Practical and sustainable synthesis of optically pure levocabastine, a H1 receptor antagonist

Article abstract of DOI:10.3390/molecules22111971

A practical and sustainable method for the synthesis of levocabastine hydrochloride (1), a H₁ receptor antagonist for the treatment of allergic conjunctivitis, that can be applied to the industrial production of the compound has been developed. Substantial improvements over the previously reported procedure are achieved via efficient preparation of an optically active key intermediate (5) without chiral resolution and with a more effective detosylation, which complements the previous procedure. Notably, our process requires no chromatographic purification and provides levocabastine hydrochloride in greater than 99.5% purity in a 14.2% overall yield.

Full text of DOI:10.3390/molecules22111971

molecules
Article
Practical and Sustainable Synthesis of Optically
Pure Levocabastine, a H1 Receptor Antagonist
Sung Kwon Kang 1,2, Dong Hyuk Nam 2, Jaeseung Ahn 2, Jaemin Lee 2, Jaehoon Sim 1,
Jeeyeon Lee 1 and Young-Ger Suh 1,3,
*
1
College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea;
skkang@ckdpharm.com (S.K.K.); jaehoonsim87@gmail.com (J.S.); jyleeut@snu.ac.kr (J.L.)
Department of Synthetic Chemistry, Chong Kun Dang Research Institute, 315-20, Dongbaekjukjeon-daero,
Giheung-gu, Yongin-si 16995, Gyeonggi-do, Korea; namdh@ckdpharm.com (D.H.N.);
jaeseung@ckdpharm.com (J.A.); jmlee88@ckdpharm.com (J.L.)
2
3
College of Pharmacy, Cha University, 120 Haeryong-ro, Pocheon 11160, Gyeonggi-do, Korea
Correspondence: ygsuh@snu.ac.kr; Tel.: +82-2-880-9174
*
Received: 23 October 2017; Accepted: 11 November 2017; Published: 15 November 2017
Abstract: A practical and sustainable method for the synthesis of levocabastine hydrochloride (1),
a H1 receptor antagonist for the treatment of allergic conjunctivitis, that can be applied to the industrial
production of the compound has been developed. Substantial improvements over the previously
reported procedure are achieved via efficient preparation of an optically active key intermediate (5)
without chiral resolution and with a more effective detosylation, which complements the previous
procedure. Notably, our process requires no chromatographic purification and provides levocabastine
hydrochloride in greater than 99.5% purity in a 14.2% overall yield.
Keywords: levocabastine; anti-histamine; H1 receptor antagonist
1. Introduction
Histamine is a low-molecular-weight amine derived from the decarboxylation of histidine.
It is an important mediator of local immune response as well as many biological processes related to
inflammation, gastric acid secretion, and neuromodulation. Because of its potent and diverse biological
activities, the systemic level of histamine must be carefully regulated during its synthesis, transport,
storage, release, and degradation [1–3].
The H1R, H2R, H3R, and H4R histamine receptors are G-protein-coupled transmembrane receptors
that transduce extracellular signals. They play an important role not only in immune modulation
but also in acute and chronic allergic inflammation [4]. Anti-histamines, acting as antagonists
to the histamine receptors, primarily block the acute allergic response. However, the expression,
signal transduction, and function of anti-histamines differ because of an affinity for each of the various
histamine receptors responsible for that symptom [5–12]. In particular, the histamine H1 receptor has
long been thought to mediate inflammatory responses by the liberation of histamine, and a number of
H1 receptor antagonists have been used to treat allergies for many years (Figure 1).
Levocabastine hydrochloride (
was discovered in 1979 by Janssen. Since then, it has been used in clinical formulations such as
eye drops and nasal sprays for the treatment of allergic conjunctivitis and rhinitis [13 15]. Despite its
clinical importance, only two synthetic methods for the preparation of levocabastine have been
reported [16 17]. These processes involve the preparation of key intermediate by chiral resolution,
the deprotection of intermediate by electrolysis, and the coupling of piperidine and ketone by
1), a selective second-generation H1 receptor antagonist,
–
,
6
5
6
7
reductive amination (Scheme 1). However, a low yield (22.8%) in the chiral resolution, the requirement
of special equipment for electrolysis, and the expensive platinum catalyst for the reductive amination
Molecules 2017, 22, 1971; doi:10.3390/molecules22111971
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Molecules 2017, 22, 1971
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remain as drawbacks when adapting this process to industrial production. Thus, there has been
an increasing need to develop a substantially improved method for the synthesis of levocabastine.
Figure 1. Representative H1 receptor antagonists.
Scheme 1. The reported synthesis of levocabastine hydrochloride.
Recently, we carefully developed a practical and efficient method for the synthesis of levocabastine
hydrochloride. Considering the previous elegant synthesis of levocabastine hydrochloride, we retained
the concept of the previous synthetic strategy, and we focused on developing a sustainable synthetic
procedure for key intermediate
Thus, the key part of our strategy involves the efficient preparation of optically pure intermediate
in a high yield from commercially available epoxide , facile detosylation in place of electrolysis,
with ketone to afford optically pure intermediate
5 and producing the final levocabastine with a high optical purity.
5
9
and a high-yielding reductive coupling of amine
as outlined in Scheme 2.
6
7
8,

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Scheme 2. Strategy for the practically improved synthesis of levocabastine hydrochloride.
2. Results and Discussion
2.1. Synthesis of Optically Pure Intermediate 5
We avoided chiral resolution, which inherently lowers the reaction yield, in our preparation of
optically pure intermediate 5 by utilizing optically active epoxide 9, as outlined in Scheme 3.
Scheme 3. Synthesis of key intermediate 5 in an optically active form.
Optically pure diol 10, prepared by N-alkylation of commercially available (S)-propylene oxide
9
with ethanolamine, was subjected to global tosylation to provide tosylate 11. Facile cyclization of 11
with benzyl cyanide afforded cyanide 12 as a 1:1 diastereomeric mixture. The hydrolysis of cyanide 12
with potassium hydroxide produced acid 13 as a 1:1 diastereomeric mixture. Finally, the esterification of
acid 13, followed by recrystallization, afforded key intermediate
than 99% dr. At this stage, we attempted the facile separation of the desired intermediate
5
with a diastereomeric purity of more
by simple
5
recrystallization of the diastereomeric mixture (instead of a delicate chiral resolution) on the basis of the
distinct physical properties of the diastereomers, particularly solubility. We thoroughly explored the
recrystallization of a number of intermediates (12, 13 and 5) and the results are summarized in Table 1.
Recrystallization of the diastereomeric mixture of cyanide 12 only slightly improved the
diastereomeric ratio (less than 53% dr) regardless of the temperature, time, or solvent (entries 1–4).
In the case of acid 13, the diastereomeric ratio was greatly improved to more than 95% dr (entries 5
and 6); however, the low yield limits the utility of this procedure. Fortunately, recrystallization
of ester
5 provided a good diastereomeric ratio (over 98% dr) and a good yield (41.5%; entries 7
and 8). Accordingly, the overall yield for the preparation of ester intermediate
approximately 24.8% (from 4.6% to 29.4%).
5 was improved by

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Table 1. Recrystallization of intermediates 12, 13 and 5.
Diastereomeric Diastereomeric Ratio
Yield (%) b
Entry
Intermediate
Temperature
Time (h)
Solvent
Ratio of 12, 13
of 12, 13 and 5 after
and 5 a
Recrystallization a
1
2
3
4
5
6
7
12
12
12
12
13
13
5
Reflux to r.t.
1
1
MeOH
MeOH/CHCl3
Acetone
40:60
40:60
53:47:00
48:52:00
50:50:00
46:54:00
98:02:00
95:05:00
99:01:00
98:02:00
70.8
68.3
66.5
71.2
23
1
40:60
R.t.
6
MeCN/MeOH
IPE
40:60
Reflux to r.t.
1
50:50:00
50:50:00
52:48:00
52:48:00
◦
40
C
1.5
16
16
IPE
22.9
41.5
38.2
◦
R.t. to 0
C
MeOH/IPE
8
5
MeOH/HEX/IPE
a
b
Diastereoselectivity was determined by HPLC;
Isolated yield. Abbreviations: r.t.—room temperature,
IPE—diisopropyl ether, HEX—n-hexane.
2.2. Deprotection of Tosylate 5
Although intermediate
6 was obtained by electrolysis of ester 5 in a good yield according
to the procedure described in a previous report [18], electrolysis requires special equipment.
Thus, we looked for a convenient and economical process for detosylation under the conditions
shown in Table 2 [19–25]. The treatment of intermediate
5 with tetra n-butylammonium fluoride
(TBAF), thiophenol, and trimethylsilane did not provide the desired product (entries 1–4). Detosylation
with low-valent titanium prepared from Ti(OiPr)4/Mg powder was also not successful (entry 5).
Interestingly, the reaction of ester
the desired product in a 68% yield (entry 6). We further optimized the detosylation conditions
(entries 7–9) on the basis of entry 6. Finally, the reaction of ester with potassium diphenylphosphide
in the best yield (69.5%), although
5 with potassium diphenylphosphide (KPPh2) [26] provided
6
5
in tetrahydrofuran (THF) at
the yield was still not ideal.
−
40 ◦C for 3 h afforded free amine
6
Table 2. Convenient detosylation of intermediate 5.
◦
Entry
Reagents (eq.)
Temperature ( C)
Reaction Time (h)
Solvent
THF
Yield (%) a
NR b
1
2
TBAF (10.0)
Thiophenol (1.3)/K2CO3
(2.0)
Reflux
5
21
DMF/MeCN
NR
3
4
5
6
7
8
9
TMSCl (1.5)/NaI (1.5)
TMSI (neat)
Mg (5.0)/Ti(OiPr)4 (1.0)
0.5 M KPPh2 in THF (1.3)
0.5 M KPPh2 in THF (1.3)
17
1
21
24
3
MeCN
—
THF
NR
NR
NR
68
69.5
43.7
30.4
80
50
−78
−40
−20
0
3
3
a
b
Isolated yield; No reaction. Abbreviations: DMF—dimethylformamide, TMSCl—trimethylsilyl chloride,
TMSI—trimethylsilyl iodide, HEX—n-hexane).
2.3. Completion of the Levocabastine Hydrochloride Synthesis
The coupling of piperidine
6 with cyclohexanone 7 is an essential step for the completion of
the levocabastine synthesis. In the previous synthesis, the use of an expensive platinum catalyst
for reductive amination was a weak point in terms of commercial production of this compound.
Thus, we focused on the development of an economical process for reductive amination using
an inexpensive reducing agent. After numerous attempts, we successfully achieved the coupling

Molecules 2017, 22, 1971
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of piperidine
6
and cyclohexanone
7
in the presence of NaBH(OAc)3. It is worth nothing that the use
of NaBH(OAc)3 as a reducing agent without a catalyst provided amine
(83:17) in a 95.5% yield. After recrystallization, amine was obtained in a 74% yield with a high
diastereomeric purity (greater than 99.9%). Having accomplished the synthesis of tertiary amine
8 as a diastereomeric mixture
8
8,
we completed the synthesis of levocabastine. The hydrogenolysis of benzyl ester 8 using ammonium
formate in the presence of Pd(OH)2 followed by salt formation with 3.0 M HCl provided levocabastine
hydrochloride 1 with an optical purity of greater than 99.9%, as outlined in Scheme 4.
Scheme 4. Completion of the synthesis of levocabastine hydrochloride (1).
3. Materials and Methods
3.1. General Information
1H-NMR spectra and 13C-NMR spectra were recorded using a Bruker DPX 400 (Bruker Biospin
Gmbh, Rheinstetten, Germany) spectrometer. All purity values were obtained by HPLC analysis
using HPLC 1200 Series from Agilent Technologies (Santa Clara, CA, USA). All NMR spectra were
measured using 400 UltraShield NMR (Bruker Biospin Gmbh, Rheinstetten, Germany). Chemical
shifts were expressed in parts per million (ppm,
δ
) and referenced to D2O (4.79 ppm for 1H), CDCl3
(7.26 ppm for H and 77.0 ppm for 13C), and CD3OD (4.87 ppm for H and 49.2 ppm for 13C).
1H-NMR data were reported in the order of chemical shift, multiplicity (s, singlet; d, doublet; q, quartet;
m, multiplet; dd, doublet of doublets; td, triplet of doublets), the number of protons, and coupling
constant in hertz (Hz). High-resolution mass spectra were obtained with a Synapt G2 instrument
(Waters Corporation, Milford, MA, USA).
1
1
HPLC analysis (compounds 11 and 12): YMC-Pack ODS AQ; 4.6 mm
×
250 mm (3 µm);
λ = 220 nm; flow rate: 0.5 mL/min; column temperature: 37 ◦C; mobile phase: (30:70) H2O/MeOH.
HPLC analysis (compounds 13 and
flow rate: 0.5 mL/min; column temperature: 37 C; mobile phase: (20:80) buffer: MeOH/buffer:
0.024 M Bu4NHSO4 solution.
5
): YMC-Pack ODS AQ; 4.6 mm
×
250 mm (3 µm); λ = 220 nm;
◦
HPLC analysis (compounds
= 210 nm; flow rate: 0.5 mL/min; column temperature: 60 C; mobile phase: (20/80) buffer:
6
,
8
and
1
): Acquity UPLC BEH Phenyl; 2.1 mm
×
100 mm (1.7 µm);
◦
λ
acetonitrile/buffer: 0.05 M Bu4NHSO4 solution.
3.2. Experimental Part
(S)-1-[(2-Hydroxyethyl)amino]propan-2-ol (10). To a stirred solution of ethanolamine (800.0 g, 13.10 mol)
◦
in purified water (1640 mL), (S)-propylene oxide (115 mL, 1.64 mol) was slowly added at 0 C.
The mixture was stirred for 1 h at the same temperature and for 4 h at room temperature. The reaction

Molecules 2017, 22, 1971
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◦
mixture was concentrated under reduced pressure at 90 C. Diol 10 was obtained as a yellow oil
(207.0 g). This product was used in the next step without further purification; 1H-NMR (400 MHz,
D2O): δ 1.15 (d, 3H, J = 6.4 Hz), 2.57–2.59 (m, 2H), 2.70–2.73 (m, 2H), 3.66 (td, 2H, J = 5.7 Hz, 2.1 Hz),
3.91 (dd, 1H, J = 6.4 Hz, 5.9 Hz). 13C-NMR (100 MHz, CDCl3):
δ 64.8, 59.6, 56.1, 50.9, 21.0. HRMS: Calcd.
for C5H13NO2 [M + H]+ 120.1025; found 120.1025.
(S)-1-({4-Methyl-N-[2-(tosyloxy)ethyl]phenyl}sulfonamido)propan-2-yl-4-methyl benzenesulfonate (11). To a stirred
solution of p-toluenesulfonylchlrode (260.0 g, 1.36 mol) in pyridine (75 mL), diol 10 (50.0 g) in pyridine
(200 mL) was slowly added at 0 ◦C. The mixture was stirred for 48 h at the same temperature and
quenched with H2O (700 mL) and dichloromethane (700 mL) at room temperature. The reaction slurry
was washed with 4.0 M HCl solution (700 mL) and 10% NaCl solution (900 mL) and was concentrated
in vacuo to afford tosylate 11 as a yellow oil (233.0 g). This product was used in the next step without
further purification; 1H-NMR (400 MHz, CDCl3):
2.46 (s, 3H), 3.15–3.28 (m, 3H), 3.33–3.39 (m, 1H), 4.06–4.13 (m, 2H), 4.77 (q, 1H, J = 6.2 Hz), 7.26–7.36
(m, 6H), 7.61 (d, 2H, J = 8.3 Hz), 7.73–7.78 (m, 4H). 13C-NMR (100 MHz, CDCl3):
145.3, 145.1, 144.3,
δ 1.21 (d, 3H, J = 6.4 Hz), 2.43 (s, 3H), 2.45 (s, 3H),
δ
135.0, 133.7, 132.5, 130.1, 128.1, 128.0, 127.5, 77.8, 68.2, 54.4, 49.0, 25.5, 21.8, 21.7, 18.3. HRMS: Calcd. for
C26H31NO8S3 [M + Na]+ 604.1110; found 604.1111.
(3S)-3-Methyl-4-phenyl-1-tosylpiperidine-4-carbonitrile (12). To a suspension of sodium amide (48.5 g, 1.24 mol)
in THF (675 mL), a solution of benzyl cyanide (115 mL, 1.64 mol) in THF (460 mL) was slowly added
at 0 ◦C. The mixture was stirred for 1 h at room temperature, and a solution of tosylate 11 (233.0 g) in
THF was added dropwise for 1 h at 0 ◦C. The reaction mixture was stirred for 2 h at 40 ◦C, cooled to
0 ◦C, and 15% NH4Cl solution (140 mL) was added. The reaction slurry was distilled until the THF
was completely removed. To the concentrated mixture, purified water (1000 mL) and dichloromethane
(1000 mL) were added, and the reaction slurry was stirred for 30 min. The organic layer was washed
with 10% NaCl solution (1000 mL) and concentrated under reduced pressure. The residue was dissolved
◦
with MeOH (230 mL). The resulting solution was stirred for 1 h at 75 C, for 30 min at room temperature,
and for 1 h at 0 ◦C. The precipitate was filtered and then dried to afford cyanide 12 as a white solid
1
(80.3 g, 70.8% for three steps); H-NMR (400 MHz, CDCl3):
δ 0.81–0.85 (m, 3H), 2.09–2.13 (m, 1H),
2.26–2.44 (m, 2H), 2.48–2.49 (m, 3H), 2.58–3.04 (m, 2H), 3.74–3.91 (m, 1H), 3.96–4.09 (m, 1H), 7.28–7.46
(m, 7H), 7.68–7.72 (m, 2H). 13C-NMR (100 MHz, CDCl3):
144.2, 144.1, 137.8, 137.6, 133.2, 133.0, 130.1,
δ
129.3, 128.6, 127.7, 127.6, 126.3, 126.0, 122.6, 119.2, 50.0, 49.7, 49.5, 44.2, 44.0, 43.8, 39.1, 38.3, 37.8, 26.6,
21.7, 14.2, 12.4. HRMS: Calcd. for C20H22N2O2S [M + H]+ 355.1480; found 355.1481; dr = 53.1:46.9.
(3S)-3-Methyl-4-phenyl-1-tosylpiperidine-4-carboxylic acid (13). To a stirred solution of cyanide 12 (80.3 g,
0.23 mol) in ethylene glycol (400 mL), potassium hydroxide (89.0 g, 1.59 mol) was added. The reaction
mixture was stirred for 44 h at 170 ◦C, cooled to room temperature, and dichloromethane (562 mL)
◦
was added. The reaction slurry was slowly quenched with 2.0 M HCl solution (900 mL) at 0 C.
The organic layer was washed with 10% NaCl solution (800 mL) and concentrated in vacuo to afford
acid 13 as a yellow oil (92.3 g). This product was used in the next step without further purification;
1H-NMR (400 MHz, CDCl3):
δ
0.78–1.14 (m, 3H), 2.28–2.39 (m, 2H), 2.41–2.45 (m, 3H), 2.53–2.90
(m, 2H), 3.00–3.18 (m, 2H), 3.62–3.95 (m, 1H), 7.25–7.38 (m, 8H), 7.58–7.66 (m, 2H). 13C-NMR (100 MHz,
CDCl3):
δ 179.3, 179.0, 143.6, 140.3, 139.0, 133.8, 129.9, 129.8, 129.0, 128.9, 127.7, 127.6, 127.5, 127.0, 126.1,
52.8, 52.1, 50.1, 48.5, 44.4, 43.1, 34.4, 25.9, 21.7, 21.6, 14.8, 13.5. HRMS: Calcd. for C20H23NO4S [M + H]+
374.1426; found 374.1423.
(3S,4R)-Benzyl-3-methyl-4-phenyl-1-tosylpiperidine-4-carboxylate (5). To a stirred solution of acid 13 (92.3 g)
in DMF (320 mL), potassium carbonate (37.6 g, 0.27 mol) and benzyl bromide (32.4 g, 0.27 mol) were
added. The reaction mixture was stirred for 3 h at room temperature, cooled to 0 ◦C, and quenched
with 10% NH4Cl solution (600 mL) and ethyl acetate (500 mL). The organic layer was washed with 10%
NaCl solution (500 mL) and concentrated under reduced pressure. The residue was clearly dissolved
with MeOH (60 mL). To the resulting solution, isopropyl ether (360 mL) was added, and the solution

Molecules 2017, 22, 1971
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◦
was stirred at room temperature for 15 h and at 0 C for an additional 1 h. The precipitate was filtered
1
and then dried to afford ester
CDCl3):
3.57–3.61 (m, 1H), 3.87–3.90 (m, 1H), 4.93 (dd, 2H, J = 21.2 Hz, 12.3 Hz), 6.96–6.98 (m, 2H), 7.17–7.21
(m, 2H), 7.23–7.33 (m, 8H), 7.57–7.60 (m, 2H). 13C-NMR (100 MHz, CDCl3):
173.8, 143.4, 140.6, 135.5,
5
as a white solid (42.9 g, 41.5% for two steps); H-NMR (400 MHz,
δ
0.79 (d, 3H, J = 7.0 HZ), 2.19–2.29 (m, 2H), 2.46 (s, 3H), 2.56–2.62 (m, 2H), 2.92–2.95 (m, 1H),
δ
133.4, 129.8, 128.8, 128.5, 128.2, 127.9, 127.6, 127.5, 126.0, 66.8, 52.4, 50.2, 44.5, 34.5, 25.9, 21.7, 13.5.
HRMS: Calcd. for C27H29NO4S [M + H]+ 464.1896; found 464.1894; dr = 99.4:0.6.
Convenient detosylation of intermediate 5 (Table 2).
(3S,4R)-Benzyl-3-methyl-4-phenylpiperidine-4-carboxylate (
ester (46 mg, 0.10 mmol) in THF (10 mL), TBAF in THF (1.00 mmol) was added at room temperature.
The reaction mixture was stirred for 5 h under refluxing conditions. No reaction (by TLC) was observed.
6, entry 1 in Table 2). To a stirred solution of
5
(3S,4R)-Benzyl-3-methyl-4-phenylpiperidine-4-carboxylate ( , entry 2 in Table 2). To a stirred solution of
6
ester (46 mg, 0.10 mmol) in THF (10 mL) and acetonitrile (10 mL), potassium carbonate (28 mg,
5
0.20 mmol) and thiophenol (14 mg, 0.13 mmol) were added at room temperature. The reaction mixture
was stirred for 21 h under refluxing conditions. No reaction (by TLC) was observed.
(3S,4R)-Benzyl-3-methyl-4-phenylpiperidine-4-carboxylate (6, entry 3 in Table 2). To a suspension of sodium
iodide (23 mg, 0.15 mmol) in ACN (10 mL), trimethylsilyl chloride (16 mg, 0.15 mmol) was slowly
◦
added at 0 C. To the mixture, ester
5 (46 mg, 0.10 mmol) was added. The reaction mixture was stirred
for 17 h under refluxing conditions. No reaction (by TLC) was observed.
(3S,4R)-Benzyl-3-methyl-4-phenylpiperidine-4-carboxylate ( , entry 4 in Table 2). To a reaction flask, ester
6
5
(49 mg, 0.11 mmol) and iodotrimethylsilane (1 mL, 0.75 mmol) were added. The reaction mixture was
stirred for 1 h at 80 ◦C. No reaction (by TLC) was observed.
(3S,4R)-Benzyl-3-methyl-4-phenylpiperidine-4-carboxylate (
6, entry 5 in Table 2). To a stirred solution of
ester (100 mg, 0.22 mmol) in THF (10 mL), Mg (26 mg, 1.08 mmol) was added at room temperature.
5
The mixture was stirred for 30 min at the same temperature and titanium isopropoxide (61 mg,
0.22 mmol) and trimethylsilyl chloride (35 mg, 0.32 mmol) were added. The reaction mixture was
stirred 21 h at 50 ◦C. No reaction (by TLC) was observed.
(3S,4R)-Benzyl-3-methyl-4-phenylpiperidine-4-carboxylate (
ester (50.0 g, 0.11 mol) in THF (500 mL), 0.5 M potassium diphenylphosphide solution (280 mL,
0.14 mol) was added dropwise at
40 ◦C. The mixture was stirred for 3 h at the same temperature.
6, entry 7 in Table 2). To a stirred solution of
5
−
To the reaction slurry, 2.0 M HCl solution (250 mL) was added, and the mixture was stirred for 2 h
at room temperature. The reaction mixture was quenched with 10% NaHCO3 solution (1000 mL)
and ethyl acetate (800 mL). The organic layer was concentrated under reduced pressure to afford
piperidine
6
as a yellow oil (67.5 g). This product was used in the next step without further purification;
0.75 (d, 3H, J = 7.4 Hz), 2.27 (td, 1H, J = 13.7 Hz, 4.2 Hz), 2.59–2.63
1H-NMR (400 MHz, CD3OD):
δ
(m, 1H), 2.75 (td, 1H, J = 13.4 Hz, 2.8 Hz), 2.97–3.00 (m, 1H), 3.09–3.24 (m, 2H), 3.31–3.35 (m, 1H),
5.12 (dd, 2H, J = 12.2 Hz, 5.8 Hz), 7.13–7.15 (m, 2H), 7.24–7.37 (m, 8H). 13C-NMR (100 MHz, CD3OD):
δ
174.8, 141.7, 137.1, 129.9, 129.5, 129.3, 129.2, 128.6, 126.9, 68.1, 53.1, 43.8, 34.5, 25.5, 13.4. HRMS: Calcd.
for C20H23NO2 [M + H]+ 310.1807; found 310.1811.
(3S,4R)-Benzyl-1-[(1S,4R)-4-cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenylpiperidine-4-carboxylate (8).
To a suspension of piperidine 6 (67.5 g) in dichloromethane (400 mL), ketone 7 (56.2 g, 0.26 mol) and
NaBH(OAc)3 (57.2 g, 0.27 mol) were added at room temperature. The reaction mixture was stirred
for 24 h and quenched with 10% NaHCO3 solution (700 mL) at the same temperature. The organic
layer was washed with 10% NaCl solution (600 mL), and concentrated in vacuo. The residue was
clearly dissolved with methanol (500 mL) at 60 ◦C. The resulting solution was stirred for 2 h at room
temperature. The precipitate was filtered and then dried to afford tertiary amine
8 as an off-white solid
(28.4 g, 51.5% for two steps); 1H-NMR (400 MHz, CDCl3):
δ
0.76 (d, 3H, J = 7.0 Hz), 1.76–1.91 (m, 6H),

Molecules 2017, 22, 1971
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2.19–2.24 (m, 3H), 2.32–2.38 (m, 2H), 2.57–2.60 (m, 1H), 2.65–2.71 (m, 2H), 2.94 (d, 2H, J = 9.2 Hz), 5.11
(dd, 2H, J = 24.6 Hz, 12.4 Hz), 7.08–7.12 (m, 2H), 7.17–7.20 (m, 2H), 7.24–7.39 (m, 8H), 7.46–7.49 (m, 2H).
13C-NMR (100 MHz, CDCl3):
δ 174.8, 163.5, 161.1, 141.9, 136.6, 136.1, 128.6, 128.5, 128.1, 127.5, 127.4,
127.0, 126.3, 122.4, 116.0, 115.8, 66.6, 62.3, 53.2, 53.0, 48.2, 43.8, 37.2, 35.1, 27.2, 26.2, 25.0, 14.6. HRMS:
Calcd. for C33H35N2O2F [M + H]+ 511.2761; found 511.2762. HPLC purity: 99.5%. Geometric isomer < 0.1%.
Levocabastine hydrochloride (
dichloromethane (210 mL) and MeOH (420 mL), ammonium formate (12.7 g, 0.20 mol) and palladium
hydroxide (5.1 g, 10 wt % compound ) were added at room temperature. The reaction mixture was
1). To a stirred solution of tertiary amine 8 (51.3 g, 0.10 mol) in
8
stirred for 3 h at the same temperature, and 7.0 M ammonia in methanol (500 mL) was slowly added.
The reaction slurry was concentrated under reduced pressure. To the concentrated mixture, MeOH
(255 mL) and IPE (1020 mL) were added, and the reaction slurry was stirred for 1 h at room temperature.
The precipitate was filtered. The obtained solid was suspended with MeOH (208 mL). To a suspended
solution, 3.0 M HCl solution in MeOH (165 mL) was slowly added, and then the reaction mixture
was stirred for 30 min at room temperature. To the reaction slurry, IPE (754 mL) was added, and the
mixture was stirred for 1 h at room temperature. The solid was filtered and then washed with IPE
(500 mL). The residue was suspended with EtOH (132 mL) and MeOH (132 mL) for 6 h at 50 ◦C and
cooled to room temperature. The solid was filtered, washed with ethanol (264 mL), and then dried
to afford levocabastine hydrochloride
(c = 1, MeOH). H-NMR (400 MHz, CD3OD):
1
as a white solid (43.1 g, 93.8% for two steps); [α]D20
0.86 (d, 3H, J = 7.6 Hz), 1.97–2.13 (m, 4H), 2.35–2.54
=
−
104.02
1
δ
(m, 5H), 2.83 (dd, 1H, J = 12.6 Hz, 2.0 Hz), 3.12 (td, 1H, J = 13.3 Hz, 2.6 Hz), 3.21–3.23 (m, 1H), 3.41–3.45
(m, 2H), 3.70–3.74 (m, 1H), 3.82–3.85 (m, 1H), 7.16–7.21 (m, 2H), 7.31–7.35 (m, 1H), 7.38–7.42 (m, 4H),
7.58–7.62 (m, 2H). 13C-NMR (100 MHz, CD3OD):
δ 176.1, 165.1, 162.7, 141.0, 137.0, 136.9, 130.0, 128.9,
128.8, 126.9, 122.7, 117.0, 116.8, 65.4, 54.9, 52.0, 50.0, 44.1, 36.5, 35.0, 25.9, 25.5, 25.4, 13.9. HRMS: Calcd.
for C26H29N2O2F [M + H]+ 421.2291; found 421.2292. HPLC purity: 99.7%. Optical purity > 99.9%.
4. Conclusions
In summary, a practical and sustainable method for the synthesis of levocabastine hydrochloride
with a high purity (>99.5% by HPLC) was accomplished in a 14.2% overall yield through nine steps
from commercially available and optically pure epoxide 9. The high optical purity was achieved
via simple recrystallization without chiral resolution. Our synthetic procedure enabled us to replace
the previous process for detosylation by electrolysis and reductive amination using an expensive
metal catalyst with convenient and economical methods, respectively. Our synthetic procedure seems
industrially suitable and could be widely utilized to secure pharmaceutically useful molecules.
Supplementary Materials: Supplementary data associated with this article can be found in the SI: NMR spectra
and HR-MS spectra of compounds 10, 11, 12, 13, 5, 6, 8 and 1; HPLC spectra of compounds 12, 5, 8 and 1.
Acknowledgments: This work was supported by the National Research Foundation of Korea grant funded by the
Ministry of Science and ICT of Korea (2009-0083533). We acknowledge the Korea Basic Science Institute, Ochang,
Korea, for providing HRMS.
Author Contributions: Y.-G. Suh and S.K. Kang conceived and designed the experiments; D.H. Nam, J. Ahn, and
S.K. Kang performed the experiments; J. Ahn and J. Lee (Jaemin Lee) analyzed the data; Y.-G. Suh, J. Sim, J. Lee
(Jeeyeon Lee), and S.K. Kang wrote the paper; all authors read and approved the final manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 5, 8, and 1 are available from the authors.
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2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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