Optically Active Mexiletine Analogues as Stereoselective Blockers of Voltage-Gated Na+ Channels

Article abstract of DOI:10.1021/jm030865y

Optically active mexiletine analogues were synthesized and evaluated in vitro as use-dependent blockers of skeletal muscle sodium channels. The mexiletine analogues were obtained by replacing either the methyl group on the stereogenic center of mexiletine [1-(2,6-dimethylphenoxy)propan-2-amine] with a phenyl group or modifying the phenoxy moiety (by removal of one or both of the methyl groups, or introducing a chlorine atom), or both. The voltage clamp recordings showed that, regardless of the substitution pattern of the aryloxy moiety, all the compounds bearing a phenyl group on the stereogenic center (3a-f) were more active than mexiletine both in tonic and phasic block. This observation was in contrast with what was observed for mexiletine, where the removal of both methyls from the aryloxy moiety caused a dramatic reduction of potency. The most potent congener, (R)-2-(2-methylphenoxy)-1-phenyle-thanamine [(R)-3b], was 27-fold more potent than (R)-mexiletine in producing a tonic block, i.e., the reduction of peak sodium current in resting conditions after application of the compound. (R)-3b maintained a use-dependent behavior, being 23-fold more potent in condition of high frequency of stimulation (phasic block). Despite what was observed with mexiletine, the stereoselectivity held in phasic block conditions. Stereoselectivity indexes were generally low, ranging from 1 to 4, but except for that of the 2,6-xylyloxy congener 3c, they were higher for the congeners bearing a phenyl ring on the stereogenic center than for mexiletine and its strictly related analogue 1-methyl-2-phenoxyethanamine (1). This finding was in agreement with Pfeiffer's rule. The introduction of a chlorine atom in the 4-position of the aryloxy moiety caused a reduction of potency and a reversal of stereoselectivity as well. On the basis of the model to date accepted for the sodium channel local anesthetic-like molecule receptor, some possible explanations of our observations will be proposed.

Full text of DOI:10.1021/jm030865y

5238
J . Med. Chem. 2003, 46, 5238-5248
Op tica lly Active Mexiletin e An a logu es a s Ster eoselective Block er s of
Volta ge-Ga ted Na + Ch a n n els
Carlo Franchini,*,§ Alessia Carocci,§ Alessia Catalano,§ Maria M. Cavalluzzi,§ Filomena Corbo,§
Giovanni Lentini,§ Antonio Scilimati,§ Paolo Tortorella, Diana Conte Camerino,‡ and Annamaria De Luca‡
Dipartimento Farmaco-Chimico and Farmaco-Biologico, Universita` degli Studi di Bari - Via E. Orabona 4, 70125 Bari, Italy,
and Istituto di Scienze del Farmaco, Universita` “G. D’Annunzio”, Via dei Vestini, 66100 Chieti, Italy
Received April 7, 2003
Optically active mexiletine analogues were synthesized and evaluated in vitro as use-dependent
blockers of skeletal muscle sodium channels. The mexiletine analogues were obtained by
replacing either the methyl group on the stereogenic center of mexiletine [1-(2,6-dimethylphe-
noxy)propan-2-amine] with a phenyl group or modifying the phenoxy moiety (by removal of
one or both of the methyl groups, or introducing a chlorine atom), or both. The voltage clamp
recordings showed that, regardless of the substitution pattern of the aryloxy moiety, all the
compounds bearing a phenyl group on the stereogenic center (3a -f) were more active than
mexiletine both in tonic and phasic block. This observation was in contrast with what was
observed for mexiletine, where the removal of both methyls from the aryloxy moiety caused a
dramatic reduction of potency. The most potent congener, (R)-2-(2-methylphenoxy)-1-phenyle-
thanamine [(R)-3b], was 27-fold more potent than (R)-mexiletine in producing a tonic block,
i.e., the reduction of peak sodium current in resting conditions after application of the compound.
(R)-3b maintained a use-dependent behavior, being 23-fold more potent in condition of high
frequency of stimulation (phasic block). Despite what was observed with mexiletine, the
stereoselectivity held in phasic block conditions. Stereoselectivity indexes were generally low,
ranging from 1 to 4, but except for that of the 2,6-xylyloxy congener 3c, they were higher for
the congeners bearing a phenyl ring on the stereogenic center than for mexiletine and its strictly
related analogue 1-methyl-2-phenoxyethanamine (1). This finding was in agreement with
Pfeiffer’s rule. The introduction of a chlorine atom in the 4-position of the aryloxy moiety caused
a reduction of potency and a reversal of stereoselectivity as well. On the basis of the model to
date accepted for the sodium channel local anesthetic-like molecule receptor, some possible
explanations of our observations will be proposed.
In tr od u ction
Mexiletine [1-(2,6-dimethylphenoxy)propan-2-amine]
(Figure 1) is a well-known orally effective antiarrhyth-
mic drug of the IB class,1-4 which is also effective in
the treatment of the muscular hyperexcitability of
myotonic syndromes.5 The clinical term myotonia is
used to identify a series of dominant and recessive forms
of genetic skeletal muscle diseases characterized by
abnormal membrane excitability and delayed muscle
relaxation after voluntary contraction. Sodium channel
myotonias, paramyotonia congenita, and hyperkaliemic
periodic paralysis are due to mutations of the gene
coding for the skeletal muscle type of voltage-gated
sodium channels.6,7 The effect of mexiletine can be
correlated with the block of voltage-dependent Na+
channels present in both cardiac and skeletal muscle
fibers,7,8 and its activity increases with the level of
depolarization and the frequency of stimulation. As well-
known, the use-dependent blockers of Na+ channels
stabilize the channels in the inactivated state.9 This
mechanism allows a higher potency on tissues charac-
terized by excessive excitability (e.g., myotonic muscles
with nonphysiological phenotypes of sodium or chlorine
F igu r e 1. Structure of mexiletine and its analogues 1 and
* To whom correspondence should be addressed. Phone: 0039-080-
3a -f, tocainide, and its phenyl analogue 2.
5442743. Fax: 0039-080-5442050. E-mail: cfranc@farmchim.uniba.it.
§ Dipartimento Farmaco-Chimico, Universita` degli Studi di Bari.
channels). As reported, cardiac and skeletal muscles
show different types of sodium channels.10 In therapy,
‡ Dipartimento Farmaco-Biologico, Universita` degli Studi di Bari.
Universita` “G. D’Annunzio”.
10.1021/jm030865y CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/31/2003

Blockers of Voltage-Gated Na+ Channels
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 24 5239
Sch em e 1a
a
Reagents and conditions: (a) NaOH/DMF; (b) RuO2/NaIO4; (c) DPPA/t-BuOH; (d) HCl(g); (e) Ac2O, Et3N/THF.
mexiletine is used as a racemate even though in vivo11
and in vitro12 studies showed the presence of stereose-
lective active sites on the cardiac sodium channel which
preferentially bind the (-)-(R)-enantiomer. (-)-(R)-
Mexiletine is more active than (+)-(S)-mexiletine also
on native skeletal muscular fibers.2,13b Nevertheless, the
use of mexiletine in the therapy of myotonic syndromes
is restricted by its side effects on the cardiac functions,
on the central nervous system (CNS), and on the
hematopoietic system.12 In the past decade our efforts
were focused on the development of new antimyotonic
drugs such as mexiletine- and tocainide-like com-
pounds.1-3,13 Recently, we have reported that in a series
of mexiletine analogues, variously substituted on the
stereogenic center, the potency of the pore-blocking
activity was positively related to lipophilicity.1 That is,
the replacement of the methyl group on the stereogenic
center of mexiletine with an isopropyl, phenyl, or benzyl
group led to a 3-10-fold increase in potency. This
tively less planar than the RX Mex structure (data not
shown).13 This easily anticipated observation suggests
that 3a -f may bind differently from Mex in the sodium
channel. The sum of these findings suggested some
sterical constraint emerging in phasic block conditions
only for the more potent compounds according to Pfeif-
fer’s rule16 and prompted us to the stereospecific syn-
thesis of the analogues 3d -f, to evaluate the relative
importance of lipophilicity and steric requirements for
potent and use-dependent block of skeletal muscle
sodium channels. The synthesis and full characteriza-
tion of new as well as previously incompletely described
compounds will be given.
Ch em istr y
Mexiletine analogues (1 and 3a -f) were prepared
following different synthetic approaches (Scheme 1-3).
(R)- and (S)-1-Methyl-2-phenoxyethylamine (1) were
obtained, allowing the enantiomerically pure 3-bromo-
2-methylpropan-1-ol (4) to react with phenol to give
2-methyl-3-phenoxypropan-1-ol (5) that in turn was
oxidized by RuO2/NaIO4. The resulting 2-methyl-3-
phenoxypropanoic acid (6) was converted into the cor-
responding carbamate 7, that by treatment with HCl(g)
afforded the product 8 (i.e., 1‚HCl) (Scheme 1) in high
yield and enantiomeric excess (>98%).
2-(2,6-Dimethylphenoxy)-1-phenylethanamine (3c) was
prepared in racemic form as depicted in Scheme 2.
The synthesis of 2-(2,6-dimethylphenoxy)-1-phenyl-
ethanone (10c) was carried out in DMSO/NaOH by
reacting 2-bromoacetophenone and 2,6-dimethylphenol
(9c). 10c was transformed into the corresponding oxime
11c, that was then reduced to racemic 3c by H2 (20 atm)
in the presence of a catalytic amount of 5% Pd/C. The
halogenated compound (()-3e was prepared following
the same route except for the last step, where the
reduction was carried out with LiAlH4 in anhydrous
Et2O under reflux in order to avoid reductive dehalo-
genation. Optically active 3a -f were prepared with
enantiomeric excess ranging between 80% and 99%,
following the route reported in Scheme 3. In this
procedure each 3a -f enantiomer was obtained starting
from (R)- or (S)-styrene oxide (13). Thus, 14a -f were
obtained by reacting the suitable optically active styrene
oxide and phenol (12). The ring-opening reaction is
virtually regiospecific in a dipolar aprotic medium, and
the isomeric purity of the alcohols so obtained can be
easily checked by EIMS.17 The chiral alcohols 14 were
transformed into 15a -f by a stereospecific substitution
reaction of the hydroxy group with phthalimide per-
formed in the presence of triphenylphosphine and
diisopropyl azodicarboxylate (DIAD) following a typical
finding was in agreement with previous results from
2,3
both our
and other research groups.4 In particular,
these results parallel those observed in the tocainide
series, where formally replacing the methyl group on
the stereogenic center with a phenyl to obtain 2 led to
a marked increase in the antiarrhytmic potency.14
However, lipophilicity alone cannot explain all aspects
of the blocking activity of the analogues bearing a
phenyl group on the stereogenic center. 2-(2,6-Dimeth-
ylphenoxy)-1-phenylethanamine (3c) was 5-10-fold more
potent than mexiletine. However, in all protocols used,
its blocking activity was devoid of stereoselectivity,
whereas with mexiletine, the stereospecific index (SSI)
in the tonic block experiments was low, but differed
significantly from unity. With mexiletine, the (R)-
enantiomer was the eutomer. Furthermore, the mexi-
letine analogue from which the two o-methyl groups on
the xylyloxy moiety were formally removed (1-methyl-
2-phenoxyethanamine, 1) showed in all protocols a
dramatic reduction of potency with respect to the parent
compound. The same was not true for 3a and 3b; the
latter was even more potent than 3c despite a reason-
ably predictable lowering of lipophilicity (the calculated
logP values15 for 3a , 3b, and 3c are 2.6 ( 0.2, 3.1 (
0.2, and 3.6 ( 0.2, respectively). 3a and 3b SSIs were
also significantly different from unity (3-4 and 2-3,
respectively), the (R)-enantiomers being more potent
and, opposite to what was observed with mexiletine, the
stereoselectivity was maintained when fibers were
stimulated by trains of depolarizing pulses (at a fre-
quency of 10 Hz), i.e., in conditions of use-dependent or
phasic block. Indeed the 3-21G*//3-21G* models of the
phenyl analogue structures show that 3a -f are rela-

5240 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 24
Franchini et al.
Sch em e 2a
a
Reagents and conditions: (a) 2-Bromoacetophenone, NaOH/DMSO; (b) EtOH/Py, NH2OH‚HCl; (c) 5% Pd/C, H2 (20 atm), EtOH or
LiAlH4.
Sch em e 3a
a
Reagents and conditions: (a) NaOH/CH3CN, reflux; (b) phthalimide, PPh3/DIAD, THF; (c) 55% aq N2H4, AcOH/EtOH; (d) HCl(g).
Mitsunobu procedure.18,34 This reaction occurs with
inversion of configuration at the stereogenic center, and
little or no racemization was observed. Finally, by
hydrazinolysis of the phthalimido aryl alkyl ethers 15a -
f, the phenyl mexiletine analogues 3a -f were obtained,
which in turn were purified as hydrochloride salts 3a -
f‚HCl. This synthetic strategy allowed the preparation
of both enantiomers of each new compound in good
yields, in high enantiomeric excesses [determined by
HPLC analyses using a Daicel Chiralcel OD column
(tris-3,5-dimethylphenylcarbamate, derivatized cellulose
film) or OD-R column], and with known absolute con-
figuration.
was 27-fold more potent than (R)-mexiletine in produc-
ing a tonic block, i.e., the reduction of peak sodium
current in resting conditions after application of the
compound, and it was 23-fold more potent in condition
of high frequency of stimulation (phasic block, that may
be considered as an indication of the antimyotonic
activity). Furthermore, 3b presented the same pattern
of stereoselectivity as that of mexiletine, (S)-3b being
approximately 3-fold less potent than (R)-3b. Other
structural modifications of the phenoxy group of 3b led
to compounds that in all cases were more potent than
mexiletine, presenting IC50 values ranging from 8 µM
to 50 µM and from 3 µM to 23 µM for tonic and phasic
block, respectively. The (R)-enantiomers of 1, 3a , and
3b behaved as eutomers. The formal introduction of a
chlorine atom in the 4-position of the aryloxy moiety of
3a , 3b, and 3c to give 3d , 3e, and 3f, respectively,
caused a reversal of stereoselectivity in both tonic and
phasic block, (S)-3d , (S)-3e, and (S)-3f being more
potent than the respective enantiomers. Furthermore,
this finding was accompanied by another intriguing
observation. The IC50 values displayed by 3a -c in
phasic block conditions point to a beneficial role of one
o-methyl group on the aryloxy moiety (3b > 3c > 3a ).
When introducing a chlorine atom in the 4-position of
this ring, a partial loss of potency was accompanied by
a reversal of the hierarchy of potency as a function of
the ortho substitution pattern, the congener with no
Biologica l Stu d ies
All above-mentioned compounds were evaluated for
activity as sodium channel blockers on single muscle
fibers. Concentrations for half-maximal tonic and use-
dependent block of sodium currents (IC50) are reported
in Table 1. Single enantiomers were tested with the aim
of evaluating the presence of stereoselectivity in block-
ing INa. The results obtained on both enantiomers of 1
demonstrate that when the propyl chain of mexiletine
is not changed, the two o-methyl groups play an
important role. In fact, (R)- and (S)-1 were less active
than (R)- and (S)-mexiletine, respectively. On the
contrary, the new compounds with a phenyl replacing
the methyl on the stereogenic center of mexiletine were
all more active than mexiletine. In particular, (R)-3b

Blockers of Voltage-Gated Na+ Channels
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 24 5241
Ta ble 1. Concentrations for Half-Maximal Block of Sodium Currents of Skeletal Muscle Fibers by Mexiletine and Its Analogues
a
The half-maximal concentration (IC50) of each compound for producing a tonic block (block of sodium channel at resting conditions
evaluated during infrequent depolarizing pulses) and the phasic block (cumulative sodium current reduction by the drug at 10 Hz
b
stimulation frequency) have been obtained by concentration-response curves (see the Experimental Section). Putative antimyotonic
activity: potency in phasic block in relation to mexiletine (see the Experimental Section), mexiletine ) 1.
o-methyl group (3d ) being the most effective in the
chloro-substituted series (3d > 3f > 3e).
as blockers of such channels. However, both basicity and
lipophilicity cannot explain all aspects of local anesthetic
action: as reported above, further stereoelectronic
aspects should be considered. The interaction of basic
local anesthetics with the binding site is assumed to
involve the protonated species. Recently, an interaction
of the cationic moiety of mexiletine with an anionic
residue of the receptor site has been proposed,21 but site-
specific mutagenesis studies disagree with this hypoth-
esis, indicating two aromatic residues (Phe and Tyr) on
the D4-S6 transmembrane segment in brain type IIA,
brain type III, and skeletal muscle Na+ channels as the
main binding sites of pore-blocking drugs.22 Probably,
D1 and D3 also contribute to the receptor,23 a major role
being played by lipophilic residues. The results herein
presented are in agreement with these assumptions.
The insertion of a phenyl group on the asymmetric
center causes a significant increase in the potency of
tonic block: all phenyl analogues of mexiletine are more
potent than (R)-mexiletine. This increase is independent
of the substituents present on the aryloxy ring and,
although less evident, is conserved in phasic block
experiments. These observations might be rationalized,
assuming the hydrophobic interaction
Discu ssion
Mexiletine is one of the few drugs currently available
for the treatment of patients suffering from myotonia.4,5
However, the use of mexiletine as an antimyotonic drug
is tainted with pharmacological promiscuity: the rec-
ommended doses for myotonic patients are in the same
range as that used to treat arrhythmia, with the
possibility of adverse effects on both the cardiac and the
nervous system functions.5b Considering that sodium
channels of cardiac and skeletal muscle tissues are
genetically distinct and consequently have different
pharmacological and kinetic properties,20,13b the pos-
sibility to develop new use-dependent sodium channel
blockers more selective on skeletal than on heart muscle
may be envisaged. The structural requirements for
molecules able to exert a potent and use-dependent
block on the sodium channels have not yet been com-
pletely defined. Different evidence points to the lipo-
philicity as the property that modulates the blocking
potency1-4 and the basicity as the property able to affect
the use-dependent blocking activity of compounds acting

5242 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 24
Franchini et al.
of the phenyl ring with one of the aromatic amino acids
scarcely involved in mexiletine binding. The stereose-
lectivity of block, though modest, does imply that at
least three binding sites are involved. The low ste-
reospecificity indexes observed may be explained, noting
that all the interaction sites putatively involved in the
binding are lipophilic. Due to molecular flexibility, the
distomer of each compound may easily access a confor-
mation that fits the relevant interaction sites. Molecular
flexibility, however, should play a minor role; otherwise
the peculiar behavior of 3c, in principle less flexible than
3b, would remain unexplained: 3c is the only potent
mexiletine analogue that presents no stereoselectivity
at all, and this means that 3c may easily fit the receptor
regardless of its stereochemistry. This observation
implicitly suggests that phenyl and amine groups are
viewed as interchangeable by the receptor, and this is
in agreement with previous observations claiming a
possible π-cation interaction between the protonated
amino group of local anesthetics24 and amitriptyline,25
and the aromatic ring of Phe. Despite what is observed
with mexiletine and some of its analogues, the stereo-
selectivity displayed in the Na+ channel blocking activ-
ity of 3a ,b,d -f does not dissipate when passing from
tonic to phasic block. Thus, the same receptor stereo-
electronic requirements should be hypothesized regard-
less of the Na+ channel state (resting or inactivated),
and the gain in potency observed at higher frequency
of stimulation might be attributed more plausibly to a
closer interaction of the ligands with the host than to a
dramatic change in the receptor conformation causing
a disclosure of further interaction sites. The reversal of
the stereoselectivity pattern and hierarchy of potency
observed when introducing a chlorine atom in the
4-position imposes the assumption of two different
fitting modes for these mexiletine analogues depending
on steric and/or electronic features at the xylyloxy ring.
Several interaction models assume that local anaes-
thetic-like molecules enter the pore, orienting the
charged amino group upward.1,23-25 Thus, the amino
group should be placed uppermost, and the rest of the
molecule should be oriented downward. Assuming as
improbable an upside down reorientation of the mol-
ecule, which would not be possible due to the negative
gradient and the dimension of the pore, it should be
assumed that 3d -f bind the receptor at a level differing
from that affected by 3a -c. The causes of this dif-
ferential mode of binding (steric, electronic, or both) are
currently under investigation.
was 25 and 20 times more potent than mexiletine in
tonic and phasic block experiments, respectively. The
4-chlorinated analogues (3d -f) were generally less
potent. However, (S)-3d was 8 times more potent than
mexiletine in exerting a phasic block and was the most
use-dependent blocking agent in the series [IC50 (tonic
block)/IC50 (phasic block) ) 8]. Thus (R)-3b and (S)-3d
might be usefully employed to explore the local anes-
thetic-like molecule receptor in the cardiac and nervous
sodium channels as well, in view of a possible pharma-
cological dissociation disclosing the access to safer drugs
selectively targeted to each of them.
Exp er im en ta l Section
P h a r m a cology. 1. P r ep a r a tion a n d Solu tion s. For
sodium current recordings, semitendinosus muscle fibers were
perfused with the following “external” solution (mM): NaCl
77, choline-Cl 38, CaCl2 1.8, Na2HPO4 2.15, NaH2PO4 0.85;
and dialyzed with the following “internal” solution (mM): CsF
105, MOPS 5, MgSO4 2, EGTA 5, Na2ATP 0.55 (pH ) 7.2 with
NaOH concentrated solution). Stock solutions of mexiletine
and its analogues were prepared in physiological and/or
“external” solutions. All the stock solutions were prepared
daily, and the final concentrations to be tested in vitro were
obtained by further diluting the stock solution as needed.
DMSO at the highest concentration used (0.2%) was without
effect on any of the parameters recorded.
2. Volta ge Cla m p Recor d in gs of Sod iu m Cu r r en t a n d
P u lse P r otocols. The voltage clamp recordings of sodium
current were performed on single muscle fibers obtained with
microsurgery from the ventral brunch of semitendinosus
muscle of Rana esculenta by means of the three vaseline gap
voltage clamp technique as detailed elsewhere.13b After an
equilibration time of 10 min, Na+ currents recordings were
performed at 10 °C. The holding potential (hp) was -100 mV.
The inward sodium traces were recorded using a voltage clamp
amplifier based on that described by Hille and Campbell26
connected via a 12-bit AD/DA interface (digidata 1200, Axon
Instruments, Forster City, CA) to an 80486 DX2/66 PC and
stored on the hard disk. The stimulation protocols and data
acquisition were driven by Clampex program (pClamp 6
software package, Axon Instruments). The currents flowing
in response to depolarizing command voltages were low pass
filtered at 10 kHz (Frequency Devices, Inc., Haverhill, MA)
visualized on an oscilloscope and sampled at 20 kHz. When
necessary, leak and capacity currents were subtracted by the
P/4 method. The acquired traces were later analyzed with the
Clampfit program (pClamp 6 software package, Axon Instru-
ments). Maximal sodium currents were elicited with test
pulses from the hp to -20 mV for 10 ms. Tonic block exerted
by the test compounds was evaluated as percent reduction of
the peak sodium current elicited by single test pulses. The
evaluation of use-dependent block by the drugs was made by
using a 10 Hz train of test pulses for a period of 30 s and by
normalizing the residual current at the end of this stimulation
protocol with respect to that in the absence of drug.
Con clu sion s
Sta tistica l An a lysis. The data were expressed as mean (
SEM. The statistical significances of the differences between
groups of means was calculated by unpaired Student’s t test.
Molar concentration of the drugs producing a 50% block of INa
(IC50) were determined by using a nonlinear least-squares fit
of the concentration-response curve as previously detailed.13b
When normalized values of the various experimental param-
eters were used, estimates of SEM and the calculated number
of normalized fibers were obtained as described previously.13b,23
Ch em istr y. Gen er a l. Yields refer to purified products and
were not optimized. The structures of the compounds were
confirmed by routine spectrometric analyses. Only spectra for
compounds to our knowledge never previously described are
given. Compounds used as starting materials were purchased
from either Aldrich Chemical Co., Inc. or Lancaster Synthesis,
Inc. in the highest commercially available quality. (-)-(R)- and
From a heuristic point of view, this study has provided
some new evidence in favor of the model presently
accepted for the local anesthetic-like molecule receptor
located in the sodium channel pore. However, our
results suggest that strictly related compounds may
bind the receptor in different ways, and much effort is
needed prior to formulation of a comprehensive receptor
model. From a practical point of view, a facile stereospe-
cific synthesis of phenyl analogues of mexiletine has
been proposed. This route gave us the access to 3a -f
which present themselves as valuable pharmacological
tools, all being more potent than mexiletine. In particu-
lar, 3b showed a marked increase in both potency and
use-dependence of action: compared to mexiletine, it

Blockers of Voltage-Gated Na+ Channels
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 24 5243
(+)-(S)-Mexiletine were prepared as previously described.19
evaporated under reduced pressure. The brown oil obtained
(0.38 g, 70% yield) was used without any further purification
Solvents were RP grade, unless otherwise indicated. Melting
points were determined on
a
Gallenkamp melting point
in the successive step: [R]20 ) +3.6 (c 2.5, CHCl3); IR (neat):
D
apparatus in open glass capillary tubes and are uncorrected.
Infrared spectra were recorded on a Perkin-Elmer Spectrum
One FT spectrophotometer, and band positions are given in
3550-2005 (CO2H), 1708 (CdO), 1244 (C-O-C) cm-1
.
1H
NMR δ 10.35 (br s, 1H exch D2O, COOH), 7.31-7.26 (m, 2H,
Ar HC-3,5), 6.98-6.90 (m, 3H, Ar HC-2,4,6), 4.20 (dd, J ) 9.1,
7.0 Hz, 1H, CHH), 4.05-4.00 (dd, J ) 9.1, 6.0 Hz, 1H, CHH),
3.05-2.91 (m, 1H, CH), 1.34 (d, J ) 7.1 Hz, 3H, CH3); MS (70
eV) m/z (%) 180 (M+, 26), 94 (100).
1
reciprocal centimeters (cm-1). H NMR and 13C NMR spectra
(300 MHz) were recorded on an FT Bruker Aspect 3000 or a
Varian Mercury 300 spectrometer using CDCl3 as solvent,
unless otherwise indicated. Chemical shifts are reported in
parts per million (ppm) relative to solvent resonance: CDCl3,
δ 7.26 (1H NMR) and δ 77.0 (13C NMR); (CD3)2SO, δ 2.50 (1H
NMR) and δ 39.5 (13C NMR). J values are given in hertz. EIMS
spectra were recorded on a Hewlett-Packard 6890-5973 MSD
gas chromatograph/mass spectrometer at low resolution; where
amine salts are concerned, MS analyses were performed on
the corresponding free base forms obtained by extraction.
Elemental analyses were performed on a Eurovector Euro EA
3000 analyzer; where indicated, C, H, and N were within (0.4
of theoretical values. Optical rotations were measured on a
Perkin-Elmer Mod 341 spectropolarimeter; concentrations are
expressed in g/100 mL, and the cell length was 1 dm; thus
(-)-(R)-2-Meth yl-3-p h en oxyp r op a n oic Acid [(-)-(R)-6].
It was prepared in 80% yield via the method above-described
for (+)-(S)-2-methyl-3-phenoxypropanoic acid but starting from
(-)-(S)-5: [R]20 ) -2.5 (c 2.5, CHCl3).
D
(-)-(S)-ter t-Bu tyl 1-Meth yl-2-p h en oxyeth ylca r ba m a te
[(-)-(S)-7]. A solution of (+)-(S)-6 (0.84 g, 4.67 mmol), diphe-
nylphosphoryl azide (DPPA, 2.57 g, 9.34 mmol), and Et3N (1.04
g, 10.27 mmol) in 50 mL of t-BuOH was stirred under reflux
for 7 h.29 After evaporation of the solvent, the residue was
dissolved in ethyl acetate and washed with 2 N HCl, and the
aqueous phase was washed with ethyl acetate. The two organic
phases were washed, separately, with 2 N NaOH and then
mixed and dried over anhydrous Na2SO4. By evaporating the
solvent under reduced pressure, 1.7 g of crude product were
obtained. After chromatography (petroleum ether/ethyl acetate
9:1) and crystallization (EtOAc-hexane), 0.4 g (34%) of a white
[R]20 values are given in units of 10-1 deg cm2 g-1. HPLC ee
D
evaluation was performed on a Waters chromatograph model
600 equipped with a U6K model injector and a 481 model
variable wavelength detector. The enantiomeric purity of 3a -
f‚HCl was determined by direct HPLC on Daicel OD or OD-R
columns as specified below (flow rate 0.5 mL/min, λ 254 nm).
The enantiomeric purity of 8 enantiomers was evaluated by
analysis of the corresponding N-acetyl derivatives (12) using
a Daicel OD-R column eluted at a flow rate of 0.5 mL/min with
40:60 CH3CN/H2O (λ 254 nm). Chromatographic separations
were performed on silica gel columns by flash chromatography
(Kieselgel 60, 0.040-0.063 mm, Merck) using the technique
described by Still et al.27 TLC analyses were performed on
solid was obtained: mp 81-82 °C; [R]20 ) -45 (c 2, CHCl3);
D
13C NMR δ 185.7 (1C), 155.3 (1C), 129.5 (2C), 121.0 (1C), 114.5
(2C), 70.8 (1C), 62.7 (1C), 45.7 (1C), 28.5 (3C), 18.2 (1C); MS
(70 eV) m/z (%) 251 (M+, 26), 57 (100). Other spectroscopic data
were in agreement with those reported in the literature.30
(+)-(R)-1-ter t-Bu tyl 1-Meth yl-2-p h en oxyeth ylca r ba m -
a te [(+)-(R)-7]. It was prepared in 30% yield via the method
above-described for (-)-(S)-7 starting from (-)-(R)-6: mp 81-
82 °C (EtOAc-hexane); [R]20 ) +48 (c 2, CHCl3).
D
(+)-(S)-1-Meth yl-2-p h en oxyeth yla m in e Hyd r och lor id e
[(+)-(S)-1‚HCl]. A solution of (-)-(S)-7 (0.57 g, 2.27 mmol) in
anhydrous Et2O (15 mL) was saturated with gaseous HCl and
stirred at room temperature for 15 min. Removal of the solvent
under reduced pressure gave a solid which was recrystallized
from EtOH-Et2O (0.38 g, 90%): mp 195-196 °C; [R]20D ) +7.7
(c 2, CH3OH); 13C NMR [(CD3)2SO] δ 157.8 (1C), 129.5 (2C),
121.1 (1C), 114.7 (2C), 68.5 (1C), 46.0 (1C), 15.0 (1C); MS (70
eV) m/z (%) 151 (M+, 3), 44 (100). Other spectroscopic data
were in agreement with those reported in the literature30 for
the (R)-enantiomer. Anal. (C9H14ClNO) C, H, N.
precoated silica gel on aluminum sheets (Kieselgel 60 F254
Merck).
,
(+)-(R)-2-Meth yl-3-ph en oxy-1-pr opan ol [(+)-(R)-5]. NaH
(60%) (0.783 g, 19.6 mmol) was added in small portions to a
stirred solution of phenol (3.68 g, 39.2 mmol) in 110 mL of
anhydrous DMF kept under a nitrogen atmosphere. After H2
evolution ceased, (-)-(R)-3-bromo-2-methyl-1-propanol [(-)-
(R)-4, 3.0 g, 19.6 mmol] was added. The reaction mixture was
stirred for 3 h, and then DMF was removed under reduced
pressure. The residue was solubilized in ethyl acetate and
washed with 0.5 N NaOH and water till neutral pH. The
organic phase was dried over anhydrous Na2SO4, and the
solvent was evaporated under reduced pressure. Purification
of the crude oil residue by column chromatography (petroleum
(-)-(R)-1-Meth yl-2-p h en oxyeth yla m in e Hyd r och lor id e
[(-)-(R)-1‚HCl]. It was prepared in 90% yield via the method
above-described for (+)-(S)-1‚HCl starting from (+)-(R)-7: mp
195-196 °C (EtOH-Et2O), lit.30 186-189 °C; [R]20 ) -4.4 (c
D
ether/EtOAc 8:2) afforded 2 g of yellowish product (61%): [R]20
D
2.3, CH3OH). Anal. (C9H14ClNO‚0.20 H2O) C, H, N.
) +6.7 (c 2, CHCl3); IR (neat): 3356 (OH), 2877, 1244 (C-
(-)-(S)-N-(1-Met h yl-2-p h en oxyet h yl)a cet a m id e [(-)-
(S)-12]. To a solution of 0.272 g of (+)-(S)-1‚HCl in 2 mL of
H2O, 2 N NaOH was added until basic, and the emulsion was
extracted three times with ethyl ether. The combined organic
extracts were dried over anhydrous Na2SO4, and then the
solvent was removed under reduced pressure to give 0.195 g
(89%) of (S)-1. (S)-1 (0.195 g, 1.29 mmol) and 0.36 mL (0.261
g, 2.58 mmol) of Et3N were solubilized in 9 mL of anhydrous
THF. To the stirred solution, kept in an ice bath, was slowly
added 0.24 mL (0.263 g, 2.58 mmol) of acetic anhydride. The
reaction mixture was stirred at room temperature for 5 h, and
the solvent was evaporated under reduced pressure. The
residue was dissolved in ethyl acetate, and the organic phase
was washed with 2 N HCl and then with NaHCO3 saturated
aqueous solution and H2O until neutral pH. The recovered
organic phase was dried over anhydrous Na2SO4 and the
solvent evaporated under reduced pressure to give 0.281 g of
a crude yellow oil. After purification by chromatography
(petroleum ether/EtOAc 8:2), 0.240 g (86%) of the desired
1
O-C) cm-1; H NMR δ 7.32-7.25 (m, 2H, Ar HC-3,5), 7.00-
6.84 (m, 3H, Ar HC-2,4,6), 4.00-3.90 (m, 2H, OCH2), 3.71 (d,
J ) 5.8 Hz, 2H, CH2OH), 2.28-2.14 (m, 1H, CH), 1.95 (br s,
1H, exch D2O, OH), 1.04 (d, J ) 6.9 Hz, 3H, CH3); 13C NMR δ
158.8 (1C), 129.5 (2C), 120.9 (1C), 114.5 (2C), 71.2 (1C), 66.2
(1C), 35.7 (1C), 13.6 (1C); MS (70 eV) m/z (%) 166 (M+, 32), 94
(100).
(-)-(S)-2-Meth yl-3-p h en oxy-1-p r op a n ol [(-)-(S)-5]. It
was prepared in 60% yield by the method above-described for
(+)-(R)-5, starting from (+)-(S)-3-bromo-2-methyl-1-pro-
panol: [R]20 ) -5.5 (c 2, CHCl3).
D
(+)-(S)-2-Meth yl-3-p h en oxyp r op a n oic Acid [(+)-(S)-6].
A mixture of EtOAc (15 mL) and 10% NaIO4 aqueous solution
(30 mL) was kept under mechanical stirring by means of Teflon
blades supporting catalytic amounts of RuO2‚H2O.13a,28
A
solution of (+)-(R)-5 (0.50 g, 3 mmol) in EtOAc (15 mL) was
added dropwise, and the mixture was stirred for 18 h. Then,
the two phases were separated, and the aqueous phase was
washed twice with ethyl acetate. The combined organic
extracts were treated with saturated NaHCO3 aqueous solu-
tion. The aqueous phase was acidified with 2 N HCl and
extracted with ethyl acetate. The so obtained organic solution
was dried over anhydrous Na2SO4 and then the solvent
product was obtained: [R]20 ) -59 (c 2.2, CHCl3), 70% ee (tR
D
12.7 min); IR (neat): 3283 (NH), 2876 (C-O-C), 1651 (CdO)
cm-1. 1H NMR δ 7.33-7.20 (m, 2H, Ar HC-3,5), 7.02-6.87 (m,
3H, Ar HC-2,4,6), 5.95 (br d, J ) 4.0 Hz, 1H, exch D2O, NH),
4.45-4.29 (m, 1H, CH), 3.96 (dd, J ) 9.0, 4.5 Hz, 1H, CHH),

5244 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 24
Franchini et al.
3.90 (dd, J ) 9.0, 4.5 Hz, 1H, CHH), 1.97 (s, 3H, COCH3), 1.29
(d, J ) 6.9 Hz, 3H, CHCH3); 13C NMR δ 169.5 (1C), 158.6 (1C),
129.5 (2C), 121.0 (1C), 114.4 (2C), 70.4 (1C), 44.6 (1C), 23.3
(1C), 17.5 (1C); MS (70 eV) m/z (%) 193 (M+, 1), 100 (100).
pressure. The residue was taken up with Et2O, and the organic
layer was extracted with 2 N HCl. The aqueous phase was
treated with 2 N NaOH until basic and then extracted with
Et2O (3 × 50 mL). The combined organic phases, washed with
water and dried over anhydrous Na2SO4, were evaporated
under reduced pressure to give a crude oil in quantitative yield
(6.6 g). (()-3c was converted into the corresponding hydro-
chloride [(()-3c‚HCl] by treating with a few drops of 2 N HCl
and removing water azeotropically. The crude solid obtained
was purified by recrystallization from EtOH-Et2O affording
5.3 g (69%) of the hydrochloride salt as white crystals: mp
242 °C; MS (70 eV) m/z (%) 241 (M+, 1), 106 (100). Spectro-
scopic data were identical to those reported below for the
individual enantiomers. Anal. (C16H20ClNO) C, H, N.
(+)-(R)-N-(1-Met h yl-2-p h en oxyet h yl)a cet a m id e [(+)-
(R)-12]. (+)-(R)-12 was prepared in 98% yield via the method
above-described for (-)-(S)-12 starting from (-)-(R)-1‚HCl:
[R]20 ) +79 (c 2, CHCl3), 98% ee (tR 11.4 min).
D
Gen er a l P r oced u r e for th e Syn th esis of 2-Ar yloxy-1-
p h en yleth a n on es (10c,e). The preparation of 2-(2,6-dimeth-
ylphenoxy)-1-phenylethanone (10c) is typical. To a magneti-
cally stirred mixture of NaOH (7.20 g, 180 mmol) and 100 mL
of DMSO was added a solution of 2,6-dimethylphenol (9c, 20.0
g, 164 mmol) in DMSO (20 mL). Then a solution of 2-bromoac-
etophenone (35.9 g, 180 mmol) in DMSO (20 mL) was added
dropwise. The resulting reaction mixture was stirred for 4 h
at room temperature and then poured onto ice. The aqueous
layer was extracted with Et2O (6 × 50 mL), and the so obtained
organic phase was washed with water, dried over anhydrous
Na2SO4, and evaporated under reduced pressure to give a
crude oil (27.2 g). Crystallization from EtOAc-petroleum ether
provided 10c as a pale yellow solid (24.8 g, 63%): mp 60-61
°C, lit.31 53 °C; IR (KBr): 1665 (CdO) cm-1; 1H NMR δ 7.98-
7.95 (m, 2H, Ar HC-2,6), 7.59-7.45 (m, 3H, Ar HC-3,4,5),
7.12-7.02 (m, 3H, ArO HC-3,4,5), 5.06 (s, 2H, CH2), 2.24 (s,
3H, CH3);32 MS (70 eV) m/z (%) 240 (M+, 25), 105 (100).
2-(4-Ch lor o-2-m eth ylph en oxy)-1-ph en yleth an on e (10e).
Obtained in 86% yield via the above-described procedure as a
crude yellow solid which was checked for purity by GC MS
and judged suitable for the next step: mp 60-61 °C (EtOH);
IR (KBr): 1690 (CdO) cm-1; 1H NMR δ 8.00-7.97 (m, 2H, Ar
HC-2,6), 7.65-7.59 (m, 1H, Ar HC-4), 7.52-7.47 (m, 2H, Ar
HC-3,5), 7.13 (d, J ) 2.5 Hz, 1H, ArO HC-3), 7.06 (dd, J )
8.6, 2.5 Hz, 1H, ArO HC-5), 6.64 (d, J ) 8.7, 1H, ArO HC-6),
5.25 (s, 2H, CH2), 2.26 (s, 3H, CH3); 13C NMR δ 194.5 (1C),
154.9 (1C), 134.6 (1C), 134.0 (1C), 130.8 (1C), 129.2 (1C), 128.9
(2C), 128.2 (2C), 126.4 (2C), 126.1 (1C), 71.2 (1C), 16.2 (1C);
MS (70 eV) m/z (%) 260 (M+, 22), 105 (100).
Gen er a l P r oced u r e for th e Syn th esis of (E,Z)-2-Ar yl-
oxy-1-p h en yleth a n on e Oxim e (11c,e). The preparation of
(E,Z)-2-(2,6-dimethylphenoxy)-1-phenylethanone oxime [(E,Z)-
11c] is typical. A mixture of 10c (24.0 g, 100 mmol), NH2OH‚
HCl (22.1 g, 320 mmol), and pyridine (15 mL) in 30 mL of
EtOH was refluxed for 3 h. Then, the solvent was evaporated,
and the residue, dissolved in CH2Cl2 was washed with 2 N
HCl. The organic layer, dried over anhydrous Na2SO4, was
then evaporated under reduced pressure to give a crude solid
which was purified by recrystallization from EtOH-H2O (3:
1) affording 11c as yellow needles (10.7 g, 42%): mp 131-132
°C. For the sake of simplicity only spectral data for the most
abundant geometrical isomer (>90%) will be given: IR (KBr):
3297 (OH), 2860, 1264 (C-O-C), 1591 (CdN) cm-1; 1H NMR
δ 9.17 (br s, 1H, exch D2O, OH), 7.80-7.77 (m, 2H, Ar HC-
2,6), 7.72-7.71 (m, 3H, Ar HC-3,4,5), 7.03-7.00 (m, 2H, ArO
HC-3,5), 6.97-6.92 (m, 1H, ArO HC-4), 5.08 (s, 2H, CH2), 2.22
(s, 6H, CH3); 13C NMR δ 156.3 (1C), 156.0 (1C), 134.1 (1C),
130.9 (1C), 129.5 (2C), 128.8 (2C), 128.4 (2C), 127.2 (2C), 124.1
(1C), 63.9 (1C), 16.4 (1C); MS (70 eV) m/z (%) 255 (M+, 36),
122 (100).
(()-2-(4-Ch lor o-2-m e t h ylp h e n oxy)-1-p h e n yle t h a n -
a m in e [(()-3e]. A solution of 2e (3.86 g, 14.0 mmol) in 50
mL of Et2O was added dropwise to a suspension of LiAlH4 (1.04
g, 28.0 mmol) in Et2O (100 mL). The reaction mixture was
refluxed for 3 h and then quenched by adding H2O. The organic
phase was filtered on Celite pellet and extracted with 1 N HCl
(3 × 50 mL). The aqueous layer, treated with 1 N NaOH until
basic, was extracted with Et2O (3 × 50 mL). The combined
organic phases, washed with water and dried over anhydrous
Na2SO4, were evaporated under reduced pressure to give (()-
3e (1.6 g, 44%) as a colorless oil. (()-3e was converted into
the corresponding hydrochloride [(()-3e‚HCl] by treating with
a few drops of 2 N HCl and removing water azeotropically.
The crude solid obtained was recrystallized from EtOH-Et2O
affording 0.75 g (18%) of the hydrochloride salt as white
crystals: mp 237 °C; MS (70 eV) m/z (%) 261 (M+, 1), 106 (100).
Spectroscopic data were identical to those reported below for
the individual enantiomers. Anal. (C15H17Cl2NO) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of 2-Ar yloxy-1-
p h en yleth a n ols (14a -f).17,33 The preparation of (-)-(R)-2-
(2,6-dimethylphenoxy)-1-phenylethanol will be described [(-)-
(R)-14c]. To a suspension of NaOH (1.06 g, 26.7 mmol) in
MeCN (50 mL) heated to 90 °C was added 3.05 g (25 mmol) of
2,6-dimethylphenol (9c) under stirring; then a solution of (+)-
(R)-styrene oxide [(+)-(R)-13] (1.00 g, 8.33 mmol) in MeCN (50
mL) was added over a period of 1.5 h. The final reaction
mixture was heated for 6.5 h and then stirred at room
temperature for 12 h. The removal, under vacuum, of the
reaction solvent gave a crude oil taken up with ethyl acetate
and washed with H2O. The organic phase was dried (Na2SO4)
and concentrated under vacuum affording a crude brown oil.
After purification on column chromatography (petroleum
ether/EtOAc 9:1), a yellowish oil was obtained which was
crystallized from EtOAc-petroleum ether to give (-)-(R)-14c
(0.91 g, 45%) as a white solid: mp 79-81 °C; [R]20 ) -20 (c
D
2, CHCl3); IR (CHCl3): 3588 (OH), 2860, 1264 (C-O-C) cm-1
;
1H NMR δ 7.47-7.29 (m, 5H, Ar), 7.03-7.01 (m, 2H, ArO HC-
3,5), 6.96-6.91 (m, 1H, ArO HC-4), 5.16 (dd, J ) 6.9, 5.0 Hz,
1H, CH), 3.90 (dd, J ) 9.6, 5.0 Hz, 1H, CHH), 3.85 (dd, J )
9.6, 6.9 Hz, 1H, CHH), 2.99 (br s, 1H, exch D2O, OH), 2.28 (s,
6H, CH3); 13C NMR δ 155.1 (1C), 139.8 (1C), 130.7 (2C), 128.9
(2C), 128.4 (2C), 128.0 (1C), 126.2 (2C), 124.1 (1C), 76.9 (1C),
73.4 (1C), 16.3 (2C); MS (70 eV) m/z (%) 242 (M+, 9), 122 (100).
(+)-(S)-2-(2,6-Dim eth ylp h en oxy)-1-p h en yleth a n ol [(+)-
(S)-14c]. 40% yield, mp 77-79 °C (EtOAc-petroleum ether);
(E ,Z)-2-(4-Ch lor o-2-m e t h ylp h e n oxy)-1-p h e n yle t h a -
n on e Oxim e [(E,Z)-11e]. 94% yield, mp 113-115 °C (EtOH);
[R]20 ) +19 (c 2, CHCl3).
D
(-)-(R)-2-P h en oxy-1-p h en yleth a n ol [(-)-(R)-14a ]. 72%
1
IR (CHCl3): 3577, 3299 (OH), 1598 (CdN) cm-1; H NMR δ
yield, mp 58-60 °C (EtOAc-petroleum ether); [R]20 ) -27
D
9.04 (br s, 1H, OH), 7.87-7.56 (m, 2H, Ar HC-2,6), 7.47-7.31
(m, 3H, Ar HC-3,4,5), 7.09 (dd, J ) 8.5, 2.7 Hz, 1H, ArO HC-
5), 7.04 (d, J ) 2.7 Hz, 1H, ArO HC-3), 6.85 (d, J ) 8.5 Hz,
1H, ArO HC-6), 5.29 (s, 2H, CH2), 2.00 (s, 3H, CH3); 13C NMR
δ 156.2 (1C), 154.7 (1C), 133.2 (1C), 130.5 (1C), 129.6 (2C),
128.9 (1C), 128.3 (2C), 127.2 (2C), 126.4 (1C), 125.7 (1C), 60.1
(1C), 16.0 (1C); MS (70 eV) m/z (%) 275 (M+, 47), 103 (100).
(c 2, CHCl3); 13C NMR δ 158.3 (1C), 139.5 (1C), 129.3 (2C),
128.5 (2C), 128.2 (1C), 126.3 (2C), 121.3 (1C), 114.6 (2C), 72.6
(1C), 72.4 (1C). All other spectral data were in agreement with
those reported in the literature for the (+)-(S)-enantiomer34
and the racemic mixture.35
(+)-(S)-2-P h en oxy-1-p h en yleth a n ol [(+)-(S)-14a ]. 88%
yield, mp 58-60 °C (EtOAc-petroleum ether); [R]20 ) +19
D
(()-2-(2,6-Dim eth ylph en oxy)-1-ph en yleth an am in e [(()-
3c]. A solution of 2c (7.01 g, 27.5 mmol) in 200 mL of EtOH
was treated with H2 at 20 atm for 24 h in the presence of 5%
Pd/C (600 mg) as a catalyst. The solution was filtered on a
kaolin pellet, and the filtrate was concentrated under reduced
(c 2, CHCl3), lit.34 +28.2 (c 1, MeOH).
(-)-(R)-2-(2-Meth ylp h en oxy)-1-p h en yleth a n ol [(-)-(R)-
14b]. 34% yield, oil; [R]20 ) -38 (c 2, CHCl3); IR (CHCl3):
D
3589 (OH), 2871, 1289 (C-O-C) cm-1; H NMR δ 7.49-7.45
1

Blockers of Voltage-Gated Na+ Channels
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 24 5245
(m, 2H, Ar HC-2,6), 7.43-7.30 (m, 3H, Ar HC-3,4,5), 7.15 (d
overlapping apparent t at 7.14, J ) 8.1 Hz, 1H, ArO HC-3),
7.14 (apparent t overlapping d at 7.15, J ) 7.8 Hz, 1H, ArO
HC-5), 6.89 (apparent t, J ) 7.8 Hz, 1H, ArO HC-4), 6.80 (d,
J ) 8.1 Hz, 1H, ArO HC-2), 5.15 (dd, J ) 8.38, 3.50 Hz, 1H,
CH), 4.13 (dd, J ) 9.48, 3.50 Hz, 1H, CHHO); 4.03 (dd, J )
9.48, 8.38 Hz, 1H, CHHO), 2.8 (br s, 1H, exch D2O, OH), 2.17
(s, 3H, CH3); 13C NMR δ 156.4 (1C), 139.8 (1C), 130.8 (1C),
128.5 (2C), 128.1 (1C), 126.8 (1C), 126.7 (1C), 126.2 (2C), 120.9
(1C), 113.3 (1C), 73.3 (1C), 72.6 (1C), 16.2 (1C); MS (70 eV)
m/z (%) 228 (M+, 35), 108 (100).
(2C), 70.0 (1C), 55.2 (1C), 16.3 (2C); MS (70 eV) m/z (%) 371
(M+, 2), 250 (100).
(-)-(R)-2-[(2,6-Dim et h ylp h en oxy)-1-p h en ylet h yl]-1H -
isoin d ole-1,3(2H)-d ion e [(-)-(R)-15c]. 81% yield, oil; [R]20
) -43 (c 2, CHCl3).
D
(-)-(S)-2-(2-P h en oxy-1-p h en yleth yl)-1H-isoin d ole-1,3-
(2H)-d ion e [(-)-(S)-15a ]. 45% yield, oil; [R]20 ) -42 (c 2,
D
CHCl3); IR (CHCl3): 1776, 1713 (CdO) cm-1; 1H NMR δ 7.86-
7.80 [m, 2H, Ar(CO)2N HC-4,7], 7.73-7.67 [m, 2H, Ar(CO)2N
HC-5,6], 7.60-7.57 (m, 2H, Ph HC-2,6), 7.41-7.31 (m, 3H, Ph
HC-3,4,5), 7.27-7.21 (m, 2H, ArO HC-3,5), 6.96-6.88 (m, 3H,
ArO HC-2,4,6), 5.79 (dd, J ) 9.9, 5.4 Hz, 1H, CH), 5.19
(apparent t, J ) 9.0 Hz, 1H, CHH), 4.54 (dd, J ) 9.6, 5.4 Hz,
1H, CHH); 13C NMR δ 168.3 (2C), 158.2 (1C), 136.5 (1C), 134.0
(2C), 131.7 (2C), 129.4 (2C), 128.8 (2C), 128.2 (2C), 123.3 (2C),
121.2 (2C), 114.9 (2C), 66.5 (1C), 54.4 (1C); MS (70 eV) m/z
(%) 343 (M+, 3), 236 (100).
(+)-(S)-2-(2-Meth ylp h en oxy)-1-p h en yleth a n ol [(+)-(S)-
14b]. 43% yield, oil; [R]20 ) +22 (c 2, CHCl3).
D
(-)-(R)-2-(4-Ch lor op h en oxy)-1-p h en yleth a n ol [(-)-(R)-
14d ]. 46% yield, oil; [R]20 ) -27 (c 2, CHCl3); IR (CHCl3):
D
3541 (OH), 2855, 1170 (C-O-C) cm-1; H NMR δ 7.38-7.27
1
(m, 5H, Ar), 7.22-7.11 (m, 2H, ArO HC-3,5), 6.82-6.74 (m,
2H, ArO HC-2,6), 5.21 (dd, J ) 8.1, 3.6 Hz, 1H, CH), 3.92 (dd,
J ) 12.5, 8.1 Hz, 1H, CHH), 3.81 (dd, J ) 12.5, 3.6 Hz, 1H,
CHH), 2.21 (br d, 1H, exch D2O, OH); 13C NMR δ 156.4 (1C),
137.3 (1C), 129.3 (2C), 128.9 (2C), 128.4 (1C), 126.3 (2C), 126.2
(1C), 117.3 (2C), 81.6 (1C), 67.5 (1C); MS (70 eV) m/z (%) 248
(M+, 3), 128 (100).
(+)-(R)-2-(2-P h en oxy-1-p h en yleth yl)-1H-isoin d ole-1,3-
(2H)-d ion e [(+)-(R)-15a ]. 31% yield, oil; [R]20 ) +42 (c 2,
D
CHCl3).
(-)-(S)-2-[2-(2-Meth ylph en oxy)-1-ph en yleth yl]-1H-isoin -
d ole-1,3(2H)-d ion e [(-)-(S)-15b]. 75% yield, oil; [R]20D ) -44
1
(c 2, CHCl3); IR (CHCl3): 1778, 1730 (CdO) cm-1; H NMR δ
7.85-7.81 [m, 2H, Ar(CO)2N HC-4,7], 7.74-7.69 [m, 2H, Ar-
(CO)2N HC-5,6], 7.61-7.59 (m, 2H, Ph HC-2,6), 7.41-7.35 (m,
3H, Ph HC-3,4,5), 7.14 (apparent t, J ) 8.1 Hz, 1H, ArO HC-
5), 7.06 (d, J ) 6.0 Hz, 1H, ArO HC-3), 6.87 (d overlapping
apparent t at 6.85, J ) 8.1 Hz, 1H, ArO HC-6), 6.85 (apparent
t overlapping d at 6.87, J ) 7.8 Hz, 1H, ArO HC-4), 5.86 (dd,
J ) 9.0, 6.0 Hz, 1H, CH), 5.11 (t, J ) 9.4 Hz, 1H, CHH), 4.58
(dd, J ) 9.0, 6.0 Hz, 1H, CHH), 1.98 (s, 3H, CH3); 13C NMR δ
168.4 (2C), 156.3 (1C), 136.6 (1C), 134.1 (2C), 131.9 (1C), 130.7
(2C), 128.8 (2C), 128.4 (1C), 128.2 (2C), 126.8 (2C), 123.4 (2C),
120.9 (1C), 111.4 (1C), 66.4 (1C), 54.4 (1C), 15.9 (1C); MS (70
eV) m/z (%) 357 (M+, 6), 250 (100).
(+)-(S)-2-(4-Ch lor op h en oxy)-1-p h en yleth a n ol [(+)-(S)-
14d ]. 37% yield, oil; [R]20 ) +36 (c 2, CHCl3).
D
(-)-(R)-2-(4-Ch lor o-2-m et h ylp h en oxy)-1-p h en ylet h a -
n ol [(-)-(R)-14e]. 42% yield, oil; [R]20 ) -26 (c 2, CHCl3);
D
IR (CHCl3): 3591 (OH), 2861, 1133 (C-O-C) cm-1; H NMR
1
δ 7.48-7.31 (m, 5H, Ar), 7.12 (s, 1H, ArO HC-3), 7.08 (d, J )
8.4 Hz, 1H, ArO HC-5), 6.70 (d, J ) 8.4 Hz, 1H, ArO HC-6),
5.14 (dd, J ) 9.2, 2.8 Hz, 1H, CH), 4.07 (dd, J ) 9.2, 9.1 Hz,
1H, CHH), 4.01 (dd, J ) 9.2, 2.8 Hz, 1H, CHH), 2.74 (br s,
1H, exch D2O, OH), 2.22 (s, 3H, CH3); 13C NMR δ 155.0 (1C),
139.6 (1C), 130.4 (2C), 128.4 (2C), 128.0 (1C), 126.3 (1C), 126.1
(2C), 125.6 (1C), 112.7 (1C), 73.5 (1C), 72.5 (1C), 16.0 (1C);
MS (70 eV) m/z (%) 262 (M+, 25), 142 (100).
(+)-(R)-2-[2-(2-Meth ylph en oxy)-1-ph en yleth yl]-1H-isoin -
d ole-1,3(2H)-d ion e [(+)-(R)-15b]. 76% yield, oil; [R]20D ) +26
(c 2, CHCl3).
(+)-(S)-2-(4-Ch lor o-2-m et h ylp h en oxy)-1-p h en ylet h a -
n ol [(+)-(S)-14e]. 39% yield, oil; [R]20 ) +24 (c 1.6, CHCl3).
D
(-)-(S)-2-[2-(4-Ch lor oph en oxy)-1-ph en yleth yl]-1H-isoin -
d ole-1,3(2H)-d ion e [(-)-(S)-15d ]. 46% yield, oil; [R]20D ) -46
(-)-(R)-2-(4-Ch lor o-2,6-d im et h ylp h en oxy)-1-p h en yl-
eth a n ol [(-)-(R)-14f]. 39% yield, oil; [R]20 ) -13 (c 1.8,
1
(c 2, CHCl3); IR (CHCl3): 1775, 1724 (CdO) cm-1; H NMR δ
D
CHCl3); IR (CHCl3): 3599 (OH), 2866, 1183 (C-O-C) cm-1
;
7.87-7.81 [m, 2H, Ar(CO)2N HC-4,7], 7.74-7.68 [m, 2H,
Ar(CO)2N HC-5,6], 7.48-7.45 (m, 2H, Ph HC-2,6), 7.39-7.27
(m, 3H, Ph HC-3,4,5), 7.09-7.03 (m, 2H, ArO HC-3,5), 6.76-
6.70 (m, 2H, ArO HC-2,6), 5.51 (dd, J ) 9.1, 4.3 Hz, 1H, CH),
4.27 (dd, J ) 14.0, 9.2 Hz, 1H, CHH), 3.91 (dd, J ) 14.0, 4.3
Hz, 1H, CHH); 13C NMR δ 167.5 (2C), 155.8 (1C), 137.4 (1C),
133.6 (2C), 131.4 (1C), 128.7 (2C), 128.4 (2C), 128.1 (2C), 125.8
(2C), 125.6 (1C), 122.9 (2C), 116.8 (2C), 76.1 (1C), 43.7 (1C);
MS (70 eV) m/z (%) 250 (M+ - 127, 100).
1H NMR δ 7.45-7.28 (m, 5H, Ar), 6.98 (s, 2H, ArO), 5.12 (dd,
J ) 6.4, 5.3 Hz, 1H, CH), 3.89 (dd, J ) 9.6, 6.4 Hz, 1H, CHH),
3.81 (dd, J ) 9.6, 5.3 Hz, 1H, CHH), 2.93 (br s, 1H, exch D2O,
OH), 2.17 (s, 6H, CH3); 13C NMR δ 153.7 (1C), 140.2 (1C), 139.6
(1C), 132.4 (1C), 128.7 (1C), 128.5 (2C), 128.3 (2C), 128.1 (1C),
126.1 (2C), 76.5 (1C), 73.3 (1C), 16.2 (2C); MS (70 eV) m/z (%)
276 (M+, 1), 156 (100).
(+)-(S)-2-(4-Ch lor o-2,6-d im et h ylp h en oxy)-1-p h en yl-
eth a n ol [(+)-(S)-14f]. 36% yield, oil; [R]20D ) +16 (c 2, CHCl3).
(+)-(R)-2-[2-(4-Ch lor oph en oxy)-1-ph en yleth yl]-1H-isoin -
d ole-1,3(2H)-d ion e [(+)-(R)-15d ]. 81% yield, oil; [R]20D ) +30
(c 2, CHCl3).
Gen er a l P r oced u r e for th e Syn th esis of 2-(2-Ar yloxy-
1-p h en yleth yl)-1H-isoin d ole-1,3(2H)-d ion es (15a -f).18 The
preparation of (+)-(S)-2-[2-(2,6-dimethylphenoxy)-1-phenyl-
ethyl]-1H-isoindole-1,3(2H)-dione [(+)-(S)-15c] will be de-
scribed. To a mixture of (-)-(R)-14c (0.87 g, 3.6 mmol),
phthalimide (0.79 g, 5.4 mmol) and triphenylphosphine (1.41
g, 5.4 mmol) in 50 mL of anhydrous THF was added dropwise
1.08 g (5.37 mmol) of diisopropylazodicarboxylate (DIAD) in
50 mL of anhydrous THF. The reaction mixture was stirred
at room temperature for 24 h. The solvent was evaporated,
and the crystals of the side products were precipitated by
addition of Et2O. After their removal by filtration, column
chromatography (petroleum ether/ethyl acetate 9:1) of the
(-)-(S)-2-[2-(4-Ch lor o-2-m eth ylph en oxy)-1-ph en yleth yl]-
1H-isoin d ole-1,3(2H)-d ion e [(-)-(S)-15e]. 79% yield, oil;
[R]20D ) -59 (c 2, CHCl3); IR (CHCl3): 1776, 1714 (CdO) cm-1
;
1H NMR δ 7.85-7.81 [m, 2H, Ar(CO)2N HC-4,7], 7.74-7.70
[m, 2H, Ar(CO)2N HC-5,6], 7.59-7.55 (m, 2H, Ph HC-2,6),
7.40-7.30 (m, 3H, Ph HC-3,4,5), 7.08 (dd, J ) 8.5, 2.2 Hz, 1H,
ArO HC-5), 7.02 (d, J ) 1.9 Hz, 1H, ArO HC-3), 6.78 (d, J )
8.6 Hz, 1H, ArO HC-6), 5.81 (dd, J ) 9.9, 5.6 Hz, 1H, CH),
5.07 (apparent t, J ) 9.7 Hz, 1H, CHH), 4.53 (dd, J ) 9.5, 5.6
Hz, 1H, CHH), 1.94 (s, 3H, CH3); 13C NMR δ 168.3 (2C), 155.0
(1C), 136.4 (1C), 134.1 (2C), 131.8 (1C), 130.5 (2C), 128.8 (2C),
128.5 (2C), 128.2 (2C), 126.4 (2C), 123.4 (2C), 112.6 (1C), 66.8
(1C), 54.4 (1C), 15.8 (1C); MS (70 eV) m/z (%) 391 (M+, 4), 250
(100).
crude oil afforded 15c (1.07 g, 80%) as a yellowish oil; [R]20
)
D
1
+35 (c 2.2, CHCl3); IR (CHCl3): 1776, 1721 (CdO) cm-1; H
NMR δ 7.87-7.82 [m, 2H, Ar(CO)2N HC-4,7], 7.73-7.69 [m,
2H, Ar(CO)2N HC-5,6], 7.58-7.55 (m, 2H, Ph HC-2,6), 7.38-
7.30 (m, 3H, Ph HC-3,4,5), 6.98-6.94 (m, 2H, ArO HC-3,5),
6.91-6.86 (m, 1H, ArO HC-4), 5.85 (dd, J ) 10.0, 5.7 Hz, 1H,
CH), 5.06 (apparent t, J ) 9.8 Hz, 1H, CHH), 4.28 (dd, J )
9.5, 5.6 Hz, 1H, CHH), 2.21 (s, 6H, CH3); 13C NMR δ 168.4
(2C), 155.3 (1C), 136.8 (1C), 134.0 (2C), 132.0 (1C), 130.8 (1C),
128.9 (2C), 128.8 (2C), 128.3 (2C), 128.2 (2C), 124.0 (2C), 123.3
(+)-(R)-2-[2-(4-Ch lor o-2-m eth ylph en oxy)-1-ph en yleth yl]-
1H-isoin d ole-1,3(2H)-d ion e [(+)-(R)-15e]. 75% yield, oil;
[R]20 ) +40 (c 2, CHCl3).
D
(+)-(S)-2-[2-(4-Ch lor o-2,6-d im eth ylp h en oxy)-1-p h en yl-
eth yl]-1H-isoin d ole-1,3(2H)-d ion e [(+)-(S)-15f]. 39% yield,
oil; [R]20 ) +12 (c 2, CHCl3); IR (CHCl3): 1775, 1711 (CdO)
D
cm-1; 1H NMR δ 7.88-7.82 [m, 2H, Ar(CO)2N HC-4,7], 7.74-

5246 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 24
Franchini et al.
7.70 [m, 2H, Ar(CO)2N HC-5,6], 7.56-7.53 (m, 2H, Ph HC-
2,6), 7.38-7.30 (m, 3H, Ph HC-3,4,5), 6.94 (s, 2H, ArO HC-
3,5), 5.81 (dd, J ) 9.9, 5.5 Hz, 1H, CH), 5.03 (apparent t, J )
9.8 Hz, 1H, CHH), 4.23 (dd, J ) 9.5, 5.5 Hz, 1H, CHH), 2.17
(s, 6H, CH3); 13C NMR δ 168.4 (2C), 154.0 (1C), 136.8 (1C),
134.1 (2C), 132.6 (2C), 139.9 (2C), 128.8 (2C), 128.5 (4C), 128.2
(2C), 123.4 (2C), 70.2 (1C), 55.1 (1C), 16.2 (2C); MS (70 eV)
m/z (%) 405 (M+, 1), 250 (100).
(m, 2H, Ph HC-2,6), 7.40-7.30 (m, 3H, Ph HC-3,4,5), 7.13 (d
overlapping apparent t at 7.12, J ) 7.2 Hz, 1H, ArO HC-3),
7.12 (apparent t overlapping d at 7.13, J ) 8.0 Hz, 1H, ArO
HC-5), 6.86 (apparent t, J ) 7.0 Hz, 1H, ArO HC-4), 6.78 (d,
J ) 8.1 Hz, 1H, ArO HC-6), 4.55 (dd, J ) 8.4, 3.8 Hz, 1H,
CH), 4.10 (dd, J ) 9.1, 4.0 Hz, 1H, CHH), 3.95 (apparent t, J
) 8.8 Hz, 1H, CHH), 2.17 (s, 3H, CH3), 1.84 (s, 2H exch D2O,
NH2); 13C NMR δ 156.6 (1C), 141.9 (1C), 130.5 (1C), 128.4 (2C),
127.5 (1C), 126.8 (2C), 126.6 (1C), 126.5 (1C), 120.4 (1C), 110.9
(1C), 73.8 (1C), 55.2 (1C), 16.1 (1C); MS (70 eV) m/z (%) 227
(M+, 8), 106 (100).
(-)-(R)-2-[2-(4-Ch lor o-2,6-d im eth ylp h en oxy)-1-p h en yl-
eth yl]-1H-isoin d ole-1,3(2H)-d ion e [(-)-(R)-15f]. 80% yield,
oil; [R]20 ) -16 (c 2, CHCl3).
D
(+)-(S)-2-(2-Meth ylp h en oxy)-1-p h en yleth a n a m in e Hy-
d r och lor id e [(+)-(S)-3b‚HCl]. 51% yield, mp 244-246 °C
(EtOH-Et2O); [R]20D ) +11.6 (c 2, EtOH; ee 99%, tR 39.7 min,
Daicel OD-R, 50:50 CH3CN/0.1 M NaClO4). Anal. (C15H18ClNO)
C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of 2-Ar yloxy-1-
p h en yleth a n a m in es (3a -f) a n d th e Resp ective Hyd r o-
ch lor id es (3a -f‚HCl).36 The preparation of (+)-(S)-2-(2,6-
dimethylphenoxy)-1-phenylethanamine [(+)-(S)-3c] and of the
corresponding hydrochloride [(+)-(S)-3c‚HCl] will be described.
To a stirred solution of (+)-(S)-15c (1 g, 2.69 mmol) in 10 mL
of absolute EtOH was added glacial AcOH (0.46 mL, 8.1 mmol)
and soon after 55% aq N2H4 (0.40 g, 8.1 mmol). The reaction
mixture was refluxed for 2 h. The precipitated solid was
filtered off and the solvent evaporated under reduced pressure.
The residue, dissolved in EtOAc, was extracted with 2 N HCl
and the aqueous layer was treated with 2 N NaOH until basic.
The aqueous layer was extracted with EtOAc (3 × 50 mL),
and the organic layer, dried over anhydrous Na2SO4, was
evaporated under reduced pressure to give 0.58 g (90%) of the
(-)-(R)-2-(2-Meth ylph en oxy)-1-p h en yleth a n a m in e [(-)-
(R)-3b]. 76% yield, oil; [R]20 ) -30 (c 2, CHCl3).
D
(-)-(R)-2-(2-Meth ylp h en oxy)-1-p h en yleth a n a m in e Hy-
d r och lor id e [(-)-(R)-3b‚HCl]. 40% yield, mp 242-243 °C
(EtOH-Et2O); [R]20 ) -13 (c 2, EtOH; ee 99%, tR 35.2 min,
D
Daicel OD-R, 50:50 CH3CN/0.1 M NaClO4). Anal. (C15H18ClNO‚
0.20H2O) C, H, N.
(+)-(S)-2-(4-Ch lor op h en oxy)-1-p h en yleth a n a m in e [(+)-
(S)-3d ]. 95% yield, oil; [R]20 ) +17.8 (c 2, CHCl3); IR
D
(CHCl3): 3382 (NH2), 2870, 1287 (C-O-C) cm-1; H NMR δ
1
expected amine (3c) as a colorless oil: [R]20 ) +11 (c 2,
D
7.46-7.41 (m, 2H, Ph HC-2,6), 7.40-7.23 (m, 3H, Ph HC-3,4,5),
7.22-7.19 (m, 2H, ArO HC-3,5), 6.85-6.80 (m, 2H, ArO HC-
2,6), 4.41 (dd, J ) 8.7, 3.6 Hz, 1H, CH), 4.04 (dd, J ) 8.9, 3.7
Hz, 1H, CHH), 3.89 (apparent t, J ) 8.9 Hz, 1H, CHH), 1.80
(s, 2H, exch D2O, NH2); 13C NMR δ 157.4 (1C), 141.7 (1C), 129.4
(2C), 128.6 (2C), 127.8 (2C), 126.9 (2C), 115.9 (2C), 74.4 (1C),
55.2 (1C); MS (70 eV) m/z (%) 247 (M+, 1), 106 (100).
MeOH); IR (CHCl3): 3380 (NH2), 2863, 1264 (C-O-C) cm-1
;
1H NMR δ 7.46-7.43 (m, 2H, Ph HC-2,6), 7.38-7.27 (m, 3H,
Ph HC-3,4,5), 7.00-6.98 (m, 2H, ArO HC-3,5), 6.93-6.88 (m,
1H, ArO HC-4), 4.45 (dd, J ) 8.8, 3.3 Hz, 1H, CH), 3.85 (dd,
J ) 8.0, 3.3 Hz, 1H, CHH), 3.81 (dd, J ) 8.8, 8.0 Hz, 1H, CHH),
2.17 (s, 6H, CH3), 1.98 (s, 2H, exch D2O, NH2); 13C NMR δ
155.0 (1C), 141.8 (1C), 130.4 (1C), 128.5 (2C), 128.1 (2C), 127.2
(2C), 126.5 (2C), 123.5 (1C), 77.2 (1C), 55.9 (1C), 15.9 (2C);
MS (70 eV) m/z (%) 241 (M+, 2), 106 (100). (+)-(S)-3c‚HCl was
obtained dissolving the free base in anhydrous Et2O and
treating with gaseous HCl for a few seconds. 38% yield, mp
275-277 °C (EtOH-Et2O), lit.37 270.3-270.9 °C (EtOH-Et2O);
(+)-(S)-2-(4-Ch lor op h en oxy)-1-p h en yleth a n a m in e Hy-
d r och lor id e [(+)-(S)-3d ‚HCl]. 80% yield, mp 223-225 °C
(EtOH-Et2O); [R]20 ) +27 (c 2, EtOH; ee 99%, tR 13.8 min,
D
Daicel OD, 95:5 hexane/i-PrOH). Anal. (C14H15Cl2NO) C, H,
N.
(-)-(R)-2-(4-Ch lor op h en oxy)-1-p h en yleth a n a m in e [(-)-
[R]20 ) +3.0 (c 2, MeOH; ee 99%, tR 27.1 min, Daicel OD-R,
(R)-3d ]. 90% yield, oil; [R]20 ) -16.5 (c 2, CHCl3).
D
D
50:50 CH3CN/0.1 M NaClO4), lit.37 +3.5 (c 0.48, MeOH, ee not
(-)-(R)-2-(4-Ch lor op h en oxy)-1-p h en yleth a n a m in e Hy-
given). Anal. (C16H20ClNO‚0.25H2O) C, H, N.
d r och lor id e [(-)-(R)-3d ‚HCl]. 80% yield, mp 234-235 °C
(EtOH-Et2O); [R]20 ) -24 (c 2, MeOH; ee 98%, tR 20.2 min,
(-)-(R )-2-(2,6-D im e t h y lp h e n o x y )-1-p h e n y le t h a n -
D
a m in e [(-)-(R)-3c]. 90% yield, oil; [R]20 ) -14 (c 2, MeOH).
D
Daicel OD, 95:5 hexane/i-PrOH). Anal. (C14H15Cl2NO) C, H,
(-)-(R )-2-(2,6-D im e t h y lp h e n o x y )-1-p h e n y le t h a n -
N.
a m in e Hyd r och lor id e [(-)-(R)-3c‚HCl]. 55% yield, mp 264-
(+)-(S)-2-(4-Ch lor o-2-m eth ylp h en oxy)-1-p h en yleth a n -
266 °C (EtOH-Et2O), lit.37 273.0-273.5 °C (EtOH); [R]20
)
a m in e [(+)-(S)-3e]. 76% yield, oil; [R]20 ) +30 (c 2, CHCl3);
D
D
IR (CHCl3): 3382 (NH2), 2867, 1296 (C-O-C) cm-1; 1H NMR
δ 7.47-7.44 (m, 2H, Ph HC-2,6), 7.40-7.28 (m, 3H, Ph HC-
3,4,5), 7.11 (d, J ) 2.3 Hz, 1H, ArO HC-3), 7.07 (dd, J ) 8.6,
2.6 Hz, 1H, ArO HC-5), 6.68 (d, J ) 8.5 Hz, 1H, ArO HC-6),
4.44 (dd, J ) 8.4, 4.0 Hz, 1H, CH), 4.05 (dd, J ) 9.0, 4.0 Hz,
1H, CHH), 3.92 (apparent t, J ) 8.7 Hz, 1H, CHH), 2.17 (s,
3H, CH3), 1.88 (s, 2H, exch D2O, NH2); 13C NMR δ 155.4 (1C),
141.8 (1C), 130.5 (1C), 128.6 (2C), 127.8 (2C), 126.9 (2C), 126.4
(1C), 125.3 (1C), 112.2 (1C), 74.3 (1C), 55.3 (1C), 16.2 (1C);
MS (70 eV) m/z (%) 261 (M+, 2), 106 (100).
-3.6 (c 2, MeOH; ee 95%, tR 30.4 min, Daicel OD-R, 50:50 CH3-
CN/0.1 M NaClO4), lit.37 -4.2 (c 0.55, MeOH, ee not given).
Anal. (C16H20ClNO) C, H, N.
(+)-(S)-2-P h en oxy-1-ph en yleth an am in e [(+)-(S)-3a]. 65%
yield, oil; [R]20 ) +35 (c 2, CHCl3); IR (CHCl3): 3381 (NH2),
D
2869, 1290 (C-O-C) cm-1; H NMR δ 7.48-7.25 (m, 7H, Ph
1
+ ArO HC-3,5), 6.98-6.89 (m, 3H, ArO HC-2,4,6), 4.43 (dd, J
) 8.8, 3.7 Hz, 1H, CH), 4.10 (dd, J ) 9.2, 3.7 Hz, 1H, CHH),
3.94 (apparent t, J ) 9.1 Hz, 1H, CHH), 1.88 (s, 2H, exch D2O,
NH2); 13C NMR δ 158.6 (1C), 141.9 (1C), 129.5 (2C), 128.6 (2C),
127.7 (1C), 126.9 (2C), 121.0 (1C), 114.7 (2C), 74.0 (1C), 55.3
(1C); MS (70 eV) m/z (%) 213 (M+, 1), 106 (100).
(+)-(S)-2-(4-Ch lor o-2-m eth ylp h en oxy)-1-p h en yleth a n -
a m in e Hyd r och lor id e [(+)-(S)-3e‚HCl]. 52% yield, mp 240-
242 °C (EtOH-Et2O); [R]20 ) +21 (c 1.9, MeOH; ee 97%, tR
(+)-(S)-2-P h en oxy-1-p h en ylet h a n a m in e H yd r och lo-
D
r id e [(+)-(S)-3a ‚HCl]. 51% yield, mp 206-208 °C (EtOH-
12.9 min, Daicel OD, 95:5 hexane/i-PrOH). Anal. (C15H17Cl2-
NO) C, H, N.
Et2O); [R]20 ) +30 (c 2, MeOH; ee 99%, tR 29.2 min, Daicel
D
OD-R, 50:50 CH3CN/0.1 M NaClO4). Anal. (C14H16ClNO) C,
H, N.
(-)-(R)-2-(4-Ch lor o-2-m eth ylp h en oxy)-1-p h en yleth a n -
a m in e [(-)-(R)-3e]. 66% yield, oil; [R]20 ) -31 (c 2, CHCl3).
D
(-)-(R)-2-P h en oxy-1-ph en yleth an am in e [(-)-(R)-3a]. 90%
(-)-(R)-2-(4-Ch lor o-2-m eth ylp h en oxy)-1-p h en yleth a n -
a m in e Hyd r och lor id e [(-)-(R)-3e‚HCl]. 48% yield, mp 240-
242 °C (EtOH-Et2O); [R]20D ) -21 (c 2, MeOH; ee 97%, tR 15.8
min, Daicel OD, 95:5 hexane/i-PrOH). Anal. (C15H17Cl2NO‚0.25
H2O) C, H, N.
yield, oil; [R]20 ) -35 (c 2, CHCl3).
D
(-)-(R)-2-P h en oxy-1-p h en ylet h a n a m in e H yd r och lo-
r id e [(-)-(R)-3a ‚HCl]. 56% yield, mp 206-208 °C (EtOH-
Et2O); [R]20 ) -27 (c 2, MeOH; ee 98%, tR 24.5 min, Daicel
D
OD-R, 50:50 CH3CN/0.1 M NaClO4). Anal. (C14H16ClNO‚0.20
H2O) C, H, N.
(+)-(S)-2-(4-Ch lor o-2,6-d im et h ylp h en oxy)-1-p h en yl-
eth a n a m in e [(+)-(S)-3f]. 63% yield, oil; [R]20D ) +8.7 (c 0.95,
(+)-(S)-2-(2-Meth ylp h en oxy)-1-p h en yleth a n a m in e [(+)-
CHCl3); IR (CHCl3): 3379 (NH2), 2858, 1290 (C-O-C) cm-1
;
(S)-3b]. 76% yield, oil; [R]20 ) +32 (c 2, CHCl3); IR (CHCl3):
1H NMR δ 7.44-7.41 (m, 2H, Ph HC-2,6), 7.38-7.28 (m, 3H,
Ph HC-3,4,5), 6.96 (s, 2H, ArO HC-3,5), 4.41 (dd, J ) 7.8, 4.0
D
3381 (NH2), 2869, 1290 (C-O-C) cm-1; 1H NMR δ 7.49-7.46

Blockers of Voltage-Gated Na+ Channels
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 24 5247
(14) Byrnes, E. W.; Mc. Master, P. D.; Smith, E. R.; Blair, M. R.;
Bayes, R. N.; Duce, B. R.; Feldman, H. S.; Ksomberg, G. H.;
Takman, B. H.; Tenthorey, P. A. New antiarrhythmic agents. 1
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(15) Calculated using Advanced Chemistry Development (ACD)
Software Solaris V 4.67, ACD.
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Hz, 1H, CH), 3.81 (dd, J ) 9.8, 4.0 Hz, 1H, CHH), 3.77 (dd, J
) 9.8, 7.8 Hz, 1H, CHH), 2.17 (s, 6H, CH3), 1.96 (s, 2H, exch
D2O, NH2); 13C NMR δ 154.0 (1C), 141.5 (1C), 132.2 (2C), 128.1
(3C), 127.3 (2C), 126.4 (2C), 104.4 (1C), 76.2 (1C), 55.8 (1C),
15.8 (2C); MS (70 eV) m/z (%) 275 (M+, <1), 106 (100).
(-)-(S)-2-(4-Ch lor o-2,6-d im et h ylp h en oxy)-1-p h en yl-
eth a n a m in e Hyd r och lor id e [(-)-(S)-3f‚HCl]. 23% yield, mp
248-250 °C (EtOH-Et2O); [R]20 ) -4.0 (c 1, EtOH; ee 80%,
D
tR 8.9 min, Daicel OD, 95:5 hexane/i-PrOH). Anal. (C16H19Cl2-
NO‚0.25 H2O) C, H, N.
(-)-(R)-2-(4-Ch lor o-2,6-d im et h ylp h en oxy)-1-p h en yl-
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eth a n a m in e [(-)-(R)-3f]. 98% yield, oil; [R]20 ) -9.0 (c 1.7,
D
CHCl3).
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(+)-(R)-2-(4-Ch lor o-2,6-d im et h ylp h en oxy)-1-p h en yl-
eth a n a m in e Hyd r och lor id e [(+)-(R)-3f‚HCl]. 40% yield,
mp 248-250 °C (EtOH-Et2O); [R]20 ) +4.3 (c 1, EtOH; ee
D
98%, tR 11.8 min, Daicel OD, 95:5 hexane/i-PrOH). Anal.
(C16H19Cl2NO) C, H, N.
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