Novel and environmentally friendly synthesis of pimavanserin (5-HT2A receptor)

Article abstract of DOI:10.14233/ajchem.2019.21808

Eco-friendly synthesis of pimavanserin was developed from the key starting material 4-isobutoxy benzylamine in three different routes using water as solvent. These reactions provide an advantage of easy workup, good yields of products and uses water as the solvent. No column purification was required for the isolation of the product.

Full text of DOI:10.14233/ajchem.2019.21808

Asian Journal of Chemistry; Vol. 31, No. 3 (2019), 723-726
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2019.21808
Novel and Environmentally Friendly Synthesis of Pimavanserin (5-HT2A Receptor)
1,2
1
2
3,*
RAJESH KUMAR RAPOLU , V.V.N.K.V. PRASADA RAJU , MURTHY CHAVALI and NAVEEN MULAKAYALA
1Granules India Limited, R & D Center, Plot No. 56, Road No. 5, ALEAP Industrial Area, Pragathi Nagar, Hyderabad-500072, India
2Department of Sciences and Humanities, Vignan's Foundation for Science, Technology and Research University (VFSTR), Vadlamudi, Guntur-
522213, India
3SVAK Lifesciences, ALEAP Industrial Area, Pragathi Nagar, Hyderabad-500090, India
*Corresponding author: E-mail: naveen071280@gmail.com
Received: 12 November 2018;
Accepted: 14 December 2018;
Published online: 31 January 2019;
AJC-19276
Eco-friendly synthesis of pimavanserin was developed from the key starting material 4-isobutoxy benzylamine in three different routes
using water as solvent. These reactions provide an advantage of easy workup, good yields of products and uses water as the solvent. No
column purification was required for the isolation of the product.
Keywords: Pimavanserin, Parkinson disease, Nuplazid, Dopamine receptor.
Several literature procedures were reported by using
diphenylphosphoryl azide compounds, chloroformate amino
protected compounds and carbonyl diimidazole intermediates
as key materials for the synthesis of pimavanserin.All the above
substances were synthesized by using hazardous reagents which
may lead to the formation of more byproducts in turn effect the
purity and yield of pimavanserin. Hence, there is a need for
the development of alternate procedures for the synthesis of
pimavanserin which is industrially feasible.
Due to continuous interest in the development ofAPI and
API impurities by our laboratory [10-12], we wish to report
the easy and convenient method for the synthesis of pimava-
serin in this article. Thus, our efforts in achieving an environ-
mental friendly, step-wise and one-pot synthetic process for
pimavanserin via three different intermediates (isothiocyanate,
urea and N-formyl) was described under green conditions.
INTRODUCTION
Parkinson's disease is neurodegenerative disease which
affects 7-10 million people worldwide every year [1]. The
number of Parkinson's disease patients are increasing world-
wide with the increase in the age of the worldwide population.
Till April 2016, there was no approved drug available in the
United States (USA) for the treatment of Parkinson's disease
psychosis (PDP). Pimavanserin [2] is the first Food and Drug
Administration (FDA) approved medicine in April 29th 2016
for the treatment of hallucinations and delusions associated with
Parkinson's disease psychosis.
Pimavanserin was discovered first time in US 6756393B2
[3]. It was developed byAcadia Pharmaceuticals and marketed
under the proprietary name NUPLAZID, as an oral tablet, for
the treatment of Parkinson's disease psychosis. Due to the
importance of pimavanserin for the treatment of hallucinations
and delusions associated with Parkinson's disease psychosis,
different synthetic routes have been reported in the literature
to prepare pimavanserin [4-9]. But, several problems were
observed in the synthetic processes of pimavanserine with the
reported methods. The processes reported were having usage
of expensive reagents, difficulty in handling in commercial
scale, requires multiple purification methods which leads to
lower yields.
EXPERIMENTAL
Solvents and reagents were obtained from commercial
sources and used without further purification. 1H NMR spectra
were recorded in CDCl3, DMSO-d6 at room temperature on a
Varian Mercury spectrometer plus 400 MHz using TMS as an
internal standard. 13C NMR spectra were obtained from aVarian
Mercury plus 100 MHz spectrometer in DMSO-d6 at room
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724 Rapolu et al.
Asian J. Chem.
temperature. IR spectra were recorded in the solid state as
KBr dispersion using a Perkin-Elmer 1650 FT IR spectrometer.
The mass spectrum (70 eV) was recorded on an HP 5989 A
LC-MS spectrometer. TLC analyses were performed on Merck
silica gel 60F254 plates.
114.5, 114.0, 73.7, 54.8, 52.3, 45.6, 43.9, 43.05, 29.8, 27.6,
18.9; Mass (m/z): 428.3 (M+H).
Synthesis of of 1-(4-isobutoxybenzyl)urea (7):A mixture
of 4-isobutoxy benzylamine (5.0 g, 0.0279 mol.), urea (10.0 g,
0.166 mol) and NaOH (0.99 g, 0.0247 mol) were heated to
120-130 ºC in a three- neck round bottom flask. The reaction
mass was stirred for 12-15 h till the starting material of the
reaction was completed by TLC. Water (50 mL, 10.0 v) was
added to the reaction mixture and the pH of the reaction mass
was adjusted to 7.0 by using concentrated HCl. Solid formation
was observed and the solids were filtered, washed with water
(20 mL, 4.0 v) and dried to get the desired compound 1-(4-
Synthesis of 1-isobutoxy-4-(isothiocyanatomethyl)-
benzene (2): A mixture of 4-isobutoxy benzylamine (10.0 g,
0.0558 mol), water (70 mL, 7.0 v) and sodium bicarbonate (18.7
g, 0.222 mol) were stirred at room temperature. The reaction
mixture was cooled to 0-5 ºC and thiophosgene (12.8 g, 0.111
mol) was added at the same temperature and stirred for about
5-6 h. After completion of the starting material by TLC, 10 %
sodium bicarbonate solution (20 mL, 2.0 v) was added and
stirred for 5-10 min. Dichloromethane (50 mL, 5.0 v) was added
to the reaction mixture and stirred for 15 min and the organic
layer was separated. Organic layer was washed with water (30
mL, 3.0 v) and dried over anhydrous Na2SO4. The solvent was
evaporated under reduced pressure to get desired 1-isobutoxy-
4-(isothiocyanatomethyl)benzene as an off white solid (10.5
g, 85.1 %). 1H NMR (DMSO-d6, 500 MHz): δ 7.28-7.30 (d, 2H),
6.95-6.96 (d, 2H), 4.82 (s, 2H), 3.73-3.74 (d, 2H), 1.96-2.03
(m, 1H), 0.96-0.98 (d, 6H). Mass (m/z): 162.8 (M-58).
Elemental analysis of C12H15NOS calcd. (found) %: C 65.10
(65.12); H 6.81 (6.83); N 6.30 (6.33).
1
isobutoxybenzyl)urea (5.0 g, 80.6 %) as off white solid. H
NMR (500 MHz, DMSO-d6): δ 7.15-6.85 (m, 4H, arom.), 6.32-
6.28 (t, 1H, -NH), 5.46 (s, 2H, -NH2), 4.08-4.07 (d, 2H, -CH2),
3.71-3.69 (d, 2H, -CH2), 2.01-1.94 (m, 1H, -CH), 0.97-0.95
(d, 6H, (-CH3)2); 13C NMR (100.40 MHz, DMSO-d6): 158.6,
157.5, 132.6, 128.7, 114.2, 73.7, 42.3, 27.7, 19.0; Mass (m/z):
223.65 [M+· + 1]. Elemental analysis of C12H18N2O2 calcd.
(found) %: C 64.84 (64.88); H 8.16 (8.19); N 12.60 (12.64).
Synthesis of pimavanserin from compund 7:A mixture
of 1-(4-isobutoxybenzyl)urea (1.0 g, 4.5 mmol) and N-(4-fluoro-
benzyl)-1-methylpiperidin-4-amine (3) (1.0 g, 4.5 mmol) were
heated to 120-130 ºC until the TLC complies (12 h). Water
(10 mL, 10.0 v) was added to the reaction mass after cooling it
to room temperature and extracted with ethyl acetate (10 mL,
10.0 v). Ethyl acetate layer was evaporated under reduced pressure
to get solid compound which was triturated using 10 % methanol
in ethyl acetate (10 mL) to get pimavanserin (1.3 g, 83.1 %).
Synthesis of N-(4-isobutoxybenzyl)formamide (9): 4-
Isobutoxy benzylamine acetate (10.0 g, 0.0558 mol) was stirred
in water (30 mL, 3.0 v) at room temperature. The pH of the
reaction mass was adjusted to 11-12 with aqueous ammonia
solution. The product was extracted using toluene (50 mL,
5.0 v). Formic acid (2.3 g) was added to the toluene layer and
it was refluxed for 4-5 h using dean-stark apparatus. After the
completion of starting material using TLC, solvent was removed
under reduced pressure and the crude residue was extracted
with hexane to get N-(4-isobutoxy-benzyl)formamide as an
Synthesis of 1-(4-fluorobenzyl)-3-(4-isobutoxy benzyl)-
1-(1-methylpiperidin-4-yl)thiourea (4): A mixture of 1-iso-
butoxy-4-(isothiocyanato-methyl)benzene (2) (5.0 g, 0.0226
mol) and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (6.0
g, 0.027 mol) in ethyl acetate (50 mL, 10.0 v) were stirred at
70-75 ºC for 4-5 h until the starting material disappears on
TLC. Ethyl acetate was evaporated under reduced pressure
and residue was purified triturated with 10 % methanol in DCM
(5 mL) to get desired compound 1-(4-fluorobenzyl)-3-(4-isobut-
oxybenzyl)-1-(1-methyl piperidin-4-yl)thiourea (8.5 g, 84.9 %)
1
as pale yellow solid. m.p. 136-139 ºC. H NMR (DMSO-d6,
500 MHz): δ 6.72-7.12 (m, 8H), 5.48-5.74 (m, 2H), 4.56-4.64
(m, 4H), 3.63-3.67 (d, 2H), 3.20-3.23 (d, 2H), 2.57-2.59 (broad,
m, 2H), 2.53(S, 3H), 1.96-2.15 (m, 5H), 0.95-1.01 (d, 6H); 13C
NMR (DMSO-d6, 125 MHz): δ 181.9, 162.2, 159.7, 157.5,
134.6, 131.4, 128.3, 128.1, 128.0, 114.9, 114.7, 113.9, 73.7,
55.9, 54.1, 48.0, 46.8, 44.7, 28.4, 27.7, 18.9; Mass (m/z): 444
(M+H). Elemental analysis of C25H34N3OSF calcd. (found) %:
C 67.65 (67.69); H 7.71 (7.73); N 9.46 (9.47).
1
off-white solid (10.0 g, 75.05 %). H NMR (DMSO-d6, 500
MHz): δ 8.39 (broad, 1H, -NH), 8.09 (s, 1H, -COH), 7.17-6.85
(m, 4H, arom.), 4.21-4.20 (d, 2H, -CH2), 3.72-3.70 (d, 2H, -
CH2), 2.01-1.95 (m, 1H, -CH), 0.97-0.95 (d, 6H, (-CH3)2); 13C
NMR (DMSO-d6): δ 164.6, 160.8, 157.8, 131.4, 130.8, 128.6,
128.3, 114.4, 114.3, 73.7, 43.9, 40.1, 27.6, 18.9. Mass (m/z):
206.5 (M-H)
Synthesis of pimavanserin from compound 9: N-(4-iso-
butoxybenzyl)formamide (2.0 g, 0.0096 mol) was stirred in
DCM (20 mL, 10.0 v) at room temperature in a three neck
round bottom flask. To this triethyl amine (3.9 g, 0.0385 mol)
was added at room temperature. The reaction was cooled to 0-
5 °C, and then triphosgene (1.98 g, 0.0066 mol.) was added in
lot wise to above reaction mixture at 0-5 °C. After complete
addition of triphosgene, the reaction mass was warmed to room
temperature and stirred for 2-3 h till the completion of the
starting material. Wash the reaction mixture with water (10
mL, 5.0 v) and dried over anhydrous Na2SO4. The organic layer
was transferred into another round bottom flask under inert
Synthesis of pimavanserin (5): 1-(4-Fluorobenzyl)-3-(4-
isobutoxybenzyl)-1-(1-methyl piperidin-4-yl)thiourea (1.0 g,
2.256 mmol) and silver carbonate (1.2 g, 4.35 mmol) in aceto-
nitrile (15 mL, 15.0 v) was stirred at room temperature until
TLC complies (24 h). The reaction mixture was filtered to
remove undissolved solids and washed the solid with aceto-
nitrile (5 mL, 5.0 v). The acetonitrile layer was evaporated under
reduced pressure to get residue, which was triturated in a mixture
of water (10 mL, 10.0 v) and methanol (2 mL, 2.0 v) to get the
pure compounds as yellow solid (0.91 g, 94.2%). m.p. 116-
1
118 ºC ; H NMR (CDCl3, 500 MHz): δ 6.76-7.19 (m, 8H),
4.44-4.46 (m, 1H), 4.26-4.33 (m, 5H), 3.66-3.68 (d, 2H), 2.86-
2.89 (d, 2H), 2.27 (s, 3H), 2.00-2.11 (m, 3H), 1.63-1.71 (m, 4H),
0.99-1.01 (d, 6H); 13C NMR (100.40 MHz, CDCl3): δ 162.0,
159.6, 157.5, 157.4, 136.9, 133.0, 128.3, 128.2, 128.1, 114.7,

Vol. 31, No. 3 (2019)
Novel and Environmentally Friendly Synthesis of Pimavanserin (5-HT2A Receptor) 725
TABLE-1
atmosphere and cooled to -65 to -60 ºC. Dimethyl sulfoxide
(DMSO) (0.82 g, 0.0105 mol) and trifluoromethanesulfonic
anhydride (0.1 mL, 0.0045 mol) were added to the reaction
mixture at -65 to -60 ºC. Reaction mixture was stirred for 10-
15 min at the same temperature. Then (N-(4-fluorobenzyl)-1-
methylpiperidin-4-amine)) (2.1 g) in DCM (10.0 v) was added
at -65 to -60 ºC. Reaction mixture was warmed to room temp-
erature and stirred for 2-3 h. The reaction mixture was washed
with water (10 mL, 5.0 v) and dried the organic layer over
Na2SO4. The solvent was evaporated under reduced pressure
and residue was triturated with acetone to give pimavanserin
(3.2 g, 77.7 %) as yellow solid.
SCREENING OF SOLVENT FOR THE SYNTHESIS OF
1-(4-FLUOROBENZYL)-3-(4-ISOBUTOXYBENZYL)-
1-(1-METHYL PIPERIDIN-4-YL)THIOUREA (4)
S. No.
Solvent
Ethyl acetate
Acetonitrile
DMF
Acetone
Methanol
Reaction
Reflux
Reflux
80-85 °C
Reflux
Reflux
Time (h)
Yield (%)
1
2
3
4
5
6
7
5
5
10
8
8
8
85
75
65
77
70
69
65
Isopropyl alcohol
Toluene
Reflux
80-85 °C
10
Oxidation was performed on compound 4 using different
oxidizing agents. Compound 4 was oxidized with several oxid-
izing agents like silver carbonate, oxone, H2O2, DMSO at room
temperature for 24 h. In all the reagents, silver carbonate was
effective to give the title compound pimavanserin (5) in excellent
yield (94.2%) (Table-2). The structure of compound was estab-
lished by its spectral data (i.e. IR, 1H NMR, 13C NMR and mass).
RESULTS AND DISCUSSION
Initially, we have chosen 4-isobutoxy benzylamine (1) as
a key starting material for the synthesis of pimavanserin. The
initial reaction was reaction of 4-isobutoxy benzylamine (1)
with thiophosgene using sodium bicarbonate in water. The
reaction was stirred at 0-5 ºC for 5-6 h to yield corresponding
1-isobutoxy-4-(isothiocyanatomethyl)benzene (2) in good yield.
The next step is reaction of compound 2with N-(4-fluorobenzyl)-
1-methylpiperidin-4-amine (3). This reaction was performed
using ethanol as solvent in refluxing conditions for 1-2 h to
get respective thiourea derivative i.e. 1-(4-fluorobenzyl)-3-(4-
isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)thiourea (4)
(Scheme-I). To improve the reaction yield various solvents
were employed i.e. methanol, acetonitrile, isopropyl alcohol,
DMF, toluene, acetone, ethyl acetate for synthesis of compound
4. Among all the solvents, ethyl acetate gave good yields for
the reaction in terms of the reaction time and yield (Table-1).
TABLE-2
SYNTHESIS OF COMPOUND 5 FROM COMPOUND 4
USING VARIOUS OXIDIZING AGENTS
S. No.
Oxidizing agent Reaction time (h)
Yield (%)
1
2
3
4
H2O2
DMSO/HCl
Oxone
24
24
24
24
72
75
78
94
Silver carbonate
In another method shown in Scheme-II, 4-isobutoxy
benzylamine (1), urea (6) and sodium hydroxide were heated
F
NCS
NH2
N
Thiophosgene
N
3
water / 0-5 oC
H
O
O
Ethyl acetate/Reflux
1
2
F
O
N
N
N
silver carbonate
F
Room temperature
O
N
S
HN
HN
O
4
5
Pimavanserin ( )
Scheme-I: Synthesis of pimavanserin (5) from isothiocyanate
HN
N
O
F
O
O
NH2
NaOH
N
H
N
N
N
H
NH2
H2N NH2
3
O
O
120-130 oC
6
O
1
7
5
F
Scheme-II: Synthesis of pimavanserin (5) from urea intermediate

726 Rapolu et al.
Asian J. Chem.
O
O
N
1. DCM, TEA &
triphosgene /
0-5 oC
NH2
NH2
NH
H
N
H
N
HCOOH, Toluene
Reflux
Toluene/H2O
.CH3COOH
O
Aq. NH3
pH 11-12
2. DMSO, TFAA,
-65 to -60 oC
F
5
O
O
O
3. DCM,
9
1
compound 3
-65 to -60 oC
Scheme-III: Synthesis of pimavanserin (5) from formamide intermediate
to 135-140 ºC for 12-15 h with continuous stirring.After comp-
letion of the reaction the reaction mass was checked by TLC
and pH adjusted with HCl solution up to 7. The resulting solid
was washed with water to yield the corresponding intermediate
compound 1-(4-isobutoxybenzyl)urea (7). Further treatment
of 1-(4-isobutoxybenzyl)urea with N-(4-fluorobenzyl)-1-
methylpiperidin-4-amine (3) was refluxed for 12 h at 120-130
ºC followed by ethyl acetate extraction to get target compound
pimavanserin (5) as yellow solid in good yields.
In an alternate method shown in Scheme-III, 4-isobutoxy
benzylamine (1) formic acid and toluene were refluxed for
4-5 h at 110 ºC using Dean-Stark apparatus.After completion of
the reaction, the reaction mass was extracted with hexane and
dried to get intermediate N-(4-isobutoxybenzyl)formamide (9).
Further, formamide intermediate 9was stirred with N-(4-fluoro-
benzyl)-1-methylpiperidin-4-amine (3) in DCM at room
temperature for 2-3 h to get final compound 5.
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Conclusion
In summary, a novel and environmentally friendly synthesis
of pimavanserin (5-HT2A receptor) via three efficient interme-
diates (isothiocyanate, urea and N-formyl) under green conditions
using water as solvent.
ACKNOWLEDGEMENTS
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The authors are thankful to the authorities of Granules
India Pvt Ltd. Hyderabad, India for providing laboratory
facilities.
CONFLICT OF INTEREST
12. N. Mulakayala, Indian J. Adv. Chem. Sci., 4, 362 (2016).
The authors declare that there is no conflict of interests
regarding the publication of this article.