 MHz, DMSO-d6) δ 7.40 (m, 2H), 7.16 (m, 1H), 3.60 (m,
2H), 3.20 (m, 2H), 3.01 (m, 2H), 2.88 (m, 4H), 2.11 (s, 6H); ESI MS
m/z 345 [M + H]+; HPLC 95.4% (AUC), tR = 11.0 min.
( )-3-(7-(3,5-Dimethyl-1H-pyrazol-4-yl)-2,7-diazaspiro[4.4]-
nonan-2-yl)-4-fluorobenzoic Acid (( )-38). Step A. A mixture of
( )-tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (( )-33, 1.07
g, 4.72 mmol) and methyl 3-bromo-4-fluorobenzoate (1.0 g, 4.29
mmol) in anhydrous 1,4-dioxane (50 mL) was degassed with N2 for 5
min. Cs2CO3 (4.16 g, 12.84 mmol), X-Phos (240 mg, 0.51 mmol), and
Pd2(dba)3·CHCl3 (0.217 g, 0.21 mmol) were then added, and the
mixture was stirred in a sealed tube at 110 °C for 16 h. The mixture was
allowed to cool to rt and then concentrated under reduced pressure.
The resulting residue was chromatographed over silica gel (0−30%
EtOAc in hexanes) to give ( )-tert-butyl 7-(2-fluoro-5-
(methoxycarbonyl)phenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate
1
(( )-34) as a yellow solid (0.480 g, 30%): H NMR (400 MHz,
acetone-d6) δ 7.33−7.31 (m, 2H), 7.12−7.07 (m, 1H), 3.84 (s, 3H),
3.56−3.44 (m, 2H), 3.42−3.27 (m, 6H), 1.99−1.91 (m, 4H), 1.42 (s,
9H); ESI MS m/z 379 [M + H]+.
Step B. To a 0 °C cooled solution of ( )-tert-butyl 7-(2-fluoro-5-
(methoxycarbonyl)phenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate
(( )-34, 0.470 g, 1.24 mmol) in CH2Cl2 (30 mL) was added TFA (3.0
mL, 39.20 mmol), and the resulting solution was stirred at rt for 16 h
while gradually warming to rt. The mixture was then concentrated
under reduced pressure and diluted with H2O (30 mL), basified with
saturated aqueous NaHCO3 solution (50 mL), and extracted with
EtOAc (3 × 50 mL). The combined organic extracts were washed with
brine (50 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude material was triturated with Et2O and
filtered to give pure ( )-methyl 4-fluoro-3-(2,7-diazaspiro[4.4]nonan-
2-yl)benzoate (( )-35) as a white solid (0.340 g, 99%, crude): ESI MS
m/z 279 [M + H]+.
Step C. To a 0 °C cooled solution of ( )-methyl 4-fluoro-3-(2,7-
diazaspiro[4.4]nonan-2-yl)benzoate (( )-35, 0.340 g, 1.22 mmol) in
anhydrous THF (10 mL) were added i-Pr2NEt (1.1 mL, 6.31 mmol)
and 3-chloropentane-2,4-dione (0.40 mL, 3.66 mmol) simultaneously,
and the resulting solution was stirred for 16 h under a N2 atmosphere
while gradually warming to rt. Upon in situ formation of ( )-36
(monitored by LC-MS; ESI MS m/z 377 [M + H]+), N2H4·H2O (0.62
mL, 12.23 mmol, 64−65% solution in H2O) was then added and the
mixture was continued to stir at rt for an additional 1 h. The mixture was
then diluted with H2O (50 mL) and extracted with EtOAc (3 × 50 mL).
The combined organic extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
resulting crude residue was chromatographed over silica gel (0−10%
CH3OH in CH2Cl2) to give ( )-methyl 3-(7-(3,5-dimethyl-1H-
pyrazol-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-4-fluorobenzoate
(( )-37) as a brown oil (65.0 mg, 14%, crude): ESI MS m/z 373 [M +
H]+.
Step C. To a 0 °C cooled solution of methyl 4-fluoro-3-((3aR,6aS)-
hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzoate (29, 0.210 g, 0.79
mmol) in anhydrous THF (10 mL) were added i-Pr2NEt (0.73 mL,
4.19 mmol) and 3-chloropentane-2,4-dione (0.27 mL, 2.39 mmol)
simultaneously, and the resulting solution was stirred for 16 h under a
N2 atmosphere while gradually warming to rt. Upon in situ formation of
diketone 30 (monitored by LC-MS; ESI MS m/z 337 [M + H]+),
N2H4·H2O (0.26 mL, 3.15 mmol, 64−65% solution in H2O) was then
added and the mixture was continued to stir at rt for an additional 1 h.
The mixture was then diluted with H2O (50 mL) and extracted with
EtOAc (3 × 50 mL). The combined organic extracts were washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The resulting crude residue was chromatographed over silica
gel (0−10% CH3OH in CH2Cl2) to give 3-((3aR,6aS)-5-(3,5-dimethyl-
1H-pyrazol-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-fluoro-
benzoate (31) as a brown oil along with an inseparable and
uncharacterized impurity (0.100 g, 35%, crude): ESI MS m/z 359
[M + H]+.
Step D. To a solution of ( )-methyl 3-(7-(3,5-dimethyl-1H-pyrazol-
4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-4-fluorobenzoate (( )-37, 60.0
mg, 0.16 mmol) in CH3OH (4 mL), THF (4 mL), and H2O (2 mL) was
added anhydrous LiOH (19.2 mg, 0.81 mmol). The reaction mixture
was stirred at rt for 16 h and concentrated under reduced pressure. The
aqueous layer was then diluted with H2O (30 mL) and neutralized to
approximately pH = 7 with 2 N aqueous HCl (monitored with Hydrion
9036
J. Med. Chem. 2021, 64, 9010−9041