624
A. Catalano et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 617–626
Methyl 40-(aminomethyl)-1,10-biphenyl-2-carboxylate 17
Prepared in 69% yield starting from 16 as described in [12].
Spectroscopic data were in agreement with [12].
ethyl acetate and washed three times with 2 N HCl and once
with NaOH. Purification by flash chromatography (EtOAc/
petroleum ether 8:2) gave 0.81 g (65%) of an slightly yellowish
oil: GC/MS m/z 422 (Mþ, 5), 70 (100); 1H-NMR: d 0.90
(t, J ¼ 7.3 Hz, 3H), 1.25–1.41 (m, 1H), 1.55–1.68 (m, 2H),
1.78–1.80 (m, 2H), 1.90–2.02 (m, 1H), 2.05–2.25 (m, 1H),
2.32 (t, J ¼ 7.6 Hz, 2H), 2.45–2.55 (m, 1H), 3.38–3.48
(m, 1H), 3.52–3.61 (m, 1H), 3.63 (s, 3H), 4.35–4.55 (m, 2H),
4.62–4.68 (m, 1H), 7.20–7.30 (m, 4H, Ar), 7.30–7.42 (m, 2H, Ar),
7.48–7.54 (m, 1H, Ar), 7.59 (br s, exch. D2O, 1H), 7.80 (m, 1H,
Ar); 13C-NMR: d 14.1 (1C), 22.7 (1C), 25.3 (1C), 27.1 (1C), 27.3
(1C), 34.6 (1C), 43.3 (1C), 47.8 (1C), 52.1 (1C), 59.8 (1C), 127.3
(3C), 128.7 (2C), 130.0 (2C), 130.9 (1C), 131.4 (1C), 137.6 (1C),
Methyl 40-{[(N-tert-butoxycarbonylpyrrolidine-2-
ylcarbonyl)amino]methyl}-1,10-biphenyl-2-carboxylate 18
To a solution of 17 (0.56 g, 2.31 mmol) in CHCl3 (100 mL), 1-N-
Boc-pyrrolidine-2-carboxylic acid (0.45 g, 2.10 mmol), EEDQ
(0.62 mg, 2.52 mmol), and Et3N (0.44 mL) were added. The
reaction mixture was refluxed for 24 h. The solvent was
evaporated and the residue was taken up with EtOAc and
washed three times with 2 N HCl, three times with 2 N NaOH
and once with water. The organic phase was dried (Na2SO4)
and concentrated under vacuum to give a yellow oil which
was purified by flash chromatography (EtOAc/petroleum
ether, 8:2) giving 0.61 g (67%) of a white solid: M.p.: 134–
1368C. LC/MS m/z 461 [Mþ þ 23]; 1H-NMR: d 1.30 (br s, 9H),
1.85–1.95 (m, 4H), 2.05–2.20 (m, 1H), 3.15–3.23 (m, 2H), 3.69
(s, 3H), 4.32–4.35 (m, 3H), 7.18–7.56 (m, 7H, Ar), 7.89–7.95
(m, 1H, Ar); 13C-NMR: d 24.9 (1C), 28.6 (3C), 31.8 (1C), 43.3 (1C),
47.4 (1C), 52.2 (1C), 60.4 (1C), 80.8 (1C), 127.4 (3C), 128.8 (2C),
130.0 (2C), 131.0 (1C), 131.5 (1C), 137.4 (1C), 140.6 (1C), 142.3
140.4 (1C), 142.4 (1C), 169.3 (1C), 171.5 (1C), 174.0 (1C); IR
ꢃ1
–
–
–
(neat): 3295 (NH), 1728 (C O), 1648 (broad, C O) cm
.
–
40-({[(1-Pentanoylpyrrolidine-2yl)carbonyl]amino}-
methyl)biphenyl-2-carboxylic acid 4
0.85 g (2.04 mmol) of compound 20 were dissolved in ethanol
(38 mL) and 1 N NaOH (15 mL) was added keeping the mix-
ture to stir and at reflux for 4 h. The solvent was removed
under reduced pressure and the crude residue dissolved in
ethyl acetate was washed three times with 2 N NaOH. The
alkaline aqueous phases were acidified with 2 N HCl and
extracted twice with ethyl acetate. The organic layers dried
over anhydrous Na2SO4 gave 0.83 g (98%) of a transparent oil,
which was crystallized from THF/hexane affording 0.54 g
of white needles: M.p.: 147–1498C; LC/MS m/z 407 [Mþ – 1];
1H-NMR: d 0.90 (t, J ¼ 7.4 Hz, 3H), 1.25–1.41 (m, 2H), 1.50–1.69
(m, 2H), 1.74–2.00 (m, 2H), 2.10–2.25 (m, 2H), 2.32
(t, J ¼ 7.6 Hz, 3H), 3.38–3.48 (m, 1H), 3.50–3.60 (m, 1H),
4.10 (dd, J ¼ 14.8, 5.5 Hz, 1H), 4.28 (dd, J ¼ 14.8, 6.3 Hz,
1H), 4.52 (d, J ¼ 6.0 Hz, 1H), 6.96 (br s, exch. D2O, 1H), 7.11
(d, J ¼ 8.0 Hz, 1H, Ar), 7.20–7.35 (m, 3H, Ar), 7.35–7.45 (m, 1H,
Ar), 7.45–7.55 (m, 2H, Ar), 7.88–8.02 (m, 1H, Ar); 13C-NMR:
d 14.0 (1C), 22.6 (1C), 25.2 (1C), 27.0 (1C), 27.9 (1C), 34.5 (1C),
43.3 (1C), 47.8 (1C), 60.0 (1C), 127.3 (1C), 127.6 (2C), 128.9 (2C),
130.5 (2C), 131.2 (1C), 131.6 (1C), 137.7 (1C), 140.5 (1C),
142.9 (1C), 170.9 (1C), 171.5 (1C), 174.1 (1C); IR (KBr):
(1C), 156.1 (1C), 169.2 (1C), 171.0 (1C); IR (KBr): 3440 (NH), 1727
ꢃ1
–
–
–
(C O), 1667 (broad, C O) cm
.
–
Methyl 40-{[(pyrrolidine-2-ylcarbonyl)amino]methyl}-
biphenyl-2-carboxylate 19
To a stirred solution of 1.7 g (3.88 mmol) 18 in ethyl acetate
(25 mL), 6.9 mL HBr (48%) were added. The crude residue was
taken up with ethyl acetate and washed twice with water. The
acidic aqueous phase was made alkaline with 2 N NaOH, then
extracted twice with ethyl acetate: the combined organic
layers dried over anhydrous Na2SO4 gave 1.06 g (81%) of a
pale yellow oil: LC/MS m/z 361 [Mþ þ 23]; 1H-NMR: d 1.65–1.82
(m, 2H), 1.90–2.05 (m, overlapping br s at 1.99 (m, 1H)), 1.99
(br s overlapping m at 1.90–2.05, exch. D2O, 1H), 2.10–2.24
(m, 1H), 2.85–2.93 (m, 1H), 2.97–3.05 (m, 1H), 3.67 (s, 3H), 3.81
(q, J ¼ 4.5 Hz, 1H), 4.48 (d, J ¼ 6.1 Hz, 2H), 7.22–7.31 (m, 4H,
Ar), 7.32–7.43 (m, 2H, Ar), 7.48–7.56 (m, 1H, Ar), 7.70–7.80
(m, 1H, Ar), 8.19 (br s, exch. D2O, 1H); 13C-NMR: d 26.4 (1C),
31.0 (1C), 42.9 (1C), 47.5 (1C), 52.1 (1C), 60.9 (1C), 127.4 (3C),
128.8 (2C), 130.0 (2C), 131.0 (1C), 131.5 (1C), 137.9 (1C), 140.6
3261 (OH), 1715, 1657, 1618 (C O) cmꢃ1. Anal. calcd.
–
–
for C24H28N2O4 ꢀ 0.25 H2O (412.99): C, 69.80; H, 6.96;
N, 6.78. Found: C, 70.07; H, 6.90; N, 6.78.
(1C), 142.4 (1C), 169.2 (1C), 175.3 (1C); IR (neat): 3224 (NH),
ꢃ1
–
1724, 1658 (C O) cm
.
tert-Butyl 2-{[(4-nitrobenzyl)amino]carbonyl}pyrrolidine-1-
carboxylate 22
–
Methyl 40-({[(1-pentanoylpyrrolidine-2-yl)carbonyl]-
amino}methyl)biphenyl-2-carboxylate 20
Prepared as described for compound 18 starting from com-
mercially available compound 21. Purification by column
chromatography (EtOAc) gave an oil, which was crystallized
from EtOAc/hexane. Yellow crystals (90%): M.p.: 128–1298C;
LC/MS m/z 372 [Mþ þ 23]; 1H-NMR: d 1.42 (br s, 9H), 1.89 (br s,
3H), 2.00–2.41 (m, 1H), 3.40 (br s, 2H), 4.31 (br s, 1H), 4.51
(br s, 2H), 7.40 (m, 2H, Ar), 7.54 (br s, 1H), 8.14 (m, 2H, Ar); 13C-
A solution of 1.0 g of compound 19 (2.96 mmol) and 0.86 mL
(6.22 mmol) Et3N in THF (110 mL) was stirred and brought to
reflux. Then 0.9 mL (8.28 mmol) valeryl chloride were added
and stirred for 16 h. The solid was filtered off and the solvent
removed under vacuum. The crude residue was dissolved in
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