Substituted Pyrrolidone Butanamides as Antiepileptics
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 545
and the mixture is brought to reflux for 8 h and stirred
overnight at room temperature. The mixture is concentrated
to dryness, purified by Prep LC (400 g SiO2, CH2Cl2-MeOH-
NH4OH 94/5/1) and crystallized hexanes-ethyl acetate to give
90 mg of pure 72 (34%). Anal. (C13H23N3O2): C, H, N.
{1-[(1S)-1-(Am in oca r bon yl)p r op yl]-5-oxo-3-p yr r olid in -
yl}m eth yl n itr a te (73). In a 500-mL, three-necked flask,
fitted with mechanical stirrer and reflux condenser under inert
atmosphere, 8.10 g (26 mmol, 1 equiv) of 70 is dissolved in
250 mL of acetonitrile. Silver nitrate (4.86 g, 28.6 mmol, 1.1
equiv) is added and the mixture is brought to reflux. After 2
h, 440 mg (2.8 mmol, 0.1 equiv) of silver nitrate is added, and
reflux is continued for a total of 4 h. After cooling, the mixture
is concentrated to dryness and purified by Prep LC (200 g SiO2,
CH2Cl2-MeOH-NH4OH 96/5.4/0.6) to give 5.7 g of crude 73.
It is crystallized from 50 mL of ethyl acetate to give 4.13 g of
pure 73 (65%). Anal. (C9H15N3O5): C, H, N.
(2S)-2-(2-Oxo-(4R)-4-{[(p h en ylsu lfon yl)a m in o]m eth yl}-
1-p yr r olid in yl)bu ta n a m id e (75). In a 500-mL pressure jar,
under inert atmosphere, 900 mg of 10% Pd adsorbed on
charcoal is suspended in 100 mL of ethanol. A solution of 8.7
g (38 mmol) of (2S)-2-[4-(azidomethyl)-2-oxo-1-pyrrolidinyl]-
butanamide (66) in 150 mL of ethanol is added and the
mixture hydrogenated on a Parr hydrogenator at a maximum
of 30 psi H2 pressure for 2 h. The mixture is degassed and
filtered on a Celite/Norite pad, the residue is washed with 2
× 100 mL EtOH, and the combined filtrates are concentrated
to dryness, to give 7.93 g of crude of (2S)-2-[4-(aminomethyl)-
2-oxo-1-pyrrolidinyl]butanamide hydrochloride (74, 100% yield),
used as such in the next step. In a 25-mL, three-necked flask,
fitted with a magnetic stirrer under inert atmosphere, 1 g (4.24
mmol, 1 equiv) of 74 is suspended in 10 mL of CH2Cl2.
Triethylamine (1.3 mL, 940 mg, 2.2 equiv) is added and the
mixture cooled to 0 °C. A solution of 0.60 mL (820 mg, 1.1
equiv) of benzenesulfonyl chloride in 2 mL of CH2Cl2 is added
dropwise over 0.25 h, and the mixture is stirred for 3 h at room
temperature. The mixture is diluted with 20 mL of CH2Cl2
and washed with 2 × 15 mL of brine, dried over MgSO4, and
concentrated to dryness, and the residue is purified by Prep
LC (350 g of SiO2, CH2Cl2-MeOH-NH4OH 95.6/4/0.4 f 93.4/
6/0.6) to give 1.1 g of pure 75 (75%). It is crystallized from 30
mL of acetonitrile. Anal. (C15H21N3O4S): C, H, N.
2-propyl-pentanoic acid methyl ester 78d . δH (250 MHz,
CDCl3): 0.90 (6H, t, J 7.5), 1.10-1.36 (4H, m), 1.65 (4H, t, J
7.5), 2.67 (2H, s), 3.69 (3H, s), 6.92 (1H, s (broad)).
2-(Cyclop r op ylm eth yl)su ccin ic Acid 1-Meth yl Ester
(79b). In a 250-mL, three-necked flask fitted with a magnetic
stirrer, under inert atmosphere, monomethyl succinate (7.5
g, 0.057 mol) in THF (100 mL) cooled at -78 °C is added
dropwise via cannula to a solution of LDA (2 M in THF, 62.7
mL) and HMPA (51 g, 0.285 mol) in THF (220 mL) at -78 °C.
After 1 h, C3H5CH2Br (10.0 g, 0.074 mol) is added dropwise
and the solution turned from red to yellow. After 2 h at -78
°C, the reaction is quenched carefully by adding HCl (3 M) in
Et2O, warmed to room temperature, and filtered. The filtrate
is concentrated in vacuo and the residue purified by chroma-
tography on silica gel (CH2Cl2-EtOH-AcOH 96/3.6/0.4 (v/v))
to give 79b (7.77 g, 73%). δH (250 MHz, C2D6SO): 0.0-0.1 (2H,
m), 0.32-0.48 (2H, m), 0.57-0.78 (1H, m), 1.44 (2H, t, J 8.4),
2.37-2.9 (3H, m + solvent signal), 3.62 (3H, s). The crude is
contaminated by 50% of the starting materiel (NRM).
4-(Cyclop r op ylm eth yl)d ih yd r ofu r a n -2-on e (81b). In a
500-mL, three-necked flask fitted with a magnetic stirrer,
KOH (2.4 M, 17 mL) is added dropwise to 79b (7.77 g, 0.041
mol) in MeOH (20 mL) at 0 °C. The reaction mixture is
concentrated in vacuo and the residue dissolved in EtOH and
cooled to 0 °C. Powdered CaCl2 (11.58 g, 0.11 mol) and NaBH4
(6.3 g, 0.16 mol dissolved with KOH (1.12 g) in EtOH (80 mL))
are added successively at 0 °C. The reaction mixture is stirred
overnight at room temperature and quenched with HCl (6 M,
100 mL), and the organic solvents are evaporated carefully.
The residue is diluted in water and extracted with CH2Cl2,
and the organic layer is dried on MgSO4, filtrated, and
evaporated to give 81b (3.76 g, 64%) which is used without
further purification. δH (250 MHz, C2D6SO): 0.0-0.1 (2H, m),
0.27-0.44 (2H, m), 0.54-0.73 (1H, m), 0.94-1.38 (2H, m),
2.03-2.71 (3H, m + solvent signal), 3.84 (1H, dd, J 8.4; 8.4),
4.34 (1H, dd, J 8.8; 8.8). The crude is contaminated by 28%
(NMR) of γ-butyrolactone.
4-Meth yl-4-p r op yld ih yd r ofu r a n -2-on e (81c) is synthe-
sized using the same method as for 81b starting from 79c. δH
(250 MHz, CDCl3): 0.94(3H, t, J 6.25), 1.16 (3H, s), 1.21-1.51
(4H, m), 2.23 (1H, d, J 17.5), 2.36 (1H, d, J 17.5), 3.94 (1H, d,
J 10.0), 4.02 (1H, d, J 10.0).
4,4-Dip r op yld ih yd r ofu r a n -2-on e (81d ) is synthesized
using the same method as for 81b starting from 79d . δH (250
MHz, CDCl3): 0.94 (6H, t, J 5.0), 1.14-1.55 (8H, m), 2.32 (2H,
s), 4.01 (2H, s).
(2S)-2-{(4R)-4-[(5-Meth yl-1H-1,2,3-tr ia zol-1-yl)m eth yl]-
2-oxo-1-p yr r olid in yl}bu ta n a m id e (76). In a 50-mL, three-
necked flask, fitted with a magnetic stirrer and reflux con-
denser under inert atmosphere, 1 g (4.44 mmol, 1 equiv) of 66
is suspended in 20 mL of toluene. 1-(Triphenylphosphora-
nylidene)acetone (1.55 g, 4.88 mmol, 1.1 equiv) is added, and
the mixture is heated to 80 °C for 24 h. After cooling, the
mixture is concentrated to dryness and purified by Prep LC
(1 kg SiO2, CH2Cl2-MeOH-NH4OH 94.5/5/0.5) It is suspended
in 15 mL of water and lyophilized to give 240 mg of pure 76
as a clear oil (42%). HPLC: >99%.
2-Meth yl-2-p r op ylsu ccin ic Acid 1-Meth yl Ester (79c).
In a 150-mL, three-necked flask fitted with a magnetic stirrer,
under inert atmosphere, methyl 2-methylpentanoate (78c) (7.0
g, 0.054 mol) is added to a solution of LDA (2 M in THF, 30
mL, 0.059 mol) cooled at -78 °C. After 1 h, the tert-butyl
bromoacetate (12.58 g, 0.065 mol) diluted in THF (20 mL) is
added dropwise. The reaction mixture is stirred at -78 °C (1
h) and room temperature (4 h), quenched with ice water, and
extracted with ether. The organic layer is dried on MgSO4,
filtered, and concentrated in vacuo to give 2-methyl-2-propyl-
succinic acid 4-tert-butyl ester 1-methyl ester (15.21 g) which
is used in the next step without further purification. In a 250-
mL, three-necked flask fitted with a magnetic stirrer, under
inert atmosphere, the crude ester (13.2 g) is stirred in TFA
(70 mL) and CH2Cl2 (100 mL) for 48 h at room temperature.
The reaction mixture is concentrated to dryness to give 79c
(13.07 g). δH (250 MHz, CDCl3): 0.90 (3H, t, J 7.5), 1.20-1.40
(5H, m + s at 1.29), 1.51-1.67 (2H, m), 2.46 (1H, d, J 13.8),
2.70 (1H, d, J 13.8), 3.69 (3H, s), 6.78 (1H, s (broad)).
4-n -P r op ylbu tyr ola cton e (81a ). In a 2-L, three-necked
flask under argon, n-PrMgBr (2.0 M in ether, 820 mL, 1.64
mol) is added dropwise to a suspension of CuI (159.4 g, 0.82
mol) in dry Et2O (450 mL) cooled at -20 °C. After 0.5 h, the
solution is cooled to -40 °C, and TMSCl (89.09 g, 0.82 mol) is
added dropwise followed by 2,3-furanone 80 (68.9 g, 0.82 mol)
dissolved in dry Et2O (addition time: 0.5 h). The suspension
is allowed to warm to room temperature and hydrolyzed with
saturated ammonium chloride. The aqueous layer is extracted
with AcOEt (3×), washed with water, dried over magnesium
sulfate, and evaporated to dryness to afford the 4-n-propyl-
butyrolactone (81a , 103 g). It is used in the next step without
further purification (distillation led to partial decomposition
of the compound). δH (250 MHz, CDCl3): 0.98 (3H, t, J 8.2),
1.22-1.57 (4H, m), 2.15 (1H, dd, J 5.4; 16.1), 2.45-2.67 (2H,
m), 3.89 (1H, dd, J 8.7; 8.7), 4.41 (1H, dd, J 8.7; 8.7).
4-Ch lor on on a n oic Acid Meth yl Ester (82e). To a solu-
tion of γ-nonalactone 81e (0.32 mL, 2 mmol) in thionyl chloride
(164 µL, 2.25 mmol) is added zinc chloride (12 mg, 0.088 mmol)
at room temperature and the mixture is stirred for 24 h. Excess
methanol is added and the reaction mixture is stirred for 0.2
h and then concentrated under reduced pressure to give 82e
used as such. MS m/z (EI): 175 (M+•),130, 96, 74.
Meth od D-1. (2S)-2-[2-Oxo-4-p r op ylp yr r olid in -1-yl]bu -
ta n a m id e (83â a n d 83r). In a three-necked flask, under
argon, TMSI (51 mL) is added to a solution of the crude 81a
(103.04 g, 0.805 mol) in CH2Cl2 (820 mL) cooled at 0 °C. The
solution is stirred for 2 h at room temperature and hydrolyzed
2,2-Dip r op ylsu ccin ic a cid 1-m eth yl ester (79d ) is syn-
thesized using the same method as for 79c starting from