A Novel Synthesis of Pimavanserin: A Selective Serotonin 5-HT2A Receptor Inverse Agonist

Full text of DOI:10.1080/00304948.2019.1697613

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: 0030-4948 (Print) 1945-5453 (Online) Journal homepage: https://www.tandfonline.com/loi/uopp20
A Novel Synthesis of Pimavanserin: A Selective
Serotonin 5-HT2A Receptor Inverse Agonist
Kun Hu, Meiju Zhang, Dongdong Wu, Yuxuan Xie & Jie Ren
To cite this article: Kun Hu, Meiju Zhang, Dongdong Wu, Yuxuan Xie & Jie Ren (2020) A Novel
Synthesis of Pimavanserin: A Selective Serotonin 5-HT2A Receptor Inverse Agonist, Organic
Preparations and Procedures International, 52:1, 69-76, DOI: 10.1080/00304948.2019.1697613
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
2020, VOL. 52, NO. 1, 69–76
https://doi.org/10.1080/00304948.2019.1697613
OPPI BRIEF
A Novel Synthesis of Pimavanserin: A Selective
Serotonin 5-HT2A Receptor Inverse Agonist
Kun Hu, Meiju Zhang, Dongdong Wu, Yuxuan Xie, and Jie Ren
School of Pharmaceutical Engineering & Life Science, Changzhou University, Changzhou, Jiangsu, China
ARTICLE HISTORY Received 2 October 2018; Accepted 1 September 2019
Psychosis in patients with Parkinson’s disease (PD) is a common, at times debilitating,
condition and represents a major unmet need in the treatment of PD.1 Pimavanserin
(1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea) is a potent
and selective serotonin 5-HT2A receptor inverse agonist without adrenergic, dopamin-
ergic, muscarinic affinity or histaminergic actions approved by the FDA in 2016.2–5 It is
in development as a treatment for psychosis symptoms, such as delusions and hallucina-
tions, associated with Parkinson’s disease (PDP),6–8 which have an impact on up to 50%
of these patients during their lifetimes.9–10 To date, reports of real-world experience
with Pimavanserin have been restricted by small sample sizes11–12 or limited scope;13–14
however, preliminary evidence shows that Pimavanserin provides antipsychotic benefits
and good tolerability to PDP patients.15–17 Also, Pimavanserin, a non-dopamine neuro-
transmitter analog, does not affect dopamine function, and it has no side effects of
exacerbation that traditional antipsychotic drugs have caused in PDP patients.18 This is
likely due to its selectivity to the 5-HT2A serotonin receptor.19 As a result,
Pimavanserin has good prospects which make its synthetic process more meaningful.
In recent years, several methods for synthesizing Pimavanserin have been reported.20–23
1) The procedure for the preparation of Pimavanserin by Thygesen published in 2006 is
illustrated in Scheme 1, which includes O-alkylation followed by an addition-elimination
reaction and oxime reduction to give an intermediate which is then reacted with the haz-
ardous phosgene. 2) In 2008, a synthetic route to Pimavanserin was published by Gant
(Scheme 2). That method has low process safety and uses the dangerous reagent diphenyl-
phosphoryl azide. In addition, column chromatography in the last step is a disadvantage.
3) In 2015, Balazs published another preparation of Pimavanserin (Scheme 3). In that
method, the starting material is expensive and not easy to obtain. This process also uses
the toxic reagent methyl chloroformate and the total yield is low. All the above methods
have such drawbacks as harsh reaction conditions, hazardous reagents, high cost, low
yields, or the necessity of column chromatography for purification.
Accordingly, there is a need for finding optimized preparations with low cost and
more eco-friendly reagents. In this article, to obviate the drawbacks of the previously
reported methods, we introduce a new, safe and efficient procedure leading to
CONTACT Kun Hu
hukun1979@163.com
School of Pharmaceutical Engineering & Life Science, Changzhou
University, Changzhou, Jiangsu, 213164, China
ß 2020 Taylor & Francis Group, LLC

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K. HU ET AL.
Scheme 1. 4-Isobutoxybenzyl isocyanate was synthesized by alkylation, oximation, reduction, and
Hofmann rearrangement using 4-hydroxybenzaldehyde as the starting material; then 4-(4-fluorobenzyla-
mino)-1-methylpiperidine was obtained by Birch reduction using 4-fluorobenzylamine and N-methyl-4-
piperidinone as the starting materials; finally 4-isobutoxybenzyl isocyanate underwent an ammonolysis
reaction with 4-(4-fluorobenzylamino)-1-methyl piperidine to give the final product, Pimavanserin.
Scheme 2. Pimavanserin was synthesized by alkylation, hydrolysis, Curtius rearrangement, and ammo-
nolysis using 4-hydroxybenzaldehyde as the starting material.

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
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Scheme 3. Pimavanserin was synthesized by acylation and ammonolysis using 4-isobutoxybenzyl-
amine as the starting material.
Pimavanserin (Scheme 4). Our strategy focused on the commercially available 4-hydrox-
yphenylacetic acid as the starting material. The use of mild and inexpensive reagents,
simple work-up and purification without using column chromatography in each step
are the main advantages of this approach.
In this procedure, Pimavanserin was obtained through a ten-step sequence using 4-
hydroxyphenylacetic acid (2) as precursor to obtain methyl 4-hydroxyphenylacetate (3) by an
esterification reaction. The resulting product 3 was transformed to methyl 4-isobutoxypheny-
lacetate (4) by alkylation with isobutyl bromide. In the subsequent reaction, compound 4
afforded 2-(4-isobutoxyphenyl)acetic acid (5) and was further converted to 2-(4-isobutoxy-
phenyl)acetamide (6) by acylation. Methyl 4-isobutoxybenzylcarbamate (7) was obtained
through Hofmann reaction of 6. Compound 7 was hydrolyzed and acylated with phenyl
chloroformate to give phenyl 4-isobutoxybenzylcarbamate (9). Finally compound 9 under-
went an ammonolysis reaction with 4-(4-fluorobenzylamino)-1-methylpiperidine (10) to give
the desired Pimavanserin. Our route is cheaper, eco-friendly and gives a high yield (total yield
33%) despite involving more steps as compared to the previously reported routes.
In conclusion, we have proposed a novel, low-cost, high yielding and eco-friendly
synthetic route to prepare Pimavanserin which can be scale-up at industrial level.
Experimental section
All chemicals including solvents and reagents were available commercially and were
used without further purification. All the reactions were monitored by thin-layer chro-
matography (TLC) performed on silica gel F254 plates at 254 nm under a UV lamp,
1
using mixed ethyl acetate (EA) and petroleum ether (PE) as the solvent. H NMR and
13C NMR spectra were recorded in CDCl3 and DMSO-d6 with TMS as internal standard
using a Bruker 400 MHz spectrometer. Purity analyses were performed on an Agilent
1220 infinity LC with C18 column (5 mm, 4.6 mm ꢀ 250 mm).
Methyl 4-hydroxyphenylacetate (3)
To a stirred solution of 4-hydroxyphenylacetic acid (500 g, 3286 mmol) in methanol
(750 mL) was added concentrated sulfuric acid (21 mL) at ambient temperature. The

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K. HU ET AL.
Scheme 4. New route to Pimavanserin.
reaction mixture was refluxed for 0.5 h. The progress of reaction was monitored by
TLC. After the reaction was completed, the mixture was concentrated under reduced
pressure. Water (500 mL) was added to the reaction mixture and the mixture was
extracted with ethyl acetate (600 mL ꢀ 2). The combined organic extracts were washed
with saturated sodium bicarbonate until the pH was neutral. The organic layer was
washed with brine (500 mL ꢀ 2), dried over anhydrous sodium sulfate, filtered and con-
1
centrated on a rotary evaporator to afford 535 g (98%) of 3 as a yellow oil. H NMR
(400 MHz, CDCl3): d 7.10 (d, J¼8 Hz, 2H), 6.73 (d, J¼8 Hz, 2H), 3.69 (s, 3H), 3.55 (s,
2H). 13C NMR (100 MHz, CDCl3): d 173.65, 155.17, 130.45, 128.38, 115.67, 52.37, 40.33.
Methyl 4-isobutoxyphenylacetate (4)
To a solution of methyl 4-hydroxyphenylacetate (535 g, 3220 mmol) dissolved in N,N-
dimethylformamide (1500 mL) was added potassium carbonate (534 g, 3864 mmol). Then

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
73
1-bromo-2-methylpropane (1324 g, 9663 mmol) was added to the reaction mixture at
ambient temperature. The reaction mixture was vigorously stirred for 12 h at 80 ꢁC. TLC
monitored the reaction process. After the reaction mixture was cooled to ambient tem-
perature, the mixture was filtered. Water (1 L) was added to the filtrate and ethyl acetate
(1 L ꢀ 2) was used to extract an organic layer. The organic extracts were combined,
washed with 1M NaOH (1 L ꢀ 2) and brine (2 L ꢀ 3), dried over anhydrous sodium sul-
1
fate, filtered and concentrated to afford 567.2 g (78.6%) of 4 as a yellow oil. H NMR
(400 MHz, CDCl3): d 7.21 (d, J¼8 Hz, 2H), 6.89 (d, J¼8 Hz, 2H), 3.73 (d, J¼8 Hz, 2H),
3.70 (s, 3H), 3.58 (s, 2H), 2.07-2.11 (m, 1H), 1.05 (d, J¼8 Hz, 6H). 13C NMR (100 MHz,
CDCl3): d 172.44, 158.42, 130.24, 125.79, 114.61, 74.43, 52.02, 40.34, 28.29, 19.30.
2-(4-Isobutoxyphenyl)acetic acid (5)
The methyl 4-isobutoxyphenylacetate (562 g, 2528 mmol) was dissolved in methanol
(600 mL). Sodium hydroxide (151.7 g, 3793 mmol) dissolved in water (300 mL) was added
subsequently. The reaction mixture was refluxed for 2 h and was monitored by TLC. After
completion of reaction, the mixture was concentrated under reduced pressure. Water
(10 L) was added to the round bottom flask, then concentrated hydrochloric acid (450 mL)
was added subsequently while stirring and a white solid precipitated. The precipitate was
filtered, washed with water (2 L ꢀ 2) and dried to obtain 497 g (94.5%) of 5 as a white
1
powder. H NMR (400 MHz, CDCl3): d 7.18 (d, J¼8 Hz, 2H), 6.86 (d, J¼8 Hz, 2H), 3.70
(d, J¼8 Hz, 2H), 3.57 (s, 2H), 2.03-2.09 (m, 1H), 1.01 (d, J¼4 Hz, 6H). 13C NMR
(100 MHz, CDCl3): d 180.18, 160.12, 131.93, 126.60, 116.23, 75.99, 41.79, 29.82, 20.84.
2-(4-Isobutoxyphenyl)acetamide (6)
A solution of 2-(4-isobutoxyphenyl)acetic acid (200 g, 960.3 mmol) dissolved in thionyl
chloride (200 mL) was refluxed for 1 h with stirring, and the reaction was monitored by
TLC. After completion of reaction, the mixture was concentrated using a rotatry evap-
orator. The resulting yellow oil was dissolved in acetonitrile (400 mL) and was added
dropwise to a round bottom flask containing ammonium hydroxide (400 mL) while
stirring on an ice bath. The reaction mixture was kept at 0 ꢁC for 1 h. TLC monitored
the total reaction. After the reaction was completed, the mixture was concentrated
under reduced pressure. The resulting white solid was washed with water (1L ꢀ 2) and
1
dried to obtain 174.2 g (87.5%) of 6 as a white powder. mp 179.9-182.3 ꢁC, H NMR
(400 MHz, CDCl3): d 7.19 (d, J¼8 Hz, 2H), 6.92 (d, J¼12 Hz, 2H), 3.73 (d, J¼4 Hz, 2H),
3.54 (s, 2H), 2.08-2.12 (m, 1H), d 1.05 (d, J¼8 Hz, 6H). 13C NMR (100 MHz, CDCl3): d
173.08, 157.82, 130.46, 128.79, 114.62, 74.17, 41.84, 28.18, 19.55.
Anal. Calcd for C12H17NO2: C, 69.54; H, 8.27; N, 6.76. Found: C, 69.26; H, 8.01; N, 6.92.
Methyl 4-isobutoxybenzylcarbamate (7)
2-(4-Isobutoxyphenyl)acetamide (50 g, 241.2 mmol) was suspended in methanol (1 L).
Then N-bromosuccinimide (64.4 g, 361.8 mmol) and 1,8 diazabicyclo [5.4.0] undec-7-
ene (73.4 g, 482.4 mmol) were added in turn. The reaction mixture was heated at reflux

74
K. HU ET AL.
until TLC showed the reaction to be complete. After completion of reaction, methanol
was removed by rotary evaporation. Water (2 L) was added to the mixture and a yellow
solid precipitated. The precipitate was filtered. The residue was dissolved in 500 mL of
ethyl acetate. The ethyl acetate solution was washed with 6 N hydrochloric acid (500 mL
ꢀ 2), 1 N sodium hydroxide (500 mL ꢀ 2) and saturated sodium chloride (500 mL ꢀ
2), and then dried over magnesium sulfate. The solvent was removed by rotary evapor-
ation. The crude product was recrystallized from hexane (200 mL) to provide 50.8 g
1
(88.8%) of 7 as a white solid. H NMR (400 MHz, CDCl3): d 7.18 (d, J¼12 Hz, 2H),
6.83 (d, J¼8 Hz, 2H), 4.25 (d, J¼4 Hz, 2H), 3.64-3.68 (m, 5H), 2.00-2.10 (m, 1H), 1.01
(d, J¼4 Hz, 6H). 13C NMR (100 MHz, CDCl3): d 158.68, 157.09, 130.48, 128.87, 114.61,
74.46, 52.13, 44.59, 28.27, 19.28.
4-Isobutoxybenzylamine (8)
A solution of potassium hydroxide (118 g, 2103 mmol) dissolved in ethanol (700 mL) was
added to methyl 4-isobutoxybenzylcarbamate (50 g, 210.70 mmol). The reaction mixture
was heated at reflux until TLC showed the reaction to be complete. After completion of
reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced
pressure. The resulting oil was diluted with dichloromethane (500 mL), and the solution
was washed with water (500 mL ꢀ 3) to remove potassium hydroxide. The organic layer
was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator
to afford 8 (crude, 44 g) as a yellow oil. The crude 8 did not require further purification for
the next step. 1H NMR (400 MHz, DMSO-d6): d 8.45 (s, 2H), 7.39 (d, J¼8 Hz, 2H), 6.92 (d,
J¼8 Hz, 2H), 3.87 (s, 2H), 3.72 (d, J¼8 Hz, 2H), 1.93-2.00 (m, 1H), 0.94 (d, J¼4 Hz, 6H).
13C NMR (100 MHz, DMSO): d 159.3, 131.0, 126.4, 114.9, 74.2, 42.1, 28.1, 19.5.
Phenyl 4-isobutoxybenzylcarbamate (9)
A mixture of potassium carbonate (40.71 g, 294.5 mmol) and 4-isobutoxybenzylamine
(44 g, 245.5 mmol) in dichloromethane (500 mL) was stirred at ambient temperature.
Then phenyl chloroformate (38.43 g, 245.5 mmol) was added dropwise over an ice bath.
The reaction mixture was stirred at room temperature until TLC showed the reaction
was completed. After completion of reaction, the reaction mixture was washed with
water (500 mL ꢀ 2), the organic layer was concentrated on a rotary evaporator to afford
crude 9. The crude product was recrystallized from methanol (200 ml) to provide 46.9 g
1
(63.9%) of 9 as a white solid. H NMR (400 MHz, DMSO-d6): d 8.23 (t, J¼6 Hz, 1H),
7.37 (t, J¼8 Hz, 2H), 7.21 (m,3H), 7.09 (d, J¼8 Hz, 2H), 6.89 (d, J¼8 Hz, 2H), 4.17 (d,
J¼4 Hz, 2H), 3.70 (d, J¼4 Hz, 2H), 1.96-1.99 (m, 1H), 0.95 (d, J¼4 Hz, 6H). 13C NMR
(100 MHz, DMSO): d 158.33, 155.04, 151.55, 131.58, 129.71, 128.99, 125.40, 122.25,
114.80, 74.21, 43.95, 28.18, 19.54.
4-(4-Fluorobenzylamino)-1-methylpiperidine (10)
To a solution of 4-fluorobenzylamine (50 g, 399.6 mmol) and N-methyl-4-piperidinone
(47.5 g, 419.8 mmol) in methanol (200 mL) was added sodium triacetoxyborohydride

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
75
(88.9 g, 419.4 mmol) within 1 h at 0 ꢁC. The reaction mixture was stirred at ambient
temperature. After consumption of the amine as monitored by TLC, the reaction mix-
ture was concentrated under reduce pressure and then quenched by adding 300 mL of
10% sodium hydroxide solution. The mixture was extracted with ethyl acetate (500 mL
ꢀ 3). The organic layer was washed with brine (500 mL ꢀ 2), dried over anhydrous
sodium sulfate, filtered and concentrated on a rotary evaporator to afford 75 g (84.5%)
1
of 10 as a yellow oil. H NMR (400 MHz, CDCl3): d 7.27-7.30 (m, 2 H), 6.98-7.02 (m,
2H), 3.78 (s, 2H), 2.83 (d, J ¼ 8 Hz, 2H), 2.48 (s, 1H), 2.26 (s, 3H), 1.87-2.02 (m, 5H),
1.40-1.50 (m, 2H). 13C NMR (100 MHz, CDCl3): d 163.08, 160.65, 136.31, 129.61,
129.53, 115.28, 115.07, 54.55, 53.66, 50.08, 48.21, 32.70.
1-(4-Fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea (1)
To a mixture of 4-(4-fluorobenzylamino)-1-methylpiperidine (37 g, 166.43 mmol) and
phenyl 4-isobutoxybenzylcarbamate (50 g, 167.01 mmol) dissolved in ethanol (1 L) was
added Et3N (20 mL). The reaction mixture was heated in an oil bath at reflux for 12 h
and was monitored by TLC. After completion of reaction, the mixture was concentrated
under reduced pressure. Then 500 mL of water was added to the reaction mixture.
After cooling to 0-5 ꢁC for 1 h, a pale yellow solid was precipitated. The precipitate was
filtered and washed with water. The crude product was recrystallized from ethyl acetate
(100 mL) to provide 60 g (84.5%) of Pimavanserin as a white solid. HPLC analysis of an
1
aliquot of the powder indicated a purity of 99.5% (determined by peak areas). H NMR
(400 MHz, CDCl3): d 7.15-7.18 (m, 2H), 6.96-7.01 (m, 4H), 6.78 (d, J¼8 Hz, 2H), 4.44-
4.47 (m, 1H), 4.26-4.33 (m, 5H), 3.67 (d, J¼4 Hz, 2H), 2.86 (d, J¼8 Hz, 2H), 2.24 (s,
3H), 2.03-2.06 (m, 3H), 1.61-1.72 (m, 4H), 1.01 (d, J¼4 Hz, 6H). 13C NMR (100 MHz,
CDCl3): d 163.26, 160.82, 158.46, 158.06, 133.77, 130.99, 128.60, 127.70, 127.62, 115.92,
115.70, 114.51, 74.46, 54.98, 51.36, 45.30, 45.17, 44.45, 29.14, 28.26, 19.27.
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