Journal of Medicinal Chemistry
Article
(6H, m), 1.32−1.43 (3H, m), 1.53−1.92 (8H, m), 1.94−2.17 (3H, m),
2.41−2.48 (3H, m), 2.96−4.55 (9H, m), 4.58−4.68 (1H, m), 4.71−
4.84 (1H, m), 4.98−5.17 (1H, m), 7.04−7.79 (5H, m), 8.51−9.18
(3H, m), 9.22−9.54 (1H, m), 11.99−12.59 (1H, m); HRMS-ESI (m/
z): [M + H] calcd for C30H43 F2N5O3, 560.3407; found. 560.3399.
(3S,8aR)-2-{(2S)-2-Cyclohexyl-2-(N-methyl-L-alanyl)amino]-
acetyl}-N-[(1R)-4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl]-
octahydropyrrolo[1,2-a]pyrazine-3-carboxamide dihydro-
chloride (26f). Compound 26f was prepared by a method similar
to that described for 24 and 26d using 23 (200 mg, 0.39 mmol),
LiOH-H2O (24.8 mg, 0.59 mmol), (4R)-4-amino-3,4-dihydronaph-
thalen-1(2H)-one (95 mg, 0.59 mmol), EDC-HCl (452 mg, 2.36
mmol), HOBt (106 mg, 0.78 mmol) and DIPEA (0.14 mL, 0.80
to give (3S,8aR)-2-[(2S)-2-amino-2-phenylacetyl]-N-[(4R)-3,4-dihy-
dro-2H-chromen-4-yl]octahydropyrrolo[1,2-a]pyrazine-3-carboxamide
as a colorless oil.
The obtained oil, N-(tert-butoxycarbonyl)-N-methyl-L-alanine 30
(118 mg, 0.581 mmol), HATU (295 mg, 0.776 mmol) and DIPEA
(0.405 mL, 2.33 mmol) were mixed in DMF (5 mL) at 0 °C, and the
reaction mixture was stirred at room temperature for 18 h. The
mixture was partitioned between EtOAc (30 mL) and water (30 mL),
and the organic layer was washed with brine (50 mL), dried over
MgSO4, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (10−80% EtOAc in n-
hexane) to give the tert-butyl [(1S)-2-({(1S)-2-[(3S,8aR)--[(4R)-3,4-
dihydro-2H-chromen-4-ylcarbamoyl]hexahydropyrrolo[1,2-a]pyrazin-
2(1H)-yl]-2-oxo-1-phenylethyl}amino)-1-methyl-2-oxoethyl]-
methylcarbamate (200 mg) as a white amorphous powder.
1
mmol). Yield: 44%, white amorphous powder (105 mg); H NMR
(DMSO-d6, 300 MHz): δ 0.63−1.46 (9H, m), 1.52−2.34 (12H, m),
2.54−2.96 (3H, m), 3.08 (1H, br s), 3.43−4.16 (6 H, m), 4.41−4.59
(1H, m), 4.51 (1H, br s), 4.62−4.84 (2H, m), 5.21 (1H, br s), 7.27−
7.79 (3H, m), 7.89 (1H, d, J = 7.7 Hz), 8.82 (2H, br s), 9.03 (1H, d, J
= 8.5 Hz), 9.33 (1H, br s), 12.09 (1H, br s); HRMS-ESI (m/z): [M
+H] calcd for C30H43N5O4, 538.3388; found. 538.3366.
The obtained amorphous powder (200 mg) was dissolved in EtOAc
(3 mL), and to the solution was added 4 M HCl in EtOAc (3 mL).
The mixture was stirred at room temperature for 2 h, and then
concentrated under reduced pressure. The residue was washed with
EtOAc (10 mL) and dried under reduced pressure to give 31a (150
1
tert-Butyl (3S,8aR)-3-[(4R)-3,4-dihydro-2H-chromen-4-
ylcarbamoyl]hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxy-
late (27). A solution of 7 (852 mg, 3.00 mmol) in THF (6 mL) was
added to lithium hydroxide monohydrate (164 mg, 3.91 mmol) in
water (2 mL) at room temperature, and the mixture was stirred at 50
°C for 3 h. To the mixture was added 1 M HCl (3.9 mL), and the
mixture was concentrated under reduced pressure to give colorless
amorphous powder. This amorphous powder was dissolved in DMF
(10 mL), and to the solution were added (R)-chroman-4-amine
hydrochloride (863 mg, 4.65 mmol), EDC-HCl (1.73 g, 9.02 mmol),
HOBt (486 mg, 3.60 mmol) and DIPEA (1.57 mL, 9.01 mmol). The
mixture was stirred at room temperature for 15 h, and then partitioned
between EtOAc (50 mL) and water (100 mL). The organic layer was
washed with brine (100 mL), dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by silica gel column
chromatography (50−100% EtOAc in n-hexane) to give 27 (1.12 g,
mg, 65%) as a white amorphous powder. H NMR (DMSO-d6, 300
MHz): δ 1.22−2.14 (10H, m), 2.41 (3H, br s), 2.64−3.29 (3H, m),
3.41−3.97 (4H, m), 4.05−4.76 (4H, m), 4.89−6.26 (2H, m), 6.67−
6.99 (2H, m), 7.06−7.64 (7H, m), 8.70−9.61 (3H, m), 12.04 (1H, br
s). Anal. Calcd for C29H39Cl2N5O4·1.4H2O·0.3Et2O: C, 56.67; H, 7.06
N, 10.94. Found: C, 56.85; H, 7.37; N, 11.23.
Benzyl {(1S)-1-(4,4-difluorocyclohexyl)-2-[(3S,8aR)-3-[(4R)-
3,4-dihydro-2H-chromen-4- ylcarbamoyl]hexahydropyrrolo-
[1,2-a]pyrazin-2(1H)-yl]-2-oxoethyl}carbamate (29b). Com-
pound 29b was prepared by a method similar to that described for
29a using 27 (1.12g, 2.79 mmol), 4 M HCl in EtOAc (7 mL, 28
mmol), (2S)-(4,4-difluorocyclohexyl)[(benzyloxycarbonyl)amino]-
ethanoic acid 28b (985 mg, 3.01 mmol), HATU (1.71 g, 4.50
mmol) and DIPEA (1.57 mL, 9.01 mmol). Yield: 82%, colorless oil
1
(1.51 g); H NMR (DMSO-d6, 300 MHz): δ 1.12−1.41 (3H, m),
1.51−2.07 (14H, m), 2.09−2.20 (1H, m), 2.87−3.21 (2H, m), 3.46−
3.73 (1H, m), 3.94−4.26 (3H, m), 4.32−4.56 (1H, m), 4.86−5.12
(4H, m), 6.71−6.79 (1H, m), 6.80−6.91 (1H, m), 7.07−7.45 (7H, m),
7.63 (1H, d, J = 8.9 Hz), 8.06−8.22 (1 H, m).
1
71%) as a white solid. H NMR (DMSO-d6, 300 MHz): δ 1.12−1.30
(1H, m), 1.32−1.47 (9H, m), 1.55−2.09 (7H, m), 2.12−2.27 (1H, m),
2.79−3.06 (2H, m), 3.36−3.51 (1H, m), 3.76−3.98 (1H, m), 4.12−
4.28 (2H, m), 4.31−4.53 (1H, m), 5.05 (1H, d, J = 1.3 Hz), 6.63−6.94
(2H, m), 7.06−7.26 (2H, m), 8.11−8.42 (1H, m).
(3S,8aR)-2-{(2S)-2-(4,4-Difluorocyclohexyl)-2-[(N-methyl-L-
alanyl)amino]acetyl}-N-[(4R)-3,4-dihydro-2H-chromen-4-yl]-
octahydropyrrolo[1,2-a]pyrazine-3-carboxamide dihydro-
chloride (31b). Compound 31b was prepared by a method similar
to that described for 31a using 29b (1.50g, 2.46 mmol), 10% Pd/C
(300 mg), N-(tert-butoxycarbonyl)-N-methyl-L-alanine 30 (716 mg,
3.52 mmol), HATU (1.79 g, 4.71 mmol), DIPEA (1.64 mL, 9.41
mmol) and 4 M HCl in EtOAc (8 mL). Yield: 58%, white amorphous
Benzyl {(1S)-2-[(3S,8aR)-3-[(4R)-3,4-dihydro-2H-chromen-4-
ylcarbamoyl]hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-oxo-
1-phenylethyl}carbamate (29a). To a solution of 27 (450 mg, 1.12
mmol) in EtOAc (3 mL) was added 4 M HCl in EtOAc (3 mL), and
the mixture was stirred at room temperature for 1 h. The mixture was
concentrated under reduced pressure, and the residue was washed with
ethyl ether (5 mL) and dried under reduced pressure to give (3S,8aR)-
N-[(4R)-3,4-dihydro-2H-chromen-4-yl]octahydropyrrolo[1,2-a]-
pyrazine-3-carboxamide dihydrochloride (410 mg). The obtained
product (200 mg, 0.534 mmol), (2S)-{[(benzyloxy)carbonyl]amino}-
(phenyl)ethanoic acid 28a (230 mg, 0.806 mmol), HATU (406 mg,
1.07 mmol) and DIPEA (0.558 mL, 3.20 mmol) were mixed in DMF
(5 mL) at 0 °C, and the reaction mixture was stirred at room
temperature for 18 h. The mixture was partitioned between EtOAc (30
mL) and water (30 mL), and the organic layer was washed with sat.
NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (10−80% EtOAc in n-hexane) to
give 29a (220 mg, 47%) as a pale-yellow amorphous powder; 1H
NMR (DMSO-d6, 300 MHz): δ 0.93−1.36 (2H, m), 1.42−2.30 (6H,
m), 2.69 (2H, s), 2.90 (1H, m), 3.37−3.63 (1H, m), 3.80−4.55 (3H,
m), 4.80−5.16 (4H, m), 5.45−5.85 (1H, m), 6.68−6.95 (2H, m),
7.02−7.19 (2H, m), 7.19−7.52 (10 H, m), 7.71−8.36 (2H, m).
(3S,8aR)-N-[(4R-3,4-Dihydro-2H-chromen-4-yl]-2-{(2S)-2-[(N-
methyl-L-alanyl)amino]-2-phenylacetyl}octahydropyrrolo[1,2-
a]pyrazine-3-carboxamide dihydrochloride (31a). To a solution
of 29a (220 mg, 0.387 mmol) in methanol (10 mL) was added 10%
Pd/C (30 mg), and the reaction mixture was stirred at room
temperature for 3 h under hydrogen atmosphere (3 atm). The mixture
was filtered through a pad of Celite, and the filtrate was concentrated
1
powder (922 mg); H NMR (DMSO-d6, 300 MHz): δ 1.23−1.48
(5H, m), 1.58−2.22 (14H, m), 2.41−2.48 (3H, m), 2.92−3.18 (1H,
m), 3.47−4.29 (7H, m), 4.44−4.75 (2H, m), 4.80−5.06 (2H, m),
6.58−7.54 (4H, m), 8.50−9.28 (3H, m), 9.33−9.73 (1H, m), 11.09−
12.69 (1H, m); Anal. Calcd for C29H43Cl2F2N5O4+2.0H2O: C, 51.94;
H, 7.06; N, 10.44. Found: C, 51.94; H, 7.20; N, 10.09.
(3S,8aR)-N-[(4R)-3,4-Dihydro-2H-chromen-4-yl]-2-[(2S)-2-[(N-
methyl-L-alanyl)amino]-2-(tetrahydro-2H-pyran-4-yl)acetyl]-
octahydropyrrolo[1,2-a]pyrazine-3-carboxamide dihydro-
chloride (31c). To a solution of 27 (450 mg, 1.12 mmol) in
EtOAc (3 mL) was added 4 M HCl in EtOAc (3 mL), and the mixture
as stirred at room temperature for 1 h. The mixture was concentrated
under reduced pressure, and the residue was washed with ethyl ether
(10 mL) and dried under reduced pressure to give (3S,8aR)-N-[(4R)-
3,4-dihydro-2H-chromen-4-yl]octahydropyrrolo[1,2-a]pyrazine-3-car-
boxamide (410 mg, 1.10 mmol). The obtained product (200 mg, 0.534
mmol), (2S)-{[(benzyloxy)carbonyl]amino}(tetrahydro-2H-pyran-4-
yl)ethanoic acid 28c (235 mg, 0.801 mmol), HATU (406 mg, 1.068
mmol) and DIPEA (0.558 mL, 3.20 mmol) were mixed in DMF (5
mL) at 0 °C, and the reaction mixture was stirred at room temperature
for 18 h. The mixture was partitioned between EtOAc (30 mL) and
water (30 mL), and the organic layer was washed with sat. NaHCO3
(50 mL) and brine (50 mL). The organic layer was dried over MgSO4,
and concentrated under reduced pressure. The residue was purified by
1241
dx.doi.org/10.1021/jm301674z | J. Med. Chem. 2013, 56, 1228−1246