POTENTIAL NOOTROPIC AGENTS: SYNTHESIS OF SOME 1,4-DISUBSTITUTED 2-OXOPYRROLIDINES AND SOME RELATED COMPOUNDS

Article abstract of DOI:10.1135/cccc19941126

4-(Aminomethyl)-1-benzyl-2-oxopyrrolidine (VI) was transformed by treatment with (4-benzhydrylpiperazin-1-yl)carbonyl chlorides IIIb-IIId and with (4-methylpiperazin-1-yl)carbonyl chloride (IIIa) to the carboxamides IVa-IVd.Heating of 1-(ethoxycarbonylmethyl)-2,4-dioxopyrrolodine (XIX) in acetonitrile in the presence of water afforded XVIIIa.Treatment with ammonia led to the diamide XVIIIc, while alkaline hydrolysis of XVIIIa gave the dicarboxylic acid XVIIIb. 4-(Aminomethyl)-1-(4-methylthiobenzyl)-2-oxopyrrolidine (XII) was prepared by the reaction of 4-(methylthio)benzylamine with itaconic acid and the following sequence of reaction ...

Full text of DOI:10.1135/cccc19941126

1126
Valenta, Urban, Taimr, Polivka:
POTENTIAL NOOTROPIC AGENTS: SYNTHESIS OF SOME
1,4-DISUBSTITUTED 2-OXOPYRROLIDINES
AND SOME RELATED COMPOUNDS
a
b
a
a
Vladimir VALENTA , Jiri URBAN , Jan TAIMR and Zdenek POLIVKA
a Research Institute for Pharmacy and Biochemistry,
130 60 Prague 3, The Czech Republic
b The J. Heyrovsky Institute of Physical Chemistry,
Academy of Sciences of the Czech Republic, 182 23 Prague 8, The Czech Republic
Received July 15, 1993
Accepted November 30, 1993
4-(Aminomethyl)-1-benzyl-2-oxopyrrolidine (VI) was transformed by treatment with (4-benz-
hydrylpiperazin-1-yl)carbonyl chlorides IIIb
– IIId and with (4-methylpiperazin-1-yl)carbonyl
chloride (IIIa) to the carboxamides IVa – IVd. Heating of 1-(ethoxycarbonylmethyl)-2,4-dioxopyrro-
lidine (XIX) in acetonitrile in the presence of water afforded XVIIIa. Treatment with ammonia led to
the diamide XVIIIc, while alkaline hydrolysis of XVIIIa gave the dicarboxylic acid XVIIIb.
4-(Aminomethyl)-1-(4-methylthiobenzyl)-2-oxopyrrolidine (XII) was prepared by the reaction of
4-(methylthio)benzylamine with itaconic acid and the following sequence of reactions starting from
the obtained carboxylic acid VII including esterification, reduction and treatment the obtained alcohol
IX with thionyl chloride, synthesis of phthalimido derivative XI and hydrazinolysis. Amine
XII added to 4-chlorophenyl isocyanate formed XIII. The compounds prepared were tested for
nootropic activity.
In recent communications we dealt with series of 2-oxopyrrolidin-1-ylacetic acid pipe-
razides1 and some amides and choline derivatives2 as potential nootropic agents and
their pharmacological effects. Our present communication concerns some of the deriva-
tives of 1,4-disubstituted 2-oxopyrrolidines synthesized within the scope of our investi-
gation.
In this series (4-hydroxy-2-oxopyrrolidin-1-yl)acetamide (oxiracetam, Neuromet®)
(XVII, ref.3) and 4-(aminomethyl)-1-benzyl-2-oxopyrrolidine (nebracetam fumarate,
WEB-1881, Memolog®) (VI, ref.4) were described as nootropic drugs. Our preceeding
experience with piperazine derivatives of 2-oxopyrrolidines led us to synthesize some
piperazine derivatives in a series of 1,4-disubstituted 2-oxopyrrolidines. 4,4′-Difluoro-
benzhydryl chloride and 2,3′-dichlorobenzhydryl chloride, respectively, reacted with
1-ethoxycarbonylpiperazine in the presence of a catalytic amount of potassium iodide
and an excess of potassium carbonate in boiling N,N-dimethylformamide to afford
compounds Ic and Id, respectively. Reaction of 2,3′-dichlorobenzhydryl chloride with
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Collect. Czech. Chem. Commun. (Vol. 59) (1994)

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Valenta, Urban, Taimr, Polivka:
1-ethoxycarbonylpiperazine in N,N-dimethylformamide led to the isolation of a crystal-
line by-product, identified as 1,2-bis(2-chlorophenyl)-1,2-bis(3-chlorophenyl)ethane
(V). The same compound but with a different melting point was previously prepared by
the reaction of 2,3′-dichlorobenzhydryl chloride with 2-(4-methyl-piperazin-1-yl)ethanol
and sodium hydride in dioxane5. Discrepancy in the melting points may be explained
by a different ratio of the racemate and the meso-form in the product.
The piperazines IIb – IId were prepared from the 1-ethoxycarbonyl derivatives Ib
(ref.6), Ic and Id by refluxing with alcoholic potassium hydroxide. The substituted
(4-benzhydrylpiperazin-1-yl)carbonyl chlorides IIIb – IIId were obtained by treatment
of the piperazines IIb – IId with excess of phosgene. Carbonyl chlorides IIIa (ref.7) and
IIIb – IIId reacting with the amine VI in equimolar amounts in the presence of triethyl-
amine in boiling dioxane afforded compounds IVa – IVd.
Refluxing 4-(methylthio)benzylamine8 with an equimolecular amount of itaconic
acid in xylene afforded the acid VII. The sequence of esterification, reduction and treat-
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1129
ment the obtained alcohol IX with thionyl chloride led to chloride X. Its reaction with
potassium phthalimide in N,N-dimethylformamide at 150 – 152 °C yielded XI, which
treated with hydrazine hydrate, gave the amine XII. By addition of 4-chlorophenyl iso-
cyanate9 to the amine XII in toluene the urea XIII was obtained.
3-(Ethoxycarbonyl)-1-(ethoxycarbonylmethyl)-4-hydroxy-2-oxopyrrolidine (XIV), an
intermediate in the synthesis of oxiracetam3 (XVII), refluxed in acetonitrile in the
presence of water for more then 20 min yielded compound XVIIIa. The same compound
was obtained by keeping a mixture of ethyl (2,4-dioxopyrrolidin-1-yl)acetate (XIX) and
acetonitrile at room temperature for four months. Refluxing mixture of XIV in acetoni-
trile for a shorter time led to XIX, which was reduced with sodium borohydride to ethyl
(4-hydroxy-2-oxopyrrolidin-1-yl)acetate (XVI). Following reaction of the last men-
tioned compounds with ammonia afforded oxiracetam3 (XVII). A reaction of XVIIIa
with ammonia in methanol led to a diamide XVIIIc. Alkaline hydrolysis of XVIIIa gave
the acid XVIIIb. Elemental analysis and spectra provide a good evidence for the struc-
ture XVIIIa and in this way also for the related structures XVIIIb and XVIIIc.
Compounds IVa – IVd, XII, XIII, XVIIIa – XVIIIc were tested by the methods of
behavioral pharmacology. The detailed results will be reported in a separate communi-
cation. Serotonin, muscarine, glutamate and NMDA receptor activity was investigated
by methods biochemical pharmacology. Some compounds significantly inhibit the
binding of [3H]MK-801 to the brain cortex membranes (compounds were used in con-
centrations of 1 000 nmol l−1, inhibition of binding in % or IC50 are given): IVb 85, IC50
38.3 µM; IVc 68; XIII 42; XVIIIa 98; XVIIIb 96; XVIIIc 34.
The prepared compounds were also tested for antimicrobial activity in vitro. Micro-
organism and the minimum inhibitory concentrations in mg ml−1 are given unless they
exceed 150 µg/ml: Proteus vulgaris, IVd 32; Streptococcus D, IVa 32; Streptococcus
pyogenes, IVa 64, IVd 64, XVIIIa 128, XVIIIb 128; Escherichia coli, XVIIIb 128.
EXPERIMENTAL
The melting points of analytical samples were determined on a Kofler block and are uncorrected; the
samples were dried in vacuo of about 40 Pa at a room temperature or at a suitably elevated tempera-
ture. UV spectra (in methanol), λmax in nm (log ε) were recorded with the Unicam SP 8000 spectro-
photometer; IR spectra (wavenumbers in cm−1) with Unicam SP 2000 or Perkin–Elmer 298
spectrophotometers, NMR spectra on a Tesla BS 567A (1H at 100 MHz, 13C at 25.14 MHz) or on a
Varian XL-200 (1H at 200,057 MHz, 13C at 50,309 MHz), chemical shifts are given in ppm (δ-scale),
coupling constants (J) in Hz. The mass spectra were measured on a Varian-MAT 44S (GC-MS) spec-
trometer. The homogeneity of the products and composition of the mixtures were checked by thin-
layer chromatography (TLC) on silica gel (Silufol UV254). Preparative chromatographic separations
were carried out on columns of silica gel (Fluka 60). The extracts were dried with Na2SO4 or K2CO3
and evaporated under reduced pressure on a rotary evaporator.
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Valenta, Urban, Taimr, Polivka:
4,4′-Difluorobenzhydryl Chloride
A solution of 4,4′-difluorobenzhydrol10 (15.0 g, 68.1 mmol) and thionyl chloride (10.7 g, 90 mmol)
in toluene (60 ml) was refluxed for 2 h. The excess of thionyl chloride and toluene was evaporated
in vacuo. The residue distilled in vacuo gave 15.2 g (94%) product, b.p. 88 – 90 °C/27 Pa (ref.11, b.p.
130 – 133 °C/200 Pa).
1-Ethoxycarbonyl-4-(4,4′-difluorobenzhydryl)piperazine (Ic)
A
mixture of 1-(ethoxycarbonyl)piperazine (10.0 g, 63 mmol), 4,4′-difluorobenzhydryl chloride
(15.2 g, 64 mmol) and triethylamine (13.0 g, 128 mmol) in chloroform (100 ml) was refluxed for 6 h,
cooled and washed with 0.1 M aqueous tartaric acid (100 ml) and water (100 ml), dried and evap-
orated. The residue was crystallized from cyclohexane (30 ml) to give 11.5 g (49%) of Ic, m.p.
120 – 123 °C. IR spectrum (Nujol): 830 (2 adjacent Ar−H), 1 120, 1 220, 1 243, (COOR); 1 502, 1
600, 1 685 (NCOOR); 2 760, 2 805 (N−CH), 3 030, 3 050, 3 070, 3 105 (Ar). 1H NMR spectrum
(CDCl3, 100 MHz): 3.24 t, 3 H, (C−CH3, J = 7); 2.32 bt, 4 H (2 × H-3 and H-5 from piperazine);
3.48 bt, 4 H (2 × H-2 and H-6 from piperazine); 4.11 q, 2 H (OCH2CH3, J = 7); 4.22 s, 1 H (Ar2CH−N);
6.98 t, 4 H (2 × H-3 and H-5 from 4-FC6H4, J(H,H) = 9; J(H,F) = 9); 7.35 dd, 4 H (2 × H-2 and H-6
from 4-FC6H4, J(H,H) = 9; J(H,F) = 6). For C20H22F2N2O (360.4) calculated: 66.65% C, 6.15% H,
10.54% F, 7.77% N; found: 66.62% C, 6.32% H, 10.25% F, 7.57% N.
1-Ethoxycarbonyl-4-(2,3′-dichlorobenzhydryl)piperazine (Id)
A mixture of 2,3′-dichlorobenzhydryl chloride5 (19.0 g, 70 mmol), 1-(ethoxycarbonyl)piperazine
(13.5 g, 85 mmol), anhydrous potassium carbonate (13.8 g, 100 mmol) and potassium iodide (0.3 g)
in N,N-dimethylformamide (60 ml) was stirred at 145 °C for 5 h and left overnight at a room tem-
perature. The solid was filtered off and the solution evaporated in vacuo. Oily residue (29.9 g) was
chromatographed on silica gel (Fluka). Elution with chloroform gave first 1.27 g less polar fraction,
m.p. 185 – 189 °C. Repeated crystallization from benzene gave 0.9 g (6%) of 1,2-bis(2-chloro-
phenyl)-1,2-bis(3-chlorophenyl)ethane (V), m.p. 195 – 200 °C. Mass spectrum, m/z(%): 470 (M+,
C26H18Cl4, 0.1), 237 (62), 235 (100), 200 (23), 199 (23), 165 (69). UV spectrum: 261 (3.03), 266.5
(3.13), 274.5 (3.02). IR spectrum (Nujol) : 690, 776, 750, 883, (3 and 4 adjacent and solitary Ar−H);
1 569, 1 590, 3 005, 3 050 (Ar). For C26H18Cl4 (472.2) calculated: 66.12% C, 3.84% H, 30.03% Cl;
found: 65.84% C, 3.89% H, 29.99% Cl. The next fraction (chloroform) provided 29.9 g (80%) oily
crude Id which was used for the next step.
1-(4,4′-Difluorobenzhydryl)piperazine (IIc)
A solution of Ic (15.0 g, 41 mmol) and potassium hydroxide (16.0 g, 280 mmol) in ethanol (25 ml)
was refluxed for 3 h. Ethanol was evaporated and the residue distributed between water (30 ml) and
toluene (160 ml). The organic layer was washed with brine (50 ml) and evaporated. The residue was
triturated with petroleum ether (25 ml) to yield crystalline IIc (8.4 g, 71%), m.p. 85 – 91 °C. Analy-
tical sample m.p. 91 – 94 °C (hexane). 1H NMR spectrum (CDCl3, 100 MHz): 1.58 bs, 1 H, (NH);
2.34 bt, 4 H (2 × H-2 and H-6 of piperazine); 2.90 bt, 4 H (2 × H-3 and H-5 of piperazine); 4.20 s,
1 H (Ar2CH); 6.98 t, 4 H (2 × H-3 and H-5 from 4-FC6H4, J(H,H) = J(H,F) = 8); 7.32 dd, 4 H (2 ×
H-2 and H-5 from 4-FC6H4, J(H,H) = 8, J(H,F) = 6). 13C NMR spectrum (CDCl3, 25.14 MHz):
46.31 t (C-3 and C-5 of piperazine); 53.26 t (C-2 and C-6 of piperazine); 74.99 d (Ar2CH); 115.37 d
(C-2 from 4-FC6H4, J(F,C) = 20.6); 129.37 d (C-3 from 4-FC6H4, J(F,C) = 7.5); 138.19 s (C-1 from
4-FC6H4); 161.83 s (C-4 from 4-FC6H4, J(F,C) = 246). For C17H18F2N2 (288.3) calculated: 70.81% C,
6.29% H, 13.18% F, 9.72% N; found: 71.07% C, 6.31% H, 12.85% F, 9.76% N.
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1-(2,3′-Dichlorobenzhydryl)piperazine (IId)
A mixture of crude Id (5.4 g, 14 mmol) and potassium hydroxide (14.0 g, 210 mmol) in ethanol
(15 ml) was stirred and refluxed for 1 h. Ethanol was distilled of and the residue was distributed
between benzene (60 ml) and water (20 ml). The benzene layer was evaporated in vacuo to give 4.2 g
(94%) oily base IId, which was characterized as the maleate hemihydrate, m.p. 157.5 – 160 °C (etha-
nol). Mass spectrum m/z: 320 (M+, C17H18Cl2N2, 4), 285 (11), 277 (13), 275 (20), 264 (11), 240 (12),
237 (29), 235 (50), 165 (32). For C21H22Cl2N2O4 . 0.5 H2O (446.3) calculated: 56.50% C, 5.19% H,
15.88% Cl, 6.28% N; found: 56.30% C, 4.91% H, 15.77% Cl, 6.06% N.
(4-Benzhydrylpiperazin-1-yl)carbonyl Chloride (IIIb)
A solution of IIb (ref.6; 14.4 g, 57 mmol) in chloroform (70 ml) was added dropwise to a stirred
solution of phosgene (8.9 g, 900 mmol) in chloroform (16 ml) at −1 °C for 1.5 h. The mixture was
stirred at 0 °C for another 1.5 h. The precipitate was filtered and washed twice with hexane (25 ml);
17.6 g crude product, m.p. 120 – 145 °C. It was dissolved in dichloromethane (200 ml), washed with
50% aqueous K2CO3 (10 ml) and water (10 ml) and evaporated in vacuo. The residue was dissolved
in benzene (20 ml) and precipitated with) hexane (5 ml). A by product was collected (4.1 g, m.p.
180 – 221 °C). The filtrate was evaporated, the residue was dissolved in hexane (20 ml) and precipi-
tated with petroleum ether (20 ml) giving 6.4 g (43%) of IIIb, m.p. 133 – 135 °C (ref.5, m.p. 140 – 141 °C).
[4-(4,4′-Difluorobenzhydryl)piperazin-1-yl]carbonyl Chloride (IIIc)
A solution of IIc (8.0 g, 27.8 mmol) in chloroform (40 ml) was added dropwise into a solution of
phosgene (6.6 g, 670 mmol) in chloroform (40 ml) at 0 °C over 40 min. The mixture was stirred at
0 °C for 2 h. A precipitated IIIc hydrochloride was filtered and washed with ether (15 ml) yield 7.2 g
(66%), m.p. 127 – 130 °C. Analytical sample m.p. 127 – 129 °C (chloroform–ether). For
C18H18Cl2F2N2O (387.3) calculated: 55.83% C, 4.68% H, 18.31% Cl, 9.80% F, 7.23% N; found:
56.12% C, 4.74% H, 18.57% Cl, 10.10% F, 7.23% N.
[4-(2,3′-Dichlorobenzhydryl)piperazin-1-yl]carbonyl Chloride (IIId)
Similar reaction of IId (11.4 g, 35.5 mmol) in chloroform (60 ml) with phosgene (10.5 g, 106 mmol)
in chloroform (65 ml) afforded 7.5 g (50%) of IIId hydrochloride, m.p. 150 – 153 °C. Analytical
sample m.p. 153 – 155 °C (chloroform–ether). For C18H48Cl4 N2O (420.2) calculated: 51.45% C,
4.32% H, 33.75% Cl, 6.67% N; found: 51.68% C, 4.30% H, 33.76% Cl, 6.90% N.
1-Benzyl-4-[(4-methylpiperazin-1-yl)carbonylaminomethyl]-2-oxopyrrolidine (IVa)
A solution of IIIa (ref.7; 3.4 g, 20 mmol) in anhydrous dioxane (25 ml) was dropped into an vigorous
stirred suspension of VI (ref.4; 4.1 g, 20 mmol) and triethylamine (2.0 g, 20 mmol) in anhydrous
dioxane (50 ml) over 30 min at 30 °C. The mixture was then stirred and refluxed for 2.5 h and left
overnight at room temperature. The solvent was evaporated in vacuo, the oily residue was disolved
in ethyl acetate (30 ml), the solution was washed with 50% aqueous K2CO3 (10 ml), and twice with
12% brine and precipitated with petroleum ether (20 ml). After standing overnight at a room tem-
perature, the solid product was filtered; 4.7 g (71%), m.p. 104 – 114 °C. Crystallization from ethyl
acetate yielded 3.2 g (48%) of pure IVa, m.p. 119 – 122 °C. The compound crystallized with a half
molecule of ethyl acetate. Crystallization from toluene gave IVa melting at 121 – 123 °C. IR spectrum
(Nujol): 700, 730 (5 adjacent Ar−H); 1 482, 3 030, 3 050, 3 075 (Ar); 1 530, 1 666 (NCONHR);
1
1 632 (NC=O in the ring); 2 740, 2 780 (NCH3). H NMR spectrum (CDCl3, 200 MHz): 2.26 s, 3 H
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

1132
Valenta, Urban, Taimr, Polivka:
(CH3N); 2.29 – 2.56 m, 7 H; 3.01 dd, 1 H (J = 10.7, J′ = 4.2, H-5); 3.14 t, 1 H (J = 6,6); 3.24 –
3.38 m, 6 H; 4.30 and 4.48, 2 H (AB system, J = 15.2, ArCH2); 5.73 t, 1 H (NH, J = 5.8); 7.15 –
7.36 m, 5 H (Ar−H). 13C NMR spectrum (CDCl3, 50.3 MHz): 31.4 d (C-4); 34.9 t (C-3); 43.4 t (C-2′
and C-6′); 43.9 t (C-5); 45.8 q (CH3N); 46.2 t (C-6); 49.9 t (NCH2Ar); 54.4 t (C-3′and 5′); 127.5 d
(C-3 and C-5 of benzyl); 127.3 d (C-4 of benzyl); 128.4 d (C-2 and C-6 of benzyl); 135.9 s (C-1 of
benzyl); 157.6 s (C-7); 173.6 s (C-2). For C18H26N4O2 (330.4) calculated: 65.42% C, 7.93% H, 16.96% N;
found: 65.63% C, 7.99% H, 16.79% N.
4-(4-Benzhydrylpiperazin-1-ylcarbonylaminomethyl)-1-benzyl-2-oxopyrrolidine (IVb)
A mixture of IIIb (4.4 g, 14 mmol), VI (2.9 g, 14 mmol), and triethylamine (2.1 g, 21 mmol) in
anhydrous dioxane (40 ml) was refluxed for 3.5 h. After cooling, the solid was collected and the
filtrate evaporated. The oily residue was chromatographed on a column of silica gel (60 g). Elution
with dichloromethane gave 4.5 g (67%) base IVb, m.p. 164 – 165 °C (benzene). IR spectrum (Nujol):
708, 740 (5 adjacent Ar−H); 1 250, 1 490, 1 599, 1 604, 3 025, 3 060, 3 080 (Ar−H); 1 519, 1 643
(NCONH), 1 679 (N−CO in the ring); 3 408 (NH). Mass spectrum, m/z: 482 (M+, C30H34N4O2,
0.01), 315 (0.1), 230 (29), 207 (37), 168 (62), 91 (99), 56 (100). 1H NMR spectrum (CDCl3, 100
MHz): 7.10 – 7.50 m, 15 H (Ar−H); 4.86 bt, 1 H (NH); 4.50 and 4.30, 2 H (AB system, J = 14,
PhCH2N); 4.22 s, 1 H (Ar2CH−N). 13C NMR spectrum (CDCl3, 25.14 MHz): 30.11 t (C-3); 31.60 d
(C-4); 43.85 t (C-2′ and C-6′); 44.14 t (C-5); 46.46 t (C-6); 50.12 t (CH2 of benzyl); 51.46 t (C-3′and
C-5′); 75.89 d (Ar2CH); 127.13 d (C-4 of benzhydryl); 127.58 d (C-4 of benzyl); 127.88 d, 128.55 d,
128.70 d (C-2, C-3, C-5 and C-6 of benzhydryl); 136,20 s (C-1 of benzyl); 142.22 s (C-1 of benz-
hydryl); 157.83 s (C-7); 173.82 s (C-2). For C30H34N4O2 (482.6) calculated: 74.65% C, 7.10% H,
11.61% N; found: 74.78% C, 7.31% H, 11,43% N.
1-Benzyl-4-[4-(4,4′-difluorobenzhydryl)piperazin-1-ylcarbonylaminomethyl]-2-oxopyrrolidine (IVc)
A similar procedure starting from VI (ref.4; 1.9 g, 9.5 mmol) and IIIc (3.4 g, 9.5 mmol) in dioxane
(35 ml) gave 5.4 g of crude oily product which was chromatographed on silica gel (50 g). Elution
with chloroform saturated with ammonia gave 2.0 g (40%) of pure base IVc, m.p. 180 – 183 °C.
Analytical sample m.p. 179 – 181 °C (benzene–hexane). IR spectrum (Nujol): 707, 749, 831 (5 and
2 adjacent Ar−H); 1 220 (Ar−F); 1 519, 1 575 (NCONH); 1 646 (NRCO in five membered cycle);
1
1 502, 1 600, 3 030, 3 065 (Ar); 3 395 (NH). H NMR spectrum (CDCl3, 200 MHz): 2.18 – 2.55 m,
7 H; 2.97 dd, 1 H (J = 10.2, J′ = 4.3; H-5); 3.11 t, 1 H (J = 6.2); 3.22 t, 1 H (J = 5.6); 3.32 m, 5 H;
4.19 s, 1 H (Ar2CH); 4.29 and 4.45, 2H (AB system, J = 14.8, PhCH2); 5.17 t, 1 H (J = 5.7, NH); 6.95 dd,
4 H, J(H,H) = 8.9, J(H,F) = 8.9, 2 × H-3 and H-5 from 4-FC6H4); 7.14 – 7.34 m, 5 H (ArH of
benzyl); 7.29 dd, 4 H (J(H,H) = 8.9, J(H,F) = 2.8, 2 × H-2 and H-6 from 4-FC6H4). 13C NMR spec-
trum (CDCl3, 50.3 MHz): 31.6 d (C-4); 35.1 t (C-3); 43.8 t (C-2′ and C-6′); 44.1 t (C-5); 46.4 t
(C-6); 50.1 t (C-6); 51.3 t (C-3′, C-5′); 74.2 d (Ar2CH); 115.4 d (2 × C-3 and C-5 from 4-FC6H4,
J(F,C) = 21.2); 127.5 d (C-4 from PhCH2); 127.9 d (C-3 and C-5 from PhCH2); 128.6 d (C-2 and
C-6 from PhCH2); 129.1 d (2 × C-2 and C-6 from 4-FC6H4, J(C,F) = 7.7); 136.2 s (C-1 of PhCH2);
137.7 s (2 × C-1 of 4-FC6H4, J(C,F) = 3.2); 157.7 s (C-7); 161.8 s (2 × C-4 of 4-FC6H4, J(C,F) =
245.9); 173.8 s (C-2). For C30H32F2N4O2 (518.6) calculated: 69.48% C, 6.22% H, 7.33 F, 10.80% N;
found: 69.43 % C, 6.25% H, 7.05% F, 10.58% N.
1-Benzyl-4-(4-(2,3′-dichlorobenzhydryl)piperazin-1-ylcarbonylaminomethyl)-2-oxopyrrolidine (IVd)
A similar procedure starting from IIId (6.5 g, 16.9 mmol) and VI (ref.4; 3.5 g, 16.9 mmol) in dioxane
(60 ml) gave 10.1 g of crude product. Similar processing like in the preparation of IVc yielded 3.5 g
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

Potential Nootropic Agents
1133
(38%) of IVd, m.p. 147 – 152 °C. Analytical sample m.p. 152 – 155 °C (benzene–hexane). IR spec-
trum (Nujol): 700, 736, 756, 780, 886 (5, 4 and 2 adjacent and solitary Ar−H); 1 487, 1 569, 1 590,
3 010, 3 050 (Ar); 1 530, 1 670 (NCONH); 1 623 (NCO in the ring); 3 330 (NH). 1H NMR spec-
trum (CDCl3, 100 MHz): 4.28 and 4.48 2 H (AB system, J = 13.0, PhCH2); 4.82 s, 1 H (Ar2CH);
4.86 bt, 1 H (NH); 7.00 – 7.80 m, 13 H (Ar−H). 13C NMR spectrum (CDCl3, 25.14 MHz): 31.67 d
(C-4); 35.18 t (C-3); 43.85 t (C-2′, C-6′); 44.22 t (C-5); 46.54 t (PhCH2); 50.20 t (C-6); 51.39 t
(C-3′, C-5′); 69.62 d (Ar2CH); 126.61 d; 127.36 d (C-4 of PhCH2); 127.65 d (C-2 and C-6 of
PhCH2); 128.03 d, 128.33 d, 128.78 d (C-3 and C-5 of PhCH2); 129.90 d, (C-5 of 3-ClC6H4); 133.93 s
(C-2 of 2-ClC6H4); 134.45 s (C-3 of 3-ClC6H4); 136.39 s (C-1 of PhCH2); 138.86 s (C-1 of
2-ClC6H4); 142.99 s (C-1 of 3-ClC6H4); 157.76 s (C-7); 173.89 s (C-2). For C30H32Cl2N4O2 (551.5)
calculated: 65.33% C, 5.85% H, 12.86% Cl, 10,16% N; found: 64.96% C, 5.71% H, 12.80% Cl,
9.99% N.
1-(4-Methylthio)benzyl-2-oxopyrrolidine-4-carboxylic Acid (VII)
A
solution of 4-methylthiobenzylamine8 (5.1 g, 33 mmol) and itaconic acid (4.3 g, 33 mmol) in
xylene (30 ml) was refluxed for 3 h. Water (0.6 ml) was separated, the mixture was cooled and ex-
tracted with 10% NaOH (45 ml). The alkaline extract was washed with ether and treated with con-
centrated hydrochloric acid; the precipitate was collected and washed with water; yield 8.4 g (95%)
of crude VII, m.p. 141 – 144 °C. Analytical sample m.p. 143.5 – 144.5 °C (ethanol). IR spectrum
(Nujol): 784 (2 solitary Ar-H); 967, 1 269, 1 276, 1 709, 2 500 (RCOOH); 1 491, 1 500 (Ar); 1 619
(RNC=O in the five-membered ring). IR spectrum (chloroform): 1 675 (RNC=O); 1 719 (RCOOH).
1H NMR spectrum (CDCl3, 100 MHz): 2.50 s, 3 H (S−CH3); 4.42 and 4.23 d, 2 H (AB system, J = 13,
ArCH2); 7.18 d, 2 H (J = 8.5, H-3′, H-5′); 7.30 d, 2 H (H-2′, H-6′, J = 8.5). 13C NMR spectrum
(CD3SOCD3, 25.14 MHz): 14.79 q (S−CH3); 33.54 t (C-3); 35.33 d (C-4); 44.97 t (C-5); 48.33 t
(C-6); 126.27 d (C-3′, C-5′); 128.48 d (C-2′, C-6′); 133.41 s (C-1′); 137.22 s (C-4′); 172.10 s (C-2);
174.56 s (COOH). For C13H15NO3S (265.3) calculated: 58.84% C, 5.70% H, 5.28% N, 12.09% S;
found: 58.71% C, 5.80% H, 5.20% N, 11.88% S.
Ethyl 1-(4-Methylthio)benzyl-2-oxopyrrolidin-4-carboxylate (VIII)
Anhydrous HCl was introduced into a stirred boiling solution of VII (8.0 g, 30 mmol) in ethanol
(90 ml) for 2 h. The reaction mixture was evaporated in vacuo, the residue was dissolved in dichloro-
methane (40 ml) and the solution was washed with 10% NaHCO3 (15 ml) and water (2 × 30 ml).
The organic layer was evaporated in vacuo and gave 8.8 g of crude liquid, which was distilled. A
1
fraction, collected at 192 – 196 °C/47 Pa, crystallized; 7.9 g (90%), m.p. 38 – 41 °C. H NMR spec-
trum (CDCl3, 100 MHz): 1.26 t, 3 H (J = 7, CH3 in Et); 2.72 m, 2 H (H-3); 3.18 m, 1 H (H-4); 3.45 d,
2 H (J = 6, H-5); 2.50 s, 3 H (CH3S); 4.16 q, 2 H (J = 7, CH2 in Et); 4.52 s, 2 H (H-6); 7.12 and
7.21, 4 H (AB system, J = 8.5, H-2′, H-3′, H-5′, H-6′). 13C NMR spectrum (CDCl3, 25.14 MHz):
14.04 q (CH3 in Et); 15.76 q (CH3S); 33.99 t (C-3); 36.06 d (C-4); 46.01 t (C-5); 48.46 t (C-6); 61.32 t
(CH2 in Et); 126.91 d (C-3′, C-5′); 128.70 d (C-2′, C-6′); 132.81 s (C-4′); 138.11 s (C-1′); 172.40 s
(COOR); 172.70 s (C-2). For C15H19NO3 (293.4) calculated: 61.40% C, 6.53% H, 4.77% N, 10.93% S;
found: 61.15% C, 6.69%% H, 4.83% N, 11.03% S.
1-(4-Methylthio)benzyl-4-hydroxymethyl-2-oxopyrrolidine (IX)
A cool solution of sodium borohydride (3.1 g, 82 mmol) in water (30 ml) was dropped into a solu-
tion of ester VIII (10.0 g, 34 mmol) in methanol (100 ml) at 0 °C. The reaction mixture was stirred
at 4 °C for 4 h, for 1 h at 10 °C and then left to reach laboratory temperature. After acidification at
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

1134
Valenta, Urban, Taimr, Polivka:
10 °C with acetic acid to pH 5.5, the mixture was evaporated in vacuo to dryness and the residue
distributed between dichloromethane (50 ml) and water (50 ml). The organic layer was evaporated;
yield 8.1 g (95%), m.p. 77 – 82 °C. Analytical sample m.p. 83 – 85 °C (benzene). IR spectrum
(Nujol): 791, 822 (2 adjacent Ar−H); 1 027, 1 057 (CH2OH); 1 492, 1 562, 3 013, 3 075 (Ar); 1 643
(N−CO in the ring); 3 265 (OH). UV spectrum (methanol): 256 (4.14). 1H NMR spectrum (CDCl3,
100 MHz): 2.20 – 2.60 m, 3 H (H-3, H-4); 2.50 s, 3 H (CH3S); 3.20 m, 2 H (H-5); 3.58 m, 2 H
(CH2−O); 4.41 s, 2 H (CH2Ar); 7.12 and 7.26, 4 H (AB system, J = 8.5, H-2′, H-3′, H-5′, H-6′).
13C NMR spectrum (CDCl3, 25.14 MHz): 15.69 q (CH3S); 33.09 d (C-4); 33.91 t (C-3); 46.09 t (C-6);
49.22 t (C-5); 64.31 t (CH2−O); 126.76 d (C-3′, C-5′); 128.63 d (C-2′, C-6′); 133.03 s (C-4′); 137.89 s
(C-1′); 174.27 s (C-2). For C13H17NO2S (251.4) calculated: 62.12% C, 6.82% H, 5.57% N, 12,76% S;
found: 61.95% C, 7.10% H, 5.56 % N, 12.95% S.
1-(4-Methylthio)benzyl-4-phthalimidomethyl-2-oxopyrrolidine (XI)
A solution of IX (6.7 g, 27 mmol) and SOCl2 (3.6 g, 30 mmol) in dichloromethane (50 ml) was
refluxed for 7 h. The solvent was evaporated, the oily residue dissolved in benzene and evaporated;
yield 7.2 g (100%) crude chloride X which was used without characterization for the next step. Crude
chloride X (7.2 g) and potassium phthalimide (5.0 g, 27 mmol) in N,N-dimethylformamide (80 ml)
were stirred and refluxed for 2.5 h. The reaction mixture was evaporated in vacuo, the residue (13.4 g)
was distributed between dichloromethane and water, the organic layer was filtered with charcoal and
evaporated. The solid residue (7.8 g, 77%, m.p. 126 – 130 °C) was crystallized from toluene–petro-
leum ether and yielded 5.4 g (53%) of XI, m.p. 131 – 133 °C (crystalline modification A). UV spec-
trum (methanol): 217 (4.66), 239 (4.14), 256 (4.17), 288 inflex (3.50). IR spectrum (Nujol): 732,
795, 810, 830 (4 and 2 adjacent Ar−H); 1 484, 1 493, 1 563, 1 600, 1 610, 3 010, 3 028, 3 050 (Ar);
1 672 (N−CO in five membered cycle); 1 702, 1 769 (CO−N−CO in the ring). 1H NMR spectrum
(CDCl3, 100 MHz): 2.20 – 2.50 m, 2 H (H-3); 2.48 s, 3 H (CH3S); 2.80 m, 1 H (H-4); 3.22 m, 2 H
(H-5); 3.72 d, 2 H (J = 7, H-7″); 4.12 and 4.55, 2 H (AB system, J = 14, Ar−CH2); 7.12 and 7.24,
4 H (AB system, J = 8.5, H-2′, H-3′, H-5′, H-6′); 7.80 m, 4 H (Ar−H from phthalimide). 13C NMR
spectrum (CDCl3, 25.14 MHz): 15.69 q (CH3S); 31.22 d (C-4); 35.18 t (C-3); 41.01 t (C-9″); 46.01 t
(C-5); 49.82 t (C-6); 123.40 d (C-2″, C-5″); 126.76 d (C-3′, C-5′); 128.63 d (C-2′, C-6′); 131.69 s
(C-4′); 133.03 s (C-1a″, C-5a″); 134.15 d (C-3″, C-4″); 137.81 s (C-1′); 168.29 s (C-1″, C-6″); 173.07 s
(C-2). For C21H20N2O3 (380.5) calculated: 66.29% C, 5.30% H, 7.36% N, 8.43% S; found: 66.58% C,
5.25 % H, 7.61% N, 8.56% S.
Crystallization from toluene provided a crystalline modification B (37%) m.p. 144 – 146 °C. For
C21H20N2O3 (380.5) calculated: 66.29% C, 5.30% H, 7.36% N, 8.43% S; found: 66.46% C, 5.47% H,
7.32% N, 8.73% S.
4-(Aminomethyl)-1-(4-methylthio)benzyl-2-oxopyrrolidine (XII)
A suspension of XI (5.0 g, 13 mmol) in ethanol (100 ml) was intensively stirred at room temperature
and 100% hydrazine hydrate (2.6 g, 52 mmol) was added. A clear solution was formed within
15 min. The reaction mixture was stirred for 4 h at 20 °C. During this time a white solid precipitated
was filtered off and the filtrate was evaporated in vacuo. The oily residue (3.3 g) was dissolved in
methanol (10 ml), the boiling solution was treated with fumaric acid (1.6 g) and the salt was precipi-
tated with ether (20 ml). The crude hemifumarate of XII (2.7 g, 68%, m.p. 195 – 198 °C) was recry-
stallized from methanol giving 2.6 g (65%) of the pure product, m.p. 201 – 203 °C. Mass spectrum,
m/z (%): 250 (M+, C13H18N2OS, 13), 233 (8), 205 (7), 152 (10), 137 (100), 122 (18), 91 (10), 74
(18), 72 (21). For C15H20N2O3S (308.4) calculated: 58.41% C, 6.54% H, 9.08% N, 10.40% S; found:
58.28% C, 6.84% H, 8.89% N, 10.47% S.
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Potential Nootropic Agents
1135
4-((4-Chlorophenylaminocarbonyl)aminomethyl)-1-(4-(methylthio)benzyl)-2-oxopyrrolidine (XIII)
A solution of 4-chlorophenylisocyanate10 (2.1 g, 14 mmol) in toluene (15 ml) was dropped over
10 min into a stirred solution of XII (3.4 g, 14 mmol) in toluene (20 ml) at 60 °C. After 40 min
stirring at 80 °C, the mixture was cooled to 20 °C, the product was precipitated by addition of petro-
leum ether (20 ml). The solid was filtered at 10 °C and washed with petroleum ether; yield 4.8 g
(87%), m.p. 144 – 147 °C. Analytical sample m.p. 146 – 147.5 °C (benzene). IR spectrum (Nujol):
819, 831 (2 H adjacent Ar−H); 1 490, 1 600, 3 020, 3 030, 3 050, 3 095 (Ar); 1 550, 1 658 (ArNH-
CONH); 1 658 (N−CO in the five membered ring); 3 300 (NH). 1H NMR spectrum (CDCl3, 100
MHz): 2.00 – 3.20 m; 2.40 s, 3 H (CH3S); 4.36 bs, 2 H (Ar−CH2−N); 6.08 bt, 1 H (C−NHCO); 7.12,
4 H and 7.20, 4 H (Ar−H); 7.86 s, 1 H (Ar−NH−CO). For C20H22ClN3O2S (403.9) calculated:
59.46% C, 5.49% H, 8.78% Cl, 10.40% N, 7,94% S; found: 59.16% C, 5.39% H, 8.82% Cl, 10.30% N,
8.15% S.
3-(1-(Ethoxycarbonylmethyl)-2-oxo-3-pyrrolin-4-yl)-1-(ethoxycarbonylmethyl)-
4-hydroxy-2-oxo-3-pyrroline (XVIIIa)
A) A suspension of XIV (ref.3; 41.0 g, 161 mmol) in acetonitrile (400 ml) and water (3.6 ml) was
stirred, gradually warmed during 0.5 h and refluxed for further 0.5 h. The solvent was evaporated
under reduced pressure. The solid residue was crystallized from ethanol (100 ml); yield 16.1 g (57 %) of
XVIIa, m.p. 190 – 192 °C. Analytical sample m.p. 194 – 195 °C (methanol). Mass spectrum, m/z (%):
352 (M+, C16H20N2O7). IR spectrum (Nujol): 1 251, 1 738 (R−COOR); 1 677 (R−N−CO−C=C− in
1
the ring); 1 620 (C=C); 2 480 (C−OH in a conjugated system). H NMR spectrum (CD3SOCD3, 200
MHz): 1.20 t, 6 H (J = 6.9, 2 × CH3 in Et); 4.06 – 4.20 m, 10 H (2 × CH2 in Et, H-6, H-6′, H-5);
4.39 s, 2 H (H-5′); 6.36 s, 1 H (H-3′). 13C NMR spectrum (CD3SOCD3, 50.3 MHz): 14.3 q (2 × CH3
in Et); 42.7 t, 43.1 t (C-6, C-6′); 50.4 t (C-5); 53.7 t (C-5′); 61.0 t (2 × CH2 in Et); 99.2 s (C-3);
116.0 d (C-3′); 147.9 s (C-4′); 169.8 s (C-7, C-7′); 170.2 s, 171.9 s, 172.7 s (C-2, C-2′, C-4). For
C16H20N2O7 (352.4) calculated: 54.53% C, 5.72% H, 7.95% N; found: 54.28% C, 5.79% H, 7.78 % N.
B) A suspension of XIX (22.0 g, 86 mmol) in acetonitrile (200 ml) was allowed to stand for 4
month at room temperature. The crude product (5.2 g, 17%, m.p. 190 – 191 °C) was crystallized
1
from methanol (40 ml), m.p. 195 – 197 °C. IR and H NMR spectra were identical with those of the
product prepared by method A.
3-(1-(Carboxymethyl)-2-oxo-3-pyrrolin-4-yl)-4-hydroxy-2-oxo-3-pyrroline-1-acetic Acid (XVIIIb)
A mixture of XVIIIa (9.3 g, 26 mmol) and potassium hydroxide (5.6 g, 10 mmol) in 90% ethanol
(150 ml) was refluxed for 2 h. After cooling, the solid was filtered, extracted with chloroform
(100 ml) and filtered again. The crude solid potassium salt of XVIIIb (9.8 g) was suspended in water
(50 ml) and treated with concentrated hydrochloric acid (14 ml) over 0.5 h at 35 °C under vigorous
stirring. The precipitate was filtered and washed four times with water (20 ml) until pH 4.5. Crystal-
lization of the crude product (7.7 g) from 50% ethanol (80 ml) gave 7.1 g (91%) acid XVIIIb, m.p.
1
260 °C (decomposition). H NMR spectrum (CD3SOCD3, 200 MHz): 4.08 s, 4 H (H-6, H-6′); 4.13 s,
2 H (H-5); 4.40 s, 2 H (H-5′); 6.36 s, 1 H (H-3′); 11.59 bs, 2 H (2 × COOH). 13C NMR spectrum
(CD3SOCD3, 50.3 MHz): 43.0 t (C-6′); 43.3 t (C-6); 50.7 t (C-5); 54.1 t (C-5′); 99.4 s (C-3); 116.1 d
(C-3′); 148.2 s (C-4′); 170.5 s, 171.5 s, 172.4 s, 172.9 s (C-2, C-2′, C-4, C-7, C-7′). For C12H12N2O7
(296.2) calculated: 48.65% C, 4.09% H, 9.46% N; found: 48.44% C, 4.16% H, 9.46 % N.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

1136
Valenta, Urban, Taimr, Polivka:
3-(1-(Carbamoylmethyl)-2-oxo-3-pyrrolin-4-yl)-2-oxo-4-hydroxy-3-pyrroline-1-acetamide (XVIIIc)
Ethyl ester XVIIIa (4.7 g, 13 mmol) was stepwise added into methanol (300 ml) saturated with
ammonia at 0 °C. The clear solution was stirred at 0 °C for 4 h and left overnight at room tempera-
ture. The reaction mixture was evaporated in vacuo to give 4.7 g solid residue. The product was
extracted with ethanol (2 × 50 ml) which provided 3.1 g (80%) of XVIIIc, m.p. 280 °C (decomposi-
1
tion). IR spectrum (Nujol): 1 668 (RNC=O in the ring); 3 190, 3 370 (CONH2). H NMR spectrum
(CD3SOCD3, 200 MHz): 3.68 s, 2 H; 3.81 s, 2 H; 3.88 s, 2 H (H-6, H-6′ H-5); 4.32 s, 2 H (H-5′);
4.66 bs, 3 H (OH and H2O); 6.05 s, 1 H (H-3′); 7.00 s, 2 H and 7.31 s, 2 H (2 × NH2). 13C NMR
spectrum (CD3SOCD3, 50.3 MHz): 39.3 t, 44.4 t (C-6, C-6′); 53.2 t (C-5); 54.3 t (C-5′); 95.3 s (C-3);
108.6 d (C-3′); 151.0 s (C-4′); 171.3 s, 171.7 s (C-7, C-7′); 172.8 s, 173.4 s (C-2, C-2′); 181.4 s
(C-4). For C12H14N4O5 . H2O (312.3) calculated: 46.15% C, 5.16% H, 17.94% N; found: 46.27% C,
5.16% H, 17.86% N.
The authors thank the following colleagues at the Research Institute for Pharmacy and Biochemistry
in Prague for cooperation: Mrs M. Vlkova (synthesis of the starting compounds and some intermedi-
ates), Dr M. Cech, Mrs R. Svatosova, and Mrs A. Svatonova (elemental analyses); Drs M. Ryska and I.
Koruna (mass spectra); Drs M. Valchar and K. Dobrovsky (biochemical pharmacology).
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Translated by the author (V. V.).
Collect. Czech. Chem. Commun. (Vol. 59) (1994)