Journal of Medicinal Chemistry
Article
pressure to give 2,2′-((3S,4R)-1-(tert-butoxycarbonyl)pyrrolidine-3,4-
diyl)diacetic acid (37) as a solid (46.75 g, 72%): 1H NMR (500 MHz,
DMSO-d6) δ 12.2 (s, 2H), 3.38 (m, 2H), 3.02 (m, 2H), 2.49 (m, 2H),
2.32 (m, 2H), 2.29 (m, 2H), 1.42 (s, 9H).
10.17 (bs, 1H), 8.06 (m, 1H), 7.59 (m, 1H), 7.53 (m, 1H), 7.27 (m, 1H),
3.42 (m, 2H), 3.38 (m, 3H), 3.01 (m, 2H), 2.36 (m, 2H), 1.96 (m, 2H);
ESI MS m/z 256 [M + H]+.
Step I. To a solution of (3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)-
octahydrocyclopenta[c]pyrrole hydrochloride (42, 0.640 g, 2.50 mmol)
in CH2Cl2 (50 mL) was added methyl 2-isocyanatobenzoate (0.442 g,
2.50 mmol), and the mixture was stirred at rt for 16 h. The mixture was
concentrated under reduced pressure and the resulting residue was
purified by flash column chromatography (Isco CombiFlash Rf unit, 40
g RediSep column, 0−30% EtOAc in hexanes) to give methyl 2-
((3aR,5r,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]-
pyrrole-2-carboxamido)benzoate as a white solid (0.700 g, 64%): ESI
MS m/z 433 [M + H]+.
Step J. To a solution of methyl 2-((3aR,5r,6aS)-5-(2-
(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-
carboxamido)benzoate (0.700 g, 1.61 mmol) in CH3OH (20 mL) and
THF (20 mL) was added aqueous 2 N NaOH (10 mL). The mixture
stirred at rt for 16 h and concentrated under reduced pressure. The
residue was diluted with H2O (25 mL) and acidified to pH 5with 2 N
HCl, and the resulting precipitate was filtered to give 2-((3aR,5r,6aS)-5-
(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole-2-
carboxamido)benzoic acid (43) as a white solid (0.668 g, 98%): mp
157−161 °C; 1H NMR (300 MHz, DMSO-d6) δ 13.46 (br s, 1H), 10.79
(s, 1H), 8.53 (d, J = 8.5 Hz, 1H), 7.96 (dd, J = 8.0, 1.5 Hz, 1H), 7.80 (m,
1H), 7.69 (m, 1H), 7.60 (m 1H), 7.48 (m, 1H), 7.36 (m, 1H), 6.99 (m,
1H), 3.65−3.62 (m, 2H), 3.47−3.38 (m, 3H), 2.86 (m, 2H), 2.27−2.22
(m, 2H), 1.66−1.59 (m, 2H); ESI MS m/z 419 [M + H]+; HPLC 98.7%
purity (AUC), tR = 14.8 min (method A).
Step D. To a suspension of 2,2′-((3S,4R)-1-(tert-butoxycarbonyl)-
pyrrolidine-3,4-diyl)diacetic acid (37, 6.97 g, 24.31 mmol) in Ac2O (50
mL) was added NaOAc (1.99 g, 24.31 mmol), and the mixture was
heated at 120 °C for 3 h. The mixture cooled to rt and filtered through
Celite. The filter cake was washed with Et2O (5 × 50 mL), and the
mother liquor was concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography (Isco CombiFlash
Rf unit, 120 g RediSep column, 0−30% EtOAc in hexanes) to give
(3aR,6aS)-tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-car-
1
boxylate (38) as a white foam (2.17 g, 40%): H NMR (500 MHz,
CDCl3) δ 3.69 (m, 2H), 3.22 (m, 2H), 2.91 (m, 2H), 2.50 (m, 2H), 2.17
(m, 2H), 1.46 (s, 9H).
Step E. To a −78 °C cooled solution of (3aR,6aS)-tert-butyl 5-
oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (38, 22.35 g,
99.2 mmol) in THF (500 mL) was slowly added a solution of LiHMDS
in THF (1.0 M, 129 mL). The mixture continued to stir at −78 °C for 30
min, and then a solution of 1,1,1-trifluoro-N-phenyl-N-
((trifluoromethyl)sulfonyl)methanesulfonamide (49.65 g, 139 mmol)
in THF (150 mL) was slowly added. The mixture stirred for an
additional 1 h at −78 °C and was then allowed to stir at rt for 2 h. The
mixture was concentrated under reduced pressure and the residue was
purified by flash column chromatography (Isco CombiFlash Rf unit, 330
g RediSep column, 0−50% EtOAc in hexanes) to give ( )-(3aS,6aS)-
tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,3a,6,6a-tetrahydro-
cyclopenta[c]pyrrole-2(1H)-carboxylate (( )-39) as a clear, viscous
oil (1.56 g, quantitative): 1H NMR (500 MHz, CDCl3) δ 5.58 (s, 1H),
3.62 (m, 1H), 3.53 (m, 1H), 3.46 (m, 2H), 3.19 (m, 1H), 2.95 (m, 2H),
2.46 (m, 1H), 1.47 (s, 9H).
Step F. To an N2 degassed mixture of ( )-(3aS,6aS)-tert-butyl 5-
(((trifluoromethyl)sulfonyl)oxy)-3,3a,6,6a-tetrahydrocyclopenta[c]-
pyrrole-2(1H)-carboxylate (( )-39, 14.79 g, 41.4 mmol), 2-trifluor-
omethylphenylboronic acid (19.70 g, 104 mmol), and a 2 M aqueous
solution of Na2CO3 (250 mL) in DME (500 mL) was added Pd(PPh3)4
(4.80 g, 4.16 mmol). The mixture was heated at 80 °C for 6 h, then
cooled to rt and diluted with H2O (500 mL). The aqueous mixture was
extracted with EtOAc (2 × 200 mL), and the combined organic extracts
were washed with H2O (200 mL), brine (200 mL), dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography (Isco CombiFlash Rf unit, 330
g RediSep column, 0−10% EtOAc in hexanes) to give ( )-(3aR,6aS)-
tert-butyl 5-(2-(trifluoromethyl)phenyl)-3,3a,6,6a-tetrahydro-
cyclopenta[c]pyrrole-2(1H)-carboxylate (( )-40) as a clear, viscous
oil (13.70 g, 94%): 1H NMR (500 MHz, CDCl3) δ 7.65 (m, 1H), 7.47
(m, 2H), 7.25 (m, 1H), 5.58 (s, 1H), 3.85−3.42 (m, 4H), 3.23 (m, 1H),
2.98 (m, 2H), 2.49 (m, 1H), 1.47 (s, 9H).
2-((3aS,6aR)-5-(2-(Trifluoromethyl)phenyl)-1,2,3,3a,4,6a-
hexahydrocyclopenta[c]pyrrole-2-carboxamido)benzoic Acid
(( )-45). Step A. To a solution of ( )-(3aR,6aS)-tert-butyl 5-(2-
(trifluoromethyl)phenyl)-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-
2(1H)-carboxylate (( )-40, 120 mg, 0.34 mmol) in CH2Cl2 (3 mL) was
added a TFA (3 mL), and the resulting solution was stirred at rt for 3 h.
The residue was dissolved in CH2Cl2 (25 mL) and washed with
saturated aqueous NaHCO3 solution (25 mL), brine (25 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure to
provide ( )-(3aS,6aR)-5-(2-(trifluoromethyl)phenyl)-1,2,3,3a,4,6a-
hexahydrocyclopenta[c]pyrrole (( )-44) as an off-white solid (0.146
mg, >99%): 1H NMR (300 MHz, CDCl3) δ 9.21 (br s, 1H), 8.18 (br s,
1H), 7.67 (d, J = 7.8 Hz, 1H), 7.51−7.34 (m, 3H), 5.57 (s, 1H), 3.82 (br
s, 1H), 3.62−3.54 (m, 2H), 3.39−3.09 (m, 4H), 2.62−2.56 (m, 1H).
Step B. A solution of ( )-(3aS,6aR)-5-(2-(trifluoromethyl)phenyl)-
1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (( )-44, 159 mg, 0.43
mmol), methyl 2-isocyanatobenzoate (91 mg, 0.51 mmol), and Et3N
(0.14 mL, 1.0 mmol) in CH2Cl2 (6 mL) was stirred at rt for 24 h. The
mixture was diluted with saturated aqueous NaHCO3 (30 mL) and
extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts
were washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The resulting residue was chromatographed
over silica gel (0−100% EtOAc in hexanes) to give ( )-methyl 2-
((3aS,6aR)-5-(2-(trifluoromethyl)phenyl)-1,2,3,3a,4,6a-hexahydro-
cyclopenta[c]pyrrole-2-carboxamido)benzoate as an off-white solid
Step G. A mixture of ( )-(3aR,6aS)-tert-butyl 5-(2-(trifluoromethyl)-
phenyl)-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
(( )-40, 8.63 g, 24.41 mmol) and 10% Pd/C (1.57 g, wet, 10% w/w) in
CH3OH (50 mL) was subjected to an atmosphere of H2 gas (40 psi)
using a Parr shaker apparatus at rt for 16 h. The mixture was filtered
through Celite, and the filtrate was concentrated under reduced
pressure. The resulting residue was purified by flash column
chromatography (Isco CombiFlash Rf unit, 40 g RediSep column, 0−
30% EtOAc in hexanes) to give (3aR,5r,6aS)-tert-butyl 5-(2-
(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-car-
boxylate (41) as a clear, viscous oil (0.910 g, 85%): 1H NMR (500 MHz,
CDCl3) δ 7.69 (m, 1H), 7.51 (m, 2H), 7.25 (m, 1H), 3.49 (m, 5H), 2.75
(m, 2H), 2.92 (m, 2H), 1.52 (m, 2H), 1.48 (s, 9H).
1
(0.114 g, 62%): H NMR (300 MHz, CDCl3) δ 8.66 (dd, J = 8.4, 0.9
Hz, 1H), 8.02−7.98 (m, 1H), 7.66−7.64 (m, 1H), 7.54−7.34 (m, 4H),
6.99−6.93 (m, 1H), 5.67 (br s, 1H), 4.02−3.90 (m, 4H), 3.81−3.67 (m,
3H), 3.37−3.31 (m, 1H), 3.16−2.97 (m, 2H), 2.58−2.53 (m, 1H).
Step C. To a stirring solution of ( )-methyl 2-((3aS,6aR)-5-(2-
(trifluoromethyl)phenyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole-
2-carboxamido)benzoate (114 mg, 0.26 mmol) in CH3OH (4 mL) and
THF (4 mL) was added a solution of LiOH·H2O (110 mg, 2.62 mmol)
in H2O (2 mL). The mixture was stirred at rt for 4 h, was diluted with
additional H2O (10 mL), and was acidified to pH 6 with 2 N HCl. The
resulting solids were collected by filtration and dried under reduced
pressure to provide ( )-2-((3aS,6aR)-5-(2-(trifluoromethyl)phenyl)-
1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole-2-carboxamido)benzoic
acid (( )-45) as a white solid (0.085 mg, 79%): mp 148−152 °C; 1H
NMR (500 MHz, DMSO-d6) δ 13.50 (bs, 1H), 10.74 (s, 1H), 8.50 (d, J
= 8.5 Hz, 1H), 7.96 (m, 1H), 7.73 (m, 1H), 7.64 (m, 1H), 7.52 (m, 2H),
7.44 (m, 1H), 7.01 (m, 1H), 5.68 (s, 1H), 3.83−3.79 (m, 1H), 3.64−
Step H. To a 0 °C cooled solution of (3aR,5r,6aS)-tert-butyl 5-(2-
(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-car-
boxylate (41, 7.94 g, 22.32 mmol) in CH2Cl2 (60 mL) was added a 2 M
HCl solution in Et2O (60 mL), and the mixture was allowed to stir at rt
for 24 h. The mixture was diluted with Et2O (200 mL) and the
precipitated product was filtered to give (3aR,5r,6aS)-5-(2-
(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole hydrochloride
1
(42) as a white solid (5.90 g, 91%): H NMR (500 MHz, CDCl3) δ
7752
dx.doi.org/10.1021/jm5010013 | J. Med. Chem. 2014, 57, 7731−7757