7340 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23
Ganellin et al.
NCHCO), 3.1 (2H, m, CH2), 2.1 (1H, m, CH(H)), 1.6 (7H, m,
CH(H), 3 × CH2); MS m/z 144 [M + H]+.
cis isomer), 2.85-3.46 (3H, m, NCH2 of butyl, CH(H) of Abu),
2.07-2.34 (1H, m, CH(H) of Abu), 1.20-1.89 (15H, m, t-Bu,
NCHCH2 of Pro, CH3CH2CH2 of butyl), 1.0 (3H, t, CH3 of Abu),
0.98 (3H, t, CH3 of butyl); MS m/z 374 [M + H]+.
N-Benzyloxycarbonyl-(2S)-aminobutyryl-(2R/S)-per-
hydroazepinecarboxylic Acid. N-Benzyloxycarbonyl-(2S)-
aminobutyric acid 3,4-dihydro-4-oxo-1,2,3-benzotriazine ester
(0.63 g, 1.64 mmol) in dimethyl formamide (3 mL) was cooled
to 0 °C. To this was added 2R/S-perhydroazepinecarboxylic
acid (0.31 g, 1.198 mmol) in dimethylformamide (2 mL)
containing triethylamine (0.2 mL). The mixture was stirred
at room temperature for 5 days. The solvent was evaporated
and the product chromatographed over silica gel using petro-
leum/ethyl acetate/acetic acid (5:4:1): yield 0.43 g (100%); 1H
NMR (200 MHz CDCl3) δ 7.25 (5H, m, Ph), 6.0 (1H, d, NH),
5.0 (2H, q, PhCH2), 4.8 (1H, m, NCHCO), 4.5 (1H, m, NCHCO),
3.6 (1H, m, NCH(H)), 3.1 (1H, m, NCH(H)), 2.3 (1H, m, CH3-
CH(H)), 1.6 (7H, m, CH3CH(H), 3 × CH2), 1.2 (2H, m, CH2),
0.8 (3H, m, CH3).
(2S)-Aminobutyryl-(4S)-fluoro-L-proline n-Butylamide
Trifluoroacetate (31) was prepared by method B from
N-(tert-butoxycarbonyl)-(2S)-aminobutyryl-(4S)-fluoro-L-pro-
1
line n-butylamide: yield 90%; H NMR (400 MHz CD3OD) δ
5.34 (0.73H, m, CHF of trans isomer), 5.27 (0.27H, m, CHF of
cis isomer), 4.65 (1H, dd, NCHCO of Abu), 4.13 (0.73H, dd,
NCHCO of Pro of trans isomer), 3.63-4.05 (2H, m, NCH2 of
Pro, 0.27H, NCHCO of Pro of cis isomer), 3.08-3.28 (2H, m,
NCH2 of butyl), 2.25-2.68 (2H, m, CH2 of Abu), 1.75-2.10 (2H,
CHCH2CHF), 1.42-1.54 (2H, m, C2H5CH2), 1.29-1.40 (2H, m,
CH3CH2CH2), 1.11 (2.19H, t, CH3 of Abu of trans isomer), 1.01
(0.81H, CH3 of Abu of cis isomer), 0.94 (0.81H, t, CH3 of butyl
of cis isomer), 0.92 (2.19H, t, CH3 of butyl of trans isomer);
MS m/z 274 [M + H]+; HPLC purity (Kromasil C-18, water/
methanol/trifluoracetic acid 70:30:0.1) 99.9%. Anal. (C13H24-
O2N3F‚CF3COOH‚0.25H2O) C H N.
N-Benzyloxycarbonyl-(2S)-aminobutyryl-(2R/S)-per-
hydroazepinecarboxylic Acid n-Butylamide was prepared
by method A from N-benzyloxycarbonyl-(2S)-aminobutyryl-
(2R/S)-perhydroazepinecarboxylic acid and purified by column
chromatography over silica gel using petroleum/diethyl ether
7:3 and then 2:3 as eluant: yield 52%; 1H NMR (200 MHz,
CDCl3) δ 7.3 (5H, m, Ph), 6.4 (1H, bd, NH), 5.3 (1H, bd, NH),
5.0 (2H, t, PhCH2), 4.7 (1H, m, NCHCO), 4.5 (1H, m, NCHCO),
3.1 (4H, m, 2 × NCH2), 0.8-1.8 (20H, m, 4 × CH2 of azepine,
2 × CH2 of butyl, CH2 of Abu, 2 × CH3); MS m/z 418 [M +
H]+.
(2S)-Aminobutyryl-(2R/S)-perhydroazepinecarboxyl-
ic Acid n-Butylamide Hydrogen Oxalate (28) was pre-
pared by method B from N-benzyloxycarbonyl-(2S)-aminobu-
tyryl-(2R/S)-perhydroazepinecarboxylic acid n-butylamide: yield
43%; 1H NMR (200 MHz, CD3OD) δ 8.0 (1H, bd, NH), 4.7 (1H,
dd, NCHCO), 4.4 (1H, m, NCHCO), 3.8 (1H, m, NCH(H)), 3.5
(1H, m, NCH(H)), 3.2 (2H, m, NCH2), 2.2 (2H, m, CH2), 1.8
(6H, m, 3 × CH2), 1.4 (6H, m, 3 × CH2), 0.9 (6H, dt, 2 × CH3);
MS m/z 289 [M + H]+; purity (Kromasil C-18; methanol/water/
trifluoroacetic acid 40:60:0.1) 99.39%. Anal. (C15H29N3O2‚1.25-
(COOH)2) C H N.
N-Benzyloxycarbonyl-(4S)-fluoro-L-proline was pre-
pared by method D from N-benzyloxycarbonyl-(4S)-fluoro-L-
proline methyl ester: mp 123-124 °C; 1H NMR (400 MHz
CDCl3) δ 7.26-7.38 (5H, m, Ar CH), 5.15-5.32 (3H, m, PhCH2,
CHF), 4.61 (1H, dd, NCHCO, Jcis ) 27.6 Hz, Jtrans ) 9.6 Hz),
3.60-3.98 (2H, m, NCH2), 2.54-2.78 (1H, m, NCHCH(H)),
2.24-2.52 (1H, m, NCHCH(H)); MS m/z 267 [M]+.
N-Benzyloxycarbonyl-(4S)-fluoro-L-proline n-Butyl-
amide was prepared by method A from N-benzyloxycarbonyl-
(4S)-fluoro-L-proline and purified by trituration with petrol:
yield 88.9%; 1H NMR (400 MHz, CDCl3) δ 7.34 (5H, bs, Ar
CH), 6.0-6.5 (1H, bd, NH), 5.21 (1H, dt, CHF, JHF ) 51.9 Hz,
JHH 3.4 Hz), 5.0-5.20 (2H, m, PhCH2), 4.48 (1H, d, NCHCO,
J ) 1.4 Hz), 3.38-4.02 (2H, m, NCH2 of Pro), 3.02-3.32 (2H,
m, NCH2 of butyl), 2.52-2.90 (1H, m, NCHCH(H) of Pro),
2.08-2.48 (1H, m, NCHCH(H) of Pro), 1.16-1.54 (4H, m, CH3-
(CH2)2), 0.87 (3H, bs, CH3 of butyl).
(4S)-Fluoro-L-proline n-Butylamide was prepared by
method B from N-benzyloxycarbonyl-(4S)-fluoro-L-proline n-
butylamide: yield 88.5%; mp 30 °C; 1H NMR (400 MHz, CDCl3)
δ 7.53 (1H, bs, NH), 5.16 (1H, dt, JHF )53.1 Hz, JHH ) 3.7 Hz,
CHF), 3.82 (1H, dd, Jcis ) 10.3 Hz, Jtrans ) 3.3 Hz, NCHCO),
3.10-3.4 (4H, m, 2 × NCH2), 2.2-2.48 (2H, m, NCHCH2), 2.12
(1H, bs, NH), 1.42-1.52 (2H, m, NCH2CH2), 1.28-1.37 (2H,
m, CH3CH2), 0.91 (3H, t, J ) 7.34 Hz, CH3).
N-(tert-Butoxycarbonyl)-(2S)-aminobutyryl-(4S)-fluoro-
L-proline n-Butylamide was prepared by method A from
(4S)-fluoro-L-proline n-butylamide. Purified by column chro-
matography over silica gel using an ethyl acetate/petrol
gradient from 20:80 to 60:40: yield 51%; mp 67-68 °C; 1H
NMR (400 MHz, CDCl3) δ 6.55 & 7.52 (1H, 2 × bs, NH of cis
and trans isomers), 5.23 & 5.31 (1H, 2 × dt, CHF of cis and
trans isomers), 5.19 (1H, bd, NH), 4.43 & 4.76 (1H, 2 × d,
NCHCO cis and trans isomers), 4.33 (0.63H, q, NCHCO of
trans isomer), 3.76-4.09 (2.37H, m, NCH2 of Pro, NCHCO of
N-Benzyloxycarbonyl-4-keto-L-proline Methyl Ester.
N-Benzyloxycarbonyl-4-hydroxy-L-proline methyl ester (5 g,
17.9 mmol) was dissolved in acetone (300 mL). With stirring,
chromic acid in sulfuric acid (15 mL, approx 4 M) was added
over 3 min. The mixture was allowed to react for 1 h and then
2-propanol (5 mL) added slowly over 20 min. The solvent was
removed and the product dissolved in ether and filtered
through Fluorisil. The solvent was removed and the residue
purified by chromatography over silica gel using an ethyl
acetate/petroleum gradient from 15:85 to 40:60 as eluant: yield
3.97 g (80%); 1H NMR (200 MHz CDCl3) δ 7.30 (5H, bs, Ar
CH), 5.0-5.2 (2H, m, PhCH2), 4,85 (1H, t, NCHCO), 3.95 (2H,
bs, NCH2), 3.6-3.7 (3H, d, OCH3), 2.80-3.05 (1H, m, CHCH(H)),
3.50-3.65 (1H, m, CHCH(H)).
N-Benzyloxycarbonyl-4-benzylidine-L-proline Methyl
Ester. Benzyltriphenylphosphonium chloride (3.68 g, 9.46
mmol), suspended in dry tetrahydrofuran (30 mL), was added
to a solution of sodium hydride (0.22 g, 9.65 mmol, 95%) in
dry tetrahydrofuran (20 mL) under nitrogen. Dry dimethyl
sulfoxide (25 mL) was added and the mixture heated at 70 °C
until homogeneous (approx 4 h). The solution was cooled to
50 °C and treated with N-benzyloxycarbonyl-4-keto-L-proline
methyl ester in dry tetrahydrofuran (10 mL) over 5 min. The
mixture was returned to 70 °C for a further 16 h and then
poured onto ice water containing KHCO3 (1.4 g). The mixture
was extracted with methylene chloride (2 × 150 mL). The
extracts were combined and dried (MgSO4), and the solvent
was removed. The residue was purified by chromatography
over silica gel using ethyl acetate/petroleum 15:85 then 35:65
as eluant: yield 2.19 g (70%); 1H NMR (400 MHz CDCl3) δ
7.05-7.50 (10H, m, Ar CH), 6.13-6.53 (1H, m, vinylic CH),
5.0-5.3 (2H, m, PhCH2), 4.30-4.73 (3H, m, NCHCO, NCH2),
3.50-3.80 (3H, dd, OCH3), 3.10-3.33 (1H, m, CHCH(H)),
2.67-3.05 (1H, m, CHCH(H)).
4-cis-Benzyl-L-proline Methyl Ester was prepared by
method B from N-benzyloxycarbonyl-4-benzylidine-L-proline
1
methyl ester: yield 67%; H NMR (400 MHz CDCl3) δ 7.12-
7.32 (5H, m, ArCH), 3.82 (1H, t, NCHCO), 3.74 (3H, s, MeO),
3.02-3.08 (1H, m, NCH(H)), 2.73-2.80 (1H, m, NCH(H)),
2.58-2.72 (2H, m, PhCH2), 1.60-1.70 (0.1H, m, trans-
PhCH2CH), 1.50-1.59 (0.9H, m, cis-PhCH2CH).
N-Benzyloxycarbonyl-(2S)-aminobutyryl-4-cis-benzyl-
L-proline Methyl Ester was prepared by the method of
Andersonb from 4-cis-benzyl-L-proline methyl ester and puri-
fied by chromatography over silica gel ethyl acetate/petroleum
15/85 and then 35/65 as eluant: yield 74%; 1H NMR (200 MHz
CDCl3) δ 9.95-7.50 (10H, m, Ar CH), 5.60 (1H, d, NH), 5.05
(2H, m, PhCH2O), 4.35-4.50 (2H, m, 2 × NCHCO), 3.60-3.95
(4H, m, OCH3, NCH(H)), 3.20-3.35 (1H, m, NCH(H)), 2.10-
2.80 (4H, m, PhCH2CH, CHCH2CH of Pro), 1.50-1.95 (3H, m,
CH2 of Abu, PhCH2CH), 0.95 (3H, t, CH3 of Abu).
N-Benzyloxycarbonyl-(2S)-aminobutyryl-4-cis-benzyl-
L-proline was prepared by method D from N-benzyloxycar-
bonyl-(2S)-aminobutyryl-4-cis-benzyl-L-proline methyl ester: