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

(I)
Pimavanserin (I) is useful in the treatment of Parkinson’s disease psychosis.

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 trade name NUPLAZID® for use in patients 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:

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 diimidazole to get urea intermediate and this intermediate condensed with dihydrochloride salt of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine to obtain Pimavanserin (I). 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 diimidazole 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 (I) & its pharmaceutically acceptable salts.

SUMMARY OF INVENTION
Particular aspects of the present invention relates to a process for the preparation of Pimavanserin (I). Pimavanserin obtained by the process of the present invention was found to substantially pure and stable. Process for the preparation of Pimavanserin comprising the steps of:
a. treating (4-isobutoxyphenyl)methanamine (V) with aqueous ammonia in

(V)
an organic solvent followed by reaction with formic acid at reflux for atleast 4 hours to get N-(4-isobutoxybenzyl)formamide (IV)

(IV)
b. reacting N-(4-isobutoxybenzyl)formamide (IV) with triphosgene in presence of base at temperature 25-30°C for 2-5 hours to provide 1-isobutoxy-4-(iso cyanatomethyl)benzene III;
c. reacting the reaction mixture of step b. with N-(4-fluorobenzyl)-1-methyl piperidin-4-amine (II) in presence of Trifluoromethanesulfonic anhydride at temperature ranging between -50°C to -80°C to get Pimavanserin (I)

(II)

(III)
d. optionally converting the Pimavanserin (I) to pharmaceutically acceptable salts.
In a further aspect of the present application also relates to a pharmaceutical composition comprising Pimavanserin of the present application and atleast one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an example of X-ray powder diffraction (“XRPD”) pattern of Crystalline Form of Pimavanserin (I).

DETAILED DESCRIPTION
As set forth herein, embodiments of the present invention provide an efficient process for the preparation of Pimavanserin (I).
In another embodiment according to present application, it provides a process for the preparation of Pimavanserin (I), comprising the steps of:
a. treating (4-isobutoxyphenyl)methanamine (V) with aqueous ammonia in

(V)
an organic solvent followed by reaction with formic acid at reflux for atleast 4 hours to get N-(4-isobutoxybenzyl)formamide (IV)

(IV)
b. reacting N-(4-isobutoxybenzyl)formamide (IV) with triphosgene in presence of base at temperature 25-30°C for 2-5 hours to provide 1-isobutoxy-4-(iso cyanatomethyl)benzene (III);
c. reacting the reaction mixture of step b. with N-(4-fluorobenzyl)-1-methyl piperidin-4-amine (II) in presence of Trifluoromethanesulfonic anhydride at temperature ranging between -50°C to -80°C to get Pimavanserin (I);

(II)

(III)
d. optionally converting the Pimavanserin (I) to pharmaceutically acceptable salts.

Individual steps of the embodiments are detailed herein below.

In process step a. of treating (4-isobutoxyphenyl)methanamine (V) with aqueous ammonia in an organic solvent followed by reaction with formic acid at reflux for atleast 4 hours to get N-(4-isobutoxybenzyl)formamide (IV).
In process step b. of reacting N-(4-isobutoxybenzyl)formamide (IV) with triphosgene in presence of base at temperature 25-30°C for 2-5 hours to provide 1-isobutoxy-4-(iso cyanatomethyl)benzene (III).
In process step c. of reacting the reaction mixture formed in step b. with N-(4-fluorobenzyl)-1-methyl piperidin-4-amine (II) in presence of Trifluoromethanesulfonic anhydride at temperature ranging between -50°C to -80°C to get Pimavanserin (I).

In one of the particular embodiment of the present invention, step b. process is performed by adding triphosgene and base to N-(4-isobutoxybenzyl)formamide (IV) at temperature 0-5°C. Reaction is maintained at temperature 25-30°C for 2-5 hours to provide 1-isobutoxy-4-(iso cyanatomethyl)benzene (III) followed by step c. is performed by reacting the reaction mixture formed in step b. with N-(4-fluorobenzyl)-1-methyl piperidin-4-amine (II) in presence of Trifluoromethanesulfonic anhydride at temperature ranging between -50°C to -80°C without isolating 1-isobutoxy-4-(iso cyanatomethyl)benzene (III) to get Pimavanserin (I).

In another particular embodiment of the present invention, step b. is performed without isolating 1-isobutoxy-4-(iso cyanatomethyl)benzene (III).

In the process step d., optionally converting the Pimavanserin (I) to pharmaceutically acceptable salts.

In one of the embodiment of the present invention, pharmaceutically acceptable salts are selected from hydrochloride, sulphuric acid and acetic acid.

In one of the embodiment of the present invention, wherein the organic solvent selected from non-polar solvent as heptane, hexane, cyclohexane, cyclopentane, toluene, xylene, diethyl ether, dichloromethane, chloroform, 1,4-dioxane or polar aprotic solvents as dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dimethyl formamide (DMF), acetone, acetonitrile or water and/or mixtures thereof.

In one of the embodiment of the present invention, wherein the base used in step b. selected from inorganic base as sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, ammonia, ammonium hydroxide and calcium carbonate or organic base is selected from sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and triethyl amine.

In yet another embodiment according to present invention, obtained compounds are 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 reaction 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?.

Substantially pure Pimavanserin (I) obtained according to the process of the present invention results in the final API purity by HPLC of more than 99% and preferably greater than 99.5% (by HPLC).

The purity of the Pimavanserin samples was measured using Chromatography. Chromatography was performed with Waters Alliance HPLC system (MILD, USA) that consists of quaternary pump equipped with 2695 separation module with inbuilt auto injector and 2996 photodiode array detector. The output signal was monitored and processed using chromelean software version 6.8.

The invention was 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 N-(4-isobutoxybenzyl)formamide (IV)
4-Isobutoxy benzyl amine (10.0 g) was stirred in water (3.0 Volumes) at room temperature. Adjusted the reaction mass pH to 11-12 with aqueous ammonia solution. The product was extracted in toluene (5.0 V). Formic acid (2.3 g) was added to the reaction mixture. The resulting reaction mixture was refluxed for 4-9 hours with azeotropic condenser. After the TLC complies, evaporated the solvent under reduced pressure and stripped out with hexane to get N-(4-isobutoxybenzyl)formamide (IV). Yield: 6.5 g (75.05%).
1HNMR (DMSO-d6): S 0.95-0.97(d,6H), 1.95-2.01(m,1H), 3.70-3.72(d,2H), 4.20-4.21(d,2H), 6.85-7.17(m,4H), 8.09(s,1H), 8.39(s,1H).
M/Z: 206.54(M+.-1).

Example 2-Preparation of Pimavanserin (I):
N-(4-isobutoxybenzyl)formamide (IV) (2.0 g) was stirred in DCM (10.0 v). To this was added triethyl amine (3.9 g) at room temperature. Triphosgene (1.98 g) was added in lot wise to above reaction mixture at 0-5oC. Reaction mass was stirred at room temperature for 2-3 hours. Wash the reaction mixture with water (5.0v) and dried over anhydrous Na2 SO4. The organic layer was transferred into another round bottom flask U/N2 atmosphere. Add Dimethyl sulfoxide (DMSO) (0.82 g) to the reaction mixture at room temperature. To this was added Trifluoromethanesulfonic anhydride (0.1 ml) at -65 to -60oC. Reaction mixture was stirred for 10-15min at room temperature. Add (N-(4-fluorobenzyl)-1-methylpiperidin-4-amine) (2.1 g) in DCM (10.0 v) at -65 to -60oC. Reaction mixture was stirred at room temperature for 2-3 hours. Washed the reaction mixture with water (5.0v) and dried the organic layer over Na2SO4. Evaporated the solvent under reduced pressure and residue was purified in 10% methanol in ethyl acetate to give Pimavanserin (I). Yield: 2.91g (69.95%). Purity: 99.61% (Area % by HPLC).
1H-NMR(CDCl3): - 0.99-1.01 (d, 6H), 1.67-1.73(m,4H), 2.00-2.14(m, 3H), 2.27(s, 3H), 2.89-2.92(d, 2H), 3.66-3.68(d, 2H), 4.26-4.39(m,5H), 4.45-4.48 (m, 1H), 6.75-7.18(m, 8H).
M/Z: 428.3 (M+.+1).

Example 3-Preparation of Crystalline Pimavanserin (I):
5 gm of Crude Pimavanserin (I) was dissolved in 10% methanol in ethyl acetate solution to give solution.
Crystalline Pimavanserin (I) was isolated by partial evaporation of the solvent followed by cooling and filtering. Yield: 3.94g (78.8% w/w). Purity: 99.75% (Area % by HPLC).

While the foregoing pages provide working examples and 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:We Claim:
1) A process for the preparation of Pimavanserin (I)
(I)
comprising the steps of:
a. treating (4-isobutoxyphenyl)methanamine (V) with aqueous ammonia in

(V)
an organic solvent followed by reaction with formic acid at reflux for atleast 4 hours to get N-(4-isobutoxybenzyl)formamide (IV)

(IV)
b. reacting N-(4-isobutoxybenzyl)formamide (IV) with triphosgene in presence of base at temperature 25-30°C for 2-5 hours to provide (III);
c. reacting the reaction mixture formed in step b. with N-(4-fluorobenzyl)-1-methyl piperidin-4-amine (II) in presence of Trifluoromethanesulfonic anhydride at temperature ranging between -50°C to -80°C to get Pimavanserin (I)

(II)

(III)
d. optionally converting the Pimavanserin (I) to pharmaceutically acceptable salts.

2) The process for the preparation of Pimavanserin (I) according to Claim 1, wherein the organic solvent selected from non-polar solvent as heptane, hexane, cyclohexane, cyclopentane, toluene, xylene, diethyl ether, dichloromethane, chloroform, 1,4-dioxane or polar aprotic solvents as dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dimethyl formamide (DMF), acetone, acetonitrile or water and/or mixtures thereof.

3) The process for the preparation of Pimavanserin (I) according to Claim 1, where in the step b. is carried without isolating 1-isobutoxy-4-(iso cyanatomethyl)benzene (III).

4) The process for the preparation of Pimavanserin (I) according to Claim 1, wherein step b. comprising the steps:
i. adding triphosgene and base to N-(4-isobutoxybenzyl)formamide (IV) at temperature 0-5°C;
ii. maintaining the reaction at temperature 25-30°C for 2-5 hours followed by condensing with N-(4-fluorobenzyl)-1-methyl piperidin-4-amine (II) in presence of trifluoromethane sulfonic anhydride at temperature ranging between -50°C to -80°C without isolating 1-isobutoxy-4-(iso cyanatomethyl)benzene (III) to get Pimavanserin (I).

5) The process for the preparation of Pimavanserin (I) according to Claim 1, wherein the base selected from inorganic base as sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, ammonia, ammonium hydroxide and calcium carbonate or organic base is selected from sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and triethyl amine.

6) Crystalline 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?.

7) Crystalline Pimavanserin (I) according to Claim – 6, prepared by process comprising the steps of:
a) preparing 10% - 15% methanol solution in ethyl acetate;
b) combining crude or pure Pimavanserin (I) with step (a) solution;
c) isolating the substantially pure crystalline Pimavanserin (I).

8) Substantially pure Pimavanserin having purity more than 99.5% (by HPLC).