Synthesis of enantiopure antiobesity drug lorcaserin

Article abstract of DOI:10.1016/j.bmc.2018.02.038

Acylation of enantiomerically pure (R)-2-(3-chlorophenyl)propan-1-amine using chloroacetyl chloride, followed by borane reduction and aluminum chloride catalyzed cyclization yielded enantiopure lorcaserin.

Full text of DOI:10.1016/j.bmc.2018.02.038

Accepted Manuscript
Synthesis of enantiopure antiobesity drug lorcaserin
Ivana Gazic Smilovic, Jerome Cluzeau, Frank Richter, Sven Nerdinger, Erwin
Schreiner, Gerhard Laus, Herwig Schottenberger
PII:
S0968-0896(17)32155-7
https://doi.org/10.1016/j.bmc.2018.02.038
BMC 14224
DOI:
Reference:
Bioorganic & Medicinal Chemistry
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Revised Date:
Accepted Date:
6 November 2017
14 February 2018
20 February 2018
Please cite this article as: Smilovic, I.G., Cluzeau, J., Richter, F., Nerdinger, S., Schreiner, E., Laus, G.,
Schottenberger, H., Synthesis of enantiopure antiobesity drug lorcaserin, Bioorganic & Medicinal Chemistry (2018),
doi: https://doi.org/10.1016/j.bmc.2018.02.038
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Synthesis of enantiopure antiobesity drug lorcaserin
Ivana Gazic Smilovica, Jerome Cluzeaua, Frank Richterb, Sven Nerdingerb,*, Erwin Schreinerb,
Gerhard Lausc, Herwig Schottenbergerc
aLek Pharmaceuticals DD, Kolodvorska 27, 1234 Mengeš, Slovenia
bSandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria
cLeopold-Franzens University, Innrain 80–82, 6020 Innsbruck, Austria
Abstract
Acylation of enantiomerically pure (R)-2-(3-chlorophenyl)propan-1-amine using chloroacetyl
chloride, followed by borane reduction and aluminum chloride catalyzed cyclization yielded
enantiopure lorcaserin.
Keywords: enantiopure, lorcaserin, obesity, 5-HT agonist
*Corresponding author
E-mail address: sven.nerdinger@sandoz.com
1

Introduction
Obesity is defined as excessive fat accumulation and poses a substantial public health challenge.
Recent estimates indicate that roughly 600 million adults worldwide are obese.1 Whereas
lifestyle modification is considered first-line therapy for obese patients, concomitant
pharmacotherapy may be beneficial to maintain the weight loss achieved. Clinical trials of new
promising antiobesity drugs have been reviewed previously.2 The 5-HT2C receptor selective
agonist lorcaserin3 has the best safety and tolerability profile of currently available medications.4
There are numerous methods of preparation disclosed in the patent literature,5–13 frequently
necessitating separation of enantiomers. Recent syntheses involve oxidative ring expansion,14
ultrafine-tuned reaction conditions for a key intermediate,15 and a convenient procedure suitable
for scale-up, however, requiring the use of a protection group and chiral resolution.16
Here we describe a new synthesis of enantiopure (R)-lorcaserin.
Results and discussion
Our synthetic approach was centered on (R)-2-(3-chlorophenyl)propan-1-amine (3) as readily
available chiral starting material. A selective ring opening17 (Scheme 1) of a cyclic sulfamidate
1, prepared from commercial (S)-(−)-1-amino-2-propanol, and subsequent removal of a Boc
group from 2 provided the enantiomerically pure amine 3.
Scheme 1. Preparation of chiral amine 3 hydrochloride.
Very recently, the crystal structure of the opposite enantiomer of the chiral cyclic sulfamidate 1
has been determined.18 The initial configuration is retained throughout the whole synthetic
sequence.
The basic concept consisted of adding C2 building blocks to the primary amino group of 3,
suitable for ring closure to obtain the seven-membered ring without disturbing the chiral centre.
The building blocks we used were chloroacetaldehyde dimethyl acetal, dimethoxy acetaldehyde,
2

and chloroacetyl chloride in order to obtain the intermediates 4 and 10. A different attempt to
prepare intermediate 4 by condensation of the amine 3 with chloroacetaldehyde and subsequent
reduction was not successful. It was also tried to synthesize the amide 10 using bromoacetyl
chloride instead of chloroacetyl chloride; however, numerous byproducts were observed in
contrast to the prior synthesis. In all cases, the intended cyclization was effected by heating the
linear precursors 4, 7, 11 or their hydrochlorides in the presence of aluminum chloride under
solvent-free conditions. However, in our hands, attempted cyclization of 10 did not produce
satisfactory results with less than 20% conversion. Catalytic hydrogenation was employed for the
reduction of the carbon–carbon double bonds in compounds 8 but reduction failed in case of
compound 5, whereas a borane reduction was adequate for the carbonyl group in compound 10.
Scheme 2. Synthesis of lorcaserin via unprotected acetal 4.
The reaction pathway19 via acetal 4 and dihydroazepine 5 (Scheme 2) was straightforward but
furnished a good number of byproducts. It was concluded that a protective group for the
secondary amine during the cyclization step was needed. Thus, the acetal 4 was tosylated to give
compound 7, which on treatment with aluminum chloride was transformed to the protected
dihydroazepine 8, followed by catalytic hydrogenation to the protected tetrahydroazepine 9
(Scheme 3).
3

Scheme 3. Synthesis of lorcaserin via tosyl-protected acetal 7.
Removal of the tosyl group by acidic hydrolysis finally gave lorcaserin 6. Chromatography was
employed for the purification of intermediates 4, 7 and 9. However, for industrial exploitation
the use of chromatographic separation has to be avoided. Another important issue was reducing
the number of steps. It was found that protection obviously was not necessary when the synthetic
pathway was chosen carefully. Removal of the unsaturation or its equivalent prior to the Friedel-
Crafts reaction permitted omission of the protection/deprotection procedure. The lack of a double
bond indicated higher stability towards the Lewis acid. The use of the protective group was
therefore dropped. This third pathway not only was the shortest, but was also standing out due to
the excellent yield. The amide 10 was obtained in almost quantitative yield and reduced to the
amine 11 in high yield. Cyclization afforded the desired product 6 (Scheme 4).
Scheme 4. Three-step synthesis of enantiopure lorcaserin 6 via amide 10.
4

The preparation of the hydrochloride 6-HCl was straightforward.20 Identity and purity were
confirmed by HPLC–MS as described previously.19
Experimental section
(S)-3-(tert-Butyloxycarbonyl)-5-methyl-1,2,3-oxathiazolidine 2,2-dioxide (1)
Prepared according to the published procedure for the opposite enantiomer.18
tert-Butyl (R)-(2-(3-chlorophenyl)propyl)carbamate (2)
In analogy with the published procedure using 3-chloroiodobenzene.17 Yield: 94%, colourless
oil. 1H NMR (300 MHz, CDCl3) δ 1.22 (d, 3H), 1.39 (s, 9H), 2.90 (m, 1H), 3.15 (m, 1H), 3.32
(m, 1H), 4.45 (br, 1H), 7.03–7.08 (m, 1H), 7.15–7.24 (m, 3H). 13C NMR (75 MHz, CDCl3) δ
19.1, 28.6 (3C), 40.1, 47.4, 79.5, 125.7, 126.9, 127.6, 130.1, 134.6, 146.6, 156.1 (C=O).
(R)-2-(3-Chlorophenyl)propan-1-amine hydrochloride (3-HCl)
Hydrochloric acid (32 mL, 6M) was added to a solution of the Boc derivative 2 (9.8 mmol) in
THF (20 mL). The emulsion was stirred at 45 °C for 3 h to give a clear solution. The solvent was
evaporated, the residue dissolved in H2O (65 mL) made alkaline with NaOH (1M). The mixture
was extracted with EtOAc (1 × 60 mL, 2 × 30 mL). The combined extracts were dried over
MgSO4, and the solvent was removed under reduced pressure to yield 1.60 g of the crude base.
Hydrogen chloride in Et2O (12 mL, 1M) was added dropwise to a solution of the base in Et2O
(20 mL). The precipitated hydrochloride was filtered, washed with Et2O (3 × 5 mL) and dried in
vacuum: 1.63 g (81%). M.p. 192 °C. 1H NMR (300 MHz, DMSO-d6) δ 1.25 (d, J = 6.9 Hz, 3H),
2.98 (m, 2H), 3.12 (m, 1H), 7.26-7.40 (m, 4H), 8.16 (br, 3H). 13C NMR (75 MHz, DMSO-d6) δ
19.2, 37.2, 44.5, 126.1, 126.9, 127.2, 130.5, 133.2, 145.4. IR (neat) ν 2967 (m), 2865 (s), 2819
(m), 1598 (m), 1507 (m), 1467 (m), 1435 (m), 1394 (m), 879 (m), 798 (m), 786 (s), 697 (s) cm–1.
(R)-2-(3-Chlorophenyl)propan-1-amine (3)
A solution of 1M NaOH (5 mL) was added to a solution of the hydrochloride 3-HCl (1.0 g, 4.9
mmol) in H2O (30 mL) and the mixture was extracted with EtOAc (1 × 50 mL, 2 × 25 mL). The
combined extracts were dried over MgSO4, and the solvent was removed under reduced pressure
to yield 0.75 g (91 %) of a colourless liquid. 1H NMR (300 MHz, DMSO-d6) δ 1.16 (d, 3H), 1.9
5

(br s, 2H), 2.66 (m, 3H), 7.16-7.34 (m, 4H). 13C NMR (75 MHz, DMSO-d6) δ 18.7, 42.6, 49.0,
125.8, 125.9, 127.1, 130.0, 132.9, 148.5. IR (neat) ν 2959, 2926, 1595, 1570, 1476, 1429, 1081,
780, 696 cm–1.
(R)-2-(3-Chlorophenyl)-N-(2,2-dimethoxyethyl)propan-1-amine (4)
To a solution of 2-(3-chlorophenyl)propan-1-amine (3) (19.6 mmol, 3.3 g) in DMF (50 mL) were
added K2CO3 (29.4 mmol, 4.1 g) and 2-chloro-1,1-dimethoxyethane (29.4 mmol, 3.3 mL) under
nitrogen atmosphere. The reaction mixture was stirred overnight at 120 °C. After cooling it down
to room temperature, H2O (30 mL) was added and extracted with EtOAc (3 × 60 mL). The
combined organic phases were washed with brine (60 mL), dried over MgSO4, filtered and
evaporated under reduced pressure. The residue was purified by flash chromatography (EtOAc :
n-heptane; EtOAc gradient elution 12–100 %) to yield a colourless oil (1.5 g, 28 % yield).
1H NMR (500 MHz, CDCl3) δ 7.22 (m, 3H), 7.10 (d, 1H), 4.41 (t, 1H), 3.33 (s, 6H), 2.91(m,
1H), 2.74 (m, 4H), 1.24 (d, 3H).
(R)-2-(3-Chlorophenyl)-N-(2,2-dimethoxyethyl)propan-1-amine hydrochloride (4-HCl)
2-(3-Chlorophenyl)propan-1-amine (3) (1 g, 4.8 mmol) in MeOH (2 mL) was treated with
dimethoxyacetaldehyde (60% in H2O, 1.46 mL, 2 equiv.) and the solution was stirred at room
temperature for 48 hours. 10% Pd/C (100 mg, 10 wt%) was added and the reaction vessel was
flushed several times with nitrogen and hydrogen alternatively. Hydrogen pressure was set at 1
atm and the reaction was stirred for 4 h. The mixture was filtered through Celite and
concentrated. The residue was dissolved in CH2Cl2 (20 mL) and washed with brine and HCl (20 /
10 mL 1M). The organic phase was dried over Na2SO4, filtered and concentrated. The residue
was dissolved in toluene (40 mL) and the solution was extracted three times with H2O (3 × 30
mL). The combined water phase was saturated with NaCl and was extracted twice with CH2Cl2
(2 × 30 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated to
give the pure product in 62% yield.
1H NMR (500 MHz, CDCl3) δ 7.33-7.22 (m, 3H), 7.18 (d, J = 7.2 Hz, 1H), 4.89 (t, J = 5.0 Hz,
1H), 3.49 (m, 1H), 3.44 (s, 3H), 3.42 (s, 3H), 3.31 (m, 1H), 3.19 (m, 1H), 3.08 (m, 1H), 3.00 (m,
1H), 1.44 (d, J = 6.9 Hz, 3H).
6

(R)-8-Chloro-1-methyl-2,3-dihydro-1H-benzo[d]azepine (5)
Acetal hydrochloride 4-HCl (50 mg, 0.25 mmol) was mixed with anhydrous AlCl3 (69 mg, 3
equiv.). Fine mixture was heated to 90 °C to obtain molten phase and stirred overnight. Solution
was diluted with CH2Cl2 (20 mL) and washed brine (20 mL). The phases were separated and
water phase was re-extracted with CH2Cl2 (10 mL). The combined organic phase was dried over
Na2SO4, filtered and concentrated. The obtained crude mixture was analyzed and the final
product was / detected with GC-MS analysis (m/z 193) and characterized by 1H NMR (estimated
yield by 1H-NMR was 65%).
1H NMR (500 MHz, CDCl3) δ 7.04 (m, 2H), 6.98 (m, J = 9.1 Hz, 1H), 6.22 (d, J = 9.7 Hz, 1H),
5.06 (1H, J = 9.7 Hz, 1H), 3.32 (m, 1H), 3.24 (m, 1H), 1.18 (d, J = 7.1 Hz, 3H).
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (6) from 9
A mixture of 8-chloro-1-methyl-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (9) (0.17 mmol,
59 mg), phenol (0.55 mmol, 53 mg), 48 % HBr (0.45 mL) and propionic acid (0.09 mL) was
stirred under reflux for 6 h. After cooling to room temperature, the reaction mixture was
quenched with H2O (2 mL) and washed with Et2O (2 × 5 mL). The aqueous phase was basified
with 8M NaOH (pH ≥ 9) and the product was extracted with CH2Cl2 (3 × 5 mL). The combined
organic phases were dried over MgSO4, filtered and evaporated to dryness. The desired product
was obtained in 80% yield and agreed with known literature3 data.
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (6) from 11-HCl
Liquid precursor 11-HCl (0.5 mmol) was placed into a test tube equipped with a magnetic stir
bar. Anhydrous AlCl3 (1.75 equiv according to starting material) was added and efficiently
mixed to obtain a paste. The mixture was slowly heated (10 °C/min) to 150 °C and stirred
overnight. A saturated solution of NaCl was added and the mixture was cooled. The pH was
adjusted to 9.5-10 using 1M NaOH and then extracted with EtOAc. The combined organic
phases were washed with brine, dried over Na2SO4 and the solvent was evaporated under
1
reduced pressure. The obtained crude mixture was analyzed using H NMR spectroscopy
(estimated yield by 1H-NMR was 62%). The NMR data were in agreement with known literature
or patent data.19
7

1H NMR (500 MHz, CDCl3) δ 7.18 (m, H), 7.11 (m, H), 7.00-6.94 (m, H), 3.20-2.78 (m, 5H),
2.75 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H).
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (6-HCl)
To a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.73 g, 3.7
mmol) in CH2Cl2 (2 ml) was added 1M HCl/Et2O (6 ml). The mixture was stirred and the
product was collected by filtration, washed with Et2O (3 ml) and dried, as described previously.20
1H NMR (300 MHz, DMSO-d6) δ 1.23 (d, J = 7.3 Hz, 3H), 2.62 (m, 1H), 2.79 (m, 2H), 2.87 (m,
13
3H), 3.05 (m, 1H), 3.65 (br s, 2H), 7.10 (m, 3H). C NMR (75 MHz, DMSO-d6) δ 17.5, 37.9,
40.9, 47.5, 53.9, 125.4, 126.3, 130.5, 131.3, 140.4, 148.0. IR (neat) ν 2979, 2939, 2879, 2684,
2643, 2598, 2499, 2429, 2399, 1580, 1484, 1390, 1104, 932, 876, 814, 645, 528, 466 cm–1.
(R)-N-(2-(3-Chlorophenyl)propyl)-N-(2,2-dimethoxyethyl)-4-methyl benzenesulfonamide (7)
A solution of 2-(3-chlorophenyl)-N-(2,2-dimethoxyethyl)propan-1-amine (4) (2.95 mmol, 0.76
g) in CH2Cl2/pyridine (8/1, 4.2 mL) was cooled to 0 °C and a solution of TsCl (5.31 mmol, 1.0
g) in CH2Cl2 (1.8 mL) was added. The reaction mixture was allowed to warm to room
temperature and stirred for 2.5 h. The reaction mixture was washed with 2M HCl (2 × 4.3 mL)
and saturated aqueous solution of NaHCO3 (4.3 mL). The organic layer was dried over MgSO4,
filtered and evaporated under reduced pressure. The residue was purified by flash
chromatography (eluent: EtOAc/n-heptane, EtOAc gradient 7-60 %) to yield a colourless oil
(0.85 g, 71 %).
1H NMR (500 MHz, CDCl3) δ 7.64 (d, 2H), 7.28 (d, 2H), 7.19 (m, 2H), 7.08 (m, 2H), 4.43 (t,
13
1H), 3.45 (m, 1H), 3.36 (d, 6H), 3.13 (m, 4H), 2.42 (s, 3H), 1.25 (d, 3H). C NMR (125 MHz,
CDCl3) δ 146.2, 143.4, 136.6, 134.2, 129.8, 129.7, 127.6, 127.2, 126.7, 125.5, 104.6, 56.5, 55.3,
55.1, 50.8, 38.2, 21.5, 18.6.
(R)-8-Chloro-1-methyl-3-tosyl-2,3-dihydro-1H-benzo[d]azepine (8)
To a suspension of AlCl3 (8.3 mmol, 1.1 g) in CH2Cl2 (15 mL) was added a solution of N-(2-(3-
chlorophenyl)propyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (7) (2.1 mmol, 0.85
g) in CH2Cl2 (10 mL) under nitrogen atmosphere. The reaction mixture was stirred for 10 min at
room temperature and then was cooled to 0 °C. After quenching with NaOH (11 mL 1M) and
8

H2O (11 mL), the phases were separated. The aqueous phase was extracted with CH2Cl2 (3 × 15
mL). The combined organic phases were dried over MgSO4, filtered and the solvent was
removed by evaporation to give a yellow solid (0.6 g, 85 % yield).
1H NMR (500 MHz, CDCl3) δ 7.72 (d, 2H), 7.32 (d, 2H), 7.10 (m, 1H), 7.05 (m, 2H), 6.89 (dd,
13
1H), 5.55 (d, 1H), 4.06 (m, 1H), 3.14 (m, 2H), 2.42 (s, 3H), 1.17 (d, 3H). C NMR (125 MHz,
CDCl3) δ 145.3, 144.2, 135.8, 132.2, 131.8, 131.5, 130.0, 129.4, 128.1, 127.0, 126.6, 126.1,
107.4, 50.3, 40.1, 21.6, 18.0.
(R)-8-Chloro-1-methyl-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (9)
To a solution of 8-chloro-1-methyl-3-tosyl-2,3-dihydro-1H-benzo[d]azepine (8) (0.54 mmol;
0.19 g) in MeOH (3 mL) was added PtO2 (20 mg) and several drops of HCl. The reaction
mixture was stirred at 25 °C under 5 bar of H2 for 48 h. After filtration through Celite pad, the
solvent was removed by evaporation under reduced pressure. The residue was dissolved in
EtOAc (6 mL), washed with H2O (6 mL), dried over MgSO4, filtered and evaporated to dryness.
The residue was purified by flash chromatography (eluent: n-heptane/EtOAc, EtOAc gradient 7-
60 %), to give 7 in 30 % yield.
1H NMR (500 MHz, CDCl3) δ 7.62 (d, 2H), 7.27 (d, 2H), 7.07 (m, 2H), 7.05 (m, 2H), 6.97 (d,
1H), 3.28-2.92 (m, 2H), 2.40 (s, 3H), 1.40 (d, 3H). 13C NMR (125 MHz, CDCl3) δ 146.0, 143.3,
137.8, 135.2, 132.4, 131.3, 129.7, 127.5, 127.1, 126.3, 53.5, 48.1, 40.0, 35.9, 21.5, 17.5.
(R)-2-Chloro-N-(2-(3-chlorophenyl)propyl)acetamide (10)
Into a cold solution of 2-(3-chlorophenyl)propan-1-amine (3) (250 mg, 1.5 mmol) in CH2Cl2 (4
mL) Na2CO3 (1.6 mmol) was added and the mixture was stirred for 15 min at 5-10 °C. Then
chloroacetyl chloride (1.6 mmol) was slowly dropped into the reaction system and stirred for a
few hours at 25 °C. The reaction mixture was diluted with H2O, phases were separated, the
organic phase was washed with brine (20 mL) and dried over MgSO4. The solvent was
evaporated under reduced pressure to afford an oily product (350 mg, 95 % yield).
1H NMR (500 MHz, CDCl3) δ 7.30-7.18 (m, 3H), 7.10 (m, 1H), 4.00 (s, 2H), 3.65 (m, 1H), 3.34
13
(m, 1H), 2.97 (m, 1H), 1.32 (d, J = 8.7 Hz, 3H). C NMR (125 MHz, CDCl3) δ 166.2, 145.8,
134.8, 130.2, 127.5, 127.3, 125.6, 46.4, 42.8, 39.6, 19.0. IR (neat) ν 3291 (br), 1656, 1537, 1381
cm–1.
9

(R)-N-(2-chloroethyl)-2-(3-chlorophenyl)propan-1-amine hydrochloride (11-HCl)
A round bottom flask was charged with 2-chloro-N-(2-(3-chlorophenyl)propyl)acetamide (10) (2
mmol) and BH3-THF complex (1M solution in THF; 2.5 equiv.) was slowly added. The reaction
mixture was vigorously stirred for 15 h at 25 °C. Afterwards the mixture was cooled to 5 °C,
quenched with MeOH and the solvent was evaporated under reduced pressure. The organic
residue was then diluted in Et2O and a solution of HCl was added dropwise. The reaction
mixture was stirred at room temperature for 1 h and then slowly cooled to precipitate white solid
material which was filtered off and dried in vacuum (353 mg, 76 % yield); mp. 160 °C).
1H NMR (500 MHz, CDCl3/acetone-d6) δ 7.24-7.16 (m, 4H), 3.91 (m, 2H), 3.44 (m, 1H), 3.21
(m, 4H), 1.38 (d, J = 8.7 Hz, 3H). 13C NMR (125 MHz, CDCl3/acetone-d6) δ 144, 134.9, 130.6,
127.9, 127.4, 125.7, 54.3, 49.3, 38.4, 36.7, 19.9. IR (neat) ν 2931, 2743, 1594, 1444, 1029 cm–1.
Conclusion
In summary, three processes for the preparation of enantiopure lorcaserin have been described.
The final process involved three synthetic transformations and proceeded in 47 % overall yield
from the chiral amine 3 in a straightforward manner to enantiopure lorcaserin.
10

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