DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation Pimavanserin of Formula (I).

(I)
BACKGROUND OF THE INVENTION

Pimavanserin of formula I, is chemically known as N-(4-fluorobenzyl)- N-(1- methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)-phenylmethy)carbamide. Pimavanserin was approved as Pimavanserin tartrate salt. It was developed by Acadia Pharmaceuticals and was approved under the brand name NUPLAZID™ is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.

(I)

David M. Weiner et.al. in the patent US 7,601,740 discloses a process for the preparation of Pimavanserin, which involves alkylation followed by ester hydrolysis and then in situ azidation. This process utilizes the hazardous reagent diphenylphosphoryl azide and also with process safety. The process is shown in the Scheme I as given below:

Scheme I
Wang Shaojie et.al. in the patent CN104961672A discloses a process for the preparation of Pimavanserin, which discloses the process is shown in the Scheme II as given below:
x
Scheme II

Jiao Peifu et.al. in the patent CN104844502A discloses a process for the preparation of Pimavanserin, which discloses the process is shown in the Scheme III as given below:

Scheme III
In both the processes i.e in Scheme II & III, chloroformate amino protected intermediates and ester compounds are used this may lead to formation of more impurities and this may lead to trouble in scale-up of the final compound.

Xu Kui et.al. in the patent CN105111135A discloses a process for the preparation of Pimavanserin, which involves 4-isobutoxy benzylamine and carbonyl dimimidazole to get urea intermediate and this intermediate condensed with dihydrochloride salt of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine to obtain Pimavanserin. According to this method more chance of formation of byproducts and this may lead to experiment efficiency and final purification of the product more difficult. The process is shown in the Scheme IV as given below:

Scheme IV

Various procedures were reported by utilizing diphenylphosphoryl azide compounds, chloroformate amino protected compounds and carbonyl dimimidazole intermediates as key materials. These substances are hazardous reagents and further may lead to formation of more byproducts which may lead to effect on purity & yield of the final substance. Hence, there still exists a need to have alternate procedures which is industrially feasible. Thus, present invention fulfills the need of the art and provides an improved and industrially feasible process for preparation of Pimavanserin & its pharmaceutically acceptable salts.

SUMMARY OF INVENTION
Particular aspects of the present invention relates to a process for the preparation of crystalline Pimavanserin (I).

(I)
In one aspect of the present invention, it relates to process for the preparation of Pimavanserin (I) comprising the steps of:
a. reacting (4-isobutoxyphenyl)methanamine of Formula (II).

(II)
with Urea in presence of base at temperature between 120-130°C to get 1-(4-isobutoxybenzyl)urea of Formula (III).

(III)
b. reacting 1-(4-isobutoxybenzyl)urea of Formula (III) with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (IV).

(IV)
in the presence of in an organic solvent at temperature between 120-130°C and separating the pure Pimavanserin of Formula (I).

Further particular aspects of the invention are detailed in the description part of the specification, wherever appropriate.

DETAILED DESCRIPTION
As set forth herein, embodiments of the present invention provide an efficient process for the preparation of Pimavanserin (I).
In one embodiment according to present application, it provides a process for the preparation of Pimavanserin (I), comprising the steps of:
a. reacting (4-isobutoxyphenyl)methanamine of Formula (II)

(II)
with urea in presence of base at temperature between 100-150°C to get 1-(4-isobutoxybenzyl)urea of Formula (III).

(III)
b. reacting the 1-(4-isobutoxybenzyl)urea (III) with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (IV).

(IV)
in the presence of in an organic solvent at temperature between 100°C – 150°C and separating the pure Pimavanserin of Formula (I).

(I)

Individual steps of the embodiments are detailed herein below.
In process step a of reacting (4-isobutoxyphenyl)methanamine of Formula (II) with urea in presence of base wherein the base selected from inorganic base as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, ammonium hydroxide and calcium carbonate in solvents such as water, cyclohexane, heptane, hexane, cyclopentane, toluene, xylene, diethyl ether, diisopropyl ether, methyl tertiary butyl ether (MTBE), dichloromethane, chloroform, 1,4-dioxane or polar aprotic solvents as dimethyl sufoxide (DMSO), tetrahydrofuran (THF), dimethyl formamide (DMF), acetone, ethanol, methanol, propanol, isopropanol, butanol, acetonitrile or mixtures The reaction is performed at temperature ranging between 100-150oC for a time duration ranging between 15-20 hours.
In one of the particular embodiment reaction in step a. is performed at a temperature ranging between 120-130oC for 12-15 hours in water.
Accordingly, 4-Isobutoxy benzyl amine, urea, sodium hydroxide heated to 120-130oC. Reaction mass is stirred for 12-15 hours. Water is added to the reaction mixture and pH was adjusted to 7.0 with concentrated HCl. Solid is filtered and washed with water and dried the compound to provide the 1-(4-isobutoxybenzyl)urea.
In process step b of reacting 1-(4-isobutoxybenzyl)urea with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine in solvent selected from water, polar aprotic solvents as dimethyl sufoxide (DMSO), tetrahydrofuran (THF), dimethyl formamide (DMF), acetone, ethanol, methanol, propanol, isopropanol, butanol, acetonitrile or mixtures. The reaction is maintained for 10-12 hours at temperature ranging between 120-130oC.
In particular embodiment of the present invention, process reaction between 1-(4-isobutoxybenzyl)urea and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine is performed in water at temperature 120-130oC for 12 hours and the pimavanserin obtained according to this step is isolated using ethyl acetate as solvent.
In one of the embodiment of the present invention, compounds obtained according to any of the process is purified by initiating either by cooling or concentration of the reaction mixture followed by cooling of the remaining solution or by using column chromatography. The purified product is then isolated from the mixture by suitable techniques such as filtration, centrifugation and the like.
In one of the embodiment according to present invention, Pimavanserin (I) characterized by X-ray powder diffraction angle peaks at 6.8, 7.9, 12.8, 13.4, 16.8, 18.8, 19.4, 20.6 and 22.0 ± 0.2° 2?
In yet another embodiment according to present invention, purification of the compound is carried in suitable solvents selected from alcohols such as methanol, ethanol, propanol, butanol and the like or aliphatic hydrocarbons such as pentane, hexane, heptane and the like or aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and the like or halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride and the like or esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate and the like or ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone or ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane and the like or diglyme, triglyme, and the like or amides such as N,N-dimethylformamide N,N-dimethylacetamide and the like or sulphoxides such as DMSO and the like or nitriles such as acetonitrile or mixtures thereof.
The invention is further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. 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.

EXAMPLES:
Example 1: Preparation of 1-(4-isobutoxybenzyl)urea (III):
A mixture of 4-Isobutoxy benzyl amine (II) (5.0 g), urea (10.0 g), sodium hydroxide (0.99 g) heated to 120-130oC. Reaction mass was stirred for 12-15 hours for the completion of TLC. To this was charged water (10.0 vl) and pH was adjusted to 7.0 with concentrated HCl. Solid was filtered and washed with water (4.0 v) and dried the compound to provide the 1-(4-isobutoxybenzyl)urea.
Input: - 5.0 g
Output: - 4.0 g (64.62 %)
Total yield: - 6.19.
H1 NMR(DMSO-d6): ? 0.95-0.97(d,6H), 1.94-2.02(m,1H), 3.69-3.71(d,2H), 4.07-4.08(m,2H), 5.46 (s,2H), 6.28-6.31 (t,1H), 6.85-7.15(m,4H)
M/Z: 223.65 M+.+1

Example 2: Preparation of Pimavanserin (I)
A mixture of 1-(4-isobutoxybenzyl)urea (III) (1.0 g) and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (IV) (1.0 g) were stirred at 120-130oC until the TLC complies (12 hours). Charged water to reaction mass at room temperature and extracted into ethyl acetate. Solvent was evaporated under reduced pressure and residue was purified using solvent system 10 % methanol in ethyl acetate to get Pimavanserin.
Input: - 1.0 g
Output: - 1.2 g (62.5%)
Total yield: - 1.92 g
99.6
1H-NMR(DMSO-d6): - 0.95-0.97 (d, 6H), 1.40-1.57(m,4H), 1.83-2.03(m, 3H), 2.08(s, 3H), 2.68-2.71(d, 2H), 3.68-3.70 (d,2H), 3.86-3.92 (m, 1H), 4.16-4.18 (d, 2H), 4.40 (s,2H), 6.82-6.84 (t, 1H), 7.08-7.12 (t, 4H), 7.21-7.25 (t, 2H). M/Z: 428 (M+.+1).

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.
,CLAIMS:1) A process for the preparation of Pimavanserin (I)

(I)
comprising the steps of:
a) reacting (4-isobutoxyphenyl)methanamine (II) with urea

(II)
in presence of base at temperature ranging between 100°C – 150°C to get 1-(4-isobutoxybenzyl)urea (III)

(III)
b) reacting 1-(4-isobutoxybenzyl)urea (III) with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (IV)

(IV)
In the presence of organic solvent at temperature ranging between 100°C – 150°C and separating the pure Pimavanserin of Formula (I);

2) The process for the preparation of Pimavanserin (I) according to claim 1, wherein the base selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, ammonia, ammonium hydroxide and calcium carbonate or their aqueous mixtures.

3) The process for the preparation of Pimavanserin (I) according to claim 1, wherein the organic solvents are selected from non-polar solvent as cyclohexane, heptane, hexane, cyclopentane, toluene, xylene, diethyl ether, diisopropyl ether, methyl tertiary butyl ether (MTBE), dichloromethane, chloroform, 1,4-dioxane or polar aprotic solvents as dimethyl sufoxide (DMSO), tetrahydrofuran (THF), dimethyl formamide (DMF), acetone, ethyl acetate, ethanol, methanol, propanol, isopropanol, butanol and acetonitrile or mixtures thereof.