A new enantioselective synthesis of antiobesity drug lorcaserin

Article abstract of DOI:10.1039/c9nj04234b

A simple and efficient enantioselective synthesis of anti-obesity drug lorcaerin starting from easily accessible 3-chlorostyrene oxide has been described for the first time employing hydrolytic kinetic resolution as a source of chirality. The protocol might also be useful in the synthesis of structural variants of lorcaserin.

Full text of DOI:10.1039/c9nj04234b

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A new enantioselective synthesis of antiobesity
drug lorcaserin†
Cite this: New J. Chem., 2019,
43, 16876
Ganesh S. Ghotekar,ab Devidas A. More,ab Viswanadh Nallaab and
ab
M. Muthukrishnan
*
A simple and efficient enantioselective synthesis of anti-obesity drug lorcaerin starting from easily
accessible 3-chlorostyrene oxide has been described for the first time employing hydrolytic kinetic
resolution as a source of chirality. The protocol might also be useful in the synthesis of structural
variants of lorcaserin.
Received 15th August 2019,
Accepted 4th October 2019
DOI: 10.1039/c9nj04234b
rsc.li/njc
Obesity has been a major health concern worldwide and it is
associated with a risk factor for chronic diseases such as diabetes,
cardiovascular diseases and certain cancers.1 The neurotransmitter
serotonin (5-hydroxytryptamine or 5-HT) has significant implications
in the regulation of numerous neurological functions including
appetite.2 Several nonselective serotoninergic drugs such as
sibutramine, dexfenfluramine etc. were introduced into the
market as weight loss agents and in due course they were
withdrawn due to the serious adverse effects (Fig. 1).3 Lorcaserin,
a selective serotonin 5-HT2C receptor agonist, has been intro-
duced into the market (Belviq, FDA approval 2012) as a novel
anti-obesity drug and it has better tolerance and safety profiles.4
Several synthetic methods have been reported for the synth-
esis of lorcaserin.5,6 In most of the cases, racemic lorcaserin has
been prepared first, followed by resolution and salification. In
addition, most of the methods utilize 2-(4-chlrophenyl)acetic
acid or 2-(4-chlorophenyl)ethanamine as starting materials.
Further, there are only two enantioselective syntheses of lorcaserin
reported, so far. In general, some of these methods suffer from
several drawbacks, such as cumbersome workup, high cost,
unstable reagents and catalysts, low overall yields and low
enantioselectivity etc.5a,d
Fig. 1 Representative serotonin modulators.
Scheme 1 Retrosynthetic analysis of lorcaserin (R)-1.
synthesis of lorcaserin (R)-1 starting from an easily accessible
epoxide, thereby devising a new approach that would enable the
synthesis of lorcaserin and related analogues in high enantio-
meric purity.
Epoxides represent one of the most widely employed func-
tional groups in synthetic transformations. Further, they serve
as important building blocks in the industrial production of a
wide variety of organic materials.7 Over the past few years,
studies in our laboratory have demonstrated the potential utility
Results and discussion
of these epoxides for the synthesis of many pharmaceutically Our retrosynthetic pathway for lorcaserin (R)-1 is depicted in
significant compounds.8 Herein we report a new enantioselective Scheme 1. We envisioned that the chiral primary alcohol (R)-4
could be visualized as a key intermediate, which can be
transformed into the advanced precursor (R)-6 via Mitsunobu
followed by Friedel–Crafts reactions. Further, compound (R)-6
can be transformed into the target lorcaserin via double bond
reduction and deprotection sequences. The requisite chiral
primary alcohol (R)-4 could be accessed from chiral 3-chloro
a Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune 411008,
India. E-mail: m.muthukrishnan@ncl.res.in
b Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9nj04234b
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Scheme 2 Synthesis of lorcaserin (R)-1.
Table 1 Optimization of the reduction conditions
styrene oxide (R)-3 by a regioselective ring opening reaction.
Chiral epoxide (R)-3, in turn, can be easily obtained in high
enantiopurity from its racemic epoxide 2 using Jacobsen’s
hydrolytic kinetic resolution strategy.
Accordingly, our synthesis commenced with the easily acces-
sible starting material 3-chloro styrene oxide 2, which was
subjected to Jacobsen’s hydrolytic kinetic resolution conditions
with 0.55 equiv. of water using the catalyst (R,R)-Salen Co(III)OAc
(0.8 mol%) at ambient temperature for 36 h (Scheme 2).9 After
completion of the reaction, the reaction mixture was chromato-
graphed over a silica gel column to give enantiomerically pure
epoxide (R)-3a from the racemic mixture in 47% yield and
499% ee along with its diol (S)-3b in 43% yield. Notably, the
undesired diol can be converted into the epoxide 2 as per a
known procedure.10 The epoxide (R)-3 was subjected to regio-
selective ring opening from the benzylic side with trimethyl-
aluminium in toluene at À78 1C to give the primary alcohol
(R)-4 in 80% yield.11 The primary alcohol (R)-4 was converted to
the desired aminoacetal derivative (R)-5a in 95% yield using
triflate protected amino acetal under Mitsunobu conditions.12
Subsequently, compound (R)-5a was subjected to intra-
molecular cyclization using aluminium chloride in dry CH2Cl2
affording the cyclized product (R)-6a in 65% yield. After suc-
cessful cyclization of compound (R)-5a, we planned to reduce
the double bond of compound (R)-6a. Initial attempts under
standard Pd/C conditions either failed or produced the unde-
sired dehalogenated product. To circumvent this problem, we
optimized the reduction conditions using various catalysts as
well as changing the N-protecting group of compound 6
(Table 1). Notably, nosyl protected compound (R)-6b with
reduction conditions using Et3SiH in TFA solvent at low
temperature (À10 1C) afforded the required product (R)-7b in
93% yield.13 Finally, cleavage of the 2-nitrobenzenesulfonyl
group with thiophenol and potassium carbonate followed by
salt formation with hydrochloric acid completed the synthesis
of lorcaserin.14 The structure of lorcaserin (R)-1 was confirmed
Entry Compound Reaction conditions
Product (%)
1
2
3
4
5
6
7
8
9
(R)-6a
(R)-6a
(R)-6a
(R)-6a
(R)-6a
(R)-6a
(R)-6a
(R)-6b
(R)-6b
(R)-6b
H2, Pd/C, THF, RT, 8 h
H2, Pd/C, MeOH, RT, 8 h
H2, Pd/C, THF, HCl, RT, 12 h NR
H2, PtO2, MeOH, RT, 2 h
LiAlH4, THF, reflux, 12 h
Et3SiH, TFA, À10 1C, 12 h
Et3SiH, TFA, RT, 12 h
NaCNBH3, AcOH, RT, 8 h
Et3SiH, TFA, À10 8C, 2 h
Et3SiH, TFA, RT, 2 h
(R)-7c (56)
(R)-7c (57)
Complex mixture
(R)-1a (o5)
NR
NR
NR
(R)-7b (93)
(R)-7b (85)
10
Fig. 2 Chiral HPLC chromatogram of lorcaserin (R)-1.
Conclusions
by means of IR, 1H NMR, and 13C NMR spectrometry and In conclusion, we have developed a new and viable alternative
HRMS analysis. Its enantiomeric purity was determined by enantioselective synthesis of the anti-obesity agent lorcaserin
chiral HPLC analysis (Fig. 2).
(R)-1, starting from 3-chloro styrene oxide 2. The enantiomeric
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excess of the starting (R)-3-chloro styrene oxide (R)-3a was preserved (0.92 g, 0.0035 mol) were dissolved in dry THF (5 mL) under an
throughout our synthetic pathway, thereby allowing efficient access argon atmosphere and the reaction mixture was cooled to 0 1C.
to lorcaserin with 499% ee. This protocol might also be useful to Diethylazodicarboxylate (0.55 mL, 0.0035) was added dropwise, and
construct structurally related benzazepine analogues.
the mixture was stirred at room temperature for 1 h. After comple-
tion of the reaction, THF was evaporated and the residue was
extracted with DCM (3 Â 10 mL), washed with 1 M NaOH (10 mL)
and brine (2 Â 10 mL), dried (Na2SO4), filtered and concentrated
under reduced pressure. Purification of the crude residue by
column chromatography [silica gel, petroleum ether/ethyl acetate,
Experimental
General methods
Solvents were purified and dried by standard procedures prior 97 : 03] afforded (R)-5a as a yellow liquid (1.0 g, 95%); [a]2D5 = +20.92
to use. 1H NMR and 13C NMR spectra were recorded on Bruker (c 5.0, CHCl3); 1H NMR (200 MHz, CDCl3): dH = 7.29–7.22 (m, 3 H),
AV-200 and AV-400 NMR spectrometers. Spectra were obtained 7.19–7.05 (m, 1 H), 4.46 (t, J = 5.3 Hz, 1 H), 3.57 (d, J = 8.1 Hz, 2 H),
in CDCl3 and DMSO-D6. The reactions were monitored by using 3.46–3.39 (m, 6 H), 3.39–3.31 (m, 1 H), 3.28–3.08 (m, 2 H), 1.29
TLC plates Merck Silica Gel 60 F254 and visualization with UV light (d, J = 6.9 Hz, 3 H); 13C NMR (100 MHz, CDCl3): dC = 144.9, 134.5,
(254 and 365 nm), and KMnO4 and anisaldehyde in ethanol as 130.0, 128.8, 127.6, 127.3, 127.2, 127.1, 125.5, 121.5, 118.3, 103.9,
development reagents. Optical rotations were measured with a 56.4, 55.3, 55.2, 50.0, 38.3, 38.0, 18.0; HRMS (ESI) calcd for
JASCO P 1020 digital polarimeter. High resolution mass spectro- C14H19ClF3NNaO4S, [M + Na]+ 412.0568; found, 412.0570.
metry (HRMS) was performed on a TOF/Q-TOF mass spectrometer.
The enantiomeric excess was determined by chiral HPLC.
(R)-N-(2-(3-Chlorophenyl)propyl)-N-(2,2-dimethoxyethyl)-4-nitro-
benzenesulfonamide (R)-5b. (R)-2-(3-Chlorophenyl)propan-1-ol
(R)-2-(3-Chlorophenyl)oxirane (R)-3a.
A mixture of rac (R)-4 (0.8 g, 0.0046 mol), N-(2,2-dimethoxyethyl)-4-nitrobenzenesulfon-
3-chlorostyrene oxide 2 (5 g, 0.032 mol) and the (R,R)-Salen Co(III)- amide (1.49 g, 0.0051 mol) and triphenylphosphine (1.84 g,
OAc complex (0.17 g, 0.00026 mol) was vigorously stirred for 15 min, 0.0070 mol) were dissolved in dry THF (10 mL) under an argon
and then cooled to 0 1C. H2O (0.32 g, 0.017 mol) was added from a atmosphere and the reaction mixture was cooled to 0 1C. Diethyl-
micro-syringe over 15 min and the resulting mixture was stirred at azodicarboxylate (1.1 mL, 0.007 mol) was added dropwise, and the
room temperature for 36 h. The resulting mixture was diluted with mixture was stirred at room temperature for 1 h. After completion
EtOAc (20 mL), dried over (Na2SO4), and concentrated under reduced of the reaction, THF was evaporated and the residue was extracted
pressure. Purification of the crude residue by column chromato- with DCM (3 Â 10 mL), washed with 1 M NaOH (10 mL) and brine
graphy [silica gel, petroleum ether/ethyl acetate, 99.5 : 0.5] afforded (2 Â 10 mL), dried (Na2SO4), filtered and concentrated under
(R)-3a as a colorless oil (2.35 g, 47%). [a]2D5 = +11.82 (c 2.9 EtOH) {Lit.9c reduced pressure. Purification of the crude residue by column
[a]2D6 +21 (c 2.9, EtOH)}; 1H NMR (400 MHz,CDCl3) dH = 7.25 (d, J = chromatography [silica gel, petroleum ether/ethyl acetate, 95 : 05]
3.2 Hz, 3 H), 7.16 (m, 1 H), 3.83 (m, 1 H), 3.13 (dd, J = 4.4, 5.1 Hz, afforded (R)-5b as a yellow solid (1.76 g, 85%); m.p. = 69–71 1C;
1 H), 2.75 (dd, J = 2.4, 5.6 Hz, 1 H); 13C NMR (100 MHz, CDCl3): dc = [a]2D5 = +20.74 (c 1.56 CHCl3); 1H NMR (400 MHz, CDCl3): dH = 8.28
139.8, 134.6, 129.8, 128.3, 125.5, 123.7, 51.7, 51.2; HRMS (ESI) calcd (d, J = 8.5 Hz, 2 H), 7.87 (d, J = 8.5 Hz, 2 H), 7.27–7.17 (m, 2 H), 7.05
for C8H8ClO, [M + H]+ 155.0258; found, 155.0261.
(m, 2 H), 4.43 (t, 1 H), 3.56–3.47 (m, 1 H), 3.37 (m, 1 H), 3.34
(R)-2-(3-Chlorophenyl)propan-1-ol (R)-4. A solution of (R) (d, J = 6.1 Hz, 6 H), 3.26 (m, 1 H), 3.19–3.15 (m, 2 H), 1.24 (d, J =
3-chlorostyrene oxide (R)-3a (2 g, 0.013 mol) in toluene (40 mL) 7.3 Hz, 3 H); 13C NMR (100 MHz, CDCl3): dC = 149.7, 145.7, 145.6,
was cooled to À78 1C. After 30 min stirring, trimethylaluminium 134.3, 129.9, 128.2, 127.4, 126.9, 125.4, 124.1, 104.0, 55.9, 55.2,
(13 mL of a 2 M solution in toluene; 0.026 mol) was added drop 54.9, 49.8, 37.9, 18.7; HRMS (ESI) calcd for C19H23ClN2NaO6S,
by drop and the reaction mixture was kept at this temperature [M + Na]+ 465.0858; found, 465.0853.
for 2 h. After completion of the reaction, 1 M HCl (10 mL)
(R)-8-Chloro-1-methyl-3-((trifluoromethyl)sulfonyl)-2,3-dihydro-
was added and the reaction mixture was extracted with EtOAc 1H-benzo[d]azepine (R)-6a. To a solution of (R)-N-(2-(3-chloro-
(3 Â 20 mL). The organic layers were combined, washed with phenyl)propyl)-N-(2,2-dimethoxyethyl)-1,1,1-trifluoromethanesulfon-
brine (2 Â 10 mL), dried (Na2SO4), filtered and concentrated amide (R)-5a (0.8 g, 0.002 mol) in CH2Cl2 (10 mL) was added AlCl3
under reduced pressure. Purification of the crude residue (1.1 g, 0.008 mol) under a nitrogen atmosphere. The reaction
by column chromatography [silica gel, petroleum ether/ethyl mixture was stirred at 0 1C for 2 h. After completion of the reaction,
acetate, 80: 20] afforded (R)-4 as a colorless liquid (1.76 g, the reaction mixture was quenched with 1 M NaOH (3 mL) and
1
80%). [a]2D5 = +16.69 (c 1.56 CHCl3); H NMR (400 MHz, CDCl3): H2O (10 mL), and subsequently extracted with CH2Cl2
d
H = 7.24 (m, 3 H), 7.13 (d, J = 7.12 Hz, 1 H), 3.68 (d, J = 6.8 Hz, (3 Â 5 mL). The organic layers were combined, washed with
2 H), 2.96–2.90 (m, 1H), 1.78 (br. s., 1 H), 1.28 (d, J = 6.8 Hz, 3 H); brine (2 Â 5 mL), dried (Na2SO4), filtered and concentrated
13C NMR (100 MHz, CDCl3): dC = 146.0, 129.7, 128.5, 127.6, 126.7, under reduced pressure. Purification of the crude residue by
125.7, 68.2, 42.1, 17.4; HRMS (ESI) calcd for C9H11ClNaO, column chromatography [silica gel, petroleum ether] afforded
[M + Na]+, 193.0391; found, 193.0195.
(R)-6a as a colorless solid (0.440 g, 65%); m.p. = 64–66 1C; [a]D23
=
(R)-N-(2-(3-Chlorophenyl)propyl)-N-(2,2-dimethoxyethyl)-1,1,1- À76.29 (c 1.56, CHCl3); 1H NMR (400 MHz, CDCl3) dH = 7.21–7.14
trifluoromethanesulfonamide (R)-5a. (R)-2-(3-chlorophenyl)propan- (m, 3 H), 6.62 (d, J = 10.5 Hz, 1 H), 5.78 (d, J = 10.5 Hz, 1 H), 4.25
1-ol (R)-4 (0.5 g, 0.0029 mol), N-(2,2-dimethoxyethyl)trifluoro- (dd, J = 5.4, 12.7 Hz, 1 H), 3.51 (d, J = 13.2 Hz, 1 H), 3.35 (quin, J =
methanesulfonamide (0.76 g, 0.0032 mol), and triphenylphosphine 7.0 Hz, 1 H), 1.27 (d, J = 7.3 Hz, 3 H); 13C NMR (100 MHz, CDCl3):
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dC = 145.4, 133.1, 130.3, 128.4, 127.0, 123.8, 121.4, 118.2, 111.5, 2.71 (dd, J = 7.3, 13.4 Hz, 1 H), 2.00 (br. s., 1 H), 1.32 (d, J =
51.7, 40.2, 16.9.
7.3 Hz, 3 H); 13C NMR (100 MHz, CDCl3): dC = 147.4, 139.7,
(R)-8-Chloro-1-methyl-3-((4-nitrophenyl)sulfonyl)-2,3-dihydro- 131.8, 130.9, 126.6, 125.7, 54.6, 47.8, 41.7, 39.0, 17.5.HRMS (ESI)
1H-benzo[d]azepine (R)-6b. To a solution of (R)-N-(2-(3-chloro- calcd for C11H15ClN, [M + H]+ 196.0888; found, 196.0889.
phenyl)propyl)-N-(2,2-dimethoxyethyl)-4-nitrobenzenesulfonamide
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine
(R)-5b (1 g, 0.0022 mol) in CH2Cl2 (10 mL) was added AlCl3 (1.2 g, hydrochloride salt (R)-1. To an ice cooled solution of (R)-8-
0.009 mol) under a nitrogen atmosphere. The reaction mixture chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (R)-1a (0.08 g)
was stirred at 0 1C for 2 h. After completion of the reaction, the in DCM (2 mL) 4 M HCl in dioxane (1 mL) was added dropwise
reaction mixture was quenched with 1 M NaOH (3 mL) and H2O under an N2 atmosphere and the reaction mixture was stirred for
(10 mL), and subsequently extracted with CH2Cl2 (3 Â 5 mL). The 2 h. The reaction mixture was concentrated under reduced pressure
organic layers were combined, washed with brine (2 Â 5 mL), and the lorcaserin hydrochloride (R)-1 precipitated out was washed
dried (Na2SO4), filtered and concentrated under reduced pressure. with diethyl ether and filtered under an N2 atmosphere (0.09 g);
Purification of the crude residue by column chromatography ee 499%, the ee was determined by chiral HPLC analysis:
[silica gel, petroleum ether] afforded (R)-6b as a yellow solid Chiralpak-IA (250 Â 4.6 mm) column; eluent: ethanol/n-hexane/
(0.5 g, 60%); m.p. = 105–106 1C; [a]2D3 = À553.40 (c 1.0 CHCl3); DEA (08:95:0.1), flow rate – 1.0 mL minÀ1, detector: 254 nm,
1H NMR (400 MHz, CDCl3): dH = 8.39 (d, J = 8.5 Hz, 2 H), 8.04 [(S)-isomer – tS: 7.708 min; (R)-isomer – tR: 8.758 min]; 1H NMR
(d, J = 8.5 Hz, 2 H), 7.13 (d, 1 H), 7.08–7.05 (m, 2 H), 6.93–6.86 (400 MHz, DMSO-d6): dH = 9.67 (br. s., 1 H), 9.30 (br. s., 1 H),
(d, J = 8 Hz 1H), 5.66–5.63 (d, J = 8 Hz, 1 H), 4.14 (dd, J = 6.1, 12.8 7.26–7.09 (m, 3 H), 3.49–3.45 (m, 1 H), 3.31–3.17 (m, 3 H), 3.02
Hz, 1 H), 3.25–3.15 (m, 2 H), 1.18 (d, J = 6.7 Hz, 3 H); 13C NMR (dd, J = 6.4, 15.6 Hz, 1 H), 2.88 (m, 2 H), 1.34 (d, J = 6.7 Hz, 3 H);
(100 MHz, CDCl3): dC = 150.3, 145.1, 144.2, 132.5, 132.1, 131.1, 13C NMR (100 MHz, DMSO-d6): dC = 145.4, 138.0, 131.6, 130.7,
128.2, 128.1, 126.8, 124.8, 124.6, 109.3, 50.6, 40.1, 17.2; HRMS 126.5, 126.1, 50.2, 44.6, 34.2, 30.9, 17.5; HRMS (ESI) calcd for
(ESI) calcd for C17H17ClN2NaO4S, [M + Na]+ 403.0490; found,
403.0488.
C
11H15NCl, [M + H]+ 196.0888; found, 196.0889.
(R)-8-Chloro-1-methyl-3-((4-nitrophenyl)sulfonyl)-2,3,4,5-tetra-
hydro-1H-benzo[d]azepine (R)-7b. To a mixture of (R)-8-chloro-1-
methyl-3-((4-nitrophenyl)sulfonyl)-2,3-dihydro-1H-benzo(d)azepine
(R)-6b (0.37 g, 0.001 mol) and triethylsilane (1.7 mL, 0.011 mol) at
À10 1C was added pre-cooled TFA (3.5 mL). The reaction mixture
Conflicts of interest
There are no conflicts to declare.
was rapidly stirred at À10 1C for 2 h, poured into ice-cold water, Acknowledgements
basified with aqueous NaHCO3, and extracted with ethyl acetate
Generous financial support from CSIR-New Delhi (HCP0008) is
gratefully acknowledged. GSG and DAM thank UGC-New Delhi
for the award of a senior research fellowship.
(3 Â 10 mL). The organic layers were combined, washed with
brine (2 Â 5 mL), dried (Na2SO4), filtered and concentrated under
reduced pressure. Purification of the crude residue by column
chromatography [silica gel, petroleum ether/ethylacetate, 97 : 03]
afforded (R)-7b as a colorless solid (0.33 g, 93%); m.p. = 152–54 1C;
Notes and references
1
[a]2D3 = +7.73 (c 2.0 CHCl3); H NMR (400 MHz, CDCl3): dH = 8.32
(d, J = 8.8 Hz, 2 H), 7.90 (d, J = 8.8 Hz, 2 H), 7.08 (m, 2 H), 6.98
(d, J = 8.0 Hz, 1 H), 3.44–3.31 (m, 4 H), 3.19–3.07 (m, 2 H), 3.00–
2.92 (m, 1 H), 1.41 (d, J = 6.9 Hz, 3 H); 13C NMR (100 MHz, CDCl3):
dC = 149.9, 145.4, 144.7, 137.0, 132.8, 131.4, 128.1, 127.7, 126.6,
124.4, 53.3, 48.0, 40.1, 35.7, 17.5; HRMS (ESI) calcd for
C17H19ClN2NaO4S, [M + Na]+ 405.0457 found, 405.0457.
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(R)-1a. To a solution of compound (R)-7b (0.3 g, 0.0008 mol) and
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