DESC:FIELD OF THE INVENTION
The present invention relates to process for the preparation of Pimavanserin of formula (I) using 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl) -1-(1-methylpiperidin-4-yl)thiourea (II) .

(I)

(II)

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. 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 & its pharmaceutically acceptable salts.

SUMMARY OF INVENTION
Particular aspects of the present invention relates to a process for the preparation of 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 (V) with thiophosgene in water

(V)
and an organic solvent in presence of base to get 1-isobutoxy-4-(isothio cyanatomethyl) benzene (IV);

(IV)
b. reacting the 1-isobutoxy-4-(isothiocyanatomethyl)benzene (IV) with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (III)

(III)
in the presence of an organic solvent at temperature between 50°C – 100°C to afford 1-(4-fluorobenzyl)-3-(4-isobutoxy benzyl)-1-(1-methyl piperidin-4-yl)thiourea (II);

II
c. treating the compound of formula (II) with an oxidizing agent in the presence of an organic solvent to get Pimavanserin (I).
(I)

d. optionally converting the Pimavanserin (I) to pharmaceutically acceptable salts.
In another aspect of the present invention relates to novel intermediate compound of formula (II)

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

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. reacting (4-isobutoxyphenyl)methanamine (V) with thiophosgene in water

(V)
and an organic solvent in presence of base to get 1-isobutoxy-4-(isothio cyanatomethyl) benzene (IV);

(IV)
b. reacting the 1-isobutoxy-4-(isothiocyanatomethyl)benzene (IV) with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (III)

(III)
in the presence of an organic solvent at temperature between 50°C – 100°C to afford 1-(4-fluorobenzyl)-3-(4-isobutoxy benzyl)-1-(1-methyl piperidin-4-yl)thiourea (II);

II
c. treating the compound of formula (II) with an oxidizing agent in the presence of an organic solvent to get Pimavanserin (I).
(I)

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

Individual steps of the embodiments are detailed herein below.
In process step of reacting (4-isobutoxyphenyl)methanamine (V) with thiophosgene in presence of base wherein the base selected from inorganic base as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, ammonia, ammonium hydroxide and calcium carbonate in 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 and acetonitrile or mixtures thereof. The reaction is performed at temperature ranging between 0-10oC for a time duration ranging between 4-6 hours.
In one of the particular embodiment according to present invention in step a, solvents are selected from Dichloromethane, Ethyl acetate, Acetonitrile and water.
Accordingly, mixture of 4-Isobutoxy benzyl amine, water, dichloromethane and sodium bicarbonate were stirred at room temperature (25-30oC). To this reaction mixture is added thiophosgene at 0-10oC and stirred the reaction mixture at 0-10oC for about 4-6 hours. To the resulting reaction mixture is charged 10% sodium bicarbonate solution and stirred the reaction mixture for 5-10 minutes separated organic and aqueous layer. The organic layer is washed with water. The organic layer dried over Na2SO4. Distilled off the solvent under vacuum to get 1-isobutoxy-4-(isothiocyanatomethyl)benzene (IV) as liquid.
In process step b of reacting 1-isobutoxy-4-(isothiocyanatomethyl)benzene (IV) with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (II) in an organic solvent selected from 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 and acetonitrile or mixtures thereof at a temperature between 50°C – 100°C for at least 5 hours to afford 1-(4-fluorobenzyl)-3-(4-isobutoxy benzyl)-1-(1-methylpiperidin-4-yl)thiourea (II).
In one of the particular embodiment according to present invention, process step b reaction is performed in ethyl acetate at temperature 70-75°C for time duration 4-5 hours.
Accordingly, process step b is performed by reacting 1-isobutoxy-4-(isothiocyanatomethyl)benzene (IV) with N-(4-fluorobenzyl)-1-methyl piperidin-4-amine (III) in ethyl acetate at temperature 70-75°C for time duration 4-5 hours. Solvent is distilled off to get crude 1-(4-fluorobenzyl)-3-(4-isobutoxy benzyl)-1-(1-methylpiperidin-4-yl)thiourea (II) and the obtained compound 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 of the present invention, crude product obtained according to step b is purified by column chromatography using solvent system such as 10% methanol in ethyl acetate.
In one of the particular embodiment according to present invention, Pimavanserin is obtained by using novel intermediate 1-(4-fluorobenzyl)-3-(4-isobutoxy benzyl)-1-(1-methylpiperidin-4-yl)thiourea (II).
In process step c of reacting 1-(4-fluorobenzyl)-3-(4-isobutoxy benzyl)-1-(1-methylpiperidin-4-yl)thiourea (II) with oxidizing agent selected from Sodium perborate, potassium permanganate, Ozone (O3), Potassium nitrate (KNO3), Potassium peroxomonosulfate (Oxone), Silver carbonate (Ag2CO3), Pyridinium chlorochromate, mixture of Dimethyl sulfoxide (DMSO) and Hydrochloric acid (HCl), Hydrogen peroxide (H2O2), mixture of Hydrogen peroxide (H2O2) & Sodium Hydroxide (NaOH), Sodium periodate (NaIO4), Sodium chlorite (NaClO2), MnO2, Potassium ferricynate (K3Fe(CN)6), HBr in Pyridine, Cummene hydrogen peroxide, Trans-3,5-dihydroperoxy-3,5-dimethyl-1,2-dioxalane (DHPDMDO), mixture of hydrochloric acid (HCl) & sodium nitrate NaNO2, tetra butyl ammonium periodate, tertiary butyl hydrogen peroxide, sodium nitrate (NaNO2) in formic acid, acetic acid, cuprous chloride in sodium hydroxide, Bromine in dioxane in organic solvent selected from 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 and acetonitrile or mixtures thereof.
In one of the particular embodiment according to present invention, process step b reaction is performed with oxidizing agents selected from Sodium perborate, potassium permanganate, Potassium nitrate (KNO3), Potassium peroxomonosulfate (Oxone), Silver carbonate (Ag2CO3), mixture of Dimethyl sulfoxide (DMSO) and Hydrochloric acid (HCl), Hydrogen peroxide (H2O2), Sodium chlorite (NaClO2), MnO2 in solvents selected from acetonitrile, ethanol, methanol or mixtures thereof.
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) is 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 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 1-isobutoxy-4-(isothiocyanatomethyl)benzene (IV)
A mixture of 4-Isobutoxy benzyl amine (V) (10.0 g), water (7.0 v), Dichloromethane (7.0 v) and Sodium bicarbonate (18.7 g) were stirred at room temperature. To this was added thiophosgene (12.8 g) at 0-10oC and stir for about 4-6 hours. To the resulting reaction mixture was charged 10% Sodium bicarbonate solution (2.0 v) and stirred for 5-10 minutes. Separated organic layer and was washed with water (3.0 v). The organic layer dried over sodiumsulfate. Evaporated solvent under reduced pressure to get 1-isobutoxy-4-(isothiocyanatomethyl)benzene (IV). Yield: 11.2 g (90.76%).

Example 2: Preparation of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methyl piperidin-4-yl) thiourea (II)
A mixture of 1-isobutoxy-4-(isothiocyanatomethyl)benzene (IV) (5.0 g) and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (III) (6.0 g) in Ethyl acetate (10.0 v) were stirred at 70-75oC until the TLC complies (4-5 hours). Solvent was evaporated under reduced pressure and residue was purified using 5 % methanol in dichloromethane to get solid compound 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methyl piperidin-4-yl) thiourea (II). Yield: 8.0 g (80.0%).
1H-NMR(DMSO-d6): - 0.95-1.01 (d, 6H), 1.96-2.15 (m,5H), 2.53(S, 3H), 2.57-2.59 (broad, m, 2H), 3.20-3.23(d, 2H), 3.63-3.67(d,2H), 4.56-4.64 (m, 4H), 5.48-5.74(m, 2H), 6.72-7.12(m, 8H).
M/Z: 444 (M+.+1).

Example 3: Preparation of Pimavanserin (I)
The compound 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methyl piperidin-4-yl) thiourea (II) (1.0 g) and silver carbonate (1.2 g) in acetonitrile (15.0 v) was stirred at room temperature until TLC complies (24-30 hours). Filtered the reaction mass to remove un-dissolved solids and washed the solid with acetonitrile (5.0 v). Evaporated the solvent under reduced pressure and residue was isolated in water (10.0 v) and methanol (2.0 v) mixture at room temperature. Yield: 0.84 g (87.5%). Purity: 95.28% (Area % by HPLC). It was further recrystallized to get pure material. Melting point in accordance with DSC 120.57°C.
1H-NMR(CDCl3): - 0.99-1.01 (d, 6H), 1.63-1.71(m,4H), 2.00-2.11(m, 3H), 2.27(s, 3H), 2.86-2.89(d, 2H), 3.66-3.68(d, 2H), 4.26-4.33(m,5H), 4.44-4.46 (m, 1H), 6.76-7.19(m, 8H).
M/Z: 428.3 (M+.+1).

Example 4: Preparation of Pimavanserin (I)
The compound 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methyl piperidin-4-yl) thiourea (II) (1.0 g) was stirred in ethanol (10.0 v) and to this was added sodium hydroxide solution (0.19 g of sodium hydroxide in 3ml water) at room temperature. To the reaction mass was added hydrogen peroxide (50%, 0.6 v) at 0-5oC and stirred for 15-20 min at 0-5oC. The reaction mass was maintained at room temperature until TLC complies (24 hours). Evaporated the solvent under reduced pressure and residue was purified using 10% methanol in ethyl acetate. Yield: 0.76 g (79.16%). Purity: 99.57% (Area % by HPLC).
1H-NMR(CDCl3): - 0.99-1.01 (d, 6H), 1.61-1.73(m,4H), 2.02-2.10(m, 3H), 2.62(s, 3H), 2.85-2.88(d, 2H), 3.66-3.68(d, 2H), 4.26-4.33(m,5H), 4.44-4.47 (m, 1H), 6.76-7.19(m, 8H).
M/Z: 428.3 (M+.+1).

Example 5: Preparation of Pimavanserin (I)
To a mixture of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methyl piperidin-4-yl) thiourea (II) (1.0 g) and Oxone (1.04 g) in acetonitrile (15.0 v) was stirred at room temperature for 5-10 minutes. Raised reaction mass temperature to 75-80oC and stirred for about 60-90 minutes. Filtered the un-dissolved solids and washed with acetonitrile (5.0 v). Solvent was evaporated under reduced pressure and residue was purified using 10% methanol in ethyl acetate. Yield: 0.81 g (79.16%). Purity: 93.77% (Area % by HPLC). It was further recrystallized to get pure material.
1H-NMR(CDCl3): - 0.99-1.01 (d, 6H), 1.60-1.73(m,4H), 2.00-2.10(m, 3H), 2.25(s, 3H), 2.84-2.87(d, 2H), 3.66-3.68(d, 2H), 4.26-4.37(m,5H), 4.44-4.46 (m, 1H), 6.75-7.19(m, 8H).
M/Z: 427.1 (M+), 426.1(M+.-1).

Example 6: Preparation of Pimavanserin (I)
The compound 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methyl piperidin-4-yl) thiourea (II) (1.0 g) was stirred in dimethylsulfoxide (3.0 v) at room temperature. To the resulting reaction mixture was added concentrated HCl solution (0.16 g) at room temperature. Stirred the reaction mixture for overnight (24 hours) and charged water (15.0v) to the reaction mixture. The product was extracted with ethyl acetate (20.0v) and evaporated solvent under reduced pressure to get crude material. The residue was purified by using 10% methanol in ethyl acetate. Yield: 0.75 g (78.12%). Purity: 96.19% (Area % by HPLC). It was further recrystallized to get pure material.
1H-NMR(CDCl3): - 0.99-1.01 (d, 6H), 1.60-1.73(m,4H), 2.02-2.10(m, 3H), 2.26(S, 3H), 2.85-2.88(d, 2H), 3.66-3.68(d, 2H), 4.26-4.33(m,5H), 4.44-4.47 (m, 1H), 6.75-7.19(m, 8H).
M/Z: 427.1 (M+).

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:We Claim:
1) A process for the preparation of Pimavanserin (I)
(I)
comprising the steps of:
a. reacting (4-isobutoxyphenyl)methanamine (V) with thiophosgene in water

(V)
and an organic solvent in presence of base to get 1-isobutoxy-4-(isothio cyanatomethyl) benzene (IV);

(IV)
b. reacting the 1-isobutoxy-4-(isothiocyanatomethyl)benzene (IV) with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (III)

(III)
in the presence of an organic solvent at temperature between 50°C – 100°C to afford 1-(4-fluorobenzyl)-3-(4-isobutoxy benzyl)-1-(1-methyl piperidin-4-yl)thiourea (II);

II
c. treating the compound of formula (II) with an oxidizing agent in the presence of an organic solvent to get Pimavanserin (I).
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 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, ethanol, methanol, propanol, isopropanol, butanol and acetonitrile or mixtures thereof.

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

4) The process for the preparation of Pimavanserin (I), according to claim 1, wherein the oxidizing agent selected from Sodium perborate, potassium permanganate, Ozone (O3), Potassium nitrate (KNO3), Potassium peroxomonosulfate (Oxone), Silver carbonate (Ag2CO3), Pyridinium chlorochromate, mixture of Dimethyl sulfoxide (DMSO) and Hydrochloric acid (HCl), Hydrogen peroxide (H2O2), mixture of Hydrogen peroxide (H2O2) & Sodium Hydroxide (NaOH). Sodium periodate (NaIO4), Sodium chlorite (NaClO2), Manganese dioxide (MnO2), Potassium ferricynate (K3Fe(CN)6), HBr in Pyridine, Cummene hydrogen peroxide, Trans-3,5-dihydroperoxy-3,5-dimethyl-1,2-dioxalane (DHPDMDO), mixture of hydrochloric acid (HCl) & sodium nitrate NaNO2, tetra butyl ammonium periodate, tertiary butyl hydrogen peroxide, sodium nitrate (NaNO2) in formic acid, acetic acid, cuprous chloride in sodium hydroxide, Bromine in dioxane.

5) A novel intermediate compound of formula (II)

II