FIELD OF THE INVENTION
Thepresent invention relates to a novel process for the preparation of pimavanserin of Formula I and pharmaceutical acceptable salts thereof;
Formula I
The present invention further relates to substantially pure amorphous form of pimavanserin tartrate and process of preparation thereof. Further, the present invention relates to substantially pure pimavanserin or pharmaceutical acceptable salts thereof wherein said pimavanserin or pharmaceutical acceptable salts are substantially free of impurities of Formula A, B, C, D, E, F, and V, wherein each impurity is less than about 0.15% w/w and less than 1% w/w of total impurities, more specifically less than 0.15% w/w of total of any impurity;

BACKGROUND OF THE INVENTION
Pimavanserin tartrate, marketed "under the trade name Nuplazid by Acadia Pharmaceuticals, is a non-dopaminergic atypical antipsychotic developed for the treatment of Parkinson's disease psychosis and schizophrenia. Pimavanserin has a unique mechanism of action relative to other antipsychotics, behaving as a selective inverse agonist of the serotonin 5-HT2A receptor, with 40-fold selectivity for this site over the 5-HT2C receptor and no significant affinity or activity at the 5-HT2B receptor or dopamine receptors.

Pimavanserin is generically disclosed in US patent number US 6,756,393 and the basic chemistry for preparation of pimavanserin tartrate is disclosed in WO 2004/064738.
The synthetic method disclosed in W05738 is mentioned under Scheme-1: Scheme-1:
US patent 7,790,899 discloses a process for preparation of pimavanserin wherein said process involves reacting 4-hydroxybenzaldehyde with isobutylbromide in the presence of dimethylformamide, potassium iodide and potassium carbonate to produce 4-isobutoxybenzaldehyde followed by reacting the 4-isobutoxybenzaldehyde with about 1.5 equivalents of NH2OH to produce 4-isobutoxybenzoxime. The 4-isobutoxybenzoxime so obtained is hydrogenated with

hydrogen in the presence of Raney-Ni and NH3 to produce (4-isobutoxyphenyl)methanamine which upon addition of acetic acid produced (4-isobutoxyphenyl)methanamine acetate. The (4-isobutoxyphenyl)methanamine acetate so obtained is treated with about 30% NaOH and extracted with toluene to produce (4-isobutoxyphenyl)methanamine followed by reaction with HCl and COCb in the presence of toluene to produce l-isobutoxy-4-(isocyanatomethyl)benzene. The l-isobutoxy-4-(isocyanatomethyl)benzene is then reacted with N-(4-fluorobenzyl)-l-methylpiperidin-4-amine to produce N-(l-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N/-(4-(2-methylpropyloxy) phenyl methyl)carbamide (Pimavanserin).
It is observed that the use of isobutyl bromide as an alkylating agent produce structural isomer impurities which are required to be removed by purification process and hence the above disclosed process is not suitable for the production at commercial scale.
Chinese patent application CN 105906551 discloses a process of preparation of
pimavanserin as mentioned below in scheme-2:
Scheme-2:

CN 105820110 A discloses a process for preparation of pimavanserin by using various salts of N-(4-fluorobenzyl)-l-methylpiperidin-4-amine as intermediates. Preparation of various salts ofN-(4-fluorobenzyl)-l-methylpiperidin-4-amine adds up a reaction step in the whole process leading to increase in time required for production of pimavanserin.
WO 2017/054786 discloses a process for the preparation of pimavanserin by
reacting N-(4-fluorobenzyl)-l-methylpiperidine-4-amine with 4-
isobutoxybenzylamine. The crude pimavanserin so obtained is crystallized by treating with organic solvent and a solution of p- toluenesulfonic monohydrate.
Although there are several processes known in the literature for the preparation of pimavanserin, however the known processes involve use of reagents which are either toxic or require peculiar conditions to be used for production at large scale. The processes known in the published literature either uses toxic chemicals such as phosgene and diphenyl phosphoryl azide which are highly explosive and unsafe to be used at large scale or uses phase transfer catalyst for the preparation of isocyanate

making process uneconomical. Moreover, use of isobutyl bromide as an alkylating agent produce structural isomer impurities which are required to be removed by purification process.
Hence, in view of the drawbacks of the processes disclosed in prior published references, there is a need to develop a process that produces pimavanserin with high purity. Based on aforesaid, the present invention is directed towards the development of a novel process for preparation of pimavanserin or its pharmaceutical acceptable salts that requires less toxic and inexpensive reagents making the process environmental friendly and more economical for large scale production.
OBJECT OF THE INVENTION
The main aspect of the present invention is to develop a novel process for the preparation of serotonin 5-HT2A receptor antagonists namely, pimavanserin or its pharmaceutical acceptable salts.
Another object of the present invention is to prepare substantially pure amorphous form of pimavanserin tartrate.
Another object of the present invention is to develop a novel process for the preparation of substantially pure pimavanserin or its pharmaceutical acceptable salts by employing less toxic and inexpensive reagents making the process more economical for large scale production.
One another object of the present invention is to develop a substantially pure pimavanserin or a pharmaceutical acceptable salts thereof, characterized by purity of 99% and above.

SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide a simple, cost effective process for the preparation of pimavanserin and pharmaceutical acceptable salts thereof.
Accordingly, the present invention provides a process of preparation of pimavanserin or a pharmaceutically acceptable salt thereof, wherein said process comprising of:
a) alkylation of compound of Formula VI with isobutyl tosylate in presence of base in an organic solvent to get compound of Formula-VII,


OH

O Formula VI

wherein R is an acid protecting group; and
b) converting compound of'Formula VI to pimavanserin or a pharmaceutical
acceptable salts thereof.
The present invention further provides a process of preparation of pimavanserin or a pharmaceutically acceptable salt thereof, wherein said process comprising of: a) reacting 2-(4-isobutoxyphenyl)acetyl chloride of Formula III with sodium azide in presence of a solvent to give l-isobutoxy-4-(isocyanatomethyl)benzene of Formula IV,

Formula III Formula IV .
wherein the reaction is performed in absence of a catalyst; and
b) converting compound of Formula VI to pimavanserin or a pharmaceutical
acceptable salts thereof.
The present invention provides a process of preparation of pimavanserin or a pharmaceutical^ acceptable salt thereof, wherein said process comprising of: a) alkylation of compound of Formula VI with isobutyl tosylate in presence of base in an organic solvent to get compound of Formula-VII,


OH

O Formula VI

wherein R is an acid protecting group;
b) hydrolysis of compound of Formula VII in presence of base to get 2-(4-
isobutoxyphenyl)acetic acid of Formula II,


HO
° O
Formula VII Formula II

c) reacting 2-(4-isobutoxyphenyl)acetic acid of Formula II with acid chloride to give 2-(4-isobutoxyphenyl)acetyl chloride of Formula III,



OH CI
Formula II Formula III.
d) reacting compound of Formula III with sodium azide in presence of solvent to give l-isobutoxy-4-(isocyanatomethyl)benzene of Formula IV,

Formula III Formula IV .
e) condensing l-isobutoxy-4-(isocyanatomethyl)benzene of Formula IV with N-(4-fluorobenzyl)-l-methylpiperidin-4-amine of Formula V in presence of organic solvent to give pimavanserin of Formula I; and


Formula IV

F
Formula V N
* O^NH

O

Formula I
f) optionally converting pimavanserin of Formula I to its pharmaceutically acceptable salts.
The present invention further relates to a process of recovery of 2-(4-isobutoxyphenyl)acetic acid of Formula II and use of said recovered compound of Formula II in preparation of pimavanserin of Formula I.
In another aspect, the present invention provides the conversion of pimavanserin to its tartrate salt of Formula I-I,


OH O *
2 " VA>H O OH
Formula-I-I
wherein said process comprising of:
a) treating pimavanserin of Formula I with L-(+)-tartaric acid in a solvent;
b) stirring at a temperature ranging from 25-80°C;
c) distilling the organic solvent and isolating pimavanserin tartrate of Formula I-I; and
d) optionally lyophilizing pimavanserin tartrate of Formula I-I of step (c) to obtain substantially pure amorphous form of pimavanserin tartrate of Formula I-I.

In another aspect, the present invention provides a process for preparation of amorphous form of pimavanserin tartrate of Formula (I-I);


N

O
OH O HO.
H

o 2 — Y T ™
O OH
Formula-I-I
comprising of;
a) dissolving crystalline pimavanserin tartrate in water to get a solution; and
b) lyophilizing the solution of step a).
According to another aspect, there is provided a pimavanserin or its pharmaceutical acceptable salts substantially free of impurities.
Another aspect of the present invention is to provide novel isolated compounds of formula A, B and E,

Formula A Formula B

Formula E

According to another aspect, there is provided a substantially pure pimavanserin or its pharmaceutical acceptable salts substantially free of impurities of Formula A, B, C, D, E, F, and V, wherein each impurity is less than about 0.15%w/w, and wherein total of impurities is less than about 1% w/w, more specifically less than 0.15% w/w of total of any impurity;

Formula A

Formula B

Formula C

Formula D

O
Formula E

0 H
N+
/xo-
Formula F

N—

r^

HN

Formula V
DETAILED DESCRIPTION
Brief Description of the accompanying drawing
Fig. 1, represents the X-ray (powder) diffraction (XRD) pattern of the crystalline
form of pimavanserin free base.

Fig. 2, represents the X-ray (powder) diffraction (XRD) pattern of the amorphous form of pimavanserin tartrate.
Definitions:
The term "substantially pure" as referred in the context of the present invention relates to substance that has purity preferably between about 95% and 100% by HPLC and total impurities between about 2%w/w to a non-detectable limit, more preferably between about 99% and 100%) of purity by HPLC and between about l%w/w and non-detectable limit of the total impurities, and, most preferably, between about 99.9% and 100% of purity by HPLC and about 0.25%w/w to a non-detectable limit of total impurities.
It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a solvent" includes mixtures of
solvents.
"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.

The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.
Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples.
In one embodiment, the present invention provides a process of preparation of pimavanserin or a pharmaceutical^ acceptable salt thereof, wherein said process comprising of:
a) alkylation of compound of Formula VI with isobutyl tosylate in presence of base in an organic solvent to get compound of Formula-VII,


OH

O Formula VI

wherein R is an acid protecting group; and
b) converting compound of Formula VI to pimavanserin or a pharmaceutical
acceptable salts thereof.
In another embodiment, the solvent used for alkylation of Formula VI with isobutyl tosylate. is selected from the group comprising of toluene, dimethyl acetamide, dimethyl formamide, N-methyl pyrrolidine, dimethyl sulfoxide, hexamethyl phosphoramide, tetrahydrofuran, dioxane, methyl-tetrahydrofuran, acetone, methyl

ethyl ketone, methanol, ethanol, methyl isobutyi ketone, and mixture thereof. The most preferred solvent is dimethyl formamide and dimethyl acetamide.
In another embodiment, the base used for alkylation of Formula VI with isobutyi tosylate is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, cesium acetate, sodium acetate and potassium acetate, sodium bicarbonate, potassium carbonate, sodium carbonate, and potassium bicarbonate.
In another embodiment, the present invention provides a process of preparation of pimavanserin or a pharmaceutically acceptable salt thereof, wherein said-process comprising of:
a) reacting 2-(4-isobutoxyphenyl)acetyl chloride of Formula III with sodium azide
in presence of a solvent to give l-isobutoxy-4-(isocyanatomethyl)benzene of
Formula IV,
y r-
o °
o
Formula III Formula IV .
wherein the reaction is performed in absence of a catalyst; and
b) converting compound of Formula VI to pimavanserin or a pharmaceutical
acceptable salts thereof.
In another embodiment, the reaction of compound of Formula III with sodium azide is carried out in presence of solvent selected from the group comprising of acetone, methanol, ethanol, methyl isobutyi ketone, methyl tert-butyl ketone, methyl ethyl ketone, dimethyl acetamide, dimethyl formamide, N-methyl pyrrolidine, dimethyl sulfoxide, hexamethyl phosphoramide, ethyl acetate, isopropyl acetate, t-butyl

acetate, tetrahydrofuran, toluene, xylene, methylene dichloride, ethylene dichloride, water and mixture thereof. The most preferred solvent is acetone or toluene.
In one another embodiment, the present invention relates to a process of preparation of pimavanserin or pharmaceutical^ acceptable salt thereof, wherein said process comprising of:
a) alkylation of compound of Formula VI with isobutyl tosylate in presence of base in an organic solvent to get compound of Formula-VII,


OH

O Formula VI

wherein R is an acid protecting group;
b) hydrolysis of compound of Formula VII in presence of base to get 2-(4-
isobutoxyphenyl)acetic acid of Formula II,



O Formula VII

c) reacting 2-(4-isobutoxyphenyl)acetic acid of Formula II with acid chloride to give 2-(4-isobutoxyphenyl)acetyl chloride of Formula III,


OH CI
Formula II Formula III.
d) reacting compound of Formula III with sodium azide in presence of solvent to give l-isobutoxy-4-(isocyanatomethyl)benzene of Formula IV,

Formula III Formula IV .
e) condensing l-isobutoxy-4-(isocyanatomethyl)benzene of Formula IV with N-(4-fluorobenzyl)-l-methylpiperidin-4-amine of Formula V in presence of organic solvent to give pimavanserin of Formula I; and

Formula V

CT 'NH
Formula IV
F
Formula I
f) optionally converting pimavanserin of Formula I to its pharmaceutically acceptable salts.

In another embodiment, the solvent used for preparation of pimavansenn or its pharmaceutical acceptable salts is selected from the group comprising of ketones, esters, amides, halogenated solvents, aliphatic hydrocarbons, aromatic hydrocarbons, ethers, pyrrolidones, sulfoxides, amides, water and mixture thereof. Preferably the solvent is selected from the group comprising of toluene, xylene, dimethyl acetamide, dimethyl formamide, N-methyl pyrrolidine, dimethyl sulfoxide, hexamethyl phosphoramide, tetrahydrofuran, dioxane, methyl-tetrahydrofuran, diethyl ether, isopropyl ether, isobutyl acetate, methyl tert-butyl ether, acetone, methyl isobutyl ketone, methyl ethyl ketone, methanol, ethanol, methyl tert-butyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate, methylene dichloride, ethylene dichloride, diethyl ether, isopropyl ether, heptane, hexane, pentane, water, and mixture thereof..
In one another embodiment, the base used for preparation of pimavanserin or its pharmaceutical acceptable salts is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, cesium acetate, sodium acetate and potassium acetate, sodium bicarbonate, potassium carbonate, sodium carbonate, and potassium bicarbonate.
In another embodiment, the solvent used for alkylation of Formula VI with isobutyl tosylate in step a) is selected from the group comprising of toluene, dimethyl acetamide, dimethyl formamide, N-methyl pyrrolidine, dimethyl sulfoxide, hexamethyl phosphoramide, tetrahydrofuran, dioxane, methyl-tetrahydrofuran, acetone, methyl ethyl ketone, methanol, ethanol, methyl isobutyl ketone, and mixture thereof. The most preferred solvent used in said step a) is dimethyl formamide and dimethyl acetamide.
In another embodiment, the base used for alkylation of Formula VI with isobutyl tosylate in step a) is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, cesium acetate, sodium

acetate and potassium acetate, sodium bicarbonate, potassium carbonate, sodium carbonate, and potassium bicarbonate.
In one another embodiment, the base used for hydrolysis of compound of Formula VII in step b) is selected from sodium hydroxide, potassium hydroxide, and lithium hydroxide.
In further embodiment, the solvent used in the step of hydrolysis of compound of •Formula VII in step b) is selected from water, methanol, ethanol, isopropanol, butanol, and mixture thereof.
In furthermore embodiment, the acid chloride used for conversion of 2-(4-isobutoxyphenyl)acetic acid to 2-(4-isobutoxyphenyl)acetyl chloride is selected from the group comprising of thionyl chloride, oxalyl chloride, and carbonyl chloride.
In a preferred embodiment, the reaction of compound of Formula III with sodium azide in step d) is carried out in presence of solvent selected from the group comprising of acetone, methanol, ethanol, methyl isobutyl ketone, methyl tert-butyl ketone, methyl ethyl ketone, dimethyl acetamide, dimethyl formamide, N-methyl pyrrolidine, dimethyl sulfoxide, hexamethyl phosphoramide, ethyl acetate, isopropyl acetate, t-butyl acetate, tetrahydrofuran, toluene, xylene,, methylene dichloride, ethylene dichloride, water and mixture thereof. The most preferred solvent used in said step d) is acetone or toluene.
In one another preferred embodiment, the organic solvent used during condensation of 1 -isobutoxy-4-(isocyanatomethyl)benzene of Formula IV with N-(4-fluorobenzyl)-l-methylpiperidin-4-amine of Formula V to give pimavanserin in step e) is selected from the group comprising of tetrahydrofuran, dioxane, acetone, methyl tetrahydrofuran, diethyl ether, isopropyl ether, toluene, xylene, methylene

dichloride, ethylene dichloride, heptane, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide and mixture thereof.
In one of the preferred embodiment, the reaction of compound of Formula III with sodium azide to give isocyanate compound of Formula IV is carried out in absence of catalyst.
In another preferred embodiment, the compound of Formula VII is obtained as a mixture of compounds of Formula Vila and Formula Vllb and is taken as such in the next step.



O "O
Formula Vllb

In further embodiment, the present invention provides a process of preparation of pimavanserin of Formula I, wherein said process further comprises purification of compound of Formula I in a suitable solvent.
In one another embodiment, the solvent used for the purification of pimavanserin of Formula I is selected from the group comprising of water, diethyl ether, isopropyl ether, hexane, pentane, heptane, methyl tert-butyl ether, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, methyl iso butyl ketone, isobutyl acetate and mixture thereof.
In other embodiment, the pimavanserin so obtained in step e) is in the crystalline form as depicted in Fig-1.

In one of the preferred embodiment, the present invention provides a process of recovery of 2-(4-isobutoxyphenyl) acetic acid of Formula II and use of said recovered compound of Formula II in preparation of pimavanserin.
In further embodiment, the pimavanserin so obtained in step e) is converted to its pharmaceutical^ acceptable salts wherein the pharmaceutically acceptable salts are selected from the group comprising of phosphate, tartrate, sulphate, nitrate, diphosphate, bicarbonate, carbonate, clavulanate, isothionate, borate, halide, nitrate, acetate, succinate, lactate, lactobionate, laurate, mandelate, malate, citrate, fumarate, maleate, oleate, oxalate, ascorbate, nicotinate, benzoate, mesylate, salicylate, stearate, tannate , tosylate, valerate, methanesulfonate, ethanesulfonate, pivalate, benzenesulfonate, p-toluensulfonate, 2-ethane disulfonate, edisylate and naphthalenesulfonate.
In a preferred embodiment, the pharmaceutical acceptable salt is a tartrate salt, fumarate salt, oxalate salt, malate salt and most preferably the salt is tartrate salt.
In a preferred embodiment, the pimavanserin so obtained in step e) is converted to pimavanserin tartrate of formula-I-I as represented below:



,N
K^. k/1 ^.O./k solvent

NN , L-(+)-Tartaric acid
H

¥ o
Formula-I

^ ^ H ^
T o

0

OH 0
2 H° AAOH 0 OH

Formula-M
In another embodiment, the process of conversion of pimavanserin to its tartrate salt of Formula I-I comprising of:
a) treating pimavanserin of Formula I with L-(+)-tartaric acid in a solvent;
b) stirring at a temperature ranging from 25-80°C;
c) distilling the solvents and isolating pimavanserin tartrate of Formula I-I; and

d) optionally lyophilizing pimavanserin tartrate of Formula I-I of step (c) to obtain substantially pure amorphous form of pimavanserin tartrate of Formula I-I.
In still another embodiment, the solvent used for reacting pimavanserin with L-(+)-tartaric acid in step a) is selected from the group comprising of acetone, tetrahydrofuran, dioxane, methanol, chloroform, carbon tetrachloride, water and mixture thereof.
In a preferred embodiment, the reaction of pimavanserin with L-(+)-tartaric acid is carried out at a temperature in the range of 25-80°C, more preferably at a temperature ranging from 50-70°C.
In yet another embodiment, the pimavanserin tartrate of Formula-I-I, produced by the process of the present invention is amorphous in nature.
In one another embodiment, the present invention provides substantially pure amorphous form of pimavanserin tartrate.
In another embodiment, the present invention provides a process for preparation of amorphous form of pimavanserin tartrate of Formula (I-I);

o
.N
H N N
o

OH O HO.
2 0 1 'OH
O OH

Formula-I-I
comprising of;
a) dissolving crystalline pimavanserin tartrate in water to get a solution; and
b) lyophilizing the solution of step a).

In yet another embodiment, the present invention provides an amorphous form of pimavanserin tartrate having a moisture content < 5.0%.
In another embodiment, the present invention provides a process for the preparation of amorphous form of pimavanserin tartrate of Formula (I-I) by dissolving crystalline form of pimavanserin tartrate of Formula (I-I) that are already known from the prior published references or by dissolving the crystalline form prepared as per the process of the present invention in water followed by lyophilisation.
In still another embodiment, the present invention provides pimavanserin or pharmaceutical acceptable salts thereof, substantially free from impurities.
In further embodiment, the present invention provides novel isolated compounds of Formula A, B and E,

Formula A

Formula B


Formula E
Moreover, the compounds of Formula A-F and Formula V are isolated as impurities during the preparation of pimavanserin and its pharmaceutical acceptable salts.

In furthermore embodiment, there is provided a substantially pure pimavanserin or pharmaceutical acceptable salts thereof, comprising impurities selected from Formula A, B, C, D, E, F, V, wherein each impurity is less than about 0.15%w/w;

o
H
N I
Formula A

O'

O H
N
I
Formula B

O'

O
0
O
N

O H

O H H

Formula C

Formula D

Formula E

Formula F

N—

Formula V
In a preferred embodiment, the present invention provides a substantially pure amorphous form of pimavanserin tartrate of Formula-I-I.
In more preferred embodiment, the present invention provides a substantially pure amorphous form of pimavanserin tartrate of Formula-I-I, wherein said amorphous form is free of any crystalline form.

In most preferred embodiment, the present invention provides a substantially pure amorphous form of pimavanserin tartrate of Formula-I-I, wherein said amorphous form is substantially free of impurities of Formula A, B, C, D, E, F and V.
In further embodiment, the present invention provides a stable amorphous form of pimavanserin tartrate substantially free of N-oxide impurity of Formula F, wherein said impurity is less than about 0.1%w/w.
In further embodiment, the present invention provides a stable amorphous form of pimavanserin tartrate substantially free of impurities of Formula A, B, C, D, E, F, V, wherein each impurity is less than about 0.15%w/w and wherein total impurity is less than 1% w/w.
In a preferred embodiment, the present invention provides a stable amorphous form of pimavanserin tartrate substantially free of impurities of Formula A, B and E, wherein each impurity is less than about 0.1%w/w and wherein total impurity is less than about 0.15% w/w.
In another preferred embodiment, the pimvanserin tartrate of Formula I-I is characterized by the particle size distribution wherein, ds>o is between 0.1 ^im to 200(im. More preferably, the pimvanserin tartrate of Formula I-I is characterized by particle size distribution wherein, d9o is between 2.0 jam to 150|im.
In still another embodiment, the present invention provides a pharmaceutical composition comprising pimavanserin tartrate prepared as per the process of the present invention.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference of the following examples, which are

provided only for purposes of illustration and should not able constructed as limited the scope of the application in any manner.
EXAMPLES
EXAMPLE 1: Synthesis of N-(4-fluorobenzyl)-l-methylpiperidin-4-amine of Formula V:
Charged 50g of 4-fluorobenzyl amine and 45.5g of 1-methyl 4-piperidone in methanol and cooled the solution to 5-10°C. Added 24ml of acetic acid and 38g of sodium cyanoborohydride and stirred the reaction mass at room temperature for 5-6 hours. Distilled off the methanol and basified the crude so obtained with aqueous sodium hydroxide solution and extracted the compound in dichloromethane. Concentrated the dichloromethane layer and collected the residual oil of N-(4-fluorobenzyl)-l-methylpiperidin-4-amine through high vacuum distillation at 135-145°C.
'H-NMR (5(ppm), H) in CDC13: 1.09 (1H, m), 1.39-1.48 (2H, m), 1.87-1.90 (2H, d), 1.97-2.0 (2H, t), 2.26 (3H, s), 2.42-2.50 (1H, m), 2.79-2.82 (2H, d), 3.78 (2H, s), 6.97-7.02 (2H, m) and 7.26-7.30 (2H, m).
Example 2: Synthesis of N-(4-fluorobenzyl)-l-methylpiperidin-4-amine of Formula V:
Charged acetic acid (476 g, 7.93 moles) in tetrahydrofuran (450 ml) and cooled in ice bath, followed by addition of sodium borohydride (80g) to the reaction mixture. Added 4-Fluorobenzyl amine (150 g, 1,2 moles) and 1-methyl 4-piperidone (136g5 1.2 moles) mixed separately in tetrahydrofuran. The said mixture was added to above suspension and stirred the reaction mass at room temperature. Distilled off the solvent and diluted with water. Added cone. HC1 (35%), stirred at 65-70°C, cooled, added toluene and then basified with aq. sodium hydroxide solution (576 g in 1.0 litre). Separated the toluene layer and distilled off under vacuum to get crude N-(4-fluorobenzyl)-1 -methylpiperidin-4-amine. Crude mass so obtained was

distilled off under high vacuum to get pure N-(4-fluorobenzyl)-l-methylpiperidin-
4-amine.
Yield-215 g (80%)
Purity > 97.0%
Example 3: Preparation of methyl (4-hydroxy phenyl) acetate of Formula VI (R= Me):
Charged 50g of p-hydroxy phenyl acetic acid in methanol and added thionyl chloride dropwise at 10-20°C. Stirred the reaction mass for 2 hrs. After completion of reaction, toluene and water were added; and pH was neutralized with aq. sodium bicarbonate solution. Separated the organic layer, washed with water and distilled under vacuum to get methyl (4-hydroxy phenyl) acetate.
Example 4: Preparation of methyl (4-hydroxy phenyl) acetate of Formula VI (R= Me):
Charged p-hydroxy phenyl acetic acid (200g, 1.31 moles) in methanol (200mL) and thionyl chloride (205g, 1.72 moles) was added. Reaction mixture was stirred at 20°-40°C. After completion of reaction, distilled off solvent under vacuum. Toluene (400 mL) and water was then added, pH was neutralized with aq. sodium bicarbonate solution. Separated the toluene layer, washed with water and distilled under vacuum to get methyl (4-hydroxy phenyl) acetate. Yield-207g (94.5 %) Purity >98.5%.
Example 5: Preparation of methyl 2-(4-isobutoxyphenyl)acetate of Formula-VII (R=Me) by using isobutyl bromide:
Charged 54g of methyl (4-hydroxy phenyl) acetate obtained from example 3 in dimethyl formamide and heated the reaction mass at 85-90°C. Added 225g of potassium carbonate and 178g of isobutyl bromide and stirred the reaction at 85°C for 20-24h. Charged DM water, acidified with aq. HCl and extracted the compound

in ethyl acetate. Collected the organic layer, concentrated under vacuum to get methyl 2-(4-isobutoxyphenyl)acetate.
Example 6: Preparation of methyl 2-(4-isobutoxyphenyl)acetate of Formula-VII (R=Me) by using isobutyl tosylate:
Charged lOg of methyl (4-hydroxy phenyl) acetate obtained from example 3 in dimethyl formamide and heated the reaction mass at 35-40°C. Added 42.Og of potassium carbonate and 28g of isobutyl tosylate and stirred the reaction at 35°C-40°C for 20-24h. Charged DM water, acidified with aq. HC1 and extracted the compound in ethyl acetate. Collected the organic layer, washed with aqueous sodium carbonate and brine solution, concentrated under vacuum to get methyl 2-(4-isobutoxyphenyl)acetate.
Example 7: Preparation of mixture of methyl 2-(4-isobutoxyphenyl)acetate of Formula-Vila and Vllb by using isobutyl tosylate:
Charged isobutyl tosylate (275g, 1.20 moles) and methyl (4-hydroxy phenyl) (200g, 1.20 moles) in N,N-dimethyl acetamide (400 mL) at 10°-40°C. Potassium carbonate (0.5 Kg, 3.6 moles) was added and reaction mass heated at 80°-120°C. After completion, reaction mass cooled followed by addition of toluene (550 mL) and water, and acidified with (35%) aq. HC1 solution. Toluene layer was separated, washed with water and distilled under vacuum to get mixture of methyl 2-(4-isobutoxyphenyl)acetate of Formula-Vila and Vllb. Yield-260 g (97 %)
Example 8: Preparation of isobutyl tosylate.
Charged Isobutanol (85g, 1.15 moles) in pyridine (200 mL) and added p-toluene sulfonyl chloride (200g, 1.05 moles) and stirred at RT. After completion of reaction, added toluene (200 mL) and water, and acidified with (35%) aq. HC1. Toluene layer was separated, washed with aqueous sodium carbonate solution, and then with water and distilled the solvents under vacuum to get isobutyl tosylate. Yield-221 g(92%)

Purity >99.0%
Example 9: Preparation of 2-(4-isobutoxyphenyl)acetic acid of Formula II:
Charged 72g of methyl 2-(4-isobutoxyphenyl)acetate obtained from example 5 in methanol and added aqueous solution of sodium hydroxide solution and stirred the reaction mass at 25°C for 1-2 hrs. Distilled off the reaction mass and diluted the crude so obtained with DM water. Acidified the aqueous layer with aq. HC1 solution. Filtered off the precipitates so obtained and such dried under vacuum to get 2-(4-isobutoxyphenyl) acetic acid. Impurities: a) 4-n-butoxy phenyl acetic acid: 0.25 to 0.50%
b) 2-(4-(2-methylprop-l-yl)oxy phenyl acetic acid: 0.25 to 0.50%
c) 2-(4-(2-methylprop-2-en-l-yl)oxy phenyl acetic acid: 0.20 to 0.25%
Example 10: Preparation of 2-(4-isobutoxyphenyl) acetic acid of Formula II:
Charged (260g, 1.17 moles) the mixture obtained in Example 7 and aqueous solution of 94 g (2.35 moles) of sodium hydroxide in 780 mL water and stirred the reaction mass at RT. Diluted with water, added activated charcoal, and filtered. Filtrate then acidified with aq. HC1 solution. The precipitates so obtained were filtered off and suck dried under vacuum to get crude 2-(4-isobutoxyphenyl) acetic acid. Crude 2-(4-isobutoxyphenyl) acetic acid was suspended in mixture of methanol and water, and stirred at 55°-60°C till clear. Solution was cooled, and precipitates were filtered off under vacuum. Wet solid dried under vacuum to get pure 2-(4-isobutoxyphenyl) acetic acid. Yield-217g(89%) Purity-99% Impurities: a) 4-n-butoxy phenyl acetic acid: below 0.10%
b) 2-(4-(2-methylprop-l-yl)oxy phenyl acetic acid: below 0.10%
c) 2-(4-(2-methylprop-2-en-l-yl)oxy phenyl acetic acid: below 0.10%
Example 11: Preparation of 2-(4-isobutoxyphenyl)acetyl chloride of Formula III:

Charged 50g of 2-(4-isobutoxyphenyl)acetic acid obtained from example 9 in dichloromethane and added thionyl chloride. Stirred the reaction mass at room temperature for lhr. Distilled off the solvent under vacuum to get 2-(4-isobutoxyphenyl)acetyl chloride.
Example 12: Preparation of 2-(4-isobutoxyphenyl)acetyI chloride of Formula III:
Charged 2-(4-isobutoxyphenyl)acetic acid (200g, 0.96 moles) in toluene (600 mL)
at RT. Added catalytic amount of DMF and (172 g, 1.44 moles), of thionyl chloride
and stirred the reaction mass at room temperature for 1-2 h. After completion of
reaction, distilled off the solvent under vacuum to get 2-(4-isobutoxyphenyl)acetyl
chloride.
Yield-218g, (98-100%)
Purity-98%.
Example 13: Preparation of l-isobutoxy-4-(isocyanatomethyl)benzene of Formula IV:
Charged 3 lg of sodium azide in DM water and cooled in ice bath. Added solution of 2-(4-isobutoxyphenyl)acetyl chloride in acetone to above prepared sodium azide solution. Stirred the reaction mass at 20-25°C for 24-30 hrs. After completion of reaction, distilled off the acetone and acidified the reaction mass thus obtained with aq. HC1 solution, and extracted the compound with dichloromethane. Separated the organic layer, washed with aq. solution of sodium carbonate. Separated the aqueous and organic layer and concentrated the organic layer under vacuum to get 1-isobutoxy-4-(isocyanatomethyl)benzene.
Example 14: Preparation of l-isobutoxy-4-(isocyanatomethyl)benzene of Formula IV:
l-isobutoxy-4-(isocyanatomethyl)benzene (220g, 0.97 moles) was charged in toluene (1.0 L). Cooled to 0°-10°C. Aqueous solution of 150 g (2.30 moles) of sodium azide in 400 mL of water was added and the reaction mass stirred at 10°-

25°C. After completion of reaction, organic layer were separated, washed first with aqueous solution of sodium carbonate and then with water to get solution of 2-(4-isobutoxyphenyl)acetyl azide in toluene. Charged solution of 2-(4-isobutoxyphenyl)acetyl azide and raised the temperature to 40°-90°C. After completion of reaction, cooled the solution to room temperature to get 1-isobutoxy-4-(isocyanatomethyl)benzene in toluene.
Recovery of 2-(4-isobutoxyphenyI)acetic acid of Formula II: The aqueous sodium carbonate layer obtained in the example 13 is diluted with de-mineralized water, and then acidified with aq. HCl solution. Stirred the aq. layer and filtered off the precipitates. Washed the precipitates with water and then dried under vacuum to get 2-(4-isobutoxyphenyl)acetic acid.
Example 15: Synthesis of Pimavanserin:
Charged 40g of N-(4-fluorobenzyl)-l-methylpiperidin-4-amine of Formula V obtained from example 1 and 25g of 4-isobutoxybenzylisocyanate in tetrahydrofuran and raised the temperature to 50-70°C. After completion of reaction, distilled off the solvent to get the crude mass. Recrystallized the crude mass with isopropyl ether to get Pimavanserin.
Example 16: Synthesis of Pimavanserin:
Charged N-(4-fluorobenzyl)-l-methylpiperidin-4-amine (213 g, 0.96 moles) of formula V obtained from example 1 into toluene solution of l-isobutoxy-4-(isocyanatomethyl)benzene at room temperature and raised the temperature to 50°-60°C. After completion of reaction, distilled'off the solvent to get the crude mass. Crude suspended in mixture of acetone and water, stirred at 50°-60°C, cooled and filtered off under vacuum. Wet solid dried at under vacuum to get pure pimavanserin. Yield - 390g, (95%) Purity-95%

Example 17: Preparation of amorphous Pimavanserin tartrate:
(A) Charged 20g of pimavanserin in 80 ml of DM water and added 3.16g of L-(+)-tartaric acid. Stirred the reaction mass at room temperature till completion of reaction. Distilled the water under reduced pressure and degassed the mass to get amorphous pimavanserin tartrate.
(B) Charged l.Og of pimavanserin tartrate in 0.5ml of DM water and 4ml of tetrahydrofuran. Stirred the reaction mass at 65-70°C followed by cooling the reaction mass to room temperature. Distilled the solvents under reduced pressure and degassed the mass to get amorphous pimavanserin tartrate.
(C) Charged l.Og of pimavanserin in tetrahydrofuran in autoclave. Added 0.16g of L-(+)-tartaric acid and stirred the reaction mass under 10 kg cm2 Nitrogen pressure at room temperature for 24 hrs. Distilled the solvent under reduced pressure at 60°C to get amorphous pimavanserin tartrate.
(D) Charged crystalline pimavanserin tartrate as obtained from example 18 and added de-mineralized water. Lyophilized the solution so obtained to get amorphous pimavanserin tartrate with purity of 99.8%.
Example 18: Preparation of crystalline Pimavanserin tartrate Charged pimavanserin (680g, 1.59 moles) in mixture of acetone and water and added L-(+)-tartaric acid (115g, 0.76 moles) and stirred at 55-60°C. Added activated charcoal (1 0% w/w), filtered and cooled the filtrate so obtained to room temperature. Filtered off the precipitates, washed with acetone, and then suck dried under vacuum. Wet solid so obtained was dried under vacuum to get crystalline Pimavanserin tartrate. Yield- 656 g, (82%) Purity- 99.7%
Example 19: Preparation of N-f(4-fluorophenyl)methyl]-N-(l-methyl-4-piperidinyl)-N'-[[4-(n-butoxy)phenyI] methyl] urea (Impurity A):
(i): Synthesis of methyl 2-(4-w-butoxyphenyI) acetate:
Charged 10 g of methyl (4-hydroxy phenyl) acetate in dimethyl formamide and heated the reaction mass at 85-90°C. Added 41 g of potassium carbonate and 33g of

/7-butyl bromide and stirred the reaction at 85°C for 20-24h. Charged DM water,
acidified with aq. HC1 and extracted the compound in ethyl acetate. Collected the
organic layer, concentrated under vacuum to get methyl 2-(4-«-butoxyphenyl)
acetate.
(ii): Preparation of 2-(4-/i-butoxyphenyI) acetic acid:
Charged 12 g of methyl 2-(4-/?-butoxyphenyl) acetate obtained in methanol and
added aqueous solution of sodium hydroxide solution and stirred the reaction mass
at 25°C for 1-2 hrs. Distilled off the reaction mass and diluted the crude so obtained
with DM water. Acidified the aqueous layer with aq. HC1 solution. Filtered off the
precipitates so obtained and dried under vacuum to get 2-(4-«-butoxyphenyl) acetic
acid.
(iii): Preparation of 2-(4-«-butoxyphenyl) acetyl chloride:
Charged 10 g of 2-(4-«-butoxyphenyl) acetic acid in dichloromethane and added
thionyl chloride. Stirred the reaction mass at room temperature for lhr. Distilled off
the solvent under vacuum to get 2-(4-n-butoxyphenyl)acetyl chloride.
(iv): Preparation of l-butoxy-4-(isocyanatomethyl)benzene:
Charged 6.25 g of sodium azide in DM water and cooled in ice bath. Added solution
of 2-(4-n-butoxyphenyl) acetyl chloride in acetone to above prepared sodium azide
solution. Stirred the reaction mass at 20-25°C for 24-30 hrs. After completion of
reaction, acidified the reaction mass with aq. HC1 solution, and extracted the
compound with dichloromethane. Separated the organic layer, washed with aq.
solution of sodium carbonate. Separated the aqueous and organic layer and
concentrated the organic layer under vacuum to get l-/7-butoxy-4-
(isocyanatomethyl) benzene.
(v): Preparation of N-[(4-fluorophenyl)methyl]-N-(l-methyl-4-piperidinyl)-
N'-[[4-(w-butoxy)phenyl]methyl]urea:
Charged 5.2 g of N-(4-fluorobenzyl)-l-methylpiperidin-4-amine and 4.5 g of (4-
(«-butoxy)phenyl)methyl isocyanate in tetrahydrofuran and raised the temperature
to 50°-70°C. After completion of reaction, distilled off the solvent to get the crude
mass. Crude mass was purified by column chromatography to get N-[(4-
fluorophenyl)methyl]-N-(l-methyl-4-piperidinyl)-N'-[[4-(n-butoxy)phenyl]

methyl] urea (Impurity-A) 'H-NMR (8(ppm), H): 0.94-0.98 (3H, t), 1.43-1.52 (2 H, m), 1.71-1.78 (2H, m), 1.78-1.82 (2H, d), 2.07-2.10 (2H, q), 2.45-2.51 (2H, m), 2.51 (3H, s), 3.18-3.21(2H, d), 3.90-3.93 (2H, t), 4.25-4.26 (2H, d), 4.36 (2H, s), 4.51-4.58 (2H, m), 6.75-6.78 (2H, m), 6.96-7.02 (4H, m) and 7.15-7.19 (2H, m).
Example 20: Preparation of N-[(4-fluorophenyl)methyl]-N-(l-methyl-4-piperidinyI)-Nf-[[4-(5ec-butoxy)phenyl]methyl]urea (Impurity B): (i): Preparation of methyl 2-(4-1seobutoxyphenyl) acetate:
Charged 10 g of methyl (4-hydroxy phenyl) acetate in dimethyl formamide and
heated the reaction mass at 85-90°C. Added 41 g of potassium carbonate and 33g of
sec-butyl bromide and stirred the reaction at 85°C for 20-24 h. Charged DM water,
acidified with aq. HC1 and extracted the compound in ethyl acetate. Collected the
organic layer, concentrated under vacuum to get methyl 2-(4-sec-butoxyphenyl)
acetate.
(ii): Preparation of 2-(4-sec-butoxyphenyl) acetic acid:
Charged 13g of methyl 2-(4-.sec-butoxyphenyl) acetate obtained in methanol and
added aqueous solution of sodium hydroxide solution and stirred the reaction mass
at 25°C for 1-2 hrs. Distilled off the reaction mass and diluted the crude so obtained
with DM water. Acidified the aqueous layer with aq. HC1 solution and extracted the
compound in ethyl acetate. Collected the organic layer, concentrated under vacuum
to get 2-(4-sec-butoxyphenyl) acetic acid.
(iii): Preparation of 2-(4-seobutoxyphenyl) acetyl chloride:
Charged lOg of 2-(4-5-ec-butoxyphenyl) acetic acid in dichloromethane and added
thionyl chloride. Stirred the reaction mass at room temperature for lhr. Distilled off
the solvent under vacuum to get 2-(4-^c-butoxyphenyl)acetyl chloride.
(iv): Preparation of l-sec-butoxy-4-(isocyanatomethyl) benzene:
Charged 6.25 g of sodium azide in DM water and cooled in ice bath. Added solution
of 2-(4-5,ec-butoxyphenyl) acetyl chloride in acetone to above prepared sodium
azide solution. Stirred the reaction mass at 20-25°C for 24-30 hrs. After completion
of reaction, acidified the reaction mass with aq. HC1 solution, and extracted the
compound with dichloromethane. Separated the organic layer, washed with aq.

solution of sodium carbonate. Separated the aqueous and organic layer and concentrated the organic layer under vacuum to get l-sec-butoxy-4-(isocyanatomethyl) benzene.
(v): Preparation of N-[(4-fluorophenyl)methyl]-N-(l-methyl-4-piperidinyl)-N,-[[4-(sec--butoxy)phenyI]methyl]urea (Impurity B):
Charged 7.4 g of N-(4-fluorobenzyl)-l-methylpiperidin-4-amine and 6.0 g of 4-sec-butoxybenzylisocyanate in tetrahydrofuran and raised the temperature to 50°-70°C. After completion of reaction, distilled off the solvent to get the crude mass. Crude mass was purified by column chromatography to get N-[(4-fluorophenyl)methyl]-N-(l-methyl-4-piperidinyl)-N,-[[4-(i,ec-butoxy)phenyl]methyl]urea (Impurity B). !H-NMR (8(ppm), H): 0.94-0.98 (3H, t), 1.24-1.27(3H, d), 1.54-1.62(1H, m), 1.66-1.86 (5H, m), 2.18-2.24 (2H, m), 2.34 (3H, s), 2.96-2.99 (2H, d), 4.22-4.27 (3H, m), 4.35 (2H, s), 4.38-4.44 (1H, m), 4.48-4.50 (1H, t), 6.74-6.78 (2H, m), 6.96-7.01 (4H, m) and 7.16-7.19 (2H, m).
Example 21: Preparation of N-f(4-fluorophenyl)methyl]-N-(l-methyl-4-piperidinyl)-Nf-[[(2-methyl-2-propen-l-yl)oxy)phenyl]methyI]urea (Impurity
C):
(i): Preparation of methyl 2-(4-(2-methylprop-2-en-l-yI)oxyphenyl) acetate:
Charged 10 g of methyl (4-hydroxy phenyl) acetate in dimethyl formamide and heated the reaction mass at 85-90°C. Added 41g of potassium carbonate and 24.4 g of 3-bromo-2-methylpropene and stirred the reaction at 85°C for 20-24 h. Charged
DM water, acidified with aq. HCl and extracted the compound in ethyl acetate.
«
Collected the organic layer, concentrated under vacuum to get methyl 2-(4-(2-
methylprop-2-en-1 -yl)oxyphenyl) acetate.
(ii): Preparation of 2-(4-(2-methylprop-2-en-l-yl)oxy)phenylacetic acid:
Charged 11 g of methyl 2-(4-(2-methylprop-2-en-l-yl)oxy)phenyl acetate obtained in from example (i) above, and added aqueous solution of sodium hydroxide solution and stirred the reaction mass at 25°C for 1-2 hrs. Distilled off the reaction mass and diluted the crude so obtained with DM water. Acidified the aqueous layer with aq. HCl solution and extracted the compound in ethyl acetate. Collected the

organic layer, concentrated under vacuum to get 2-(4-(2-methylprop-2-en-l-yl)oxy)phenylacetic acid.
(Hi): Preparation of 2-(4-seobutoxyphenyl) acetyl chloride: Charged 8g of 2-(4-(2-methylprop-2-en-l-yl)oxy)phenyl acetic acid in dichloromethane and added thionyl chloride. Stirred the reaction mass at room temperature for lhr. Distilled off the solvent under vacuum to get 2-(4-(2-methylprop-2-en-l-yl)oxy)phenyl acetyl chloride.
(iv): Preparation of 2-(4-(2-methylprop-2-en-l-yl)oxy) phenyl acetyl chloride: Charged 5.0 g of sodium azide in DM water and cooled in ice bath. Added solution of 2-(4-(2-methylprop-2-en-l-yl)oxy)phenyl acetyl chloride in acetone to above prepared sodium azide solution. Stirred the reaction mass at 20-25°C for 24-30 hrs. After completion of reaction, acidified the reaction mass with aq. HC1 solution, and extracted the compound with dichloromethane. Separated the organic layer, washed with aq. solution of sodium carbonate. Separated the aqueous and organic layer and concentrated the organic layer under vacuum to get (4-(2-methylprop-2-en-l-yl)oxyphenyl) methylisocyanate.
(v): Preparation of N-[(4-fluorophenyl)methyl]-N-(l-methyl-4-piperidinyl)-N'-[[4-(2-methylprop-2-en-l-yl)oxy)phenyl]methyl]urea (Impurity C): Charged 7.2 g of N-(4-fluorobenzyl)-l-methylpiperidin-4-amine and 5.4 g of (4-(2-methylprop-2-en-l-yl)oxyphenyl) methyl isocyanate in tetrahydrofiiran and raised the temperature to 50°-70°C. After completion of reaction, distilled off the solvent to get the crude mass. Crude mass was purified by column chromatography to get N-[(4-fluorophenyl)methyl]-N-(l-methyl-4-piperidinyl)-N'-[[4-(2-methyl prop-2-en-l-yl)oxy)phenyl] methyl] urea (Impurity C). 'H-NMR^Sfcpm)): 1.466-1.492 (2 H, d), 1.57-1.64 (2H, m), 1.75 (3H, s), 2.12 (2H, m), 2.29 (3H, s), 2.83-2.86 (2H, d), 3.97 (1H, m), 4.17-4.19 (2H, d), 4.41-4.43 (2H, d), 4.93 (1H, s), 5.03 (1H, s), 6.84-6.87 (2H, m), 6.88-6.91 (1H, m), 7.09-7.13 (4H, m) and 7.22-7.26 (2H, m).
Example 22: Synthesis of N,N,«bis[[4-(2-methylpropoxy)phenyl]methyl]urea (Impurity D):
(i): Preparation of 2-(4-isobutoxyphenyl) acetyl chloride:

Charged 12 g of 2-(4-n-butoxyphenyl) acetic acid in dichloromethane and added thionyl chloride. Stirred the reaction mass at room temperature for lhr. Distilled off the solvent under vacuum to get 2-(4-isobutoxyphenyl)acetyl chloride. (ii) Preparation of get l-isobutoxy-4-(isocyanatomethyl)benzene: Charged 7.5g of sodium azide in DM water and cooled in ice bath. Added solution of 2-(4-isobutoxyphenyl)acetyl chloride in acetone to above prepared sodium azide solution. Stirred the reaction mass at 20-25°C for 24-30 hrs. After completion of reaction, distilled off the acetone and acidified the reaction mass thus obtained with aq. HC1 solution, and extracted the compound with dichloromethane. Separated the organic layer, washed with aq. solution of sodium carbonate. Separated the aqueous and organic layer and concentrated the organic layer under vacuum to get 1-isobutoxy-4-(isocyanatomethyl)benzene.
(ii): Preparation of N,N'-bis[[4-(2-methylpropoxy) phenyl]methyl]urea (Impurity D):
Charged 10.2 g of l-(4-isobutoxyphenyl) methanamine and 15.2 g of 1-isobutoxy-4-(isocyanatomethyl) benzene in tetrahydrofuran and raised the temperature to 50°-70°C. After completion of reaction, distilled off the solvent to get the crude mass. Crude mass was purified by column chromatography to get N,N'-bis[[4-(2-methylpropoxy) phenyl]methyl]urea (Impurity-D). ^-NMR (8(ppm), H): 0.95-0.97 (12H, d), 1.94-2.04 (2H, m), 3.69-3.71 (4H, d), 4.12-4.14 (4H, d), 6.26-6.29 (2H, t), 6.83-6.87 (4H, d) and 7.13-7.15 (4H, d).

WE CLAIM
1. A process for preparation of pimavanserin or a pharmaceutically acceptable salt thereof, wherein said process comprising of:
a) alkylation of compound of Formula VI with isobutyl tosylate in presence of base in an organic solvent to get compound of Formula-VII,
Formula VI
Formula VII
wherein R is an acid protecting group; and
b) converting compound of Formula VI to pimavanserin or a pharmaceutical
acceptable salt thereof.
2. The process as claimed in claim 1, wherein said solvent is selected from the group comprising of toluene, dimethyl acetamide, dimethyl formamide, N-methyl pyrrolidine, dimethyl sulfoxide, hexamethyl phosphoramide, tetrahydrofuran, dioxane, methyl-tetrahydrofuran, acetone, methyl ethyl ketone, methanol, ethanol, methyl isobutyl ketone, and mixture thereof; and wherein said base is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, cesium acetate, sodium acetate and potassium acetate, sodium bicarbonate, potassium carbonate, sodium carbonate, and potassium bicarbonate.
3. A process for preparation of pimavanserin or a pharmaceutically acceptable salt thereof, wherein said process comprising of:
a) reacting 2-(4-isobutoxyphenyl)acetyl chloride of Formula III with sodium azide in presence of a solvent to give l-isobutoxy-4-(isocyanatomethyl)benzene of Formula IV,

Formula III Formula IV .
wherein said reaction is performed in absence of a catalyst; and
b) converting compound of Formula VI to pimavanserin or a pharmaceutical
acceptable salts thereof.
4. The process as claimed in claim 3, wherein said solvent is selected from the group comprising of acetone, methanol, ethanol, methyl isobutyl ketone, methyl tert-butyl ketone, methyl ethyl ketone, dimethyl acetamide, dimethyl formamide, N-methyl pyrrolidine, dimethyl sulfoxide, hexamethyl phosphoramide, ethyl acetate, isopropyl acetate, t-butyl acetate, tetrahydrofuran, toluene, methylene dichloride, ethylene dichloride, xylene, water and mixture thereof.
5. A process for preparation of pimavanserin of Formula I or a pharmaceutical acceptable salt thereof, wherein said process comprising of:
a) alkylation of compound of Formula VI with isobutyl tosylate in presence of base in an organic solvent to get compound of Formula-VII,
Formula VI
Formula VII
wherein R is an acid protecting group;

b) hydrolysis of compound of Formula VII in presence of base to get 2-(4-isobutoxyphenyl)acetic acid of Formula II,
Formula VII Formula II .
c) reacting 2-(4-isobutoxyphenyl)acetic acid of Formula II with acid chloride to give 2-(4-isobutoxyphenyl)acetyl chloride of Formula III,
Formula II Formula III.
3
d) reacting compound of Formula III with sodium azide in presence of solvent to give l-isobutoxy-4-(isocyanatomethyl)benzene of Formula IV,
Formula III Formula IV .
5
e) condensing l-isobutoxy-4-(isocyanatomethyl)benzene of Formula IV with N-(4-fluorobenzyl)-l-methylpiperidin-4-amine of Formula V in presence of organic solvent to give pimavanserin of Formula I; and

Formula IV
Formula I
f) optionally converting pimavanserin of Formula I to its pharmaceutical^ acceptable salts.
6. The process as claimed in claim 5, wherein said solvent used in step (b) is selected from water, methanol, ethanol, isopropanol, butanol, and mixture thereof, and wherein said base used in step (b) is selected from sodium hydroxide, potassium hydroxide, and lithium hydroxide.
7. The process as claimed in claim 5, wherein wherein said solvent used in step (d) is selected from the group comprising of acetone, methanol, ethanol, methyl isobutyl ketone, methyl tert-butyl ketone, methyl ethyl ketone, dimethyl acetamide, dimethyl formamide, N-methyl pyrrolidine, dimethyl sulfoxide, hexamethyl phosphoramide, ethyl acetate, isopropyl acetate, t-butyl acetate, tetrahydrofuran, toluene, methylene dichloride, ethylene dichloride, xylene, water and mixture thereof; and wherein said solvent used in step (e) is selected from the group comprising of tetrahydrofuran, dioxane, acetone, methyl tetrahydrofuran, diethyl ether, isopropyl ether, toluene, xylene, chlorinated hydrocarbons, heptane, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide and mixture thereof.
8. The process as claimed in claim 5, wherein said reaction of compound of Formula III with sodium azide in step (d) is carried out in absence of catalyst.

9. The process as claimed in claim 5, wherein said process further comprises of purification of pimavanserin of Formula I in a suitable solvent.
10. The process as claimed in claim 9, wherein said purification of pimvanserin of Formula I is carried out in presence of solvent selected from the group comprising of water, diethyl ether, isopropyl ether, hexane, pentane, heptane, methyl tert-butyl ether, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, methyl iso butyl ketone, isobutyl acetate and mixture thereof.
11. The process'as claimed in claim 5, wherein said process further comprises of recovery of 2-(4-isobutoxyphenyl)acetic acid of Formula II.
12. The process as claimed in claim 5, wherein said conversion of pimavanserin of Formula I to its pharmaceutical acceptable salt selected from tartrate salt comprises of:

a) treating pimavanserin of Formula I with L-(+)-tartaric acid in a solvent;'
b) stirring at a temperature ranging from 25-80°C; and
c) distilling the solvents and isolating pmavanserin tartrate of Formula I-I; and
d) optionally lyophilizing pimavanserin tartrate of Formula I-I of step (c) to obtain substantially pure amorphous form of pimavanserin tartrate of Formula I-I.
13. The process as claimed in claim 12, wherein said solvent is selected from
acetone, tetrahydrofuran, dioxane, methanol, chloroform, carbon
tetrachloride, water and mixture thereof.
14. Substantially pure pimavanserin or pharmaceutical acceptable salts thereof,
, substantially free of impurities of Formula A, B, C, D, E, and V, wherein
each impurity is less than about 0.15% w/w,

15. A stable amorphous form of pimavanserin tartrate substantially free of impurities of Formula A, B, C, D, E, F, and V, wherein each impurity is less than about 0.15%w/w and wherein total impurity is less than 1% w/w.
16. Isolated compounds of Formula A, B and E;

Formula A

Formula B

Formula E
17. A process for preparation of amorphous form of pimavanserin tartrate of Formula (I-I),
Formula-I-I
comprising of;
a) dissolving crystalline pimavanserin tartrate in water to get a solution; and
b) lyophilizing the solution of step a).
18. The process as claimed in claim 17, wherein said amorphous pimavanserin tartrate has moisture content of < 5%.