Novel Synthesis of Antiobesity Drug Lorcaserin Hydrochloride

Article abstract of DOI:10.1021/acs.oprd.5b00144

A novel synthesis of antiobesity drug lorcaserin hydrochloride was accomplished in six steps. N-protection of 2-(4-chlorophenyl)ethanamine with di-tert-butyl dicarbonate, N-alkylation with allyl bromide, deprotection, intramolecular Friedel-Crafts alkylation, chiral resolution with l-(+)-tartaric acid, and the final salification led to the target molecule lorcaserin hydrochloride in 23.1% overall yield with 99.9% purity and excellent enantioselectivity (>99.8% ee). This convenient and economical procedure is remarkably applicable for scale-up production.

Full text of DOI:10.1021/acs.oprd.5b00144

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Full Paper
Novel Synthesis of anti-obesity Drug Lorcaserin Hydrochloride
Qihua Zhu, Junwei Wang, Xueguo Bian, Lingzhi Zhang, Ping Wei, and Yungen Xu
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00144 • Publication Date (Web): 14 Aug 2015
Downloaded from http://pubs.acs.org on August 17, 2015
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Novel Synthesis of anti-obesity Drug Lorcaserin
Hydrochloride
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†
,‡,£
†,‡,£
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‡
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*,†, ‡
Qihua Zhu , Junwei Wang , Xueguo Bian , Lingzhi Zhang , Ping Wei , Yungen Xu
†
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University,
Nanjing 210009, China
‡
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
§
Nanjing Yi Gong Pharmaceutical Co. Ltd., Nanjing, 210009, China
£
Both authors contributed equally to this work
Corresponding Author
*Yungen Xu: E-mail: xyg@cpu.edu.cn. Tel: +86(25)83271244. Fax: +86(25)83271487.
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ABSTRACT
A novel synthesis of anti-obesity drug lorcaserin hydrochloride was accomplished in six steps.
N-protection of 2-(4-chlorophenyl)ethanamine with di-tert-butyl dicarbonate, N-alkylation with
allyl bromide, deprotection, intramolecular Friedel-Crafts alkylation, chiral resolution with L-
(+)-tartaric acid and the final salification led to the target molecule lorcaserin hydrochloride in
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3.1% overall yield with 99.9% purity and excellent enantioselectivity (>99.8% ee). This
convenient and economical procedure is remarkably applicable for scale-up production.
KEYWORADS: Anti-obesity Drug; Lorcaserin Hydrochloride; Synthesis; Scale-up Production
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INTRODUCTION
Lorcaserin (Figure 1), a selective serotonin 5-HT2C receptor agonist, is a novel anti-obesity
drug approved by the Food and Drug Administration (FDA) on June 27, 2012 for the treatment
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of obesity.
Figure 1. Lorcaserin (1).
Several synthetic methods have been reported for the synthesis of lorcaserin. Initially, Smith,
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Jeffrey et al. disclosed a process for preparation of lorcaserin (Scheme 1), which proceeded in
eight-steps, with complicated workups, laborious purification procedures, and used fairly
expensive, unstable, environmentally-unfriendly reagents and catalysts, such as
Bis(pyridine)iodonium tetrafluoroborate (IPy BF ) and palladium acetate, resulting in merely
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.7% overall yield. These drawbacks impeded this approach to application for industrial
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production. Some other methods published in patents also suffered from several drawbacks,
such as complicated purification process, low overall yields and the employment of
environmentally-unfriendly reagents. All these disadvantages made them unsuitable for
industrial-scale production.
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Scheme 1. Initial Synthesis of 1, Lorcaserin
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Most of the synthetic endeavors published recently for the synthesis of lorcaserin used 2-(4-
chlorophenyl)acetic acid or 2-(4-chlorophenyl)ethanamine as the key starting material. In
method 1, condensation of 2-(4-chlorophenyl)acetic acid with isopropyl alcohol amine, reduction
of the amide, chlorinated, Friedel-Crafts alkylation, chiral resolution and salification gave
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b
lorcaserin hydrochloride via six steps (Scheme 2). Some issues of method 1 for large-scale
synthesis are described below, 1) the use of expensive condensing agent 3,4,5-
trimethoxybenzeneboronic acid and reducing agent borane; 2) the dangerous workup steps; 3)
large amounts of environmentally-unfriendly acid generated from thionyl chloride and 4) the
relatively low 11.6% overall yield.
Method 2 was carried out by using 2-(4-chlorophenyl)ethanamine as the starting material.
Subsequent reaction with 2-chloropropionyl chloride, Friedel-Crafts alkylation, reduction and
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chiral resolution led to lorcaserin in 7.2% overall yield (Scheme 2). Although this route is
shorter, the use of toxic and expensive borane is still a problem. Moreover, the Friedel-Crafts
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alkylation was conducted in the absence of solvent in high temperature using large amounts of
aluminum chloride which led to a complicated workup step and reduced the yield. From a scale-
up standpoint, it is also an undesirable method.
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Most notable for us were two asymmetric routes in method 3 and method 4, both avoiding the
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resolution step by the introduction of chirality in starting material or intermediate (Scheme 2).
However, organic catalysts and chiral ligand were charged and the reaction were conducted on
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millimole scale. And in method 4 the products were purified by flash chromatography, this
isolation approach is a typical technique for research-scale which is not feasible for the pilot
plant. Therefore，it is necessary to design a novel method for the preparation of lorcaserin to
large-scale production.
Scheme 2. Recent Synthesis of 1, Lorcaserin
Method 1
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Method 2
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Method 3
Method 4
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RESULTS AND DISCUSSION
Herein we report a scalable and operationally convenient method that does not have the
aforementioned disadvantages to the preparation of lorcaserin in a fairly high overall yield,
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which undergoes N-protection of 2-(4-chlorophenyl)ethanamine with di-tert-butyl dicarbonate,
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N-alkylation with allyl bromide, N-deprotection with HCl-saturated EtOAc solution,
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intramolecular Friedel-Crafts alkylation, chiral resolution with L-(+)-tartaric acid and the final
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salification (Scheme 3). This scale-up synthesis process is a better alternative to patent which
needs column chromatography to separate the monoallyl compound and was only conducted on
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mmol.
The innovation of this synthetic route is to avoid the use of reducing agent such as
borane/THF, which not only reduced the cost and simplified the operation, but also improved the
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yield compared to the routes mentioned before.
A
key intermediate, N-(4-
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chlorophenethyl)prop-2-en-1-amine hydrochloride (15) was identified in our synthetic route.
The racemic form of lorcaserin was obtained conveniently by an intramolecular Friedel-Crafts
alkylation of 15 with an excellent yield (92.3%).
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Scheme 3. Novel Synthesis of 1, Lorcaserin
The involvement of this simple intermediate 15 provided several major benefits. First, the
application of some expensive or dangerous reducing agents, such as borane/THF, were avoided
in the subsequent reaction. Second, the reaction conditions required for the intramolecular
Friedel-Crafts alkylation of 15 are found to be milder than those used for intermediate 10 or 11.
In particular, the transformation of 11 into racemic lorcaserin was conducted in a solvent-free
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system, and required to be in the presence of an excess of aluminum chloride, which lead to
complicated workup step and reduce the yield. In contrast, the intramolecular Friedel-Crafts
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alkylation of 15 can be carried out at 110 C in 1,2-dichlorobenzene. Furthermore, the
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hydrochloride form of 15 can undergo intramolecular Friedel-Crafts reaction easily, which
further simplifies the reaction procedure.
In order to obtain the key intermediate 15 efficiently, a range of experiments were carried out
to find the appropriate synthetic routes (Scheme 4).
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Scheme 4. Synthetic Routes of the Key Intermediate 15
Route 1
Route 2
Route 3
Route 4
In route 1, N,N-diallyl-N-(4-chlorophenethyl)prop-2-en-1-amine (15'') was the main byproduct
which could not be avoided, and column chromatography was needed to purify N-allyl-N-(4-
chlorophenethyl)prop-2-en-1-amine (15'). Taking this issue into consideration, we introduced
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protection groups, such as acetyl and trifluoroacetyl, onto the amino group of 2-(4-
chlorophenyl)ethanamine in route 2 and 3. However, it was still difficult to obtain the pure
compound 15' since the acetyl and trifluoroacetyl groups was difficult to be removed completely
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6,13
in the deprotection step.
Additionally, different recrystallization systems were tested to get
pure compound 15', however, none of them could provide satisfactory yield and purity. To solve
the above-mentioned problems, route 4 was designed as shown in Scheme 4.
Catalyzed by 4-dimethylaminopyridine, the reaction of 2-(4-chlorophenyl)ethanamine with di-
tert-butyl dicarbonate provided 13. Intermediate 14 could readily be prepared by coupling 13
with allyl bromide in the presence of potassium carbonate, potassium hydroxide and tetrabutyl
ammonium bromide. Product 15 was obtained in excellent yield (89.8%) by treating 14 with
HCl-saturated EtOAc solution, and could be used in the next reaction directly without
purification or transforming into the free base form.
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Table 1. Reaction condition optimization of Friedel-Crafts alkylation in the synthesis of racemic
lorcaserin
a
Solvent
Temperature
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b
Entry
Subject
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Catalyst
Yield (%)
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80 C
H SO4
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CHCl3
80 C
H SO4
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Chlorobenzene
Chlorobenzene
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120 C
H SO4
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1,2-dichlorobenzene 110 C
AlCl3
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1,2-dichlorobenzene 110 C
H SO4
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a
Conditions were typically as follows: the compound 15 was dissolved in the solvents listed in
the left at rt, to which were added cyclization agents listed in the right, then the mixture was
stirred for 3~6h; or compound 15 was added into Conc.H SO . Isolated yield. “--” represents
that no product is formed.
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In order to synthesize racemic lorcaserin (7), a variety of cyclization conditions of the Friedel-
Crafts alkylation reaction were explored. As illustrated in Table 1, most cyclization conditions
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furnished 7 in moderate yields. Notably, using the CHCl /Conc.H SO system gave poor results
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and directly applying Conc.H SO failed to initiate the reaction. Thus, AlCl was finally
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employed as the catalytic agent in 1,2-dichlorobenzene to synthesize 7 in high yield (92.3%).
Intermediate 15 and anhydrous AlCl were added into a reaction vessel under the protection of
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nitrogen gas, which was followed by the addition of 1,2-dichlorobenzene. After stirring at 110 C
for 3-6h, cooled, the reaction mixture was quenched with ice water. The water layer was washed
with hexane and the pH was adjusted to 13 with 50% NaOH aqueous solution, and then extracted
with EtOAc. The combined organic layer was washed with brine, dried with anhydrous sodium
sulfate, filtered, and concentrated. The crude product could be purified in the following
resolution step.
The last step, chiral resolution with L-(+)-tartaric acid and salification led to the target
molecule lorcaserin hydrochloride. First, L-(+)-tartaric acid aqueous solution was added into a
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solution of 7 in acetone at 50 C. After stirring for 3h at this temperature, additional acetone was
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introduced, the mixture was cooled to 5~10 C and stirred for another 5h. The precipitate was
filtered and dried under vacuum to yield a crude product of lorcaserin tartrate(16), which was
followed by a further recrystallization from the mixed solvent of acetone and water to afford 16
in 33.2% yield with 99.9% purity and >99.8% ee. Furthermore, 16 was transformed into its free
base form followed by converting to its hydrochloride (1) through the addition of HCl-saturated
EtOAc solution.
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CONCLUSION
In summary, a safe, efficient, and scalable process for the synthesis of lorcaserin hydrochloride
was developed. This new six-step process enabled the production of the desired product starting
from readily available and inexpensive 2-(4-chlorophenyl)ethanamine with an overall yield of
23.1%, which is at least twice as much as others. To the best of our knowledge, compared to the
reported procedures, this approach was the most efficient, economical and convenient route to
synthesize lorcaserin in a large scale.
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EXPERIMENTAL SECTION
General Methods. All chemicals and solvents were either purchased or purified by standard
techniques and used without any further purification. TLC was carried out using Yantai thin
layer chromatography silica gel plates. Melting points were recorded on an RY-1 melting point
apparatus and were uncorrected. MS spectra were acquired on Agilent 1100 series LC/MSD Tarp
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(
SL). The HNMR and C NMR spectra were recorded on a BRUKER AV-300 or AV-500
NMR spectrometer using TMS as the internal standard. Product purities were determined by
HPLC conducted on an Shimadzu LC-15C system using a reverse-phase C18 column, and
MeCN-H O was used as the mobile phase.
2
tert-Butyl 4-chlorophenethylcarbamate (13).
To a solution of 2-(4-chlorophenyl)ethanamine (1.50 kg, 9.64 mol) in CH Cl (5 L) were
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2
added a solution of di-tert-butyl dicarbonate (2.30 kg, 10.54 mol) in CH Cl (5 L) and catalytic
2
2
o
amount of DMAP at 0 C. The reaction mixture was stirred at room temperature for 2 h. After
completion of the reaction, the mixture was poured into water (10 L) and extracted with
dichloromethane. The organic layer was washed successively with water (5 L) and brine (5 L×
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), dried overnight with anhydrous Na SO , filtered, concentrated and dried under vacuum to
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afford white solid product 13 (2.35 kg, 95.5%). Mp: 61-63 C (Mp: 61.5-62.5 C) .
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H NMR (300 MHz, CDCl ): δ = 7.29-7.24 (m, 2H), 7.15-7.08 (m, 2H), 3.33 (t, J = 6.5 Hz, 2H
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), 2.76 (t, J = 7.0 Hz, 2H), 1.43 (s, 9H ).
+
MS (ESI, 70 eV): m/ z = 278.1 [M+Na] .
tert-Butyl allyl(4-chlorophenethyl)carbamate (14).
To a solution of tert-butyl 4-chlorophenethylcarbamate (2.35 kg, 9.19 mol) in toluene (10 L)
were added K CO (1.59 kg, 11.50mol), KOH (0.69 kg, 12.30 mol), allyl bromide (1.59 kg,
2
3
1
3.14 mol) and tetrabutyl ammonium bromide (0.15 kg, 0.47 mol) at room temperature. The
o
reaction mixture was stirred at 80 C for 5h, then cooled to room temperature. The pH of the
solution was adjusted to 4~5 by addition of 15% aqueous hydrochloric acid, the toluene layer
was then separated, and the water layer was extracted with toluene (5 L). The combined organic
layer was washed successively with water (10 L) and brine (8 L×2), dried overnight with
anhydrous Na SO , filtered and concentrated to afford 14 (2.62 kg, 96.3%) as yellow oil.
2
4
1
H NMR (300 MHz, CDCl ): δ = 7.25 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 7.5 Hz, 2H), 5.75-5.70
3
(m, 1H), 5.13-5.07 (m, 2H), 3.76-3.67 (m, 2H), 3.36 (t, J = 7.2 Hz, 2H), 2.78 (t, J = 7.3 Hz, 2H),
1
.44 (s, 9H).
+
MS (ESI, 70 eV): m/ z = 318.1 [M+Na] .
N-(4-chlorophenethyl)prop-2-en-1-amine hydrochloride (15).
To a stirred solution of 14 (2.62 kg, 8.86 mol) in EtOAc (1L) was added HCl-saturated EtOAc
solution slowly until pH=2 and stirred at room temperature until completion of the reaction (by
TLC). The precipitate was filtered, washed with EtOAc (1 L) and dried under vacuum to give 15
o
(1.85 kg, 89.8%) as white crystal. Mp: 196-198 C.
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H NMR (300 MHz, DMSO-d ): δ = 9.40 (bs, 2H), 7.40 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.4
6
Hz, 2H), 6.00-8.86 (m, 1H), 5.49-5.37 (m, 2H), 3.57 (d, J = 6.6 Hz, 2H), 3.10-3.05 (m, 2H),
.00-2.90 (m, 2H).
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+
MS (ESI, 70 eV): m/ z = 196.1 [M+H] .
8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (7).
To a stirred solution of 15 (1.85 kg, 7.97 mol) in 1,2-dichlorobenzene (8 L) under the
protection of nitrogen was added anhydrous AlCl (1.59 kg, 11.92 mol). The reaction mixture
3
o
was then heated and stirred at 110 C for 4h. Upon completion of the reaction (by TLC), the
reaction mixture was cooled to room temperature and quenched with ice water (10 L) slowly.
The water layer was washed with hexane (5L) and the pH was adjusted to 13 with 50% NaOH
aqueous solution,and then extracted with EtOAc (5 L×3). The combined organic layer was
washed with brine (10 L×2), dried with anhydrous Na SO , filtered and concentrated to afford
2
4
crude product 7 (1.44 kg, 92.3%) as yellow oil. The crude product was used in the following
reaction without purification.
1
H NMR (300 MHz, CDCl ): δ = 7.14 (d, J = 2.0 Hz, 1H), 7.08 (dd, J = 8.0, 2.1 Hz, 1H), 7.00
3
(
d, J = 8.0 Hz, 1H), 3.10-2.84 (m, 6H), 2.71 (dd, J = 13.3, 7.6 Hz, 1H), 1.32 (d, J = 7.2 Hz, 3H).
+
MS (ESI, 70 eV): m/ z = 196.0 [M+H] .
(
R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine tartrate (16).
To a solution of 7 (1.44 kg, 7.36 mol) in acetone (9 L) was added a solution of L-(+)-tartaric
o
acid (0.28 kg, 1.86 mol) in water (900 mL) under stirring at 50 C. The reaction was maintained
at this temperature for 3h. Additional acetone (1 L) was introduced and stirred for another 5h
o
after cooling to 5~10 C. The precipitate was filtered and dried under vacuum to furnish the
crude product of 16 as white crystal. The product of lorcaserin tartrate was then recrystallized
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from an acetone-water solution (3:1, v/v; 5 L) to give the pure product lorcaserin tartrate as white
crystal (0.66 kg, 33.2%). HPLC purity: 99.9%, Chiral Purity: 99.9%.
HPLC for 16 (t = 9.0 min) purity 99.9%: 5 μm C-18 250 mm × 4.6 mm, flow rate = 1 mL/min,
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5°C, gradient elution from 20:88 A/B for 30 min to 75:25 A/B
over 30 min; A = acetonitrile; B = phosphoric acid in water (pH = 6.0); UV λ =
2
20 nm.
Chiral HPLC for 16 (t = 20.3 min) purity 99.9%: 5 μm AD-RH 250 mm × 4.6 mm, flow rate =
R
1 mL/min, 35°C, isocratic A/B/C = 92:8:0.1; A = n-hexane; B = isopropanol; C = diethylamine;
UV λ =220 nm.
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepinehydrochloride(1)
To a solution of 16 (0.66 kg, 2.44 mol) in water (3 L) was added 20% K CO aqueous
2
3
solution. The pH was adjusted to 8~9 and extracted with cyclohexane (5 L×2). The combined
organic layer was washed with brine (5 L×2), dried with anhydrous Na SO , filtered and
2
4
concentrated to afford lorcaserin as yellow oil. To a stirred solution of lorcaserin free base in
anhydrous ethanol (500 mL) was added HCl-saturated EtOAc solution slowly until pH = 2 and
stirred for another 5h at room temperature. The reaction solution was concentrated and then
stirred for 1h in methyl tert-butyl ether (2 L) at room temperature. The precipitate was filtered,
washed with methyl tert-butyl ether (200 mL) and dried under vacuum to give lorcaserin
o
hydrochloride (1) (0.52 kg, 91.2%). HPLC purity: 99.9%, Chiral Purity: 99.9%. Mp: 198-199 C.
1
H NMR (300 MHz, DMSO-d ): δ = 9.61 (bs, 2H), 7.28-7.21 (m, 3H), 3.54-3.44 (m, 1H),
6
3
3
.33-3.18 (m, 3H), 3.01 (dd, J = 15.7, 7.1 Hz, 1H), 2.91-2.83 (m, 2H), 1.34 (d, J = 7.2 Hz, 3H).
1
3
C NMR (75 MHz, DMSO-d ): δ = 145.4, 138.1, 131.5, 126.4, 126.0, 114.5, 50.1, 44.5, 34.1,
6
0.8, 17.5.
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+
MS (ESI, 70 eV): m/ z = 196.1 [M+H] .
HPLC for 1 (t = 9.0 min) purity 99.9%: Intersil ODS-3 5 μm C-18 250 mm × 4.6 mm, flow
R
rate = 1 mL/min, 35°C, gradient elution from 20:88 A/B for 30 min to 75:25 A/B
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over 30 min; A = acetonitrile; B = phosphoric acid in water (pH = 6.0); UV λ =
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20 nm.
Chiral HPLC for 1 (t = 21.6 min) purity 99.9%: Daicel AD-RH 5 μm 250 mm × 4.6 mm, flow
R
rate = 1 mL/min, 35°C, isocratic A/B/C = 92:8:0.1; A = n-hexane; B = isopropanol; C =
diethylamine; UV λ =220 nm.
AUTHOR INFORMATION
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The Project was supported by the Enterprise innovation drug incubation base of the Ministry of
Science and Technology, China (Grant No. 2012ZX09401-006) and the Enterprises-Universities-
Researches prospective joint research programs of Jiangsu Province, China (BY2015072-02).
REFERENCES
(1) Nikolic, D.; Toth, P. P.; Ferlita, A.; Bartolo, V. D.; Montalto, G.; Banach, M.; Rizzo, M.
Clin. Lipidol. 2014, 9, 179.
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1
1
1
1
1
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2
2
2
2
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(
2) (a) Smith, J.; Smith, B. 5HT2C receptor modulators. U.S. Patent 2003225057, 2003. (b)
Smith, B.; Smith, J. 5HT receptor modulators. U.S. Patent 6953787, 2005.
2C
(3) (a) Weigl, U.; Porstmann, F.; Straessler, C.; Ulmer, L.; Koetz, U. Processes for the
preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related
thereto. U.S. Patent 20090143576, 2009. (b) Gharbaoui, T.; Tandel, S. K.; Ma, Y.; Carlos, M.;
Fritch, J. R. Processes for preparing (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
and intermediates thereto. WO Patent 2008070111, 2008. (c) Smith, B.; Gilson, C.; Schultz, J.;
Smith, J. Benzazepine derivatives useful for the treatment of 5HT2C receptors associated
diseases. WO Patent 2005003096, 2005. (d) Liu, J. F. Deuterated Lorcaserin. WO Patent
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
009051747, 2009. (e) Burbaum, B. W.; Gilson, C. A.; Aytes, S.; Estrada, S. A.; Sengupta, D.;
Smith, B.; Rey, M.; Weigl, U. Processes for preparing 3-benzazepines. WO Patent 2005019179,
005.
2
(
4) (a) Stavber, G.; Jerome, C.; Frank, R.; Gerhard, L.; Ivana, G. S. Novel synthetic process to
8-chloro-1-methyl-benzo[d]azepine, novel intermediates and the production thereof. WO Patent
014173928, 2014. (b) Stavber, G.; Ivana, G. S.; Jerome, C.; Frank, R. Preparation of chiral 1-
2
methyl-2,3,4,5-1H-benzodiazepine via asymmetric reduction of alpha-substituted styrenes. WO
Patent 2014202765, 2014.
(5) In, J.; Hwang, S.; Kim, C.; Seo, J. H.; Kim, S. Eur. J. Org. Chem. 2013, 5, 965.
(6) Smith, B. M.; Smith, J. M.; Tsai, J. H.; Schultz, J. A.; Gilson, C. A.; Estrada, S. A.; Chen,
R. R.; Park, D. M.; Prieto, E. B.; Gallardo, C. S.; Sengupta, D.; Dosa, P. I.; Covel, J. A.; Ren, A.;
Webb, R. R.; Beeley, N. R. A.; Martin, M.; Morgan, M.; Espitia, S.; Saldana, H. R.; Bjenning,
C.; Whelan, K. T.; Grottick, A. J.; Menzaghi, F.; Thomsen, W. J. J. Med. Chem. 2008, 51, 305.
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(
7) (a) Alirio, P. R.; Sandra, S.; Vladimir, K.; Elena, S.; Gisela, M. N.; Angel, F. G. J.
Heterocyclic Chem. 2001, 38, 837. (b) Castro, J. R.; Puentes, C. O.; Kouznetsov, V. V.;
Stashenko, E. E.; Poveda, J. C.; Bahsas, A.; Amaro-Luis, J. Heterocycl. Commun. 2002, 8, 365.
10
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(
c) Vargas, M.; Leonor, Y.; Castelli, M. V.; Kouznetsov, V. V.; Urbina, G.; Juan, M.; Lopez, S.
N.; Sortino, M.; Enriz, R. D.; Ribas, J. C.; Zacchino, S. Bioorg. Med. Chem. 2003, 11, 1531.
(8) (a) Liu, J. F. Deuterated Lorcaserin. WO Patent 2009051747, 2009. (b) Anderson, C. M.;
Shanahan, W. R. Administration of Lorcaserin to individuals with renal impairment. WO Patent
2012030939, 2012.
(9) Stavber, G.; Jerome, C. Novel synthetic processes to 8-chloro-3-benzo[d]azepine via
Friedel-Crafts alkylation of olefin. WO Patent 2014187768, 2014.
(10) (a) Gharbaoui, T.; Tandel, S. K.; Ma, Y.; Carlos, M.; Fritch, J. R. Processes for preparing
(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates thereto. WO
Patent 2008070111, 2008. (b) Smith, B.; Gilson, C.; Schultz, J.; Smith, J. Benzazepine
derivatives useful for the treatment of 5HT2C receptors associated diseases. WO Patent
2
005003096, 2005.
(11) Choi, E.; Lee, C.; Cho, M.; Seo, J. J.; Yang, J. S.; Oh, S. J.; Lee, K.; Park, S. -K.; Kim, H.
M.; Kwon, H. J.; Han, G. J. Med. Chem. 2012, 55, 10766.
(12) Burbaum, B. W.; Gilson, C. A.; Aytes, S.; Estrada, S. A.; Sengupta, D.; Smith, B.; Rey,
M.; Weigl, U. Processes for preparing 3-benzazepines. WO Patent 2005019179, 2005.
(13) (a) Bird, C. W.; Wee, A. G. H. Tetrahedron. 1985, 41, 2019. (b) Pellegrino, S.; Ruscica,
M.; Magni, P.; Vistoli, G.; Gelmi, M. L. Bioorg. Med. Chem. 2013, 21, 5470.
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14) Zubkov, F. I.; Nikitina, E. V.; Kouznetsov, V. V.; Duarte, L. D. A. Eur. J. Org. Chem.
2
004, 24, 5064.
(15) Vargas, L. M.; Rozo, W.; Kouznetsov, V. Heterocycles. 2000, 53, 785.
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