A practical synthesis of the serotonin 5-HT(2a) receptor antagonist MDL 100907, its enantiomer and their 3-phenolic derivatives as precursors for [11C ]labeled PET ligands

Article abstract of DOI:10.1016/S0968-0896(00)00175-9

A practical synthesis of the 3-phenolic precursor of MDL 100907, a selective 5-HT(2A) receptor antagonist, is described. The route was also applied to the enantiomeric series, thus affording the direct precursors of both 3-[¹¹C]MDL 100907 and its enantiomer as ligands for positron emission tomography. Similar methodology was developed for the direct synthesis of MDL 100907 and its enantiomer, MDL 100009. The routes utilized classical optical resolution of the N-nor intermediates in at least 98% enantiomeric excess and easily afforded multigram amounts of the chiral precursors of a variety of N- and 3-O-substituted enantiomers. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(00)00175-9

Bioorganic & Medicinal Chemistry 8 (2000) 2427±2432
A Practical Synthesis of the Serotonin 5-HT2A Receptor
Antagonist MDL 100907, its Enantiomer and their 3-Phenolic
Derivatives as Precursors for [11C]Labeled PET Ligands
Thomas Ullrich and Kenner C. Rice*
Laboratory of Medicinal Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases,
National Institutes of Health, Building 8, Room B1-21, Bethesda, MD 20892-0815, USA
Received 18 April 2000; accepted 31 May 2000
AbstractÐA practical synthesis of the 3-phenolic precursor of MDL 100907, a selective 5-HT2A receptor antagonist, is described.
The route was also applied to the enantiomeric series, thus a€ording the direct precursors of both 3-[11C]MDL 100907 and its
enantiomer as ligands for positron emission tomography. Similar methodology was developed for the direct synthesis of MDL
100907 and its enantiomer, MDL 100009. The routes utilized classical optical resolution of the N-nor intermediates in at least 98%
enantiomeric excess and easily a€orded multigram amounts of the chiral precursors of a variety of N- and 3-O-substituted enan-
tiomers. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
studies, as MDL 100907 is partly metabolized to its 3-
OH-analogue MDL 105725, (+)-4. Labeling in the 2-
position [(+)-2] would therefore lead to extensive for-
mation of labeled 3-OH-analogue, which may be
expected to enter the brain and thus interfere with the
interpretation of [11C]MDL 100907 uptake.9
MDL 100907 (+)-1a, (R)-(+)-a-(2,3-dimethoxyphenyl)-
1-[2-(4-¯uorophenyl)ethyl]-4-piperidinemethanol (Fig. 1),
exhibits very high anity and selectivity for serotonin 5-
HT2A receptors.1 Its outstanding in vivo potency was
documented in several pharmacological assays and led
to application studies for a variety of disease states and
conditions.2 Positron emission tomography (PET) is an
e€ective way to quantitatively measure receptor-related
parameters in vivo. The availability of a high anity and
selective 5-HT2A receptor ligand appropriately labeled
would be of great interest as a tool to study the role of
this receptor in several psychiatric disorders such as
depression3 and schizophrenia.4 Although other radio-
ligands have been used to study the 5-HT2A receptor,
including [11C]N-methylspiperone,5 [18F]setoperone,6
and [18F]altanserin,7 they either lack the necessary
selectivity or have radio-metabolites which cross the
blood±brain barrier. Carbon-11-labeled MDL 100907
has been synthesized and evaluated as a useful radio-
ligand for 5-HT2A receptor mapping in PET studies.8
Radiolabeling by means of replacement of either of the
O-methyl groups with an [11C]methyl substituent has
been reported.8,9 The 3-labeled compound 3, however,
appears to be more useful for monkey and human PET
A useful route to (+)-3 has recently been described by
Huang et al.,10 employing synthesis of the racemic phe-
nolic precursor molecule (Æ)-4, followed by chiral deriva-
tization with (S)-(+)-a-methoxyphenylacetic acid and
¯ash chromatography separation. In an e€ort to
improve practical aspects of the synthesis, we decided to
modify this strategy in two respects:
(a) The optical resolution should be performed at an
earlier stage of the synthesis, in particular before
adding the p-¯uorophenethyl substituent to the
piperidine moiety. This would provide the possi-
bility of introducing a variety of N-substituents,
representing lipophilic domains of the compound,
into the already optically resolved and protected
material. Deprotection would then allow O-sub-
stitution.
(b) The method of optical resolution of (Æ)-5b should
allow the preparation of both equally accessible
enantiomers and convenient handling on a multi-
gram scale, rather than being limited by the com-
mon disadvantages of silica gel chromatography.
*Corresponding author. Tel.: +1-301-496-1856; fax: +1-301-402-
0589; e-mail: kr21f@nih.gov
0968-0896/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(00)00175-9

2428
T. Ullrich, K. C. Rice / Bioorg. Med. Chem. 8 (2000) 2427±2432
temperature up to 60 ꢀC led to higher yields (50±60%)
but was detrimental to enantioselectivity and further-
more resulted in partial O-demethylation in the adjacent
aromatic methoxy-substituent to give phenolic derivative
7.10 When ( )-DIP-chloride was prepared in situ, fol-
lowing a reported procedure,14 no improvement was
achieved. We decided then to focus our endeavors on
optical resolution via formation of diastereomeric salts,
as described in the following.
The t-Boc-protected Weinreb amide 8 and regioselec-
tively ortho-lithiated TBDPS-guaiacol 9b were prepared
according to the literature2,15 and reacted to a€ord
ketone 10b (Scheme 2). N-Deprotection with TFA and
reduction of the carbonyl group with NaBH4 gave
racemic alcohol 5b. The latter was successfully optically
resolved by means of salt formation with (+)- and ( )-
mandelic acid, respectively. The diastereomeric salts
were isolated and recrystallized twice from methanol.
Aqueous work up a€orded the enantiomers in a purity
of ee>98% each, as evaluated with (R)-( )-1,10-
binaphthyl-2,20-diyl hydrogen phosphate ( )-BNP as an
Figure 1.
The radiolabeled enantiomer 2-O-[11C]MDL 100009,
( )-2, was also investigated in PET studies and showed
nonspeci®c, uniform brain distribution without regional
localization, being consistent with the lower anity of
MDL 100009 for the 5-HT2A receptor.11 Availability of
larger quantities of MDL 100009 and its labeled derivative
was therefore considered desirable with respect to their
use as potential controls in various biological studies.
1
appropriate H NMR-shift reagent for determining the
enantiomeric ratio of amines.16 The benzylic proton
adjacent to the hydroxyl group was characterized by an
isolated doublet (4.6 ppm) down®eld from all other ali-
phatic signals. When 1.0 Æ 0.3 equiv of weight of ( )-
BNP was added to the racemic compound in CDCl3, the
peak multiplied to 2 doublets with a shift di€erence of
approx. 0.1±0.2 ppm (Varian Gemini 300 FT-NMR
spectrometer). Chemical shift changes of this signal were
strictly linear with respect to the relative concentration of
amine and ( )-BNP. Higher concentrations of ( )-BNP
caused signi®cant proton signal broadening, and were
detrimental to the accuracy of spectrum interpretation,
whereas lower concentrations led to insucient peak
splitting.
Results and Discussion
We initially examined asymmetric synthesis in order to
overcome the drawbacks of chromatographic puri®ca-
tion of diastereomers. This study involved the reduction
of ketone 6 (Scheme 1), a precursor of MDL 100907, the
preparation of which had been described in patent lit-
erature.2 As a reagent of choice, B-chlorodiisopino-
campheylborane (DIP-chloride) was considered for its
high reactivity towards a variety of aralkyl ketones with
predictable stereochemistry and high enantiomeric
yields.12 However, when ketone 6 was treated with com-
mercial ( )-DIP-chloride in THF at between 25 and
0 ꢀCÐconditions reported to be most appropriate for
this type of reaction13Ðno signi®cant conversion could
be observed. Using CHCl3 instead of THF gave between
25 and 30% of desired product (+)-1a, but optical
purity was found to be less than 70% ee. Elevation of
Resolved compounds (+)- and ( )-5b underwent N-
alkylation with (2-bromoethyl)-4-¯uorobenzene, which
was obtained by treatment of commercial 4-¯uoro-
phenethyl alcohol with PBr3.17 Subsequent cleavage of
the TBDPS-group was not performed by usual employ-
ment of strong bases18 or TBAF.19 Alternatively, the
Scheme 1.

T. Ullrich, K. C. Rice / Bioorg. Med. Chem. 8 (2000) 2427±2432
2429
Scheme 2. Reagents: (i) n-BuLi, THF, 50 ꢀC, 61±84%; (ii) a. TFA, 25±30 ꢀC; b. NaBH4, MeOH, 25±30 ꢀC, 71±74%; (iii) a. optical resolution; b.
(4-F-Ph)C2H4Br, NaHCO3, DMF, 80 ꢀC, 72±80%; (iv) NH4F (5 equiv), MeOH, 60 ꢀC, 88%; (v) CH2N2, MeOH/Et2O, rt, 79%.
inorganic nucleophile NH4F a€orded deprotected mate-
rial selectively without the common work up problems
caused by the phase-transfer properties of TBAF.20 After
chromatographic puri®cation, (+)- and ( )-4 were
obtained as crystalline materials in multi-gram quantities.
order to reach purities >98% ee, resulting in slightly
lower overall yields than in the case of (+)- and ( )-5b.
Analysis of the optical purity was performed with the
1
same H NMR shift reagent as mentioned above.
Phenolic compound (+)-4 could be easily transformed
into (+)-1a under mild methylation conditions, using
diazomethane in MeOH/Et2O, a method successfully
described for multifunctional aminoalkylphenols.22 The
(+)-1a thus obtained was identical with the sample
prepared by N-alkylation of (+)-5a.
As the described strategy of optical resolution proved to
be very convenient and the enantiomers could be
obtained in substantial overall yields, we applied a par-
allel methodology to the synthesis of MDL 100907 1a
which we also needed for further biological studies. This
synthetic route dispenses with the two steps of intro-
duction and cleavage of the TBDPS group, veratrole 9a
(R=Me) being the starting material (Scheme 2). Ketone
10a was synthesized as described in the literature,2 while
the deprotection/reduction step was carried out as
mentioned above. Optical resolution of 5a was achieved
correspondingly. Whereas employment of mandelic acid
did not a€ord crystalline salts, we succeeded using (+)-
and ( )-di-O,O0-p-toluyltartaric acid, respectively. After
we completed optical resolution of 5a, a similar method
using the same chiral acids was independently published
in patent literature,21 being in line with our ®ndings.
Three recrystallizations of the diastereomeric salts from
MeOH, respectively, were found to be mandatory in
Absolute con®gurations for the enantiomers of 1a and 4
are reported in the literature.2,10 Since (+)-4 is derived
from ( )-5b via ( )-1b and a€orded (R)-(+)-1a on
methylation, the absolute con®gurations of these pre-
cursors are R and those of their enantiomers are S.
These results are in agreement with the con®guration
previously stated10 for (+)-4.
Conclusion
The present method represents a facile route to the
[11C]MDL 100907 precursor, MDL 105725, and its

2430
T. Ullrich, K. C. Rice / Bioorg. Med. Chem. 8 (2000) 2427±2432
enantiomer. Apart from few synthetic steps and high
yields, its outstanding feature is the formation of salts
for optical resolution, which a€ords either of the desired
enantiomers and allows practical synthesis of the com-
pound on a multi-gram scale. Furthermore, it o€ers the
possibility to introduce various lipophilic domains by
N-alkylation into an already resolved molecule, as well
as 3-O-substituents. In addition, simpli®ed methodology
is described for the synthesis of multi-gram quantities of
MDL 100907 and its enantiomer, MDL 100009. Both
accomplishments contribute to a remarkable improve-
ment of synthetic routes previously reported.
Hz, 1H), 6.70 (t, J=8 Hz, 1H), 6.86 (dd, J=8, 2 Hz, 1H),
7.33±7.48 (m, 6H), 7.73 (d, J=8 Hz, 4H); MS (CI with
NH3) m/z 574 (M+1). Anal. calcd for C34H43NO5Si: C,
71.16; H, 7.55; N, 2.44; found: C, 70.92; H, 7.77; N, 2.34.
General procedure for Boc-deprotection and reduction of
the carbonyl group
Ketone 10a or 10b (70 mmol) was carefully and gradu-
ally dissolved in tri¯uoroacetic acid (160 mL) with
cooling at 25±30 ꢀC. After 30 min of stirring at room
temperature, the solution was diluted with 500 mL of
ether and carefully neutralized with NH4OH and ice bath
cooling. The layers were separated and the aqueous layer
was extracted 3Â with ether. The combined organic
extracts were washed with water, dried (Na2SO4), ®l-
tered and evaporated to a€ord a viscous oil that was
dissolved in anhydrous MeOH (400 mL) and stirred
under a nitrogen atmosphere. NaBH4 (140 mmol) was
added gradually at 25±30 ꢀC, and the solution was stir-
red until no more gas evolved. After evaporation of the
solvent, the residue was taken up in NH4OH and extrac-
ted 3Â with CHCl3. The combined organic extracts were
washed with brine, dried (Na2SO4), ®ltered and evapo-
rated to a€ord a viscous oil that crystallized when tri-
turated with diisopropyl ether.
Experimental
General methods
Unless otherwise indicated, all reagents were purchased
from commercial suppliers and used without further
puri®cation. TLC analyses were carried out on Analtech
silica gel GHLF 0.25 mm plates, and spots were visua-
lized with UV light and I2. Chromatography refers to
¯ash chromatography using Fluka silica gel 60, 220±240
mesh. Melting points were measured in open glass
capillaries on a Thomas-Hoover melting point appara-
tus and are uncorrected. Optical analyses were carried
1
out on a Perkin Elmer 341 polarimeter. H NMR spec-
(Æ)-ꢀ-(2,3-Dimethoxyphenyl)-4-piperidinemethanol ((Æ)-
5a). The compound was obtained as colorless crystals
(71%); Rf 0.4 (silica gel, 5:1 MeOH:NH4OH); mp 169±
tra were recorded at 300 MHz on a Varian Gemini
spectrometer and are reported as ppm down®eld from
Me4Si with multiplicity, number of protons, and cou-
pling constant(s) in Hertz indicated parenthetically. The
following abbreviations are used to indicate spin multi-
plicities: s (singlet), bs (broad singlet), d (doublet), dd
(doublet of doublets), t (triplet) or m (multiplet). Mass
spectra (MS) were recorded on a VG 7070E spectrometer
or a Finnigan 4600 spectrometer. Elemental analyses (C,
H, and N) were performed by Atlantic Microlabs Inc.,
Norcross, GA, and the obtained results were within
0.4% of the theoretical values.
170 ꢀC; H NMR (CDCl3) d 1.18±1.40 (m, 3H), 1.65±
1
1.85 (m, 1H), 1.86±2.14 (m, 2H), 2.43±2.67 (m, 2H),
2.97±3.09 (m, 1H), 3.11±3.19 (m, 1H), 3.89 (s, 6H), 4.62
(d, J=8 Hz, 1H), 6.81±6.97 (m, 2H), 7.04 (t, J=8 Hz,
1H); MS (CI with NH3) m/z 252 (M+1); anal. calcd for
C14H21NO3: C, 66.90; H, 8.42; N, 5.57; found: C, 66.66;
H, 8.42; N, 5.58.
(Æ)-ꢀ-[2-Methoxy-3-[(1,1-dimethylethyl)diphenylsilyl]oxy-
phenyl]-4-piperidinemethanol ((Æ)-5b). The compound
was obtained as colorless crystals (74%); Rf 0.35 (silica
gel, 7:3:0.5 CHCl3:MeOH:NH4OH); mp 166±168 ꢀC; 1H
NMR (CDCl3): d 1.14 (s, 9H), 1.18±1.37 (m, 3H), 1.75
(bs, 1H), 1.94±2.07 (m, 1H), 2.22±2.41 (m, 2H), 2.54 (m,
1H), 2.98±3.10 (m, 1H), 3.11±3.19 (m, 1H), 3.97 (s, 3H),
4.64 (d, J=8 Hz, 1H), 6.44 (dd, J=8, 2 Hz, 1H), 6.65 (t,
J=8 Hz, 1H), 6.80 (dd, J=8, 2 Hz, 1H), 7.33±7.48 (m,
6H), 7.73 (d, J=8 Hz, 4H); MS (CI with NH3) m/z 476
(M+1); anal. calcd for C29H37NO3Si: C, 73.22; H, 7.84;
N, 2.94; found: C, 72.96; H, 7.87; N, 2.81.
4-[2-Methoxy-3-[(1,1-dimethylethyl)diphenylsilyl]oxybenz-
oyl] - 1 - piperidinecarboxylic acid 1,1 - dimethylethyl ester
(10b). n-Butyllithium (64.5 mL of a 2.5 M solution in
hexane, 161 mmol) was added to a stirred solution of (2-
methoxyphenoxy)-(1,1-dimethylethyl)diphenylsilane11 9b
(58.4 g, 161 mmol) under nitrogen at 0 ꢀC. The ice bath
was removed and the solution was allowed to stir for 2 h.
After cooling to 50ꢀC, 4-(N-methoxy-N-methyl-car-
boxamido)-1-piperidinecarboxylic acid 1,1-dimethyl ester2
8 (41.8 g, 153 mmol) was added dropwise to the stirred
solution, followed by warming to room temperature
and stirring for 2 h. Saturated aqueous NH4Cl was
added; the layers were separated and the aqueous layer
was extracted 3Â with ether. The combined organic
extracts were washed with brine, dried (Na2SO4), ®l-
tered and evaporated to a€ord a viscous oil. Filtration
of the residue through silica gel 60 with 10:1 petroleum
ether:EtOAc gave 53.5 g (61%) of 10b as a colorless oil:
Rf 0.4 (silica gel, 10:1 petroleum ether:EtOAc); 1H NMR
(CDCl3) d 1.15 (s, 9H), 1.44 (s, 9H), 1.45±1.70 (m, 2H),
1.73±1.85 (m, 2H), 2.79±2.91 (m, 2H), 3.13±3.26 (m,
1H), 3.92 (s, 3H), 4.03±4.16 (m, 2H), 6.62 (dd, J=8, 2
Optical resolution of 5a
(Æ)-5a (44.7 g, 178 mmol) and (+)-di-O,O0-p-toluyl-d-
tartaric acid (68.7 g, 178 mmol) were taken up in hot
MeOH (1L) and evaporated to dryness. The residue was
recrystallized from i-PrOH (without refrigerating). After
2 h, the precipitated material was collected on a Buchner
funnel, dried and recrystallized 3Â from MeOH. The
resolved diastereomeric salt (40.3 g) was then partitioned
between NH4OH and CHCl3, and after separation of the
organic layer, the aqueous phase was extracted 2Â with
CHCl3. The combined organic extracts were washed

T. Ullrich, K. C. Rice / Bioorg. Med. Chem. 8 (2000) 2427±2432
2431
with brine, dried (Na2SO4), ®ltered and evaporated to
a€ord 15.9 g (71%) of (R)-(+)-5a as colorless crystals:
mp 194±195 ꢀC; [a]2d0 +6.6ꢀ (c 0.1, MeOH); anal. calcd
for C14H21NO3: C, 66.90; H, 8.42; N, 5.57; found: C,
66.68; H, 8.37; N, 5.62.
DMF (100 mL) was stirred for 90 min at 85 ꢀC. After
evaporation of the solvent, the residue was taken up in
NH4OH and extracted 3Â with EtOAc. The combined
organic extracts were washed 3Â with brine, dried
(Na2SO4), ®ltered and evaporated.
The combined mother liquors from recrystallization
were evaporated and free-based with NH4OH/CHCl3 in
the same manner, to yield 28.8 g (115 mmol) of mixed
base, which was treated with ( )-di-O,O0-p-toluyl-l-tar-
taric acid (44.4 g, 115 mmol) in MeOH (300 mL), as
described above. 17.0 g (76%) of (S)-( )-5a was
obtained as colorless crystals: mp 194±195 ꢀC; [a]d20 7.1ꢀ
(c 0.1, MeOH); anal. calcd for C14H21NO3: C, 66.90; H,
8.42; N, 5.57; found: C, 66.77; H, 8.41; N, 5.63.
(R)-(+)-ꢀ-(2,3-Dimethoxyphenyl)-1-[2-(4-¯uorophenyl)
ethyl]-4-piperidinemethanol (+)-1a (MDL 100907). Alky-
lation of (R)-(+)-5a as above a€orded (R)-(+)-1a. The
compound crystallized when triturated with diisopropyl-
ether and gave colorless crystals (95%); mp 113±115 ꢀC;
Rf 0.7 (silica gel, 90:8:2 CHCl3:MeOH:NH4OH); [a]d20
+14.2ꢀ (c 0.1, MeOH); lit.2 [a]2d0 +13.9ꢀ; 1H NMR
(CDCl3) d 1.23±1.56 (m, 3H), 1.61±1.77 (m, 1H), 1.83±
2.26 (m, 3H), 2.53 (t, J=8 Hz, 2H), 2.77 (t, J=8 Hz, 2H),
2.88±2.98 (m, 1H), 3.06±3.14 (m, 1H), 3.84 (s, 6H), 4.62
(d, J=8 Hz, 1H), 6.81±6.99 (m, 4H), 7.05 (t, J=8 Hz,
1H), 7.08±7.17 (m, 2H); MS (CI with NH3) m/z 598
(M+1); anal. calcd for C22H28FNO3: C, 70.75; H, 7.56;
N, 3.75; found: C, 70.68; H, 7.52; N, 3.79.
NMR and mass spectral data for both enantiomers are
identical with (Æ)-5a. Enantiomeric purity was deter-
mined after each step of recrystallization by combining
5 mg of the free-based sample with 5 mg of (R)-( )-1,10-
binaphthyl-2,20-diyl hydrogen phosphate in 0.6 mL of
CDCl3 and performing 1H NMR. The limit of detection
of enantiomeric impurity was found to be <2% ee.
After two recrystallizations from MeOH no enantio-
meric impurity was detected. The salt was then recrys-
tallized a ®nal time.
(S)-( )-ꢀ-(2,3-Dimethoxyphenyl)-1-[2-(4-¯uorophenyl)
ethyl]-4-piperidinemethanol ( )-1a (MDL 100009). Alky-
lation of (S)-( )-5a as above a€orded (S)-( )-1a. Yield:
96%. Analytical data are identical with (R)-(+)-1a,
except for: [a]2d0 14.3ꢀ (c 0.1, MeOH); anal. calcd for
C22H28FNO3: C, 70.75; H, 7.56; N, 3.75; found: C,
70.62; H, 7.49; N, 3.80.
Optical resolution of 5b
(Æ)-5b (48.1 g, 101 mmol) and ( )-mandelic acid (15.4
g, 101 mmol) were taken up in hot MeOH (600 mL) and
evaporated to dryness. The residue was recrystallized
from MeOH (without refrigerating). After 2 h, the pre-
cipitated material was collected on a Buchner funnel,
dried and recrystallized from MeOH again. The resolved
diastereomeric salt (26.0 g) was then partitioned between
NH4OH and CHCl3, and after separation of the organic
layer, the aqueous phase was extracted 2Â with CHCl3.
The combined organic extracts were washed with brine,
dried (Na2SO4), ®ltered and evaporated to a€ord 19.3 g
(80%) of (R)-( )-5b as colorless crystals: mp 187±
189 ꢀC; [a]2d0 46.8ꢀ (c 0.1, MeOH); anal. calcd for
C29H37NO3Si: C, 73.22; H, 7.84; N, 2.94; found: C,
73.07; H, 7.80; N, 2.93.
(S)-(+)-ꢀ-[2-Methoxy-3-[(1,1-dimethylethyl)diphenylsilyl]
oxyphenyl]-1-[2-(4-¯uorophenyl)ethyl]-4-piperidinemetha-
nol (+)-1b. Alkylation of (S)-(+)-5b as above a€orded
(S)-(+)-1b. The compound was obtained as a colorless
oil (95%); Rf 0.3 (silica gel, 10:1 CHCl3:MeOH); [a]d20
+30.0ꢀ (c 0.1, MeOH); H NMR (CDCl3) d 1.13 (s,
1
9H), 1.10±1.36 (m, 3H), 1.40 (m, 1H), 1.71±2.07 (m, 3H),
2.53 (t, J=8 Hz, 2H), 2.79 (t, J=8 Hz, 2H), 2.88±3.00
(m, 1H), 3.06±3.17 (m, 1H), 3.98 (s, 3H), 4.64 (d, J=8
Hz, 1H), 6.43 (dd, J=8, 2 Hz, 1H), 6.64 (t, J=8 Hz,
1H), 6.80 (dd, J=8, 2 Hz, 1H), 6.93±7.05 (m, 2H), 7.11±
7.21 (m, 2H), 7.29±7.47 (m, 6H), 7.73 (d, J=8 Hz, 4H);
MS (CI with NH3) m/z 598 (M+1). Anal. calcd for
.
C37H44FNO3Si 3/4H2O: C, 72.69; H, 7.50; N, 2.29;
found: C, 72.31; H, 7.30; N, 2.27.
The combined mother liquors from recrystallization
were evaporated and free-based with NH4OH/CHCl3 in
the same manner, to yield 37.8 g (79.5 mmol) of mixed
base, which was treated with (+)-mandelic acid (12.1 g,
79.5 mmol) in MeOH (500 mL), as described above.
20.2 g (84%) of (S)-(+)-5b was obtained as colorless
crystals: mp 187±189 ꢀC (CHCl3); [a]d20 +45.5ꢀ (c 0.1,
MeOH); anal. calcd for C29H37NO3Si: C, 73.22; H, 7.84;
N, 2.94; found: C, 72.95; H, 7.79; N, 2.90. NMR and
mass spectral data for both enantiomers are identical
with (Æ)-5b. Enantiomeric purity was determined as
mentioned above.
(R)-( )-ꢀ-[2-Methoxy-3-[(1,1-dimethylethyl)diphenylsilyl]
oxyphenyl]-1-[2-(4-¯uorophenyl)ethyl]-4-piperidinemetha-
nol ( )-1b. Alkylation of (R)-( )-5b as above a€orded
(R)-( )-1b. Yield: 95%. Analytical data are identical
with (S)-(+)-1b, except for: [a]2d0 30.8ꢀ (c 0.1, MeOH);
.
anal. calcd for C37H44FNO3Si H2O: C, 72.16; H, 7.53;
N, 2.27; found: C, 71.89; H, 7.49; N, 2.41.
ꢀ-(2-Hydroxy-3-methoxyphenyl)-1-[2-(4-¯uorophenyl)
ethyl]-4-piperidinemethanol (7) by chiral reduction. A
solution of 1-[2-(4-¯uorophenyl)ethyl]-4-[1-oxo-1-(2,3-
dimethoxyphenyl)methyl]piperidine2 6 (500 mg, 1.35
mmol) in anhydrous CHCl3 (5 mL) was treated with
commercial ( )-Ipc-chloride (650 mg, 2.03 mmol) at
25 ꢀC and stirred for 8 h at 0 ꢀC and 48 h at ambient
temperature. The mixture was quenched with 2 equiv of
acetaldehyde, stirred overnight, and partitioned between
NH4OH and ether. The aqueous phase was extracted
General procedure for N-alkylation
A suspension of the appropriate, optically resolved amine
5a or 5b (21.4 mmol), NaHCO3 (32.1 mmol), and (2-bro-
moethyl)-4-¯uorobenzene (21.4 mmol) in anhydrous

2432
T. Ullrich, K. C. Rice / Bioorg. Med. Chem. 8 (2000) 2427±2432
2Â with CHCl3. The combined organic extracts were
washed with brine, dried (Na2SO4), ®ltered and evapo-
rated to dryness. Chromatography of the residue with
90:10:1 CHCl3:MeOH:NH4OH gave fractions of
unreacted starting material 7 (150 mg, 30%), partially
resolved 1a (210 mg, 42%, ee=58% in favor of the (+)-
isomer) and partially resolved 7 (76 mg, 16%, ee=39%
in favor of the (+)-isomer) as colorless crystals when
triturated with diisopropyl ether: mp 147±149 ꢀC (lit.10
Acknowledgements
We acknowledge Dr. Michael A. Channing for very
helpful discussions, and Noel Whittaker who provided
all mass spectroscopy data reported.
References and Notes
1. Kehne, J. H.; Baron, B. M.; Carr, A. A.; Chaney, S. F.;
Elands, J.; Feldman, D. J.; Frank, R. A.; Van Giersbergen, P.
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macol. Exp. Ther. 1996, 277, 968.
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Frost, J. J.; Ravert, H. T.; Wilson, A. A.; Rosenbaum, A. E.;
Gjedde, A.; Douglass, K. H.; Petronis, J. D.; Folstein, M. F.;
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6. Blin, J.; Pappata, S.; Kiyosawa, M.; Crouzel, C.; Baron, J.
C. Eur. J. Pharmacol. 1988, 147, 73.
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vaux, A.; Degueldre, C.; Hermanne, J. P.; Guillaume, M.;
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ꢀ
1
147±149 C); H NMR (CDCl3) d 1.26±1.59 (m, 3H),
1.73±1.81 (m, 1H), 1.82±2.14 (m, 3H), 2.52 (t, J=8 Hz,
2H), 2.73 (t, J=8 Hz, 2H), 2.88±2.99 (m, 1H), 3.06±3.17
(m, 1H), 3.87 (s, 3H), 4.58 (d, J=8 Hz, 1H), 6.72±6.86
(m, 3H), 6.93 (t, J=8 Hz, 2H), 7.08±7.18 (m, 2H); MS
(CI with NH3) m/z 360 (M+1); anal. calcd for
.
C21H26FNO3 1/4H2O: C, 69.30; H, 7.43; N, 3.85; found:
C, 69.62; H, 7.29; N, 3.87.
(R)-(+)-ꢀ-(3-Hydroxy-2-methoxyphenyl)-1-[2-(4-¯uoro-
phenyl)ethyl]-4-piperidinemethanol (+)-4. A solution of
(R)-( )-1b (12.8 g, 21.4 mmol) and NH4F (3.96 g, 107
mmol) in anhydrous MeOH (150 mL) was stirred for 15
min at 60 ꢀC. After evaporation of the solvent, the resi-
due was taken up in NH4OH and extracted 3Â with
CHCl3. The combined organic extracts were washed
with brine, dried (Na2SO4), ®ltered and evaporated to
yield a viscous oil. Chromatography of the residue with
5:1 CHCl3:MeOH gave 6.77 g (88%) of (R)-(+)-4 as a
colorless oil which crystallized from hexane: Rf 0.7
(silica gel, 5:1 CHCl3:MeOH); mp 75±80 ꢀC (decomp);
[a]2d0 +21.9ꢀ (c 0.1, MeOH); lit.10 [a]2d2 +22.2ꢀ (c 1.58,
1
MeOH); H NMR (CDCl3) d 1.19±1.58 (m, 3H), 1.62±
1.79 (m, 1H), 1.85±2.14 (m, 3H), 2.54 (t, J=8 Hz,
2H), 2.76 (t, J=8 Hz, 2H), 2.88±3.00 (m, 1H), 3.06±
3.17 (m, 1H), 3.81 (s, 3H), 4.64 (d, J=8 Hz, 1H),
6.81±7.07 (m, 5H), 7.08±7.18 (m, 2H); MS (CI with
10. Huang, Y.; Mahmood, K.; Mathis, C. A. J. Labelled
Compd. Radiopharm. 1999, 42, 949.
11. Mathis, C. A.; Mahmood, K.; Huang, Y.; Simpson, N. R.;
Gerdes, J. M.; Price, J. C. Med. Chem. Res. 1996, 6, 1.
12. Ramachandran, P. V.; Brown, H. C. Recent Advantages in
Asymmetric Reductions with B-Chlorodiisopinocampheylborane;
ACS Symposium Series 641. American Chemical Society:
Washington, DC, 1996.
13. Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V.
J. Am. Chem. Soc. 1988, 110, 1539.
14. Zhao, M.; King, A. O.; Larsen, R. D.; Verhoeven, T. R.;
Reider, P. J. Tetrahedron Lett. 1997, 38, 2641.
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G.; Solomon, D. H. Tetrahedron 1997, 53, 13915.
16. Ravard, A.; Crooks, P. A. Chirality 1996, 8, 295.
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Soc. 1977, 99, 3059.
.
NH3) m/z 360 (M+1); anal. calcd for C21H26FNO3 3/
4H2O: C, 67.63; H, 7.43; N, 3.76; found: C, 67.28; H,
7.06; N, 3.58.
(S)-( )-ꢀ-(3-Hydroxy-2-methoxyphenyl)-1-[2-(4-¯uoro-
phenyl)ethyl]-4-piperidinemethanol ( )-4. Deprotection
of (S)-(+)-1b as above a€orded (S)-( )-4. Yield: 88%.
Analytical data are identical with (+)-4, except for: [a]d20
22.2ꢀ (c 0.1, MeOH); anal. calcd for C21H26FNO3
.
1/4H2O: C, 69.30; H, 7.34; N, 3.85; found: C, 69.57; H,
7.36; N, 3.81.
Methylation of (+)-4 to (+)-1a (MDL 100907). A freshly
distilled, ethereal solution of diazomethane (4 mL) was
gradually added to a stirred solution of (+)-4 (50 mg,
0.14 mmol) in MeOH (0.5 mL) at room temperature.
The completion of the reaction was monitored by TLC.
After 8 h, the solution was evaporated to dryness, and
the residue was ®ltered through silica gel 60 (10:1
CHCl3:MeOH) to give 41 mg (79%) of (+)-1a. Ana-
lytical data are identical with those for (+)-1a
obtained by N-alkylation, except for: [a]2d0 +14.3ꢀ (c
0.1, MeOH).
18. Ireland, R. E.; Obrecht, D. M. Helv. Chim. Acta 1986, 69,
1273.
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