2628
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13. (a) Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.;
Njolito, E.; Wang, F.; Sun, Y.; Armstrong, J. D.;
Grabowski, E. J. J.; Tillyer, R. D.; Spindler, F.; Malan,
C. J. Am. Chem. Soc. 2004, 126, 9918; (b) Ikemoto, N.;
Simmons, B. L.; Williams, M.; Feng, X.; Yang, C. PCT
Int. WO2004/083212 A1, 2004 (Merck & Co., Inc.).
[1,2]diazepanÆ2HCl (3.36 g, 18 mmol), EDCI (3.45 g,
18 mmol) and triethylamine (8.36 mL, 60 mmol) in
CH2Cl2 (50 mL) was stirred for 12 h at room temperature.
The reaction mixture was diluted with brine and CH2Cl2.
The organic layer was dried and evaporated. The residue
was purified by silica gel column chromatography to give
[3-[1,2]diazepan-1-yl-3-oxo-1-(2,4,5-trifluorobenzyl)pro-
14. Compound 10e; A mixture of 3-(R)-tert-butoxycarbonyla-
mino-4-(2,4,5-trifluorophenyl)butyric acid (2 g, 6 mmol),
hexahydro pyridazineÆ2HCl (2.86 g, 18 mmol), EDCI
(3.45 g, 18 mmol) and triethylamine (8.36 mL, 60 mmol)
in CH2Cl2 (50 mL) was stirred for 12 h at room temper-
ature. The reaction mixture was diluted with brine and
CH2Cl2. The organic layer was dried and evaporated. The
residue was purified by silica gel column chromatography
to give [3-oxo-3-(tetrahydropyridazin-1-yl)-1-(2,4,5-triflu-
orobenzyl)propyl]carbamic acid tert-butyl ester (1.6 g,
1
pyl]carbamic acid tert-butyl ester (2.2 g, 90%). H NMR
(CDCl3, 200 MHz) d 7.07–7.03 (m, 1H), 6.71–6.87 (m,
1H), 5.63 (d, J = 8.4 Hz, 1H), 4.15–4.13 (m, 1H), 3.64 (t,
J = 5.0 Hz, 1H), 3.46 (t, J = 5.0 Hz, 1H), 3.93–3.89 (m,
4H), 2.74 (dd, J = 13.1, 5.4 Hz, 1H), 2.58 (dd, J = 19.8,
4.6 Hz, 1H), 1.71–1.56 (m, 6H), 1.36 (s, 9H). To a mixture
of (R)-[3-[1,2]diazepan-1-yl-3-oxo-1-(2,4,5-trifluoroben-
zyl)propyl]carbamic acid tert-butyl ester (200 mg,
0.482 mmol) and Et3N (97 mg, 0.962 mmol)in CH2Cl2
(10 mL) was added benzoyl chloride (101 mg, 0.722 mmol)
and the mixture was stirred for 3 h at room temperature.
The solvents were evaporated, and the residue was purified
by silica gel column chromatography to give (R)-tert-butyl
4-(2-benzoyl-1,2-diazepan-1-yl)-4-oxo-1-(2,4,5-trifluor-
ophenyl)butan-2- ylcarbamate (210 mg, 84%). 1H NMR
(CDCl3, 200 MHz) d 7.61–7.37 (m, 5H), 7.20–7.02 (m,
1H), 7.01–6.83 (m, 1H), 5.50-5.20 (m, 1H), 4.45–3.99 (m,
3H), 3.98–2.40 (m, 5H), 1.90–1.50 (m, 6H), 1.37 (s, 9H).
To a solution of (R)-tert-butyl 4-(2-benzoyl-1,2-diazepan-
1-yl)-4-oxo-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate
(220 mg, 0.423 mmol) in EtOAc (2 mL) was added 4M-
HCl/1,4-dioxane (2 mL) and the mixture was stirred for
16 h at room temperature. The solvents were evaporated,
and the residue was crystallized with ether to give (R)-3-
amino-1-(2-benzoyl-1,2-diazepan-1-yl)-4-(2,4,5-trifluor-
ophenyl)butan-1-one hydrochloride (143 mg, 75%). 1H
NMR (DMSO-d6, 500 MHz) d 8.41–8.20 (br s, 2H), 7.70–
7.22 (m, 7H), 4.25–3.89 (m, 1H), 3.83–3.68 (m, 2H), 3.55–
3.30 (m, 2H), 3.18–2.67 (m, 4H), 1.82–1.46 (m, 6H);
HRMS (free base, C22H24F3N3O2): calcd, 419.1821 found,
419.1837. Analytical HPLC method A: tR = 3.17 min
(99.9% purity); method B: tR = 6.31 min (98.4% purity).
15. Lankas, G. R.; Leiting, B.; Sinha Roy, R.; Eiermann, G.
J.; Biftu, T.; Chan, C.-C.; Edmondson, S. D.; Feeney, W.
P.; He, H.; Ippolito, E. E.; Kim, D.; Lyons, K. A.; Ok, H.
O.; Patel, R. A.; Petrov, A. N.; Pryor, K. A.; Qian, X.;
Reigle, L.; Woods, A.; Wu, J. K.; Zaller, D.; Zhang, X.;
Zhu, L.; Weber, A. E.; Thornberry, N. A. Diabetes 2005,
54, 2988.
1
66%). H NMR (CDCl3, 300 MHz) d 7.11–7.02 (m, 1H),
6.92–6.83 (m, 1H), 5.53 (d, J = 8.5 Hz, 1H), 4.18–4.11 (m,
1H), 3.68–3.12 (m, 3H), 2.88–2.67 (m, 6H), 1.72–1.58 (m,
4H), 1.37 (s, 9H). To a mixture of (R)-[3-oxo-3-(tetrahyd-
ropyridazin-1-yl)-1-(2,4,5-trifluorobenzyl) propyl]carbam-
ic acid tert-butyl ester (300 mg, 0.747 mmol) and Et3N
(208 lL, 1.495 mmol) in CH2Cl2 (10 mL) was added
benzoyl chloride (158 mg, 1.121 mmol) and the mixture
was stirred for 2 h at room temperature. The solvents were
evaporated, and the residue was purified by silica gel
column chromatography to give (R)-[3-(2-benzoyltetra-
hydropyridazin-1-yl)-3-oxo-1-(2,4,5-trifluorobenzyl)pro-
pyl] carbamic acid tert-butyl ester (375 mg, 99%). 1H
NMR (CDCl3, 300 MHz) d 7.61–7.40 (m, 5H), 7.11–7.02
(m, 1H), 6.92–6.83 (m, 1H), 5.30–5.50 (m, 1H), 4.70–4.50
(m, 1H), 4.13–3.95 (m, 2H), 3.10–2.40 (m, 5H), 1.90–1.54
(m, 4H), 1.37 (s, 9H); LC-MS m/e (relative intensity) 506
(M+H)+. To a solution of (R)-[3-(2-benzoyltetrahydropy-
ridazin-1-yl)-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbam-
ic acid tert-butyl ester (360 mg, 0.712 mmol) in EtOAc
(2 mL) was added 4M-HCl/1,4-dioxane (2 mL) and the
mixture was stirred for 12 h at room temperature. The
solvents were evaporated, and the residue was crystallized
with ether to give (R)-3-amino-1-(2-benzoyltetrahydropy-
ridazin-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one
HCl
(290 mg, 92%). 1H NMR (DMSO-d3, 300 MHz) d 8.16
(br s, 3H), 7.60–7.21 (m, 7H), 4.40–4.20 (m, 1H), 3.80–3.60
(m, 2H), 2.96–2.86 (m, 6H), 2.09–1.68 (m, 4H); HRMS
(free base, C21H22F3N3O2): calcd, 405.1664 found,
405.1638. Analytical HPLC method A: tR = 3.46 min
(99.1% purity); method B: tR = 6.06 min (95.8% purity).
Compound 10f; A mixture of 3-(R)-tert-butoxycarbonyla-
mino-4-(2,4,5-trifluorophenyl)butyric acid (2 g, 6 mmol),
16. Sung, Y. Y.; Lee, Y. S.; Jung, W. H.; Kim, H. Y.; Cheon,
H. G.; Yang, S. D.; Rhee, S. D. Biochem. Biophys. Res.
Commun. 2005, 338, 1779.