2394 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12
Aranapakam et al.
dine-4-carboxylic acid hydroxyamide was isolated as a HCl
4-carboxylic acid was prepared starting from 4-(4-butoxyben-
zenesulfonyl)-1-(3,4-dichlorobenzyl)piperidine-4-carboxylic acid
ethyl ester (14.0 g, 26.5 mmol) dissolved in THF/methanol (100:
50 mL/mL) and 10 N NaOH (20 mL). The resulting reaction
mixture was worked up as outlined in example 19 (step 6).
Yield: 7.87 g, 60%. Off-white solid. Mp 239 °C. MS, m/z: 501.9
(M + H)+.
salt, a brown powder. Yield: 20%. Mp 137 °C. MS, m/z: 477.0
1
(M + H)+. H NMR (300 MΗz, DMSO-d6): δ 0.96 (t, J ) 7.11
Hz, 3H), 1.48 (m, 2H), 1.73 (m, 2H), 2.27 (m, 2H), 2.47 (m,
2H), 2.78 (m, 2H), 3.35 (m, 2H), 3.77 (s, 2H), 4.08 (t, J ) 6.3
Hz, 3H), 4.32 (s, 2H), 7.03 (t, 2H), 7.15 (m, 3H), 7.36 (t, J )
7.8 Hz, 1H), 7.64 (d, J ) 9 Hz, 2H), 9.36 (s, 1H), 10.22 (s, 1H).
Anal. (C24H32 N2O6S) C, H, N.
Starting from 1-(3,4-dichlorobenzyl)-4-(4-butoxybenzene-
sulfonyl)piperidine-4-carboxylic acid (7.7 g, 15.5 mmol) and
following the procedure outlined in example 19 (step 7), 4.05
g of 1-(3,4-dichlorobenzyl)-4-(4-butoxybenzenesulfonyl)piperi-
dine-4-carboxylic acid hydroxyamide was isolated as a HCl
salt, a white solid. Yield: 48%. Mp 256.8 °C. MS, m/z: 516 (M
4-(4-Meth oxyben zen esu lfon yl)-1-(4-th iop h en -2-ylben -
zyl)p ip er id in e-4-ca r boxylic Acid Hyd r oxya m id e (60).
4-(4-Methoxybenzenesulfonyl)-1-(4-thiophen-2-ylbenzyl)piperi-
dine-4-carboxylic acid ethyl ester was prepared starting from
1-(4-bromobenzyl)-4-(4-methoxybenzensulfonyl)piperidine-4-
carboxylic acid ethyl ester (3 g, 6.05 mmol) and 2-(tributyl-
stannyl)thiophene (6.8 g, 18.14 mmol) in the presence of
tetrakispalladium(0) in boiling toluene. Yield: 1.58 g, 52%.
Brown solid. Mp 130 °C. MS, m/z: 500 (M + H)+.
4-(4-Methoxybenzenesulfonyl)-1-(4-thiophen-2-ylbenzyl)pi-
peridine-4-carboxylic acid was prepared starting from 4-(4-
methoxybenzenesulfonyl)-1-(4-thiophen-2-ylbenzyl)piperidine-
4-carboxylic acid ethyl ester (1.3 g, 2.61 mmol) dissolved in
THF/methanol (3:1, 150 mL) and 10 N NaOH (20 mL). The
resulting reaction mixture was worked up as outlined in
example 19 (step 6). Yield: 950 mg, 77%. Brown solid. Mp
235°C. MS, m/z: 471.8 (M + H)+.
Starting from 4-(4-methoxybenzenesulfonyl)-1-(4-thiophen-
2-ylbenzyl)piperidine-4-carboxylic acid (920 mg, 1.95 mmol)
and following the procedure outlined in example 19 (step 7),
510 mg of 4-(4-methoxybenzenesulfonyl)-1-(4-thiophen-2-yl-
benzyl)piperidine-4-carboxylic acid hydroxyamide was isolated
as a HCl salt, a brown solid. Yield: 50%. Mp 166 °C. MS, m/z:
487 (M + H)+. 1H NMR (300 MΗz, DMSO-d6): δ 2.12-2.21
(m, 2H), 2.50 (m, 2H), 2.78 (m, 2H), 3.39 (m, 2H), 3.87 (s, 3H),
4.29 (d, 2H), 7.17 (m, 3H), 7.54-7.75 (m, 8H), 9.36 (s, 1H),
10.07 (s, 1H). Anal. (C24H26 N2O5S2) C, H, N.
1
+ H)+. H NMR (300 MΗz, DMSO-d6): δ 0.94 (t, 3H), 1.43 (q,
2H), 1.71 (q, 2H), 2.27 (m, 4H), 2.72 (m, 2H), 4.10 (t, 2H), 4.24
(s, 2H), 7.12-7.15 (d, J ) 8.9, 2H), 7.51-7.53 (d, J ) 8.1, 1H),
7.63-7.65 (d, J ) 8.8, 2H), 7.72-7.75 (d, J ) 9.9, 2H), 7.87 (s,
1H), 9.36 (s, 1H), 10.5 (s, 1H), 11.2 (s, 1H). Anal. (C23H28
Cl2N2O5S) C, H, N.
-
[4-(Ben zyloxy)ben zen esu lfon yl]-1-ben zylp ip er id in e-4-
ca r b oxylic Acid H yd r oxa m id e (63). [4-(Benzyloxy)ben-
zenesulfonyl]-1-benzylpiperidine-4-carboxylic acid ethyl ester
was prepared according to the general method outlined in
example 19 (step 5) starting from [4-(benzyloxy)benzenesulfo-
nyl]acetic acid ethyl ester (12.35 g, 37 mmol) and bis(2-
chloroethyl)benzylamine hydrochloride (9.24 g, 40 mmol).
Yield: 12.0 g, 60%. Brown oil. MS, m/z: 494 (M + H)+.
[4-(Benzyloxy)benzenesulfonyl]-1-benzylpiperidine-4-car-
boxylic acid was prepared starting from [4-(benzyloxy)ben-
zenesulfonyl]-1-benzylpiperidine-4-carboxylic acid ethyl ester
(11.8 g, 24 mmol) dissolved in THF/methanol (75:75 mL/mL)
and 10 N NaOH (20 mL). The resulting reaction mixture was
worked up as outlined in example 19 (step 6). Yield: 5.58 g,
50%. White solid. MS, m/z: 466.2 (M + H)+.
Starting from [4-(benzyloxy)benzenesulfonyl]-1-benzylpip-
eridine-4-carboxylic acid (5.59 g, 12 mmol) and following the
procedure outlined in example 19 (step 7), 1.2 g of [4-(benzyl-
oxy)benzenesulfonyl]-1-benzylpiperidine-4-carboxylic acid hy-
droxamide was isolated as a white solid. Yield: 20%. Mp 117.8
°C (HCl salt). MS, m/z: 481 (M + H)+. 1H NMR (300 MΗz,
DMSO-d6): δ 2.2 (m, 2H), 2.49 (m, 4H), 2.5 (s, 3 H), 2.6 (m,
2H), 5.2 (s, 2H), 7.25-7.23 (d, 2H), 7.5 (d, 4H), 7.68-7.71 (d,
2H), 9.33 (s, 1H), 10.11 (s, 1H). Anal. (C26H28 N2O5S) C, H, N.
[4-(4-Ch lor oben zyloxy)ben zen esu lfon yl]-1-(4-m eth yl-
ben zyl)p ip er id in e-4-ca r boxylic Acid Hyd r oxa m id e (64).
[4-(4-Chlorobenzyloxy)benzenesulfonyl]-1-(4-methylbenzyl)pi-
peridine-4-carboxylic acid ethyl ester was prepared according
to the general method outlined in example 19 (step 5) starting
from [1-(4-chlorobenzyloxy)benzenesulfonyl]acetic acid ethyl
ester (5.47 g, 15 mmol) and 1-(4-methylbenzyl)bis(2-chloro-
ethyl)amine hydrochloride (5.23 g, 18 mmol). Yield: 8.0 g, 96%.
Brown oil. MS, m/z: 542.0 (M + H).
4-(4-Meth oxyben zen esu lfon yl)-1-(4-pyr idin -2-ylben zyl)-
p ip er id in e-4-ca r boxylic Acid Hyd r oxya m id e (61). 4-(4-
Methoxybenzenesulfonyl)-1-(4-pyridin-2-ylbenzyl)piperidine-
4-carboxylic acid ethyl ester was prepared according to the
general method outlined in example 60, starting from 1-(4-
bromobenzyl)-4-(4-methoxybenzensulfonyl)piperidine-4-car-
boxylic acid ethyl ester (4.65 g, 9.38 mmol) and 2-(tributyl-
stannyl)pyridine (12.08 g, 32.8 mmol). Yield: 2.79 g, 60%.
Brown oil. MS, m/z: 495.1 (M + H)+.
4-(4-Methoxybenzenesulfonyl)-1-(4-pyridin-2-ylbenzyl)pip-
eridine-4-carboxylic acid was prepared starting from 4-(4-
methoxybenzenesulfonyl)-1-(4-pyridin-2-ylbenzyl)piperidine-4-
carboxylic acid ethyl ester (1.83 g, 3.7 mmol) dissolved in THF/
methanol (3:1, 150 mL) and 10 N NaOH (10 mL). The resulting
reaction mixture was worked up as outlined in example 19
(step 6). Yield: 1.38 g, 80%. Off-white solid. Mp 217°C. MS,
m/z: 466.9 (M + H)+.
Starting from 4-(4-methoxybenzenesulfonyl)-1-(4-pyridin-2-
ylbenzyl)piperidine-4-carboxylic acid (1.32 g, 2.83 mmol) and
following the procedure outlined in example 19 (step 7), 480
mg of 4-(4-methoxybenzenesulfonyl)-1-(4-pyridin-2-ylbenzyl)-
piperidine-4-carboxylic acid hydroxyamide was isolated as a
HCl salt, a white powder. Yield: 33%. Mp 214 °C. MS, m/z:
482.0 (M + H)+. 1H NMR (300 MΗz, DMSO-d6): δ 2.30 (m,
2H), 2.80 (m, 2H), 3.42 (d, J ) 12.5 Hz, 2H), 3.75 (m, 2H),
3.88 (s, 3H), 4.36 (s, 2H), 7.15 (d, J ) 8.9 Hz, 2H), 7.59-7.74
(m, 4H), 7.84-7.95 (m, 3H), 8.55 (d, J ) 8.1 Hz, 1H), 8.79 (s,
1H), 9.14 (s, 1H), 10.68 (s, 1H), 11.17 (s, 1H). Anal. (C25H27
N3O5S) C, H, N.
1-(3,4-Dich lor oben zyl)-4-(4-bu toxyben zen esu lfon yl)p i-
p er id in e-4-ca r boxylic Acid Hyd r oxya m id e (62). 4-(4-
Butoxybenzenesulfonyl)-1-(3,4-dichlorobenzyl)piperidine-4-
carboxylic acid ethyl ester was prepared according to the
general method outlined in example 19 (step 5), starting from
(4-butoxybenzenesulfonyl)acetic acid ethyl ester (13.2 g, 44
mmol) (3,4-dichlorobenzyl)bis(2-chloroethyl)amine hydrochlo-
ride (14.3 g, mmol). Yield: 14.1 g, 60%. White solid. Mp 86
°C. MS, m/z: 527.9 (M + H)+.
[4-(4-Chlorobenzyloxy)benzenesulfonyl]-1-(4-methylbenzyl)-
piperidine-4-carboxylic acid was prepared starting from [4-(4-
chlorobenzyloxy)benzenesulfonyl]-1-(4-methylbenzyl)piperidine-
4-carboxylic acid ethyl ester (7.9 g, 124 mmol) dissolved in
THF/methanol (50:50 mL/mL) and 10 N NaOH (20 mL). The
resulting reaction mixture was worked up as outlined in
example 19 (step 6). Yield: 4.6 g, 61%. Off-white solid. Mp
204 °C. MS, m/z: 514.2 (M + H)+.
Starting from [4-(4-chlorobenzyloxy)benzenesulfonyl]-1-(4-
methylbenzyl)piperidine-4-carboxylic acid (4.2 g, 8 mmol) and
following the procedure outlined in example 19 (step 7), 1.3 g
of [4-(4-chlorobenzyloxy)benzenesulfonyl]-1-(4-methylbenzyl)-
piperidine-4-carboxylic acid hydroxamide was isolated as a
yellow solid. Yield: 29%. Mp 172 °C (HCl salt). MS, m/z: 528.9
(M + H)+. 1H NMR (300 MΗz, DMSO-d6): δ. 2.2-2.4 (m, 5H),
2.5-2.62 (m, 4H), 2.7-2.9 (m, 2H), 4.2-4.45 (m, 2H), 5.25 (s,
2H), 7.2-7.75 (m, 12H), 9.40 (brs, 1H), 10.42 (brs, 1H). Anal.
(C27H29Cl N2O5S) C, H, N.
1-(4-Meth oxy)ben zyl-4-[4-(4-ch lor op h en oxy)ben zen e-
su lfon yl]piper idin e-4-car boxylic Acid Hydr oxyam ide (66).
1-(4-Methoxy)benzyl-4-[4-(4-chlorophenoxy)benzenesulfonyl]-
piperidine-4-carboxylic acid ethyl ester was prepared according
1-(3,4-Dichlorobenzyl)-4-(4-butoxybenzenesulfonyl)piperidine-