Synthesis and pharmacology of 6-substituted benztropines: Discovery of novel dopamine uptake inhibitors possessing low binding affinity to the dopamine transporter

Article abstract of DOI:10.1021/jm0490235

A series of 6α- and 6β-substituted benztropines were synthesized. A marked enantioselectivity was observed for the 6β-methoxylated benztropines, the (1R)-isomers being more potent than the corresponding (1S) compounds. The racemic 6α-methoxy-3-(4′,4″- dif

Full text of DOI:10.1021/jm0490235

J. Med. Chem. 2005, 48, 3337-3343
3337
Synthesis and Pharmacology of 6-Substituted Benztropines: Discovery of Novel
Dopamine Uptake Inhibitors Possessing Low Binding Affinity to the Dopamine
Transporter
Daniele Simoni,*,† Marcello Rossi,† Valerio Bertolasi,§ Marinella Roberti, Daniela Pizzirani,
Riccardo Rondanin,† Riccardo Baruchello,† Francesco Paolo Invidiata,‡ Manlio Tolomeo,X Stefania Grimaudo,X
Stefania Merighi,| Katia Varani,| Stefania Gessi,| Pier Andrea Borea,| Silvia Marino,| Sabrina Cavallini,|
Clementina Bianchi,| and Anna Siniscalchi|
Dipartimento di Scienze Farmaceutiche, Universita` di Ferrara, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy,
Dipartimento di Chimica, Universita` di Ferrara, Dipartimento di Scienze Farmaceutiche, Universita` di Bologna,
Dipartimento Farmacochimico Tossicologico e Biologico, Universita` di Palermo, Divisione di Ematologia e Servizio A.I.D.S.,
Policlinico, Universita` di Palermo, Italy, and Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia,
Universita` di Ferrara, Italy
Received December 1, 2004
A series of 6R- and 6â-substituted benztropines were synthesized. A marked enantioselectivity
was observed for the 6â-methoxylated benztropines, the (1R)-isomers being more potent than
the corresponding (1S) compounds. The racemic 6R-methoxy-3-(4′,4′′-difluorodiphenylmethoxy)-
tropane (5g) was the most potent compound. It has been found that modifications at the
6-position of benztropine might reduce the DAT binding affinity, maintaining otherwise a
significant dopamine uptake inhibitory activity. A reinvestigation of the absolute configuration
of 6â-methoxytropinone proved the 6R configuration for the (+)-enantiomer.
Introduction
tigated in order to discover appropriate molecular
modifications that may lead to the discovery of cocaine
antagonists or partial agonists.7-13
Cocaine (1) is a potent stimulant of the central
nervous system, and its widespread abuse has an
extremely negative impact in our society. The develop-
ment of therapeutic agents that will assist addicted
individuals during detoxification programs is therefore
particularly desirable.
Among the structural classes of compounds interact-
ing with DAT, which have provided interesting results
as potential medications to treat cocaine abuse, the
benztropine group has also received particular atten-
tion.5,6 The introduction of a 2-carbomethoxy group into
benztropine (2) by Meltzer14 et al. resulted in a new
class of compounds with the (1S) derivative exhibiting
significant DAT affinity and the most potent represen-
tative being difluoropine (4). Hydroxylation at the 6-7
positions of difluoropine, produced, on the contrary, a
significant decrease in binding affinity.7 Meltzer et al.
have hypothesized that this class of dopamine uptake
inhibitors are more like the GBR series in their mode
of binding to the DAT.15 Benztropine is an anticholin-
ergic DAT inhibitor, equipotent to cocaine, which is
clinically used for the treatment of movement disorders
that accompany Parkinson’s disease. Structurally, benz-
tropine possesses a tropane ring, as found in cocaine,
and a diphenylmethane ether group, as found in the
GBR series.16 Drug design strategies have focused
mainly on the substitution pattern in the aromatic
moiety and the replacement of the N-methyl group by
other substituents.5,17-20 Unlike cocaine, the benztropine
analogues, despite their high affinity for the DAT,
generally have not demonstrated a cocaine-like behav-
ioral profile in animal models. After considerable re-
search in this area, Newman and co-workers have
hypothesized that this class of dopamine uptake inhibi-
tors may access a DAT binding site distinct from that
of cocaine, so explaining their discrepant behavioral
profile.5,17 In preclinical studies aimed at gauging its
possible use in the treatment of cocaine abuse, 4′,4′′-
Cocaine is a nonselective drug that interacts with a
variety of pharmacologically distinct sites. It binds with
high affinity to the transporter sites for the neurotrans-
mitters dopamine (DA), serotonin (5-hydroxytryptamine,
5-HT), and noradrenaline (NA), thereby inhibiting the
reuptake of these amines into the presynaptic neurons.1-4
Since the dopamine transporter (DAT) is considered to
be the main target of the biochemical action of cocaine
as well as of its behavioral effects, many intervention
strategies have focused on the dopaminergic pathway.1-6
The search for potential anti-cocaine medications has
led to an extensive study of the structure-activity
relationships (SAR) of 1 at the dopamine transporter,
and 2-substituted 3-aryltropanes have been extensively
studied as cocaine congeners and developed as tools to
explore the DAT.1,2,6 This broad class of compounds has
provided interesting insight into the nature of the
dopamine transporter pharmacophore.1,2,6 Additionally,
6- and 7-substituted tropanes have been widely inves-
* To whom correspondence should be addressed. Tel.: +39-0532-
291291. Fax: +39-0532-219296. E-mail: smd@dns.unife.it.
† Dipartimento di Scienze Farmaceutiche, Universita` di Ferrara.
§ Dipartimento di Chimica, Universita` di Ferrara.
Dipartimento di Scienze Farmaceutiche, Universita` di Bologna.
‡ Dipartimento Farmacochimico Tossicologico e Biologico, Universita`
di Palermo.
X Divisione di Ematologia e Servizio A.I.D.S., Policlinico, Universita`
di Palermo.
| Dipartimento di Medicina Clinica e Sperimentale, Sezione di
Farmacologia, Universita` di Ferrara.
10.1021/jm0490235 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/05/2005

3338 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
Simoni et al.
Scheme 1. Chemical Resolution of the
(()-6â-Methoxytropinone (7) and Synthesis of Chiral
6â-Methoxylated Benztropinesa
Figure 1. Structures of cocaine, benztropine, and analogues.
a Reagents and conditions: (a) 90% EtOH, 50 °C; (b) PtO2, H2,
absol EtOH, 70 psi, 14 h; (c) x,y-benzhydrol, p-TsOH monohydrate,
benzene, reflux, 24 h.
between dopamine uptake inhibitors, a common binding
domain may not be accessed by all of these compounds.
Chemistry. Regarding the synthesis of stereoisomers
(+)-6a-c and (-)-6a-c, we considered, as previously
communicated,22 that the chiral methoxytropinones
(+)-7 and (-)-7, possessing the known configuration at
the carbon atom bearing the methoxy functionality,
would constitute appropriate starting materials for their
preparation (Scheme 1). Previous investigations had
indicated the 6S configuration of the (+)-6â-methoxy-
tropinone.23 Consequently, we referred to literature
indications to assign, incorrectly, stereochemistry in our
communications.12,22 In contrast, we have now proved
unequivocally that (+)-6a-c and their synthetic precur-
sor (+)-6â-methoxytropinone (+)-7 are actually 6R as
detailed below. Briefly, the (-)-6â-methoxytropinone
(-)-(7) was obtained from the racemic (()-7 when
D(-)-tartaric acid was used for the resolution and (+)-
6â-methoxytropinone (+)-(7) was obtained utilizing the
L(+)-tartaric acid. Sodium borohydride reduction of
(+)-7 gave a mixture of the two alcohols (-)-8 and (-)-9
that were each esterified with (1′S)-(-)-camphanic
chloride to obtain the pure diastereoisomers (-)-10 and
(+)-11 respectively (Figure 3). The absolute configura-
tion of (-)-10 (suitable crystals of (+)-11 could not be
obtained by these means), determined by X-ray crystal-
lographic analyses, confirmed the R configuration at C6
(Figure 4). Consequently, the 6R configuration was also
attributed to the precursor (+)-7, and the 6S configu-
ration was assigned to the enantiomer (-)-7.
Figure 2. General structure of benztropines synthesized for
SAR studies.
difluorobenztropine (3) has shown some promise in the
attenuation of cocaine effects in animal studies.21
We have recently undertaken a structural investiga-
tion at the two-carbon bridge region of benztropine, and
we communicated that 6â-methoxy-4′,4′′-difluoro- and
-4′-chlorobenztropine possess high binding affinity (IC50
) 25-32 nM) to DAT, as compared to benztropine (IC50
) 118 nM) and cocaine (IC50 ) 150 nM), when evaluated
under identical assay conditions.22 Herein, we report the
synthesis and pharmacological characterization of a
novel series of 6-substituted benztropines 5a-i (Figure
2, Schemes 2, 3) and the 6-benzhydrylated tropanes 24
and 25 (Scheme 4). We also report the full details of
the synthesis and biological activity of our previously
communicated 6-methoxybenztropines (+)-6a-c and
(-)-6a-c (Figure 2).22 A reinvestigation of the absolute
configuration of the (+)- and (-)-6â-methoxytropinone
will be also discussed.
The 6â-hydroxy-4′,4′′-difluorobenztropine (()-5c dem-
onstrated a profile of activity similar to the parent 4′,4′′-
difluorobenztropine (3).19 Some of the novel synthesized
benztropines showed together a reduction of DAT bind-
ing affinity a concomitant improvement of the dopamine
uptake inhibitory activity. The present paper provides
further support that, despite structural commonalties
In the following step (Scheme 1), the stereoselective
reduction (H2 and PtO2 as catalyst) of the ketones (+)-7
and (-)-7 produced the corresponding alcohols deriva-
tives (-)-8 and (+)-8 in optically pure form. These were
reacted with the appropriate benzhydrols in the pres-
ence of p-toluenesulfonic acid and refluxed with a

6-Substituted Benztropines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9 3339
Kishner conditions, was effected in two steps by Mit-
sunobu chemistry. Thus, the 6â-hydroxy derivative 21
was reacted with p-nitrobenzoic acid and triphenylphos-
phine in the presence of diethyl azodicarboxylate to give
the ester intermediate 22, which was in turn hydrolyzed
with LiOH/THF/H2O to provide the 6R-hydroxy ana-
logue 23. Finally, the benzhydryl derivatives (()-24 and
(()-25 were obtained as described above for 5g,h.
Biological Results and Discussion
Binding affinities of all novel synthesized compounds
were evaluated in radiolabeled ligand displacement
assays for DAT in the brain. Compounds were examined
for their ability to displace [3H]WIN 35,428 and [3H]-
paroxetine from the dopamine and serotonin transport-
ers in rat caudate putamen. Additionally, all compounds
were tested for their ability to inhibit high-affinity
uptake of [3H]dopamine into striatal nerve endings
(synaptosomes). Biological data are reported in Table
1. There was a good correlation between uptake inhibi-
tion and binding values (r ) 0.949, P < 0.001), as shown
in Figure 5.
Figure 3. Camphanic derivatives and synthetic precursor.
The enantiomers (1S,6R)-(+)-6a-c and (1R,6S)-(-)-
6a-c were prepared to investigate whether stereochem-
istry could play a role in binding and uptake activity of
chiral benztropines. In general, the 6â-methoxylated
chiral benztropines retain activity relative to their
parent structures, benztropine and cocaine, in both
binding and functional assays (Table 1). The enantio-
mers (-)-6a-c, bearing the (1R)-configuration, were
more potent than the corresponding (1S) stereoisomers
(+)-6a-c. All the newly synthesized methoxylated benz-
tropines lacked SERT activity. In particular, a marked
enantioselectivity is seen for (-)-6b being 23 times more
potent than (+)-6b. Thus, while a 2-carbalkoxy-benz-
tropine series showed a strong biological preference for
the (1S)-configuration,14,19,20 the above-described chiral
6-methoxylated benztropines show preference for the
(1R)-configuration.
Interestingly, the (()-6R-methoxy-4′,4′′-difluorobenz-
tropine 5g is the most potent analogue in the reported
series of methoxylated benztropines. Unlike the 6â-
methoxylated derivatives, 5g demonstrates, moreover,
a notable binding affinity for SERT. On the contrary,
an increased bridge-steric bulk, as in the MOM-
protected compounds 5a-c and 5h, resulted in a
reduced binding affinity as compared with the methoxy
derivatives.
Remarkable results were obtained when a hydroxyl
group was introduced into the benztropine two-carbon
bridge. Introduction of functionalities at the cocaine 6,7-
bridge has attracted the attention of a number of
research groups.7-13 In general, steric bulk at both
positions has reduced the affinity of these compounds
for the dopamine transporter, but the 6- or 7-hydroxyl
group in 2-carbomethoxy-3-aryltropanes is tolerated
when an appropriate substituent is present at the
3-position, with comparable potency and better selectiv-
ity for DAT.6,7,9 As reported in Table 1, the hydroxylated
benztropines 5d,e demonstrated binding affinities in the
micromolar range. It is remarkable that the hydroxy-
lated 4′,4′′-difluorobenztropine 5f and 5i24 showed bind-
ing and dopamine uptake activity similar to the parent
3.5 Of interest, while the binding affinity of 5d,e is
Figure 4. ORTEP view of compound (-)-10 displaying the
thermal ellipsoids at 30% probability.
Dean-Stark apparatus to afford, in appreciable yields,
the desired chiral benztropines (+)-6a-c and (-)-6a-
c.
Preparation of the hydroxylated racemic benztropines
5a-c is outlined in Scheme 2. The racemic hydroxytro-
pinone 12 was methoxymethylated with dimethoxy-
methane in the presence of 4 Å molecular sieves and
with p-toluenesulfonic acid as catalyst to give 13 in 62%
yield. The stereoselective reduction of 13 by means of
hydrogen and PtO2 as catalyst at 50 psi produced in 88%
yield the tropine derivative 14 which was reacted with
the appropriate benzhydryl chlorides in the presence of
tributylamine and refluxed for 8 h in dry dimethylfor-
mamide to afford the MOM-protected benztropines 5a-
c. Conversion of the latter into racemic 5d-f was
achieved by treatment with a 10% HCl-MeOH solution
at 65 °C.
The synthesis of the 6R-substituted tropinones (()-
5g-i is outlined in Scheme 3. The ketone derivative 15
was reduced with DIBAL-H in dichloromethane solution
to give the 6R-hydroxy derivative 16 and then hydro-
lyzed with 10% HCl to produce the 6R-hydroxytropinone
17. As described above for the MOM-derivative 13, the
hydroxytropinone 17 was easily methoxymethylated to
give the MOM-protected derivative 18. The stereose-
lective reduction of the racemic tropinones 18 and 19
(Scheme 3) by means of hydrogen and PtO2 produced,
in approximately 90% yield, the tropines 20a,b. Reduc-
tion of 18 and 19 was also achieved by means of NaBH4,
which produced 20a,b as the only isomers. Tropines
20a,b were reacted as described above for (-)-8 and 14,
to give in appreciable yields the desired (()- 5g,h.
Exposure of 5h to a solution of 10% HCl-MeOH at 65
°C gave (()-5i in 40% yield.
The 6R- and 6â-(4′,4′′-difluorodiphenylmethoxy)tro-
panes (()-24 and (()-25 were prepared as outlined in
Scheme 4. Inversion of the bridge hydroxyl group of 21,
in turn obtained by reduction of (()-12 under Wolff-

3340 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
Scheme 2. Synthesis of 6â-Hydroxylated Benztropinesa
Simoni et al.
a Reagents and conditions: (a) Dimethoxymethane, CH2Cl2, 4 Å molecular sieves, p-TsOH, 40 °C; (b) PtO2, H2, EtOH, 40 psi, 12 h; (c)
x,y-benzhydryl chloride, Bu3N, DMF, 160 °C; (d) HCl 37%, MeOH, 65 °C, 3 h.
Scheme 3. Synthesis of 6R-Hydroxylated Benztropinesa
a Reagents and conditions: (a) DIBAL-H, CH2Cl2, -78 °C to 0 °C, 1 h; (b) aq HCl, MeOH, 65 °C, 10 h; (c) dimethoxymethane, CH2Cl2,
4 Å molecular sieves, p-TsOH, 40 °C; (d) PtO2, H2, EtOH, 40 psi, 12 h; (e) 4,4′-difluorobenzhydrol, p-TsOH monohydrate, benzene, reflux,
24 h; (f) 4,4′-difluorobenzhydryl chloride, Bu3N, DMF, 160 °C; (g) 37% HCl, MeOH, 65 °C, 3 h.
Scheme 4. Synthesis of benztropines 24 and 25a
Table 1. Binding Affinities and Uptake Inhibition Data for
Chiral and Racemic Benztropines
DA[3H]WIN 35,428 [3H]DA uptake 5HT[3H]paroxetine
compd
cocaine
binding IC50 (nM)a
IC50 (nM)a
binding IC50(nM)a
150 ( 20
353.1 ( 36.4
(citalopram)
0.5 ( 0.1 nM
benztropine
(()-5a
118 ( 9
403 ( 115
1083.7 ( 244.3
193.7 ( 38.2
79.7 ( 10.8
149.4 ( 7.7
39.1 ( 4.6
8.1 ( 1.9
4500 ( 600
400 ( 64
340 ( 70
1300 ( 300
600 ( 85
12 ( 3
>104
(()-5b
>104
(()-5c
>104
(()-5d
>104
(()-5e
>104
(()-5f
11000 ( 1300
280 ( 25
3500 ( 400
>104
(()-5g
10 ( 2
12.4 ( 1
(()-5h
2500 ( 300
140 ( 25
975 ( 85
276 ( 40
750 ( 70
32 ( 2
490.9 ( 80.5
162.3 ( 22.8
239.7 ( 23.1
138.8 ( 25.7
519 ( 29
(()-5i
(1S)-(+)-6a
(1R)-(-)-6a
(1S)-(+)-6bb
(1R)-(-)-6bb
(1S)-(+)-6cb
(1R)-(-)-6cb
(()-24
>104
>104
>104
a Reagents and conditions: (a) NH2NH2‚H2O, EtOH, KOH, 130
°C/190 °C; (b) DEAD, 4-nitrobenzoic acid, P(Ph)3, toluene, 70 °C.
(c) LiOH‚H2O, H2O, THF, rt, 3 h; (d) 4,4′-difluorobenzhydryl
chloride, Bu3N, DMF, 160 °C, 8 h.
179 ( 9
>104
95 ( 5
25 ( 3
165 ( 10
>104
104 ( 11
>104
900 ( 100
1125 ( 130
347 ( 48.5
199 ( 28.8
>104
(()-25
2000 ( 200
considerably diminished in comparison with benz-
tropine, their potency in inhibiting [3H]dopamine uptake
(DAUI) is higher than cocaine; in fact, their dopamine
uptake activity is 7-15 times higher than the binding
activity. Contrary to our expectations, the binding
activities of 24 and 25 were not particularly interesting;
however, their uptake activity was also quite surprising,
being higher than their binding values. To the best of
our knowledge these differences in binding vs DAUI,
as found for 5d,e 24, and 25, have not been previously
encountered in benztropine analogues lacking a 2-posi-
a Values are expressed as mean ( SE (n ) 3-9). b Data as
reported in ref 22.
tion substituent. During the course of this work, it was
reported that 2â-carboalkoxy-substituted-(bis[4-fluo-
rophenyl]methoxy)tropanes, unlike the parent 3, were
more potent in inhibiting dopamine uptake than in
binding to the dopamine transporter.19 However, these
results are quite different from our findings since the
2-carbalkoxy-substituted benztropines possess, unlike
the hydroxylated benztropines 5d,e and derivatives 24,

6-Substituted Benztropines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9 3341
[R]20 ) -22.79 (c ) 0.5, H2O) [lit.23 [R]20 ) +23.9 (c ) 2,
D
D
H2O)]. The mother liquors from above were evaporated to
dryness, dissolved in water, treated with K2CO3 until pH 8,
and extracted with diethyl ether (20 mL × 6). The dried
extracts (Na2SO4) were evaporated to give a colorless oil (1.44
g, 8.51 mmol). Treatment of the oil with (+)-L-tartaric acid
(1.13 g, 8.51 mmol) gave a salt which was recrystallized and
converted to the free base as described for the R isomer. The
salt (1.81 g, 5.7 mmol) had mp 126-127 °C and [R]20D ) +22.06
(c ) 0.5, H2O). The (1S)-6â-methoxytropinone (+)-7 obtained
had [R]20 ) + 23.8 (c ) 0.5, H2O).
D
General Procedures for the Synthesis of Target Com-
pounds. (1R)-3R-[Bis(4-fluorophenyl)methoxy]-6â-meth-
oxy-8-methyl-8-aza-bicyclo[3.2.1]octane (-)-(6c). The 6â-
methoxytropine (+)-(8) (130 mg, 0.759 mmol), 4,4′-difluoro-
benzhydrol (335 mg, 1.52 mmol), and p-toluenesulfonic acid
monohydrate (216 mg, 1.13 mmol) were solubilized in benzene
(30 mL) and placed in a flask fitted with a Dean-Stark
apparatus. The reaction mixture was heated to reflux for 18
h. Additional 4,4′-difluorobenzhydrol (167 mg, 0.759 mmol) and
p-toluenesulfonic acid monohydrate (36 mg, 0.19 mmol) were
added, and the reaction mixture was refluxed for other 6 h.
Solvent was removed in vacuo and the residue dissolved in
H2O (20 mL), neutralized with NH4OH to pH 9, and extracted
with CH2Cl2 (15 mL × 3). The combined extracts were dried
(Na2SO4) and concentrated to dryness. The residue was
purified by flash chromatography (CHCl3:MeOH 95:5) to give
100 mg (35%) of title compound as a pale yellow oil. HCl salt
mp 65 °C; [R]20D ) -5.7 (c ) 0.29, H2O). Anal. (C22H25F2NO2):
C, H, N.
Figure 5. Correlation of IC50 values for [3H]dopamine uptake
vs [3H]WIN35428 binding Ki values (n ) 3-9 determinations
per value). Correlation and probability were determined by
using Pearson’s correlation analysis: r ) 0.949 (95% confi-
dence interval 0.824-0.986, P < 0.001).
25, high binding affinity. Interpretation of these findings
is not easy: as hypothesized for the 2-carboalkoxy-
substituted benztropines,19 the disparity in potency in
the functional assay compared to binding constants may
be related to assay conditions (e.g. 33 °C for uptake
experiments vs 0 °C for binding experiments, or differ-
ent ion concentrations in the buffers) and may be not
reflected in vivo.
Thus, the increased potency of the DA uptake inhibi-
tion of compounds 5d,e, 24, and 25 suggests that
substitution at the bridgehead region of benztropine
may provide an interesting opportunity for the con-
struction of new classes of DA-uptake inhibitors with a
novel profile of activity.
In summary, bridge-methoxylation of benztropine
produced compounds possessing high DAT activity, and
the 1R isomers are more potent than the corresponding
1S isomers. Among the results obtained, perhaps the
most interesting observation relates to the disparity in
DA-uptake potency and binding constants as found for
compounds 5d,e, 24, and 25. We observed that, in some
cases, manipulation at the two-carbon bridge region of
benztropine significantly altered the biological activity
of the compounds, and potent DA-uptake inhibitors,
possessing a low binding affinity to the DAT, have been
discovered. However, some other compounds retained
high activity for both DAT binding and inhibition. Our
work is currently continuing in the exploration of other
6,7-bridge-substituted benztropines.
(1R)-3R-Diphenylmethoxy-6â-methoxy-8-methyl-8-aza-
bicyclo[3.2.1]octane (-)-(6a). As described for (-)-(6c) start-
ing from (+)-8 and benzhydrol. Colorless oil (42% yield); HCl
salt mp 191 °C; [R]20 ) -7.9 (c ) 0.49, H2O). Anal. (C22H27-
D
NO2): C, H, N.
(1R)-3R-[(4-Chlorophenyl)phenyl-methoxy]-6â-methoxy-
8-methyl-8-aza-bicyclo[3.2.1]octane (-)-(6b). As described
for (-)-(6c) starting from (+)-8 and 4-chlorobenzhydrol. Color-
less oil (46% yield); [R]20 ) -0.5 (c ) 0.9, MeOH). Anal.
D
(C22H27ClNO2): C, H, N.
(1S)-3R-[Bis(4-fluorophenyl)methoxy]-6â-methoxy-8-
methyl-8-aza-bicyclo[3.2.1]octane (+)-(6c). As described for
(-)-(6c) starting from (-)-8 and 4,4′-difluorobenzhydrol. Yield
46%. HCl salt mp 65 °C; [R]20 ) +6.5 (c ) 0.35, H2O). Anal.
D
(C22H25F2NO2): C, H, N.
(1S)-3R-Diphenylmethoxy-6â-methoxy-8-methyl-8-aza-
bicyclo[3.2.1]octane (+)-(6a). As described for (-)-(6c) start-
ing from (-)-8 and benzhydrol. Yield 42%. HCl salt mp 190
°C; [R]20 ) + 9.1 (c ) 0.45, H2O). Anal. (C22H27NO2): C, H,
D
N.
(1S)-3R-[(4-Chlorophenyl)phenylmethoxy]-6â-methoxy-
8-methyl-8-aza-bicyclo[3.2.1]octane (+)-(6b). As described
for (-)-(6c) starting from (-)-8 and 4-chloro-benzhydrol. Yield
66%; [R]20D ) +0.8 (c ) 1.0, MeOH). Anal. (C22H27ClNO2): C,
H, N.
Experimental Section
Different results from literature data23 have been obtained
with the following:
(()-3R-Diphenylmethoxy-6â-methoxymethoxy-8-meth-
yl-8-aza-bicyclo[3.2.1]octane (5a). A solution of the alcohol
14 (250 mg, 1.08 mmol), dry tributylamine (0.23 mL, 1.2
equiv), and benzhydryl chloride (0.35 mL, 2 equiv) in dry
dimethylformamide (7 mL) was refluxed for 8 h under N2
atmosphere. The dark solution was concentrated in vacuo to
about one-half of its original volume, diluted with H2O (20 mL),
and extracted with diethyl ether (50 mL × 3); the combined
organic layers were washed with saturated aqueous Na2CO3
(30 mL) and brine and dried over anydrous Na2SO4. The crude
product obtained after solvent distillation was purified by flash
chromatography to afford 5a as a colorless oil (210 mg, 42%):
Rf 0.3 (AcOEt:MeOH:NH4OH 5:1:0.1). MALDI-TOF MS: [MH]+
368. Anal. (C23H29NO3): C, H, N.
Resolution of (()-6â- Methoxy-8-methyl-8-aza-bicyclo-
[3.2.1]octan-3-one (7). The tropinone 7 (4.0 g, 24 mmol)
dissolved in 90% EtOH (5 mL) was added dropwise to a hot
solution of (-)-D-tartaric acid (3.55 g, 24 mmol) solubilized in
90% EtOH (25 mL). The crude hydrogen tartrate salt (3.5 g)
was filtered and recrystallized once from 90% EtOH and once
from 96% EtOH, to give (1R)-6â-methoxytropinone hydrogen
D-tartrate as a white crystalline solid (2.43 g, 7.6 mmol) with
mp 124 °C (lit. mp 128.5-131.5 °C)23 and [R]20 ) -23.6 (c )
D
0.5, H2O) [lit.23 [R]20 ) +23.9 (c ) 2, H2O)]. The salt was
D
dissolved in water (5 mL) basified with NaOH (1.22 g)
solubilized in water (5 mL) and then saturated with K2CO3 (3
g). The free base was extracted with ether (20 mL × 6). The
dried extracts (Na2SO4) were concentrated to give (1R)-6â-
methoxytropinone (-)-7 as a colorless oil (1.13 g, 6.7 mmol)
that solidified on standing: mp 42 °C (lit. mp 43-45 °C);23
(()-3R-[(4-Chlorophenyl)phenylmethoxy]-6â-meth-
oxymethoxy-8-methyl-8-aza-bicyclo[3.2.1]octane (5b). As
described for 5a by means of 4-chlorobenzhydryl chloride.
White solid (44% yield): mp 151-153 °C; Rf 0.5 (AcOEt:MeOH:

3342 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
Simoni et al.
NH4OH 5:1:0.1). MALDI-TOF MS: [MH]+ 402.9. Anal. (C23H28-
ClNO3): C, H, N.
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(()-3R-[Bis(4-fluorophenyl)methoxy]-6â-meth-
oxymethoxy-8-methyl-8-aza-bicyclo[3.2.1]octane (5c). As
described for 5a by means of 4,4′-difluorobenzhydryl chloride.
White solid (49% yield): mp 194-196 °C; Rf 0.45 (AcOEt:
MeOH:NH4OH 5:1:0.1). MALDI-TOF MS: [MH]+ 404. Anal.
(C23H27F2NO3): C, H, N.
(()-3R-Diphenylmethoxy-8-methyl-8-aza-bicyclo[3.2.1]-
octan-6â-ol (5d). Forty milligrams (0.108 mmol) of 5a was
dissolved in MeOH (3 mL), and 100 µL of 37% HCl was added
at 0 °C. The reaction was stirred at 60 °C until the starting
material completely disappeared (TLC AcOEt:MeOH:NH4OH
3:1:0.1). After 3 h, the reaction mixture was basified with
saturated NaHCO3 (5 mL) and extracted with CH2Cl2 (10 mL
× 3), and the combined organic layers were washed with brine
and dried over anydrous Na2SO4. The crude product was
purified by flash chromatography (AcOEt:MeOH:NH4OH 2:1:
0.1) to afford the desired alcohol 5d as a colorless oil (33 mg,
94%). Rf 0.2 (AcOEt:MeOH:NH4OH 3:1:0.1). MALDI-TOF
MS: [MH]+ 324.8. Anal. (C21H25NO2): C, H, N.
(()-3R-[(4-Chlorophenyl)phenylmethoxy]-8-methyl-8-
aza-bicyclo[3.2.1]octan-6â-ol (5e). As described for 5d start-
ing from 5b. The crude product was purified by flash chroma-
tography (AcOEt:MeOH:NH4OH 3:1:0.1, Rf 0.3) to afford a
white solid (95% yield): mp 242-244 °C. MALDI-TOF MS:
[MH]+ 359. Anal. (C21H24ClNO2): C, H, N.
(()-3R-[Bis-(4-fluorophenyl)methoxy]-8-methyl-8-aza-
bicyclo[3.2.1]octan-6â-ol (5f). As described for 5d starting
from 5c. The crude product was purified by flash chromatog-
raphy (AcOEt:MeOH:NH4OH 5:1:0.1) to afford a white solid
(94% yield): mp 228-231 °C; Rf 0.25 (AcOEt:MeOH:NH4OH
3:1:0.1). MALDI-TOF MS: [MH]+ 360. Anal. (C21H23F2NO2):
C, H, N.
(()-3R-[Bis(4-fluorophenyl)methoxy]-6R-methoxy-8-
methyl-8-aza-bicyclo[3.2.1]octane (5g). As described for
(-)-(6c) starting from 20a. Colorless oil (yield. 39%). MALDI-
TOF MS: [MH]+ 374. Anal. (C22H25F2NO2): C, H, N.
(()-3R-[Bis(4-fluorophenyl)methoxy]-6R-meth-
oxymethoxy-8-methyl-8-aza-bicyclo[3.2.1]octane (5h). As
described for 5a from compound 20b by means of 4,4′-
difluorobenzhydryl chloride. Colorless oil (42% yield): Rf 0.5
(AcOEt:MeOH:NH4OH 5:1:0.1). MALDI-TOF MS: [MH]+ 404.
Anal. (C23H27F2NO3): C, H, N.
(()-3R-[Bis-(4-fluorophenyl)methoxy]-8-methyl-8-aza-
bicyclo[3.2.1]octan-6R-ol (5i). As described for 5d starting
from 5h. The crude product was purified by flash chromatog-
raphy (AcOEt:MeOH:NH4OH 6:1:0.1) to afford a white solid
(40% yield): mp 214-216 °C; Rf 0.35 (AcOEt:MeOH:NH4OH
3:1:0.1). MALDI-TOF MS: [MH]+ 361. Anal. (C21H23F2NO2):
C, H, N.
(()-6R-[Bis-(4-fluorophenyl)methoxy]-8-methyl-8-aza-
bicyclo[3.2.1]octane (24). As described for 5a by means of
4,4′-difluorobenzhydryl chloride and alcohol 23. White solid
(57% yield): mp 250-253 °C; Rf 0.45 (AcOEt:MeOH:NH4OH
5:1:0.1). MALDI-TOF MS: [MH]+ 344. Anal. (C21H23F2NO): C,
H, N.
(()-6â-[Bis-(4-fluorophenyl)methoxy]-8-methyl-8-aza-
bicyclo[3.2.1]octane (25). As described for 5a by means of
4,4′-difluorobenzhydryl chloride and alcohol 21. White solid
(62% yield): mp 224-226 °C; Rf 0.4 (AcOEt:MeOH:NH4OH
5:1:0.1). MALDI-TOF MS: [MH]+ 344. Anal. (C21H23F2NO): C,
H, N.
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Acknowledgment. This work was supported in part
by the Ministero dell’Universita` e della Ricerca Scien-
tifica e Tecnologica, Rome, Italy.
Supporting Information Available: Experimental de-
tails for synthesis, characterization, and biological evaluation
for all new compounds listed in Schemes 1-4 and Table 1.
X-ray crystallographic data in CIF file for compound (-)-10.
This material is available free of charge via Internet at http://
pubs.acs.org.
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