A practical synthesis of enantiopure 7-alkoxy-4-aryl- tetrahydroisoquinoline, a dual serotonin reuptake inhibitor/histamine H 3 antagonist

Article abstract of DOI:10.1021/op700183q

An efficient synthesis of compound 1 featuring a novel sequential Friedel-Crafts alkylation strategy to construct the 4-aryl- tetrahydroisoquinoline core structure has been developed. Resolution with (D/L)-di-p-toluoyl-tartaric acid is utilized to provide the enantiomerically pure material. Overall, the route is concise and amenable for large-scale synthesis.

Full text of DOI:10.1021/op700183q

Organic Process Research & Development 2007, 11, 1043–1050
A Practical Synthesis of Enantiopure 7-Alkoxy-4-aryl-tetrahydroisoquinoline, a Dual
Serotonin Reuptake Inhibitor/Histamine H3 Antagonist
Xiaohu Deng,* Jimmy T. Liang, Jing Liu, Heather McAllister, Carsten Schubert,† and Neelakandha S. Mani
Johnson & Johnson Pharmaceutical Research & DeVelopment, LLC., 3210 Merryfield Row, San Diego,
California 92121, U.S.A.
Abstract:
1), which involves two low-yielding steps and multiple chro-
matographic purifications including one chiral HPLC separation,
is not suitable for large-scale synthesis.3b For scale-up purposes,
a novel sequential Friedel–Crafts alkylation strategy was devised
to rapidly construct the 4-aryl-tetrahydroisoquinoline core
structure, followed by a practical resolution to provide the
enantiomerically pure material. We expect this sequence be
applicable to the syntheses of similar 4-aryl-tetrahydroisoquino-
line compounds.
An efficient synthesis of compound 1 featuring a novel sequential
Friedel–Crafts alkylation strategy to construct the 4-aryl-tetrahy-
droisoquinoline core structure has been developed. Resolution with
(D/L)-di-p-toluoyl-tartaric acid is utilized to provide the enantio-
merically pure material. Overall, the route is concise and amenable
for large-scale synthesis.
Introduction
Selective serotonin reuptake inhibitors (SSRIs) represent a
very important class of antidepressant drugs; for example,
Prozac and Zoloft, both SSRIs, are among the most commonly
prescribed drugs for depression. However, SSRIs do not treat
some of common symptoms associated with depression such
as cognitive impairment and fatigue, even as mood improves.1
Histamine H3 inhibitors, in contrast, have been shown to
improve cognition and increase wakefulness in preclinical
pharmacology experiments.2 With the expectation that a sero-
tonin reuptake inhibitor with histamine H3 activity may improve
efficacy for the treatment of depression, a series of dual
serotonin reuptake inhibitors/histamine H3 antagonists were
designed in our laboratories.3 These compounds share the
common structural feature of a 4-aryl-tetrahydroisoquinoline
core tethered with a H3 pharmacophore side chain. Among
the analogs prepared, compound 1 has high affinity for both
the histamine H3 receptor and the serotonin reuptake transporter;
good selectivity against a panel of over 50 receptors, ion
channels and transporters; and favorable pharmacokinetic
properties including good oral bioavailability and high exposure
and receptor occupancy in the rat brain. A practical synthesis
to provide multigram quantities of 1 was needed for further
pharmacological evaluation. The initial discovery route (Scheme
Results and Discussion
The first challenge we faced in this project was to set the
stereogenic center of compound 1 without resorting to chiral
HPLC separation. Enantioselective syntheses of tetrahydroiso-
quinoline alkaloids have been extensively studied in the
literature,4 mostly involving the use of chiral auxiliaries.5 Other
successful strategies include stereoselective intramolecular cy-
clization of chiral precursors6 and deracemization of diaryl-
methane derivatives.7 From a practical and economical stand-
point, however, we reasoned that a classic resolution would be
our best choice.8 Ideally, chiral resolution should be performed
at the earliest possible stage to avoid wastage of the precious
advanced intermediates. Hence, compound 4 was considered a
suitable candidate. The first four steps of the discovery route
* To whom correspondence should be addressed. E-mail: xdeng@
prdus.jnj.com.
(4) (a) Rozwadowska, M. D. Heterocycles 1994, 39, 903–931. (b)
Chrzanowska, M.; Rozwadowska, M. D. Chem. ReV. 2004, 104, 3341–
3370.
† Johnson & Johnson, 665 Stockton Drive, Exton, PA 19341, U.S.A.
(1) (a) Nierenberg, A. A.; Keepe, B. R.; Leslie, V. C.; Alpert, J. E.; Pava,
J. A.; Worthington, J. J.; Rosenbaum, J. F.; Fava, M. J. Clin. Psychiatry
1999, 60, 221–225. (b) Fava, G. A.; Fabbri, S.; Sonino, N. Prog.
Neuro-Psychopharmacol. Biol. Psychiatry 2002, 26, 1019–1037.
(2) Letavic, M. A.; Barbier, A. J.; Dvorak, C. A.; Carruthers, N. I. Prog.
Med. Chem. 2006, 44, 181–206.
(5) (a) Anan, H.; Tanaka, A.; Tsuzuki, R.; Yokota, M.; Yatsu, T.; Honda,
K.; Asano, M.; Fujita, S.; Furuya, T.; Fujikura, T. Chem. Pharm. Bull.
1991, 39, 2910–2914. (b) Munchhof, M. J.; Meyers, A. I. J. Org.
Chem. 1995, 60, 7086–7087. (c) Philippe, N.; Levacher, V.; Dupas,
G.; Queguiner, G.; Bourguignon, J. Org. Lett. 2000, 2, 2185–2187.
(d) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P. Org. Biomol.
Chem. 2003, 1, 1701–1706. (e) Asami, M.; Taketoshi, A.; Miyoshi,
K.; Hoshino, H.; Sakakibara, K. Chem. Lett. 2007, 36, 64–65.
(6) Philippe, N.; Denivet, F.; Vasse, J-L; Santos, J. S. O.; Levacher, V.;
Dapas, G. Tetrahedron 2003, 59, 8049–8056.
(3) (a) Keith, J. M.; Gomez, L. A.; Letavic, M, A.; Ly, K. S.; Jablonowski,
J. A.; Seierstad, M.; Barbier, A. J.; Wilson, S. J.; Boggs, J. D.; Fraser,
I. C.; Mazur, C.; Lovenberg, T. W.; Carruthers, N. I. Bioorg. Med.
Chem. Lett. 2007, 17, 702–706. (b) Letavic, M. A.; Keith, J. M.;
Jablonowski, J. A.; Stocking, E. M.; Gomez, L. A.; Ly, K. S.; Miller,
J. M.; Barbier, A. J.; Bonaventure, P.; Boggs, J.; Wilson, S. J.; Miller,
K.; Lord, B.; McAllister, H. M.; Tognarelli, D. J.; Wu, J.; Abad, M. C.;
Lovenberg, T. W.; Carruthers, N. I. Bioorg. Med. Chem. Lett. 2007,
17, 1047–1051.
(7) Prat, L.; Mojovic, L.; Levacher, V.; Dupas, G.; Queguiner, G.;
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(8) (a) Den Hollander, C. W.; Leimgruber, W.; Mohacsi, E. U.S. Patent
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10.1021/op700183q CCC: $37.00
Published on Web 11/16/2007
2007 American Chemical Society
Vol. 11, No. 6, 2007 / Organic Process Research & Development
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Scheme 1. Discovery synthesis of 1, a dual serotonin reuptake inhibitor/histamine H3 antagonist
Scheme 2. Acid-mediated cyclization of alcohol 5
Scheme 3. Common disconnections for the construction of
the 4-aryl-tetrahydroisoquinoline core
(Scheme 1) were readily scalable to provide compound 3 in
160-g scale. However, the subsequent acid-catalyzed cyclization
and reduction steps afforded a low yield of 4-aryl-tetrahydroiso-
quinoline 4 (40%). To solve this problem, alcohol 5, which
literature precedents suggested to be more reactive towards the
acid-mediated cyclization reaction,9 was prepared by the reduc-
tion of 3 with NaBH4 in EtOH in quantitative yield. The
cyclization reaction of alcohol 5 could be catalyzed with various
acids such as MeSO3H, H2SO4, AlCl3, BF3 ·Et2O, FeCl3 and
SnCl4. Conversion was usually excellent; however, a mixture
of the two possible regioisomers (Scheme 2) was invariably
observed. After screening numerous reaction conditions, 6 equiv
of MeSO3H in CH2Cl2 was found to give the best regioselec-
tivity at 4:1 ratio favoring the desired product 4. Fortunately,
the undesired regioisomer 6 was easily removed by recrystal-
lization from hot EtOAc. Using this method, 100 g batches of
compound 4 were readily prepared without any column chro-
matography purification.
unsuccessful. We speculated that the flexible alkoxy side chain
might have impeded the crystallization process. Thus, replace-
ment of the side chain with a more rigid group that is easily
removable for future manipulation, such as a benzyl group,
should greatly enhance the possibility of a successful resolution.
Based on these considerations as well as the need of addressing
the inherent regioselectivity problem of the acid-mediated
cyclization step to prepare compound 4, we decided to explore
a more efficient route to the 4-aryl-tetrahydroisoquinoline core.
Following the isolation of Cherylline, a rare type of natural
phenolic alkaloid, by Brossi and co-workers in 1970,11 synthesis
of 4-aryl-tetrahydroisoquinoline has attracted considerable at-
With racemic compound 4 in hand, resolution via diaster-
eomeric salt formation was investigated. A panel of com-
mercially available optically pure acids10 was explored in several
common solvents such as EtOH, IPA, CH3CN and EtOAc.
Unfortunately, all of the experiments failed to afford any
crystalline salts. Attempts to resolve compound 1 were also
(9) Hara, H.; Shirai, R.; Hoshino, O.; Umezawa, B. Chem. Pharm. Bull.
1985, 33, 3107–3112.
(10) L-Tartaric acid, L-malic acid, dibenzoyl-L-tartaric acid, di-p-toluoyl-
D-tartaric acid, (S)-(–)-2-pyrrolidone-5-carboxylic acid, (R)-(–)-10-
camphorsulfonic acid, (S)-(+)-mandelic acid, (S)-(+)-6-methoxy-R-
methyl-2-naphthalene acetic acid, di-O-isopropylidene-2-keto-L-gulonic
acid, deoxycholic acid, L-glutamic acid, (R)-(–)-thiazolidine-4-car-
boxylic acid, D-quinic acid, L-aspartic acid, D-isoascorbic acid, (1R,3S)-
(+)-camphoric acid, D-lactobionic acid, (S)-(–)-2-(phenylcarbamoy-
loxy)propionic acid, D-glucuroic acid.
(11) Brossi, A.; Grethe, G.; Teitel, S.; Wildman, W. C.; Bailey, D. T. J.
Org. Chem. 1970, 35, 1100–1104.
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Scheme 4. Retrosynthetic analysis
Scheme 5. Synthesis of compound 11
tention due to its potential applications for the treatment of
depression,12 estrogen-related disorders,13 Alzheimer’s disease
and Parkinson’s disease.14 In the literature, four distinct discon-
nections are most commonly employed for the construction of
the 4-aryl-tetrahydroisoquinoline core, as shown in Scheme 3:
(a) Pictet–Spengler cyclization of 7 with formaldehyde;15 (b)
acid-catalyzed intramolecular cyclization of compound 8 (usu-
ally a ketone or alcohol),16 which was adopted in the discovery
synthesis of compound 1; an interesting variation of this strategy
involving a Pd-catalyzed intramolecular cross-coupling reaction
has also been recently reported;17 (c) nucleophilic addition of a
metal species to ketone 9;11,18 (d) intramolecular olefination
followed by a reduction.19
The requisite precursor 11 was easily prepared in a two-
step sequence.20 Reductive amination of 3-benzyloxybenzal-
dehyde with commercially available (2,2-dimethoxy-ethyl)-
methylamine followed by a Friedel–Crafts cyclization in a 6 N
aqueous HCl solution provided 11 in excellent yield on 50-g
scales (Scheme 5). Notably, the Friedel–Crafts cyclization took
place regioselectively at the para position of the benzyloxy
group. No ortho regioisomer was observed.
The key transformation, alkylation of compound 11 with
thioanisole, was then investigated. Direct Friedel–Crafts alkyla-
tion on benzyl alcohols is rarely found in the literature,6,21
presumably because benzylic carbocations (the active species
in the Friedel–Crafts alkylation) tend to decompose to the
corresponding olefins. Indeed, our initial attempt by adding 1
equiv of triflic anhydride to a solution of compound 11 with
10 equiv of thioanisole in CH2Cl2 yielded only 15% of
compound 10. Nevertheless, a variety of Brönsted and Lewis
acids were screened as the catalysts (Table 1). MeSO3H and
H2SO4 led to primarily decomposition (entries 2 and 3). The
Lewis acids FeCl3 and AlCl3 afforded no reaction (entries 4
and 5), and TiCl4 caused decomposition (entry 6). SnCl4
furnished desired product 10 in 34% yield, but the reaction was
messy (entry 7). Switching to BF3 ·Et2O afforded much cleaner
reactions. Two equivalents of BF3 ·Et2O were required for the
reaction to go to completion, presumably because the eliminated
H2O consumes 1 equiv of the Lewis acid (entries 9–11); 54%
isolated yield was obtained.22 Further increasing to 4 equiv of
BF3 ·Et2O did not improve the yield (entry 12). CH2Cl2 was
the preferred solvent; changing to tert-butyl methyl ether
(MTBE) led to no reaction or diminished yield (entries 8 and
13). It is important to note that the BF3 ·Et2O-mediated
Friedel–Crafts reaction took place exclusively at the para
position of thioanisole, and no detectable ortho substitution
product was observed. The attempts to promote this reaction
with catalytic amounts of water-stable Lewis acids such as
La(OTf)3 and Yb(OT)3 were not successful (entries 14–16),
The type c disconnection was particularly appealing to us
because of the better control of regioselectivity. However, the
literature methods involved the use of expensive organometallic
nucleophiles. Furthermore, two subsequent steps after the
nucleophilic addition were required to furnish the 4-aryl-
tetrahydroisoquinoline core (dehydration of the alcohol addition
product followed by reduction of the olefin). We reasoned that
a direct alkylation at the benzylic position of a suitable
tetrahydroisoquinoline precursor with electron-rich thioanisole
would provide a shorter overall sequence and easy access to
the required precursors. Therefore, a new strategy featuring
sequential Friedel–Crafts alkylations was devised, as depicted
in Scheme 4.
(12) (a) Jacob, J. N.; Nichols, D. E. J. Med. Chem. 1981, 24, 1013–1015.
(b) Maryanoff, B. E.; McComsey, D. F.; Gardocki, J. F.; Shank, R. P.;
Costanzo, M. J.; Nortey, S. O.; Schneider, C. R.; Setler, P. E. J. Med.
Chem. 1987, 30, 1433–1454.
(13) Chesworth, R.; Zawistoski, M. P.; Lefker, B. A.; Cameron, K. O.;
Day, R. F.; Mangano, F. M.; Rosati, R. L.; Colella, S.; Petersen, D. N.;
Brault, A.; Lu, B.; Pan, L. C.; Perry, P.; Ng, O.; Castleberry, T. A.;
Owen, T. A.; Brown, T. A.; Thompson, D. D.; Dasilva-Jardine, P.
Bioorg. Med. Chem. Lett. 2004, 14, 2729–2733.
(14) Wanner, K. T.; Beer, H.; Hoefner, G.; Ludwig, M. Eur. J. Org. Chem.
1998, 9, 2019–2029.
(15) (a) Bates, H. A. J. Org. Chem. 1981, 46, 4931–4935. (b) Bates, H. A.
J. Org. Chem. 1983, 48, 1932–1934. (c) Bates, H. A.; Bagheri, K.;
Vertino, P. M. J. Org. Chem. 1986, 51, 3061–3063. (d) Katakawa, J.;
Yoshimatsu, H.; Yoshida, M.; Zhang, Y.; Irie, H.; Yajima, H. Chem.
Pharm. Bull. 1988, 36, 3928–3932. (e) Ruchirawat, S.; Tontoolarug,
S.; Sahakitpichan, P. Heterocycles 2001, 55, 635–640.
(16) (a) Hara, H.; Shirai, R.; Hoshino, O.; Umezawa, B. Heterocycles 1983,
20, 1945–1950. (b) Zara-Kaczian, E.; Deak, G.; Szollosy, A.; Brlik,
J. Acta Chim. Hung. 1990, 127, 743–755. (c) Toda, J.; Sonobe, A.;
Ichikawa, T.; Saitoh, T.; Horiguchi, Y.; Sano, T. ARKIVOC 2000, 1,
165–180.
(20) Dyke, S. F.; Bather, P. A.; Garry, A. B.; Wiggins, D. W. Tetrahedron
1973, 29, 3881–3888.
(21) (a) Piccolo, O.; Azzena, U.; Melloni, G.; Delogu, G.; Valoti, E. J.
Org. Chem. 1991, 56, 183–187. (b) Noji, M.; Ohno, T.; Fuji, K.;
Futaba, N.; Tajima, H.; Ishii, K. J. Org. Chem. 2003, 68, 9340–9347.
(c) Branchaud, B. P.; Blanchette, H. S. Tetrahedron Lett. 2002, 43,
351–353.
(17) Honda, T.; Namiki, H.; Satoh, F. Org. Lett. 2001, 3, 631–633.
(18) Renaud, J.; Bischoff, S. F.; Buhl, T.; Floersheim, P.; Fournier, B.;
Halleux, C.; Kallen, J.; Keller, H.; Schlaeppi, J. M.; Stark, W. J. Med.
Chem. 2003, 46, 2945–2957.
(22) After the reaction was complete, only product 10 and unreacted
thioanisole were observed on HPLC and TLC analysis. Decomposition
of starting material 11 might have occurred, which led to weakly or
non-chromophoric side products.
(19) Couture, A.; Deniau, E.; Lebrun, S.; Grandclaudon, P. J. Chem. Soc.,
Perkin Trans. 1 1999, 789–794.
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Table 1. Acid-mediated Friedel–Crafts alkylation of
Whereas the mesylation of alcohol 4 went smoothly in quantita-
tive yield, we identified that the problem of the low yield resided
on the weak nucleophilicity of 4-fluoropiperidine. The chloride
ions present in the starting material were competing with
4-fluoropiperidine in the displacement of the mesylate (Scheme
7), resulting in byproduct 15. Once chloride 15 was formed,
displacement of 15 with 4-fluoropiperidine only took place at
a much higher temperature (ca. 200 °C). To solve this problem,
the 4-fluoropiperidine free base was freshly prepared from the
commercially available hydrochloride salt by partitioning
between water-immiscible tert-amyl alcohol and aqueous NaOH
solution. The tert-amyl alcohol solution of the 4-fluoropiperidine
free base24 was then used directly in the displacement reaction
of the mesylate at 100 °C to afford 1 in excellent yield. After
recrystallization from hot EtOH, pure (+)-(S)-1 was obtained
in 75% isolated yield. HPLC analysis indicated no racemization
occurred during the whole synthesis.
compound 11
entry
acid
solvent
result
15%a
1
1.0 equiv Tf2O
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MTBE
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MTBE
CH2Cl2
CH2Cl2
CH3NO2
2
2 equiv MeSO3H
1.5 equiv H2SO4
1.1 equiv FeCl3
decomposition
decomposition
SM
3
4
5
3.0 equiv AlCl3
SM
6
1.1 equiv TiCl4
decomposition
34%
7
1.1 equiv SnCl4
8
1.1 equiv SnCl4
decomposition
SM
9
0.5 equiv BF3 ·Et2O
1.2 equiv BF3 ·Et2O
2.0 equiv BF3 ·Et2O
4.0 equiv BF3 ·Et2O
2.0 equiv BF3 ·Et2O
0.1 equiv La(OTf)3
0.1 equiv Yb(OTf)3
0.1 equiv La(OTf)3
10
11
12
13
14
15
16
incomplete
54%
Conclusions
51%
In conclusion, a practical synthesis of enantiomerically pure
(+)-(S)-1 was developed (Scheme 8). This route features a novel
sequential Friedel–Crafts reaction strategy to construct the
4-aryl-tetrahydroisoquinoline core structure. A classic resolution
using D-di-p-toluoyl-tartaric acid was successfully performed
to provide enantiomerically pure material. Overall, this route
is concise, high-yielding and amenable for large-scale synthesis.
SM
SMb
SMb
SMb
a Ten equivalents of thioanisole were used. b No desired reaction was observed
even at reflux temperature overnight.
probably because the Lewis acids coordinate to the basic tertiary
amine. Nonetheless, to the best of our knowledge, this sequence
represented the first example of construction of a 4-aryl-
tetrahydroisoquinoline core structure through sequential Friedel–
Crafts reactions.
Experimental Section
General. All reagents and solvents were purchased from
commercial sources and used without further purification. H
1
and 13C NMR spectra were recorded on Bruker 500 (1H, 500
MHz; 13C, 125 MHz) or 400 (1H, 400 MHz; 13C, 100 MHz)
NMR spectrometers. Flash column chromatography was per-
formed using Merck silica gel 60. Reaction was monitored by
HPLC analysis (HP 1100, Agilent ZORBAX Eclipse XDB-
C8 column, 5 µm, 4.6 mm × 150 mm, flow rate 0.75 mL/min,
gradient (acetonitrile/water containing 0.05% trifluoroacetic
acid) of 1% acetonitrile/99% water to 99% acetonitrile/1% water
ramp over 8 min, then hold at 99% acetonitrile/1% water).
HRMS (ESI) was performed on a Bruker µTof. Analytical chiral
analysis was performed on a Hewlett Packard 1100 HPLC or
a Jasco 1580 series SFC. Melting points were determined in
open capillaries on a Mel-Temp apparatus and are uncorrected.
3-(3-Methylaminomethylphenoxy)propan-1-ol (2). To a
solution of 3-hydroxy-benzaldehyde (68 g, 0.56 mol, 1.0 equiv)
in CH3CN (1 L) were added K2CO3 (115 g, 0.83 mol, 1.5 equiv)
and 3-bromopropan-1-ol (93 g, 0.67 mol, 1.2 equiv) sequentially
at room temperature. The reaction mixture was stirred at reflux
temperature for 3 h and then cooled to room temperature.
EtOAc (500 mL) and H2O (500 mL) were added. The organic
layer was washed with water (500 mL × 2), brine (500 mL)
and dried over MgSO4. Evaporation of the solvents afforded
3-(3-hydroxy-propoxy)-benzaldehyde as a colorless oil (HPLC
retention time: 7.32 min, 101 g, 0.56 mol, 100%), which was
used directly in the next reaction. The crude 3-(3-hydroxy-
propoxy)-benzaldehyde was dissolved in EtOH (700 mL).
With gram quantities of racemic 10 in hand, we screened a
panel of commercially available optically pure acids10 and di-
p-toluoyl-tartaric acid stood out as the acid of choice. With 0.5
equiv of D-di-p-toluoyl-tartaric acid, the R enantiomer was
preferably precipitated from EtOH/CH3CN as a crystalline
diastereomeric hemi-tartrate salt 13 in >99% ee in 33%
recovery. Recrystallization of the mother liquor afforded another
crop of 13 in >99% ee to give an overall 40% recovery. A
single crystal X-ray structure of 13 was obtained to assign the
absolute stereochemistry (Figure 1). Basification of the diaster-
eomeric salt 13 with aqueous Na2CO3 solution afforded enan-
tiopure free base (–)-(R)-10, which was derivatized to compound
4. In comparison with enantiopure sample 4 previously sepa-
rated by chiral HPLC, the desired enantiomer was found to be
the S configuration. The same chiral resolution was then
performed with L-di-p-toluoyl-tartaric acid to provide (+)-(S)-
10 in identical results.23
Debenzylation of (+)-(S)-10 followed by alkylation with
3-bromopropan-1-ol furnished (+)-(S)-4 in 80% yield for two
steps (Scheme 6).
The final stage of synthesis of 1 is the introduction of the
4-fluoropiperidine moiety. The discovery conditions (Scheme
1) provided the desired compound 1 in only 35% yield even
with 4 equiv of expensive 4-fluoropiperidine hydrochloride.
(23) Attempts to racemize the undesired (–)-(R)-10 under strong basic
conditions or Pd-catalyzed hydrogenation conditions were not suc-
cessful.
(24) Neat 4-fluoropiperidine free base is highly volatile and difficult to
handle.
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Figure 1. X-ray structure of compound 13.
Scheme 6. Synthesis of compound 4
ethanone (125 g, 0.51 mol, 1.0 equiv) in portions over 20 min.
The reaction mixture was stirred at room temperature for 1 h.
After removal of the solvent via evaporation, the residue was
partitioned between EtOAc (1 L), saturated NaHCO3 aqueous
solution (500 mL) and water (500 mL). The aqueous layer was
further extracted with EtOAc (500 mL). The combined organic
layers were dried over MgSO4 and concentrated to afford 3 as
a colorless oil (165 g, 0.46 mol, 90%). No further purification
was performed. HPLC retention time: 7.00 min. 1H NMR (500
MHz, CDCl3, δ): 7.87 (dt, J ) 8.6, 1.9 Hz, 2H), 7.25–7.18 (m,
3H), 4.94–6.87 (m, 2H), 6.82–6.77 (m, 1H), 4.08 (t, J ) 6.0
Hz, 2H), 3.83 (t, J ) 6.0 Hz, 2H), 3.72 (s, 2H), 3.61 (s, 2H),
2.50 (s, 3H), 2.35 (s, 3H), 2.02 (penta, J ) 6.0 Hz, 2H). 13C
NMR (125.7 MHz, CDCl3, δ): 197.0, 158.9, 145.9, 139.9,
132.3, 129.3, 128.8, 124.8, 121.6, 115.0, 113.7, 65.6, 63.1, 62.0,
60.2, 42.9, 32.1, 14.7. HRMS-ESI (m/z): [M + H]+ calcd for
C20H26NO3S 360.1628, found 360.1627.
Scheme 7. Displacement of compound 4
3-[3-({[2-Hydroxy-2-(4-methylsulfanylphenyl)ethyl]-meth-
ylamino}-methyl)-phenoxy]-propan-1-ol (5). To a solution of
3 in MeOH (1 L) was added a solution of NaBH4 (9.7 g, 0.26
mol, 0.5 equiv) in H2O (70 mL) drop wise at 0 °C. The reaction
mixture was stirred at room temperature for 2 h. Aqueous 2
mol/L HCl solution was then added cautiously to quench the
unreacted NaBH4. After removal of MeOH via evaporation,
the residue was partitioned between EtOAc (1.2 L), saturated
NaHCO3 (600 mL) and water (600 mL). The aqueous layer
was further extracted with EtOAc (600 mL). The combined
organic layers were dried over MgSO4 and concentrated to
afford 5 as a colorless oil (167 g, 0.46 mol, 100%). No further
purification was performed. HPLC retention time: 6.85 min.
1H NMR (500 MHz, CDCl3, δ): 7.30–7.20 (m, 5H), 6.92–6.86
(m, 2H), 6.84–6.80 (m, 1H), 4.71 (dd, J ) 10.4, 3.5 Hz, 1H),
4.13 (t, J ) 6.0 Hz, 2H), 3.86 (t, J ) 5.9 Hz, 2H), 3.70 (d, J
) 13.1 Hz, 1H), 3.48 (d, J ) 13.1 Hz, 1H), 2.62–2.46 (m, 2H),
2.46 (s, 3H), 2.32 (s, 3H), 2.04 (penta, J ) 6.0 Hz, 2H). 13C
NMR (125.7 MHz, CDCl3, δ): 159.0, 139.9, 139.2, 137.4,
129.4, 126.8, 126.5, 121.5, 115.1, 113.4, 69.1, 65.7, 65.4, 62.3,
60.4, 41.9, 32.0, 16.1. HRMS-ESI (m/z): [M + H]+ calcd for
C20H28NO3S 362.1784, found 362.1777.
MeNH2 (40 wt % in water, 58 mL, 0.67 mol, 1.2 equiv) was
added over 20 min at 0 °C. After 10 min, NaBH4 (10.6 g, 0.28
mol, 0.5 equiv) was carefully added as solid. The reaction
mixture was stirred at 0 °C for 3 h. Aqueous 2.0 mol/L HCl
solution was slowly added until pH ) 2.0 to quench the
unreacted NaBH4. EtOH was evaporated, and the residue was
dissolved in H2O (700 mL). After being washed with EtOAc
(300 mL), the aqueous layer was basified with NaOH pellet to
pH ) 12 and then extracted with CH2Cl2 (300 mL × 3). The
combined organic layers were dried over MgSO4 and concen-
trated to afford 2 as a colorless oil (92 g, 0.48 mol, 85%). No
further purification was performed. HPLC retention time: 5.04
min. 1H NMR (500 MHz, CDCl3, δ): 7.23 (t, J ) 7.9 Hz, 1H),
6.94 (t, J ) 1.8 Hz, 1H), 6.89 (d, J ) 7.5 Hz, 1H), 6.81 (dd, J
) 8.2, 2.4 Hz, 1H), 4.13 (t, J ) 6.0 Hz, 2H), 3.83 (t, J ) 5.9
Hz, 2H), 3.74 (s, 2H), 2.44 (s, 3H), 2.02 (penta, J ) 6.0 Hz,
2H). 13C NMR (125.7 MHz, CDCl3, δ): 159.1, 140.3, 129.5,
120.9, 114.3, 113.7, 65.7, 60.2, 55.5, 35.4, 32.1. HRMS-ESI
(m/z): [M + H]+ calcd for C11H18NO2 196.1332, found
196.1328.
3-[2-Methyl-4-(4-methylsulfanylphenyl)-1,2,3,4-tetrahy-
droisoquinolin-7-yloxy]propan-1-ol (4). To a solution of 5
(185 g, 0.51 mol, 1.0 equiv) in CH2Cl2 (4 L) in an ice bath
was added methanesulfonic acid (296 g, 3.08 mol, 6.0 equiv)
drop wise under N2 (the internal temperature was kept below
20 °C). After the addition, the ice bath was removed, and the
reaction mixture was stirred at room temperature for 2 h.
2-{[3-(3-Hydroxypropoxy)benzyl]-methylamino}-1-(4-me-
thylsulfanylphenyl)ethanone (3). To a solution of 2 (100 g,
0.51 mol, 1.0 equiv) and EtNPri2 (80 g, 0.62 mol, 1.2 equiv) in
THF (1 L) was added 2-bromo-1-(4-methylsulfanyl-phenyl)-
Vol. 11, No. 6, 2007 / Organic Process Research & Development
•
1047

Scheme 8. A practical synthesis of (+)-S-1
Aqueous NaOH solution was then added cautiously to quench
the reaction until pH ) 12. The aqueous layer was further
extracted with CH2Cl2 (1 L). The combined organic layers were
dried over MgSO4 and concentrated to yield crude product as
a thick oil. EtOAc (∼2 mL/g) was added, and the solution was
heated to 70 °C to form a homogeneous solution. Upon cooling,
the desired regioisomer 4 precipitated as a white solid (∼75
g). The mother liquor was concentrated, and the above
procedure was repeated to give another crop of pure material
(∼12 g). The combined yield was 50% (87 g, 0.25 mol). HPLC
retention time: 7.02 min. Rf ) 0.37 (10% MeOH in EtOAc).
Mp: 49–52 °C. 1H NMR (500 MHz, CDCl3, δ): 7.24–7.16 (m,
2H), 7.14–7.08 (m, 2H), 6.80–6.74 (m, 1H), 6.68–6.60 (m, 2H),
4.24–4.12 (m, 1H), 4.08 (t, J ) 6.0 Hz, 2H), 3.84 (t, J ) 6.0
Hz, 2H), 3.69 (d, J ) 14.9 Hz, 1H), 3.58 (d, J ) 14.9 Hz, 1H),
3.03–2.95 (m, 1H), 2.56–2.46 (m, 1H), 2.46 (s, 3H), 2.41 (s,
3H), 2.02 (penta, J ) 6.0 Hz, 2H). 13C NMR (125.7 MHz,
CDCl3, δ): 157.0, 142.0, 136.4, 136.1, 130.4, 129.5, 129.4,
126.9, 113.2, 111.4, 65.8, 61.9, 60.6, 58.6, 45.9, 44.7, 32.0,
16.1. HRMS-ESI (m/z): [M + H]+ calcd for C20H26NO2S
344.1679, found 344.1687. The chiral HPLC retention times
(Chiralcel OJ-H column, 80/20 hexanes/EtOH, 0.9 mL/min, 25
°C) are 11.18 min for the desired (+)-(S)-enantiomer and 16.67
min for undesired (-)-(R)-enantiomer, respectively. Optical
rotation of the (+)-(S)-enantiomer: observed [R]20D ) +30.0°
(c 1.0, EtOH).
3-[2-Methyl-4-(4-methylsulfanylphenyl)-1,2,3,4-tetrahy-
droisoquinolin-5-yloxy]-propan-1-ol (6). The undesired re-
gioisomer was isolated via flash chromatography with MeOH/
EtOAc as the eluents. Rf ) 0.6 (10% MeOH in EtOAc). HPLC
retention time: 6.77 min. Mp: 67–71 °C. 1H NMR (500 MHz,
CDCl3, δ): 7.18–7.12 (m, 3H), 7.07–7.02 (m, 2H), 6.74 (d, J
) 7.6 Hz, 1H), 6.66 (d, J ) 8.1 Hz, 1H), 4.18 (t, J ) 4.2 Hz,
1H), 3.98–3.92 (m, 1H), 3.84 (d, J ) 15.0 Hz, 1H), 3.80–3.72
(m, 1H), 3.45–3.30 (m, 3H), 2.74 (d, J ) 4.4 Hz, 2H), 2.44 (s,
3H), 2.32 (s, 3H), 1.80–1.60 (m, 2H). 13C NMR (125.7 MHz,
CDCl3, δ): 156.6, 143.8, 137.2, 135.0, 128.6, 127.2, 126.8,
124.7, 118.7, 109.0, 65.1, 61.4, 60.0, 58.3, 46.2, 40.5, 31.7,
16.4. HRMS-ESI (m/z): [M + H]+ calcd for C20H26NO2S
344.1679, found 344.1671.
(3-Benzyloxybenzyl)-(2,2-dimethoxyethyl)-methylamine
(12). In a 1-L three-neck round-bottom flask cooled in a room
temperature water bath, (2,2-dimethoxy-ethyl)-methyl-amine
(12.1 mL, 94.2 mmol, 1.0 equiv) was added to a solution of
3-benzyloxy-benzaldehyde (20.0 g, 94.2 mmol, 1.0 equiv) in
CH2Cl2 (300 mL). NaBH(OAc)3 (24.0 g, 113 mmol, 1.2 equiv)
was added in portions. The reaction mixture was stirred at room
temperature for 18 h. Saturated aqueous NaHCO3 solution (300
mL) was added, and the mixture was stirred for 2 h. The organic
layer was separated, dried over Na2SO4, and evaporated to
afford 12 as a colorless oil (29.2 g, 92.3 mmol, 98%). HPLC
retention time: 7.88 min. 1H NMR (500 MHz, CDCl3, δ): 7.47
(pseudo d, J ) 7.4 Hz, 2H), 7.41 (pseudo t, J ) 7.2 Hz, 2H),
7.35 (tt, J ) 7.3, 1.3 Hz, 1H), 7.25 (t, J ) 7.3 Hz, 1H), 7.04
(pseudo s, 1H), 6.96 (d, J ) 7.7 Hz, 1H), 6.90 (dd, J ) 8.2,
2.0 Hz, 1H), 5.09 (s, 2H), 4.55 (t, J ) 5.3 Hz, 1H), 3.58 (s,
2H), 3.36 (s, 6H), 2.59 (d, J ) 5.3 Hz, 2H), 2.33 (s, 3H). 13
C
NMR (125.7 MHz, CDCl3, δ): 158.9, 140.6, 137.2, 129.2,
128.6, 127.9, 127.5, 121.7, 115.4, 113.6, 103.0, 69.9, 62.9, 58.4,
53.3, 43.3. HRMS-ESI (m/z): [M + H]+ calcd for C19H25NO3
316.1907, found 316.1911.
7-Benzyloxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-
ol (11). In a 3-L one-neck round-bottom flask equipped with a
magnetic stir bar, 12 (100 g, 0.32 mol, 1.0 equiv) was diluted
in 6 mol/L aqueous HCl solution (600 mL). The reaction
mixture was stirred at 40 °C for 18 h and then cooled to 0 °C.
With vigorous stirring, NaOH pellets were slowly added until
pH ) 13. The basic aqueous solution was extracted with EtOAc
(200 mL × 3). The combined organic layers were dried over
Na2SO4 and concentrated to afford a slightly yellow oil. The
crude oil was purified on a plug of silica gel (20 cm OD, 4 in.
height) with 95/5 EtOAc/MeOH as the eluents to afford 11 as
a yellow solid (77 g, 0.28 mol, 90%). HPLC retention time:
6.87 min. 1H NMR (500 MHz, CDCl3, δ): 7.45–7.43 (m, 2H),
7.41–7.38 (m, 2H), 7.36–7.34 (m, 2H), 6.90 (dd, J ) 8.4, 2.6
Hz, 1H), 6.59 (d, J ) 2.5 Hz, 1H), 5.07 (d, J ) 2.3 Hz, 2H),
4.57 (pseudo s, 1H), 3.50 (br s, 1H), 3.48 (d, J ) 15.0 Hz,
1H), 3.18 (d, J ) 15.0 Hz, 1H), 2.98 (ddd, J ) 11.7, 2.8, 1.2
Hz, 1H), 2.50 (dd, J ) 11.7, 2.7 Hz, 1H), 2.46 (s, 3H). 13C
NMR (125.7 MHz, CDCl3, δ): 158.1, 137.0, 136.3, 130.6,
129.1, 128.6, 128.0, 127.4, 113.9, 111.9, 70.0, 66.6, 60.7, 57.8,
1048
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Vol. 11, No. 6, 2007 / Organic Process Research & Development

46.0. HRMS-ESI (m/z): [M + H]+ calcd for C17H19NO2
270.1489, found 270.1484.
(125.7 MHz, CDCl3, δ): 171.5, 165.8, 157.5, 143.3, 138.7,
137.2, 136.8, 131.3, 130.3, 130.1, 129.5, 128.9, 128.6, 128.0,
127.7, 127.5, 127.4, 126.9, 114.8, 111.6, 73.7, 70.0, 58.4, 55.2,
42.5, 41.3, 21.6, 15.8. Optical rotation: observed [R]20D ) –0.8°
(c 1.0, CH2Cl2).
The same resolution was performed with (L)-di-p-toluolyl-
tartaric acid to provide the diastereomeric pure salt (S)-13 in a
similar yield. Basification of (S)-13 with aqueous Na2CO3
solution afforded enantiopure free base (+)-(S)-10. Analytic data
were identical to the sample previously isolated with chiral
HPLC.
7-Benzyloxy-2-methyl-4-(4-methylsulfanylphenyl)-1,2,3,4-
tetrahydroisoquinoline (10). In a 500-mL 1-neck round-bottom
flask equipped with a magnetic stir bar, 11 (33.9 g, 0.12 mol,
1.0 equiv) and thioanisole (14.8 mL, 0.12 mol, 1.0 equiv) were
dissolved in CH2Cl2 (200 mL). BF3 ·Et2O (32 mL, 0.25 mol,
2.0 equiv) was added drop wise at 0 °C. After stirring at 0 °C
for 2 h and then at room temperature overnight, the reaction
was quenched cautiously with 2 mol/L KOH aqueous solution
until pH ) 13. CH2Cl2 (200 mL) was added, and the insoluble
white solids were removed by filtration. The aqueous layer was
further extracted with CH2Cl2 (100 mL × 2). The combined
organic layers were dried over Na2SO4 and concentrated to
afford a dark oil. The crude oil was purified on a plug of silica
gel (20 cm o.d., ca. 4 in. height) with EtOAc as the eluent to
afford 10 as a colorless oil (25.4 g, 67 mmol, 54%). HPLC
(+)-(S)-2-Methyl-4-(4-methylsulfanylphenyl)-1,2,3,4-tet-
rahydroisoquinolin-7-ol [(+)-(S)-14]. In a 250-mL one-neck
round-bottom flask equipped with a magnetic stir bar, (+)-(S)-
10 (3.32 g, 8.8 mmol, 1.0 equiv) was diluted in a mixed solvent
of AcOH (23 mL) and aqueous HCl solution (37 wt %, 8 mL).
The mixture was heated at 60 °C for 8 h and then cooled to
room temperature. The solvents were evaporated, and the
residue was partitioned between EtOAc (60 mL) and cold
saturated Na2CO3 solution (60 mL). The aqueous layer was
further extracted with EtOAc (25 mL). The combined organic
layers were dried over Na2SO4 and concentrated to afford 14
as an off-white solid (2.42 g, 8.5 mmol, 96%). No further
1
retention time: 8.75 min. H NMR (500 MHz, CDCl3, δ):
7.48–7.31 (m, 5H), 7.19 (d, J ) 8.3 Hz, 2H), 7.11 (d, J ) 8.1
Hz, 2H), 6.78 (J ) 8.4 Hz, 1H), 6.72 (dd, J ) 6.0, 2.5 Hz,
1H), 6.69 (d, J ) 2.2 Hz, 1H), 5.02 (s, 2H), 4.17 (t, J ) 7.0
Hz, 1H), 3.69 (d, J ) 14.9 Hz, 1H), 3.58 (d, J ) 14.9 Hz, 1H),
2.98 (dd, J ) 5.8, 5.6 Hz, 1H), 2.51 (dd, J ) 8.6, 2.8 Hz, 1H),
2.47 (s, 3H), 2.41 (s, 3H). 13C NMR (125.7 MHz, CDCl3, δ):
157.0, 142.1, 137.1, 136.4, 136.0, 130.3, 129.48, 129.45, 128.5,
127.9, 127.4, 126.8, 113.5, 111.8, 70.0, 61.9, 58.6, 45.9, 44.7,
16.1. HRMS-ESI (m/z): [M + H]+ calcd for C24H26NOS
376.1730, found 376.1746. The chiral HPLC retention times
(Chiralcel OD-H 250 mm × 4.6 mm column, 9/1 hexane/EtOH,
1.0 mL/min, 43 bar, 25 °C) are 8.04 min for the desired (+)-
(S)-enantiomer and 7.14 min for the undesired (-)-(R)-
enantiomer, respectively. Optical rotation of the (+)-(S)-
1
purification was performed. H NMR (500 MHz, CDCl3, δ):
7.18 (d, J ) 8.3 Hz, 2H), 7.08 (d, J ) 8.3 Hz, 2H), 6.66 (d, J
) 8.4 Hz, 1H), 6.50 (dd, J ) 5.8, 2.6 Hz, 1H), 6.43 (d, J ) 2.5
Hz, 1H), 4.17 (dd, J ) 5.8, 3.1 Hz, 1H), 3.65 (d, J ) 14.9 Hz,
1H), 3.52 (d, J ) 14.9 Hz, 1H), 3.02 (m, 1H), 2.50 (dd, J )
9.2, 2.3 Hz, 1H), 2.46 (s, 3H), 2.42 (s, 3H). 13C NMR (125.7
MHz, CDCl3, δ): 154.8, 141.3, 136.3, 135.4, 130.4, 129.4,
128.1, 126.8, 114.8, 112.7, 61.8, 58.1, 45.5, 44.1, 16.0. HRMS-
ESI (m/z): [M + H]+ calcd for C17H20NOS: 286.1260, found:
286.1268. The chiral HPLC retention times (Chiralcel OJ-H
250 mm × 4.6 mm column, 85/15 hexane/EtOH, 1.0 mL/min,
47 bar, 25 °C) are 9.52 min for the desired (+)-(S)-enantiomer
and 14.0 min for the undesired (-)-(R)-enantiomer, respectively.
enantiomer: observed [R]20 ) +23.9° (c 1.0, EtOH).
D
Bis-7-benzyloxy-2-methyl-4-(4-methylsulfanylphenyl)-
1,2,3,4-tetrahydroisoquinoline, (D)-Di-p-toluolyltartaric Acid
(13). In a 1-L Erlenmeyer flask, 10 (24.6 g, 65 mmol, 1.0 equiv)
and (D)-di-p-toluoyl-tartaric acid (12.6 g, 33 mmol, 0.5 equiv)
were combined in EtOH (500 mL) and CH3CN (200 mL). The
mixture was heated until all solids dissolved. A small amount
of diastereomeric pure 13 (1–2 wt %) was added as seeds.25
The mixture was allowed to cool to room temperature and stand
for 5 h. The precipitated crystals were collected by filtration
and washed with EtOH to afford 13 (12.5 g) in >99% ee based
on HPLC analysis.26 The mother liquor was concentrated and
recrystallized twice with seeding to afford another 2.6 g of 13
in >99% ee. The combined recovery was 15.1 g in 40% yield.
A single crystal X-ray structure was obtained to assign the
absolute stereochemistry of 13 as the R configuration. Mp:
136–138 °C. 1H NMR (500 MHz, CDCl3, δ): 7.94 (d, J ) 8.1
Hz, 4H), 7.41–7.31 (m, 10H), 7.16 (d, J ) 8.3 Hz, 4H), 7.11
(d, J ) 8.0 Hz, 4H), 7.03 (d, J ) 8.3 Hz, 4H), 6.73–6.68 (m,
4H), 6.60 (d, J ) 1.7 Hz, 2H), 5.88 (s, 2H), 4.98 (s, 4H), 4.30
(dd, J ) 5.6, 4.8 Hz, 2H), 4.04 (d, J ) 15.3 Hz, 2H), 3.92 (d,
J ) 14.3 Hz, 2H), 3.36 (dd, J ) 6.6, 5.6 Hz, 2H), 2.77 (t, J )
23.3 Hz, 2H), 2.61 (s, 6H), 2.46 (s, 6H), 2.33 (s, 6H). 13C NMR
Optical rotation of the (+)-(S)-enantiomer: observed [R]20
+25.6° (c 1.0, EtOH).
)
D
(+)-(S)-3-[2-Methyl-4-(4-methylsulfanylphenyl)-1,2,3,4-
tetrahydroisoquinolin-7-yloxy]-propan-1-ol [(+)-(S)-4]. To
a solution of (+)-(S)-14 (1.54 g, 5.4 mmol, 1.0 equiv) in THF
(20 mL) was added KOBut (0.73 g, 6.5 mmol, 1.2 equiv) was
added at room temperature. After 10 min, 3-bromo-propanol
(0.90 g, 6.5 mmol, 1.2 equiv) was added. The reaction mixture
was stirred at 45 °C for 18 h and then cooled to room
temperature. H2O (20 mL) and EtOAc (20 mL) were added.
The organic layer was separated, dried with Na2SO4, and
concentrated to afford a thick oil. The crude oil was stirred in
Et2O (7 mL) and hexane (3 mL) for 48 h.27 The precipitated
solid was collected by filtration to give pure 4 (1.38 g, 4.0 mmol,
75%). The analytical data are identical to the sample previously
prepared.
(S)-7-[3-(4-Fluoro-piperidin-1-yl)-propoxy]-2-methyl-4-(4-
methylsulfanylphenyl)-1,2,3,4-tetrahydroisoquinoline [(+)-(S)-
1]. To the solution of (+)-(S)-4 (22.5 g, 65.6 mmol, 1.0 equiv)
and EtNPri2 (12.7 g, 99 mmol, 1.5 equiv) in CH2Cl2 (200 mL)
was added MsCl (8.25 g, 72 mmol, 1.1 equiv) was added via
(25) Without seeding, the ee of the precipitated crystal was ca. 60%.
(26) Diastereomeric salt 13 was basified with aqueous Na2CO3 solution to
free base 10. The ee was measured on 10.
(27) Too much solvent prevented the precipitation of the product.
Vol. 11, No. 6, 2007 / Organic Process Research & Development
•
1049

syringe under N2. After stirring at room temperature for 1.5 h,
the reaction was complete. The organic layer was washed with
saturated NaHCO3 (100 mL), dried over MgSO4, and concen-
trated to afford the corresponding mesylate (HPLC retention
time: 7.78 min), which was used in the next reaction right away.
Commercial starting material 4-fluoropiperidine hydrochloride
(12.8 g, 92 mmol, 1.4 equiv) was dissolved in 2 mol/L NaOH
aqueous solution (200 mL), which was extracted with tert-amyl
alcohol (200 mL). The tert-amyl alcohol layer was dried over
MgSO4 and filtered directly into the reaction vessel. The
mesylate previously prepared and EtNPri2 (34 g, 264 mmol,
4.0 equiv) were added sequentially. The reaction solution was
stirred at reflux temperature under N2 for 8 h and then cooled
to room temperature. The solvents were evaporated, and the
residue was dissolved in CH2Cl2 (500 mL). The organic layer
was washed with saturated NaHCO3 (200 mL), dried over
Na2SO4, and concentrated. Recrystallization of the crude product
from hot EtOH afforded pure 1 as a white solid (21 g, 49 mmol,
75%). HPLC retention time: 6.55 min. Mp: 97–99 °C. 1H NMR
(500 MHz, CDCl3, δ): 7.18 (dt, J ) 8.3, 1.8 Hz, 2H), 7.10 (dt,
J ) 8.3, 1.8 Hz, 2H), 6.76 (d, J ) 8.5 Hz, 1H), 6.66–6.58 (m,
2H), 4.76–4.56 (m, 1H), 4.15 (dd, J ) 7.8, 6.0 Hz, 1H), 3.97
(t, J ) 6.3 Hz, 2H), 3.68 (d, J ) 15.2 Hz, 1H), 3.58 (d, J )
14.8 Hz, 1H), 2.97 (ddd, J ) 11.3, 5.5, 0.8 Hz, 1H), 2.65–2.48
(m, 5H), 2.46 (s, 3H), 2.40 (s, 3H), 2.42–2.32 (m, 2H),
2.00–1.80 (m, 6H). 13C NMR (125.7 MHz, CDCl3, δ): 157.2,
142.2, 136.4, 136.1, 130.3, 129.5, 129.1, 126.9, 113.3, 111.4,
89.34, 89.32, 88.0, 66.2, 62.0, 58.6, 55.1, 49.70, 49.66, 45.9,
44.7, 31.6, 31.4, 27.1, 16.1. HRMS-ESI (m/z): [M + H]+ calcd
for C25H34FN2OS 429.2370, found 429.2362. The chiral SFC
retention times (Chiralcel AD-H column, 30% IPA/0.2% Et3N,
100 bar, 2 mL/min, 25 °C) are 10.5 min for the desired (+)-
(S)-enantiomer and 5.9 min for the undesired (–)-(R)-enanti-
omer, respectively. Optical rotation of the (+)-(S)-enantiomer:
observed [R]20 ) +25.6° (c 1.0, EtOH).
D
7-(3-Chloropropoxy)-2-methyl-4-(4-methylsulfanylphenyl)-
1,2,3,4-tetrahydroisoquinoline (15). Compound 15 was iso-
lated as the major byproduct when 4-fluoro-piperidine hydro-
chloride was used directly in the alkylation reaction. HPLC
1
retention time: 8.42 min. H NMR (500 MHz, CDCl3, δ):
7.24–7.16 (m, 2H), 7.14–7.08 (m, 2H), 6.77 (d, J ) 8.5 Hz,
1H), 6.67–6.60 (m, 2H), 4.21–4.14 (m, 1H), 4.07 (t, J ) 5.8
Hz, 2H), 3.74 (t, J ) 6.4 Hz, 2H), 3.70 (d, J ) 14.8 Hz, 1H),
3.59 (d, J ) 14.8 Hz, 1H), 3.02–2.95 (m, 1H), 2.56–2.46 (m,
1H), 2.46 (s, 3H), 2.41 (s, 3H), 2.26–2.16 (m, 2H). 13C NMR
(125.7 MHz, CDCl3, δ): 156.9, 142.0, 136.3, 136.1, 130.4,
129.5, 129.4, 126.9, 113.3, 111.4, 64.2, 61.8, 58.5, 45.9, 44.7,
41.5, 32.3, 16.1. HRMS-ESI (m/z): [M + H]+ calcd for
C20H25ClNOS 362.1340, found 362.1333.
Acknowledgment
We wish to thank Mr. Jozef Proost in Johnson & Johnson
PRD BEERSE, Belgium, for conducting chiral HPLC separa-
tion of compound 4, and Dr. Jiejun Wu for analytical support.
Supporting Information Available
1H and 13C spectra of compounds 1–6 and 10–15 and X-ray
data of compound 13. This material is available free of charge
via the Internet at http://pubs.acs.org.
Received for review August 10, 2007.
OP700183Q
1050
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