Field of the Invention
The present invention relates to an improved and efficient process for the preparation of
polymorphic form of l-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(l- methylpiperidin-4-
yl)urea tartrate. More preferably, the present invention relates to an improved and
efficient process for the preparation of polymorphic Form C of l-(4-fluorobenzyl)-3-(4-
isobutoxybenzyl)-l-(l- methylpiperidin-4-yl)urea tartrate.
Background of the Invention
l-(4-Fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(l-methylpiperidin-4-yl)urea is known as
pimavanserin and has been developed as pimavanserin tartrate salt by Acadia
Pharmaceuticals which has been approved for use in patients with Parkinson's disease
psychosis. Pimavanserin tartrate is represented structurally as Formula I.
O OH
HO
OH
OH O
Formula 1
Pimavanserin synthesis is disclosed in US 7601740, wherein the process involves the
reaction of N-(4-fluorobenzyl)-1 -methylpiperidine-4-amine with 1 -isobutoxybenzyl
isocyanate. The patents disclose the preparation of intermediate 1-isobutoxybenzyl
isocyanate via two processes, wherein one process involves reaction of 2-(4-
isobutoxyphenyl)acetic acid with diphenyl phosphoryl azide and the other process
involves reaction of 4-isobutoxybenzylamine with phosgene or its equivalents. The
methods mentioned in the patent suffer a number of disadvantages, the main
disadvantage involves use of 4-isobutoxybenzyl isocyanate, as isocyanates are known
toxic and are highly reactive compounds and thus are very unsafe to handle at industrial
scale. The said patent does not disclose any polymorph of pimavanserin tartrate.
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US 7732615 and US 7790899 disclosed pimavanserin tartrate in crystalline polymorphic
Form-A, Form-B, Form-C, Form-D, Form-E, Form-F, amorphous pimavanserin tartrate
and further disclosed polymorph Form-Y of pimavanserin base. Of all the disclosed
polymorphs crystalline Form-C is the most stable Form as per the disclosure of US'615.
The patent also disclose the process for the preparation of crystalline Form-C utilizing
various solvents such as, tetrahydrofuran, methyl ethyl ketone and acetone. The disclosed
processes for the preparation of pimavanserin tartrate polymorph Form-C involves use of
seed material, extensive reaction times in the range of 29 hours to 104 hours at room to
reflux temperature. Use of such long reaction times makes the process highly energy
consuming with long cycle times and thus make the process inefficient for large scale
application.
CN 105523993 disclosed a process for the preparation of crystalline Form-C of
pimavanserin tartrate by grinding pimavanserin tartrate Form-A in mortar for about 40 to
60 minutes to reduce particle size to 0.3 to 10 jam, subsequently heating the milled
powder and cooling to obtain pimavanserin tartrate Form-C. The disclosed process
involving grinding process to obtain a crystalline Form does not give consistent results
and is not operationally feasible for large scale production of active pharmaceutical
ingredients,
CN 105924381 disclosed a process for the preparation of pimavanserin tartrate Form-C
by crystallizing pimavanserin tartrate using refluxing acetone for 3 to 6 hours, wherein
acetone is used in 6-8 volumes. The process suffers disadvantage as it results in the
Formation of mixture of crystalline Forms of pimavanserin tartrate and the process does
not consistently provide same polymorph. Since the reaction time of 6 hours maximum
does not provide enough time for the initial polymorph to dissolve completely and
change into desired polymorph. Thus the disclosed process aiming to prepare
pimavanserin tartrate Form-C is not efficient as it does not provide desired results thus is
not applicable for large scale production.
Based upon the prior art disclosed processes for the preparation of pimavanserin tartrate
Form-C, it is understood that they suffer one or the other disadvantage in terms of
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difficulty in operation, crystallinity of product or very long reaction times. Thus, keeping
in view the stability of pimavanserin tartrate Form-C being most stable and its
importance, there remains an urgent need for the development of an efficient and
convenient process for the preparation of polymorph of pimavanserin tartrate.
Object and Summary of the Invention
The principal object of present invention is to provide a process for the preparation of
Form-C of l-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(l-methylpiperidin-4-yl)urea
tartrate, which alleviates the drawbacks associated with prior art disclosed processes.
An another object of the present invention is to provide an efficient and convenient
process for the preparation of Form-C of l-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(lmethylpiperidin-
4-yl)urea tartrate.
A yet another object of the present invention is to provide a process for the preparation of
Form-C of l-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(l-methylpiperidin-4-yl)urea
tartrate free from degradation impurities.
In an embodiment, the present invention provides a process for the preparation of l-(4-
fluorobenzyl)-3-(4-isobutoxybenzyI)-l-(l-methylpiperidin-4-yl)urea tartrate Form-C,
comprising the steps of,
(a) suspending 1 -(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1 -(1 -methylpiperidin-4-
yl)urea tartrate in about 3 to 5 volumes of acetone at reflux;
(b) continuing reflux of reaction mixture from step (a) for about 15 to 18 hours;
(c) cooling the reaction mixture to crystallize solid;
(d) continuing stirring for another 18-24 hours and
(e) isolating 1 -(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1 -(1 -methylpiperidin-4-
yl)urea tartrate Form-C.
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Description of the drawings
Fig 1: X-ray powder diffraction pattern of pimavanserin tartrate Form-C obtained as per
the process of present invention.
Detailed description of the Invention
The stability and action of an active pharmaceutical ingredient greatly depends upon its
polymorphic stability and a stable polymorph preparation needs a robust and reproducible
process. At times, when a compound exists in more than one polymorphic Form, the
process adopted for the preparation plays an important role in providing the most stable
polymorph and various aspects such as selection of solvents, their ratios and conditions
used for carrying out the process are most critical to the process. Therefore, it is a
challenge for the present inventors to reach at such reaction conditions and selection of
solvents such that they provide pimavanserin tartrate in its most stable crystalline Form
i.e. Form-C with required purity standards, wherein the process should not involve
working difficulties, involve high costs, expensive techniques/reagents, rather the process
should be simple, reproducible, environment friendly and economical.
Pimavanserin tartrate is having crystalline Form-C as most thermodynamically stable
polymorphic Form in comparison to its other known polymorphic Forms and in the light
of absence of an efficient and reproducible process for the preparation of pimavanserin
tartrate Form-C having scalable capability, the inventors of present invention brought
about a robust process for the preparation of pimavanserin tartrate Form-C. The process
developed is not only robust and reproducible, the process provides pimavanserin tartrate
which is free of degradation impurities, particularly Af-(4-fluorobenzyl)-lmethylpiperidin-
4-amine (Impurity 1) and in turn does not require multiple purifications
to attain standard purity requirements. Thus, the process is low on solvent consumption
and hence is economic for large scale production. Further, the process is studied and
developed to ensure the thermodynamic stability of the resulting crystalline pimavanserin
tartrate by allowing the stirring for a sufficient time to seize the polymorphic character.
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-X 2&-Q9- 2 018 IB : 3 4
™Xi
N
I
Impurity 1
In an embodiment, the present invention provides a process for the preparation of l-(4-
fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(l-methylpiperidin-4-yl)urea tartrate Form-C,
comprising the steps of,
(a) suspending l-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(l-methylpiperidin-4-
yl)urea tartrate in about 3 to 5 volumes of acetone at reflux;
(b) continuing reflux of reaction mixture from step (a) for about 16 to 20 hours;
(c) cooling the reaction mixture to crystallize solid;
(d) continuing stirring for another 18-24 hours and
(e) isolating l-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(l-methylpiperidin-4-
yl)urea tartrate Form-C.
According to the present invention, the process step (a) involves suspending l-(4-
fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(l-methylpiperidin-4-yl)urea tartrate in about 3 to
5 volumes of acetone. The reaction mixture is heated to reflux temperature. The reaction
mixture is then optionally seeded with l-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(lmethylpiperidin-
4-yl)urea tartrate polymorph Form-C. The reaction mixture so obtained
is further refluxed for another 16 to 20 hours giving sufficient time for Formation of
thermodynamically stable polymorph.
According to the present invention, the reaction mixture obtained is slowly cooled to a
temperature of about 5-20 °C, preferably 10-15 °C over a period of about 2 to 5 hours.
The stirring of reaction mixture is continued at this temperature for another 18-24 hours
in order to ensure complete conversion to thermodynamically stable polymorph Form-C.
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. According to the present invention, the crystallized solid is then isolated using processes
such as filtration, centrifugation and the like under nitrogen. The resulting pimavanserin
tartrate Form-C is dried using processes such as vacuum drying optionally under
nitrogen.
According to present invention, the pimavanserin tartrate Form-C obtained is having
chromatographic purity not less than 99.5%, preferably not less than 99.8%.
According to the present invention, pimavanserin tartrate Form-C is having characteristic
peaks at 8.2, 18.3, 19.4 and 23.6 degrees 20 ±0.2 in X-ray powder diffraction pattern and
the polymorphic purity is not less than 80%.
The pimavanserin tartrate used as starting material may be present in any polymorphic
Form and is prepared using the process known in the prior art, preferably prepared by the
process disclosed in our co-pending application PCT/IN2018/050053.
The major advantages realized in the present invention as compared to prior art processes
are absence of degradation impurity, consistency, cost-effectiveness and easy to operate
on large-scale.
Having described the invention with reference to certain preferred embodiments, other
embodiments will become apparent to one skilled in the art from consideration of the
specification. The invention is further defined by reference to the following examples
describing in detail the preparation of pimavanserin tartrate Form C. It will be apparent to
those skilled in the art that many modifications, both to materials and methods, may be
practiced without departing from the scope of the invention.
Example
Example 1: Preparation of l-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(lmethylpiperidin-
4-yl)urea (pimavanserin) tartrate Form-C:
A mixture of pimavanserin tartrate (25 gram) in acetone (125 ml) is heated to reflux
temperature while stirring. The reaction mixture is seeded with pimavanserin tartrate
Form-C (0.25 gram). The resulting reaction mixture is stirred further at reflux
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temperature for about .18 hours and then is slowly cooled to about 10-20 °C. The stirring
is continued at this temperature for about 22 hours. The solid obtained was filtered and
washed with acetone and dried to obtain pimavanserin tartrate Form-C, having XRD as
shown in Fig.l.
Yield: 92.0%
Purity: 99.86%
Example 2: Preparation of l-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(lmethylpiperidin-
4-yl)urea (pimavanserin) tartrate Form-C:
A mixture of pimavanserin tartrate (100 gram) in acetone (500 ml) is heated to reflux
temperature while stirring. The reaction mixture is seeded with pimavanserin tartrate
Form-C (1.25 gram). The resulting reaction mixture is stirred further at reflux
temperature for about 18 hours and then is slowly cooled to about 10-20 °C. The stirring
is continued at this temperature for about 22 hours. The solid obtained was filtered and
washed with acetone and dried to obtain pimavanserin tartrate Form-C, having XRD as
shown in Fig.l.
Yield: 92.0%
Purity: 99.86%

Claims:
1. A process for the preparation of preparation of Form-C of l-(4-fluorobenzyl)-3-
(4-isobutoxybenzyl)-l-(l-methylpiperidin-4-yl)urea tartrate, comprising,
(a) suspending l-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(l-methyipiperidin-4-
yl)urea tartrate in about 3 to 5 volumes of acetone at reflux;
(b) continuing reflux of reaction mixture from step (a) for about 15 to 18 hours;
(c) cooling the reaction mixture to crystallize solid;
(d) continuing stirring for another 18-24 hours and
(e) isolating Form-C of l-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(lmethylpiperidin-
4-yl)urea tartrate.
2. The process according to claim 1, wherein optionally seeding with pimavanserin
tartrate Form-C is done before step (b).
3. The process according to claim 1, wherein the cooling at step (c) is done to a
temperature of 5-20 °C.
4. The process according to claim 1, wherein the polymorphic purity of Form-C of
l-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(l-methylpiperidin-4-yl)urea tartrate
is not less than 80%.