Synthesis of beta-proline like derivatives and their evaluation as sodium channel blockers

Article abstract of DOI:10.1002/jhet.5570440519

(Chemical Equation Presented) A simple and convenient procedure for the preparation of beta-proline like derivatives in their racemic and optically active forms has been reported. The compounds have been screened for their potential activity as sodium cha

Full text of DOI:10.1002/jhet.5570440519

Sep-Oct 2007
1099
Synthesis of Beta-Proline Like Derivatives and Their Evaluation as
Sodium Channel Blockers
Marilena Muraglia[1], Carlo Franchini[1], Filomena Corbo* [1], Antonio Scilimati[1], Maria
Stefania Sinicropi[2], Annamaria De Luca[3], Michela De Bellis[3], Diana Conte
Camerino[3] and Vincenzo Tortorella[1].
[1] Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, via E. Orabona 4,
70125 Bari, Italy
[2] Dipartimento di Scienze Farmaceutiche, Facoltà di Farmacia Università della Calabria,
Arcavacata di Rende (CS), Italy
[3] Dipartimento Farmaco-Biologico, Facoltà di Farmacia, Università degli Studi di Bari, via E. Orabona 4,
70125 Bari, Italy
Received Novembre 27, 2006
H
N
H
N
H
N
N
NH2
R
N
O
O
O
Bn
Tocainide
5
6: R=H
7: R=Bn
A simple and convenient procedure for the preparation of beta-proline like derivatives in their racemic
and optically active forms has been reported. The compounds have been screened for their potential
activity as sodium channel blockers.
J. Heterocyclic Chem., 44, 1099 (2007).
The preliminary structure-activity relationships
obtained with this series of compounds suggest that a
greater lipophilicity (due to the pyrrolidine ring) and a
greater basicity (associated with the secondary aminic
group) with respect to Tocainide, are crucial for high
sodium channel blocking activity. On the other hand, this
activity is strongly reduced by the introduction of methyl
groups on one or both the nitrogen atoms, likely following
modification of the pKa and/or constraints of molecular
conformation. Among all ꢀ-proline-like derivatives (1-4,
Figure 1) the (R)-1 was found to be the most interesting
congener [6-7].
INTRODUCTION
As part of an ongoing program on the research of potent
and selective sodium channel blockers, in this article we
report the synthesis and biological evaluation of 1-benzyl-
N-(2,6-dimethylphenyl)-3-pyrrolidinecarboxamide
both in racemic and optically active forms.
Previously we synthesized some alpha-proline like
derivatives (Figure 1) that have partial structural analogy
with the cardiovascular drug Tocainide [1-5], a molecule
capable of blocking the voltage-gated sodium channel.
(7)
Figure 1
On the basis of these results, we decided to synthesize
derivatives 5-7 (Figure 2), with the aim to investigate
further the role of basicity and lipophilicity in drug-
receptor interaction.
H
N
R2
N
1: R1=H; R2=H
NH2
2: R1=CH3; R2=H
3: R1=H; R2=CH3
4: R1=CH3; R2=CH3
N
O
O
R1
This was carried out: a) by spacing out the aminic
group from the stereogenic centre and freezing it in
position 3 of a pyrrolidine ring in order to improve pKa
values (beta-proline like derivatives 6, 7); b) by
introducing a benzyl group on the nitrogen atom of the
pyrrolidine ring, increasing lipophilicity, to produce
compounds 5 and 7.
Tocainide
The serious disadvantages correlated to its clinical use,
lead us to plan and prepare the alpha-proline derivatives.
Our rationale for the preparation of these compounds
was that, although the structural requirements for the
voltage-gated sodium channel blockers have not yet been
fully identified, different theories indicate lipophilicity
and basicity as pivotal molecular properties for this
activity.
The first important result of this investigation was an
improvement of the biological profile obtained by
constraining both the stereogenic centre and the terminal
aminic group of Tocainide into a rigid pyrrolidine ring
(Table 1).
Figure 2
H
N
H
N
N
R
N
O
O
Bn
6: R=H
7: R=Bn
5

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M. Muraglia, C. Franchini, F. Corbo, A. Scilimati, M. S. Sinicropi,
A. De Luca, M. De Bellis, D. C. Camerino and V. Tortorella
Vol 44
corresponding, commercially available, optically pure
1-benzylpyrrolidin-3-ol (S)-10 and (R)-10. (S)-10 and (R)-
10 were in turn converted (97% yield) into (S)-11 and (R)-
11, using methanesulfonyl chloride and Et3N [12]. Nitrile
(R)-12 and (S)-12 were obtained by a SN2 displacement
reaction of the mesylates (S)-11 and (R)-11 (99% yield),
respectively in the presence of tetrabutylammonium-
cyanide and sodium cyanide in DMSO [12].
The ꢁ-proline esters (R)-13 and (S)-13 were prepared
from (R)-12 and (S)-12 by being dissolved in anhydrous
CH3OH, reacted with gaseous HCl followed by a basic
workup (98% yield) [12]. In the final step, (R)-13 and (S)-
13 were in turn slowly added to a solution of 2,6-
dimethylaniline and n-BuLi (2.09 M in hexane) in
anhydrous THF to give the desired (R)-7 and (S)-7 (63%)
yield.
The most interesting result was observed for 1-benzyl-
N-(2,6-dimethylphenyl)-3-pyrrolidinecarboxamide 7, as
reported in the “Results and Discussion” section. Such a
result prompted us to develop a synthesis for both
enantiomers of 7 [(+)-(R)-7 and (ꢀ)-(S)-7], with the aim of
evaluating the influence of stereochemistry on sodium
channel blocking activity.
In this paper we will report the synthetic procedures
and the pharmacological results of this new series of
Tocainide analogous.
RESULTS AND DISCUSSION
In this paper, we pursued the rationalization of the
design and synthesis of compounds potentially useful as
sodium channel blockers, with the aim of investigating the
molecular determinants responsible for blocking the
activity of the channel.
Finally, the synthesis of (±)-(R,S)-1-benzyl-N-(2,6-
dimethylphenyl)-2-pyrrolidinecarboxamide 5, starting
from compound 1, was performed in the presence of
benzyl bromide, K2CO3 dissolved in a mixture of
dioxane/H2O (50% yield).
In particular, we planned and synthesized a new series
of molecules carrying a beta-proline ring instead of an
alpha-proline ring (Scheme 1).
All the new products were characterized by 1H and 13C-
NMR, mass spectra, optical rotation, IR and elemental
analysis data. Furthermore free amines of 7 underwent ee
evaluation by HPLC as reported in the “Experimental”
section.
All proline-like derivatives were tested on sodium
currents of adult skeletal muscle fibers by the voltage-
clamp method [13].
Moreover, we synthesized compound 5 by introducing
a benzyl group on the heterocyclic nitrogen atom of 1,
resulted in the production of the most active among the
alpha-proline series.
Scheme 1 outlines the synthetic approach used to
prepare (R,S)-1-benzyl-N-(2,6-dimethylphenyl)-3-pyrrol-
idinecarboxamide 7, which involves
a
dipolar
cycloaddition reaction [8].
N-(2,6-Dimethylphenyl)-2-propenamide (8), obtained
by a condensation reaction of 2-propenoyl chloride and
2,6-dimethylaniline in the presence of EEDQ [9] reacting
with N-benzyl-N-(methoxymethyl)trimethylsilylmethyl-
amine (9) [10] gave the expected 1,3-cycloaddition
reaction, in the presence of a catalytic amount of
trifluoroacetic acid, so as to afford the corresponding
pyrrolidine-3-carboxamide 7 [11]. Compound 6 was
obtained by treating 7 with H2 in the presence of Pd/C,
resulting in a 74% yield.
Scheme 2
OH
OSO2CH3
CN
*
*
*
MsCl, Et3N
EtOAc
Bu4NCN/NaCN
DMSO
N
N
N
(S)- and (R)-10
(S)- and (R)- 11
(R)- and (S)-12
HCl g
CH3OH an
Scheme 1
NH2
O
O
O
OCH3
N
*
*
N
H
O
O
H
N
N
n-BuLi, THF an
N
H
N
H
8
CF3CO2H
CH2Cl2
H2, Pd/C
MeOH
+
N
N
H
N
Si
(R)- and (S)-7
(R)- and (S)-13
7
6
O
9
It is important to note that the simple exchange of
the alpha- with a beta-proline like-ring (1 vs 6) did
not substantially change the drug potency and
produces a decrease in the use-dependent behavior,
as reported in Table 1. The insertion of a benzyl
The enantiomers (R)- and (S)-1-benzyl-N-(2,6-
dimethylphenyl)-3-pyrrolidinecarboxamide [(+)-(R)-7 and
(ꢀ)-(S)-7, Scheme 2] were prepared starting from the

Sep-Oct 2007
Synthesis of Beta-Proline Like Derivatives and Their Evaluation as Sodium Channel Blockers
1101
Table 1
Ratio of potency valuesa for both tonic and phasic block of 1-7.
Compound
Absolute conf.
Ratio of potencya
Phasic blockd
cLogPb
pKab
Tonic blockc
Tocainide
1
(R)
(R, S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
1
3.5
5.3
2.5
1.9
5.5
1.7
5.6
1
11.6
20.8
6.1
2.7
9.6
1.2
4
0.6
0.76 ± 0.48
1.72 ± 0.29
8.10
9.37
2
3
4
1.48 ± 0.27
1.71 ± 0.39
2.10 ± 0.40
8.67
9.19
8.49
< 1
2
(S)
1.4
5
6
7
(R, S)
(R, S)
(R, S)
(R)
19.5
6.2
20.2
28.6
22.4
17.1
7.1
122.7
158.9
117.4
3.00 ± 0.34
1.82 ± 0.27
3.26 ± 0.34
7.83
10.01
8.47
(S)
a
The ratio of potency values have been obtained normalizing the IC50 values of each compound tested with respect to those of (R)-Tocainide, for
both tonic (580 ± 11 μM) and phasic block (use-dependent block) at 10 Hz (270 ± 5 μM). b Calculated using Advanced Chemistry Development
(ACD) Software Solaris V4.76. c Tonic block: block of sodium channel at resting conditions evaluated during infrequent depolarizing pulses. d
Phasic block: cumulative sodium current reduction by the drug at 10 Hz stimulation frequency, obtained by concentration-response curves.
group on the nitrogen atom of the pyrrolidine ring
(5, 7) causes an increase of both tonic and phasic
block (see Table 1). In particular, the N-benzylated
compound 7, having a combined increase of lipo-
philicity (due to the insertion of a benzyl group) and
basicity (the amino group is spaced out from the
chiral carbon atom) has shown the highest increment
of potency among all synthesized compounds. In fact
it was 20.2 fold more potent than Tocainide for tonic
block of sodium currents and up to 100 fold (122.7)
more potent than the parent compound at high
frequency of stimulation [14].
The methodologies described here may find useful
applications in the synthesis of drug intermediates and
other bioactive compounds carrying the beta-proline
heterocyclic moiety.
Currently compound 7 is a highly promising molecule
that could be used both for pharmacological investigations
such as channelopathies (e.g. myotonia) and as a new
“lead” for searching still more potent and selective
sodium channel blockers.
EXPERIMENTAL
No significative difference was detected between the
optically active compounds (+)-(R)-7 and (ꢀ)-(S)-7.
The ratio of potency values for tonic and phasic
block, reported in Table 1, suggests that potency and
use-dependent behaviour are strongly increased both
by the introduction of a benzyl group on the aminic
nitrogen and also by increasing the distance between
the two aromatic rings. This probably means that the
introduction of a hydrophobic group in the molecule,
together with an increment in lipophilicity of the
whole molecule, would play an important role in
establishing specific hydrophobic interactions with
the binding site. Among all Tocainide analogous
evaluated in vitro and reported in this paper,
compound 7 has been identified as the most potent
sodium channel blocker.
All chemicals were purchased from Aldrich in the highest
quality commercially available. The structures of the compounds
were confirmed by routine spectrometric and spectroscopic
analyses. Only spectra for compounds not previously described
are given.
Melting points are uncorrected and were recorded on
Gallenkamp melting point apparatus in open glass capillary
tubes. The IR spectra were recorded on a Perkin-Elmer
Spectrum One FT spectrophotometer and band positions were
1
given in reciprocal centimeters (cmꢀ1). H NMR spectra (300
MHz) were recorded on a FT Bruker Aspect 3000 spectrometer
using CDCl3 as the solvent, unless otherwise indicated.
Chemical shifts were reported in part per million (ppm) relative
to solvent resonance: CDCl3, ꢁ 7.26 (1H NMR). Amino proton
assignments were confirmed by D2O exchange. J values are
given in Hz. EIMS spectra were recorded with a Hewlett-
Packard 6890-5973 MSD gas chromatograph/mass spectrometer
at low resolution. Elemental analyses were performed on a
Eurovector Euro EA 3000 elemental analyzer, were indicated, C,
H, and N were within ± 0.4 of the theoretical values. Optical
CONCLUSIONS
rotations were measured on
spectropolarimeter; concentrations were expressed in g/100 mL
a Perkin-Elmer Mod 341
In conclusion, we have reported synthetic procedures
for the synthesis of beta-proline like derivatives in their
racemic and optically active forms.
and the cell length was 1 dm, thus [ꢂ]20 values were given in
D
units of 10ꢀ1 deg cm2 gꢀ1. Silica gel chromatographic separations

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M. Muraglia, C. Franchini, F. Corbo, A. Scilimati, M. S. Sinicropi,
A. De Luca, M. De Bellis, D. C. Camerino and V. Tortorella
Vol 44
pyrrolidinecarboxamide (7) which was recrystallized from
EtOAc/hexane to give white crystals in 51% yield. Mp
105.7ꢁ107.7 °C; ir (CHCl3): 3662, 3057, 1709, 1368, 1107 cm–1.
IR (KBr): 3620, 3050, 1660, 1640, 1550, 1250, 770, 700 cm-1;
1H nmr (300 MHz, CDCl3), ꢂ: 8.90–8.70 (br s, 1H, NH that
exchange with D2O), 7.40–7.28 (m, 5H, phenyl protons), 7.10–
7.03 (s, 3H, phenyl protons), 3.77–3.73 (d, 1H, J= 12.57 Hz,
CHHPh), 3.72–3.68 (d, 1H, J= 12.57 Hz, CHHPh), 3.25–2.97
(m, 3H), 2.53–2.30 (m, 3H), 2.26–2.08 (multiplet overlapped to
a singlet at 2.13ppm, 7H: 1H of the pyrrolidine ring and 6H of
the two CH3);ms (70 eV, electron impact) m/z 308 (M+, 11), 293
(14), 217 (14), 188 (11), 176 (13), 160 (25), 132 (27), 120 (25),
91 (100). Anal. Calcd for C20H24N2O: C, 77.89; H, 7.84; N, 9.08.
Found: C, 77.90; H, 7.87; N, 9.10.
were performed by chromatography with silica gel (Kieselgel
60, 40-63 μm, Merk) packed in glass columns, using the
technique described by Still et al. [15]. The weight of the silica
gel was approximately 100 times that of the substance, unless
otherwise noted. The eluting solvent indicated in parentheses,
for each purification was determined by TLC, that was
performed on precoated silica gel on aluminium sheets
(Kieselgel 60 F254, Merck). TLC plates were visualised with UV
light and/or in an iodine chamber. HPLC analyses were
performed on an Agilent chromatograph model 1100 equipped
with a diode array detector. The ee of 7 and its enantiomers was
determined by direct HPLC analysis on a Daicel Chiralpak IA
column (flow 0.8 ml/min, ꢀ 230 nm, eluent: hexane/i-PrOH/
Et2NH, 85/15/0.15).
1-Benzyl-N-(2,6-dimethylphenyl)-3-pyrrolidinecarboxamide
[(+)-(R)-7 and (–)-(S)-7]. n-BuLi (2.09 M in hexane; 0.72 mL,
1.496 mmol) was added to a solution of 2,6-dimethylaniline
(0.18 mL, 1.496 mmol) in anhydrous THF (3 mL) kept at -15 °C
and under nitrogen atmosphere. The resulting yellow mixture
was stirred for 1 h at -15 °C. Then, a solution of methyl 1-
benzylpirrolidine-3-carboxylate [(R)-13 or (S)-13)] (0.150 g,
0.68 mmol) in THF (7 mL) was slowly added. The reaction
mixture was first stirred at -15°C for 6 h, and then for 12 h at
room temperature. Hence, the solvent was evaporated under
vacuum. The residue was washed with water (3x25 mL) and
extracted three times with EtOAc. The combined organic
extracts were dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. Column chromatography
(silica gel; mobile phase: EtOAc) of the reaction crude gave 1-
benzyl-N-(2,6-dimethylphenyl)-3-pyrrolidinecarboxamide [(R)-7
(±)-(R,S)-1-Benzyl-N-(2,6-dimethylphenyl)-2-pyrrolidine
carboxamide [(±)-(R,S)-5]. 1 (0.196 g; 0.92 mmol) in dioxane
(16 mL), was added to a solution of K2CO3 (0.362 g, 2.622
mmol) in water (8 mL). The reaction mixture was stirred at 70
°C. Then, a solution of benzylbromide (173 mg, 1.012 mmol) in
dioxane (12 mL) was dropwise added over 15 minutes. When
the addition was completed the resulting mixture was stirred for
1 h. The dioxane was evaporated under reduced pressure and the
residue was diluted with water and extracted with EtOAc. The
organic layer was washed with 2 N HCl. The aqueous phase was
treated with 2 N NaOH (up to pH=11) and extracted with EtOAc
(3x25 mL). The latter organic layers were dried over Na2SO4,
filtered, and evaporated to dryness. The crude product was
recrystallized from EtOAc/petroleum ether to give 5 as a white
solid in 50% yield. Mp 134-138 °C (EtOAc/hexane); ir: (CHCl3)
3800-3700, 3060, 3000, 2977, 2941, 1671, 1590, 1495, 941,
920, 810 cmꢁ1. 1H nmr (300 MHz, CDCl3), ꢂ 9.10-8.90 (br s, 1H,
NHCO: exchange with D2O), 7.34-7.26 (m, 5H, phenyl protons),
7.10-7.08 (m, 3H, phenyl protons), 4.17-4.08 (m, 2H), 3.78-3.40
(m, 2H), 3.20-3.12 (m, 1H), 2.50-2.26 (m, 2H), 2.19 (s, 6H),
1.96-1.82 (m, 2H); ms (70 eV, electron impact) m/z 308 (M+, 2),
161 (27), 160 (100), 92 (9), 91 (74), 65 (7). Anal. Calcd for
C20H24N2O: C, 77.89; H, 7.84; N, 9.08. Found: C, 77.85; H,
7.83; N, 9.09.
or (S)-7] as a yellow oil in 63% yield. (+)-(R)-7 had [ꢃ]20
=
D
+1.8 (c 1, CHCl3, ee 98%, tR 8.5 min); (ꢁ)-(S)-7 had [ꢃ]20D = –
1.56 (c 0.6, CHCl3, ee 97%, tR 7.7 min). Both (R)- and ir, 1H nmr
and ms spectra were identical with those reported for (R,S)-7.
Anal. Calcd for (R)-7 (C20H24N2O): C, 77.89; H, 7.84; N, 9.08.
Found: C, 77.56; H, 7.98; N, 8.71. Anal. Calcd for (S)-7
.
(C20H24N2O 0.125 EtOAc): C, 77.08; H, 7.89; N, 8.77. Found:
C, 77.48; H, 8.03; N, 8.39.
(±)-(R,S)-N-(2,6-Dimethylphenyl)-3-pyrrolidinecarbox-
amide [(±)-(R,S)-6]. Compound 7 (0.150 g, 0.53 mmol) and
10% Pd/C (0.06 g) were suspended in CH3OH (20 mL) and
treated with H2 (6 bar) for 5 h at room temperature. Then, the
catalyst was filtered off and the organic layer was evaporated
under reduced pressure to give 6 as a white solid in 74% yield.
N-(2,6-Dimethylphenyl)-2-propenamide (8). To 2,6-
dimethylaniline (1 g, 8.2 mmol, 1 mL) in 100 mL of anhydrous
CH2Cl2 under a nitrogen atmosphere and cooled to 0 °C, Et3N
(3.6 g, 35 mmol, 4.87 mL) was added. Then, a solution of 2-
propenoyl chloride (1.06 g, 11.7 mmol, 0.95 mL) in anhydrous
CH2Cl2 (5 mL) was added dropwise over 10 minutes. The
resulting mixture was first stirred at 0 °C for 2 h, and then at
room temperature for further 12 h. Then, the reaction mixture
was treated with 1 N HCl (2 x 25 mL). The organic layer,
separated from the aqueous phase, was washed with saturated
aqueous NaHCO3 and then with brine until the pH became
neutral. The organic phase was dried over anhydrous Na2SO4,
filtered and concentrated under vacuum. The crude product was
recrystallized from EtOAc/petroleum ether to give 8 as yellow
crystals (98% yield). Mp 146–147 °C [lit. [9] 143–144 °C
(EtOAc)]; ir (CHCl3): 3662, 3058, 2990, 2929, 1709 (C=O)
1
Mp 127–128 °C; ir (CHCl3): 3264, 1652 (C=O) cm–1; H nmr
(300 MHz, CDCl3), ꢂ 8.10–7.98 (br s, 1H, NHCO that exchange
with D2O), 7.13–7.07 (m, 3H, phenyl protons), 3.39–3.36 (m,
1H), 3.26–3.17 (m, 1H), 3.03–2.87 (m, 3H), 2.27–2.10 (m, 9H:
2H of the pyrrolidine ring, 6H of the two CH3 and 1H of NH:
exchange with D2O); ms (70 eV, electron impact) m/z 218 (M+,
25), 203 (26), 176 (90), 121 (100), 91 (16), 70 (47), 41 (24).
(±)-(R,S)-1-Benzyl-N-(2,6-dimethylphenyl)-3-pyrrolidine-
carboxamide [(±)-(R,S)-7]. To a solution of 9 [10] (1.0 g, 4.03
mmol) in CH2Cl2 (10 mL) kept at 0 °C were added N-(2,6-
dimethylphenyl)-2-propenamide (8) (0.847 g; 4.84 mmol) and 1
M CF3COOH solution in CH2Cl2 (0.4 mL). Then, the stirred
reaction mixture was allowed to reach room temperature and
stirred for further 3 h. The organic layer was washed with
saturated aqueous NaHCO3 (2x25 mL) and with brine, dried
over anhydrous Na2SO4, filtered and concentrated under
vacuum. Column chromatography (silica gel, eluent: EtOAc) of
the reaction crude provided 1-benzyl-N-(2,6-dimethylphenyl)-3-
1
cm-1; H nmr (300 MHz, CDCl3), ꢂ 8.45–8.24 (br s, 1H, NHCO:
exchange with D2O), 7.20–7.05 (m, 3H, phenyl protons), 6.52–
6.40 (dd, 1H, J= 17.30 Hz and 2.33 Hz), 6.39–6.29 (dd, 1H, J=
17.30 Hz and 9.34 Hz), 5.81–5.77 (dd, 1H, J= 9.34 Hz and 2.33
Hz), 2.24 (s, 6H); ms (70 eV,electron impact) m/z 175 (M+, 75),
147 (15), 122 (13), 121 (100), 55 (52).
1-Benzylpyrrolidin-3-yl-methanesulfonate [(+)-(R)-11 and
(–)-(S)-11]. (R)- or (S)-1-benzylpyrrolidin-3-ol (10) (5 g, 28.2

Sep-Oct 2007
Synthesis of Beta-Proline Like Derivatives and Their Evaluation as Sodium Channel Blockers
1103
1
mmol) was dissolved in EtOAc (11 mL). To the mixture cooled
by an ice-salt bath, Et3N (5.69 g, 56.5 mmol, 7.83 mL) and
methanesulfonyl chloride (3.85 g, 33.9 mmol) were added. After
3 h, 2 N NaOH (38 mL) was added to the reaction mixture kept
at -5 °C. The biphasic mixture was vigorously stirred for 10
minutes at -5 °C. The layers were separated and the organic
phase was washed three times with water. The combined
extracts were dried over anhydrous Na2SO4, filtered, and
evaporated under reduced pressure to afford 5.762 g (97% yield)
[ꢀ]20 = +17 (c 1, CHCl3); ir, H nmr and ms spectra were in
D
agreement with those reported in the literature [12].
REFERENCES AND NOTES
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Pharmacol. 1997, 356, 777.
of (R)-11 or (S)-11 as a yellow clear oil. (+)-(R)-11: [ꢀ]20
=
D
+13.6 (c 1, CH3OH); (–)-(S)-11: [ꢀ]20D = ꢁ12.8 (c 1, CH3OH); ir,
1H nmr and ms spectra were in agreement with those reported in
the literature [12].
1-Benzylpyrrolidin-3-carbonitrile [(–)-(R)-12 and (+)-(S)-
12]. Compounds (–)-(R)-12 and (+)-(S)-12 were prepared
according to the literature procedure starting from compound
[6] Hille, B. J. Gen. Physiol. 1977, 69, 497.
(-)-(S)-11 and(+)-(R)-11 respectively. [ꢀ]20 = –25.8 (c 1,
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D
CHCl3) for (R)-enantiomer; [ꢀ]20D = + 26.2 (c 1, CHCl3) for (S)-
enantiomer. Both (R)- and (S)-12 ir, 1H nmr and ms spectra were
in agreement with those reported in the literature [12].
Methyl 1-benzylpyrrolidine-3-carboxylate [(–)-(R)-13 and
(+)-(S)-13]. Anhydrous CH3OH (41 mL) was saturated with
gaseous HCl at 0 °C, under a nitrogen atmosphere. Then, 1-
benzylpyrrolidin-3-carbonitrile [(R)-12 or (S)-12] (0.5 g, 268
mmol) and water (0.5 mL) were added and the mixture allowed
to reach room temperature. The pink reaction mixture obtained
was vigorously stirred at room temperature for 21 h. Then, the
solvent was removed under reduced pressure and the residue
treated with 4 N NaOH (up to pH=11). The aqueous layer was
then extracted with EtOAc (3x25mL). The combined organic
phases were washed twice with water, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure to
afford the product (–)-(R)-13 or (+)-(S)-13 as a brown oil (98%
yield). (–)-(R)-13 had [ꢀ]20D = –17.5 (c 1, CHCl3); (+)-(S)-13 had
[10] Terao, Y.; Kotaki, H.; Imai, N.; Achiwa, K. Chem. Pharm. Bull.
1985, 33, 2762.
[11] Scilimati, A.; Franchini, C.; Tortorella, V.; Corbo, F.; Lentini, G.;
Conte Camerino, D.; De Luca, A. Italian Patent MI2001A 000085 2001.
[12] Thomas, C.; Orecher, F.; Gmeiner, P. Synthesis 1998, 33, 1491.
[13] Talon, S.; De Luca, A.; De Bellis, M.; Desaphy, J-F.; Lentini, G.;
Scilimati, A.; Corbo, F.; Franchini, C.; Tortorella, P.; Jockusch, H.;
Conte-Camerino, D. Brit. J. Pharmacol. 2001, 134, 1523.
[14] De Luca, A.; Talon, S.; De Bellis, M.; Desaphy, J.F.; Lentini, G.;
Corbo, F.; Scilimati, A.; Franchini, C.; Tortorella, V.; Conte Camerino,
D. Mol. Pharmacol. 2003, 64(4), 932.
[15] Still, W. C.; Kahn, M.; Mitra, J. Org. Chem. 1978, 43, 2923.