Field of Invention :
The present invention relates to the high yielding, safe, efficient and industrially viable process for the synthesis of N-(4-fluorobenzyl)-N-(l-methylpiperidinyl)-N'-(4-(2-methylpropyloxy)-phenylmethyl carbamide (Formula 1), also known as Pimavanserin free base, using l-(4-fluorobenzyl)-3-(4-isobutoxybenzylidene)-l-(l-methylpiperidin-4-yl)urea (Formula 9) as a novel intermediate.

Background of the Invention :
Pimavanserin, namely N-(4-fluorobenzyl)-N-(I-methylpiperidinyl)-N'-(4-(2-methylpropyloxy)-phenylmethyl carbamide (Formula 1), was developed by Acadia Pharmaceuticals and was approved under the trade name NUPLAZID® as tartrate salt, is a 5HT2A inhibitor and a non-dopaminergic atypical antipsychotic for psychosis-like behaviors and has the potential to treat various other neuropsychiatric disorders such as schizophrenia and Parkinson's disease.
Pimavanserin free base and its synthesis are disclosed in US 7,601,740 and US 7,790,899. The '740 patent reveals the synthesis of Pimavanserin free base, which includes O-alkylation followed by ester hydrolysis and then in situ azidation using diphenylphosphoryl azide. This process suffers from the safety and environmental aspects as it utilizes the hazardous reagent diphenylphosphoryl azide besides column chromatographic separation step. The process is described by the following Scheme I.

Scheme-I

The US patent 7,790,899 describes another process, which includes O-alkylation followed by reductive amination of aldehyde to obtain amino intermediate which is then reacted with the hazardous reagent phosgene to give the key isocyanate intermediate (Scheme II).
Scheme-II

In WO2016/14I003 (Teva Pharmaceutical Industries, IL) is reported a strategy in which carbamate derivative of primary amine is reacted with secondary amine to afford the Pimavanserin free base. Thus, by reacting benzyl amine with carbonyldiimidazole(CDI) to form a carbamate of primary amine, which in turn reacts with the secondary amine to afford Pimavanserin free base (Scheme III).

Scheme-Ill

Alternatively, the primary amine may also be reacted in the presence of a base in a suitable solvent with 4-nitrophenyl chloroformate to form a carbamate which then reacts with secondary amine to afford Pimavanserin free base (Scheme IV), as reported in the same patent application.
Scheme IV

The same patent application describes yet another process, which uses hydroxamic acid derivative as an intermediate for producing Pimavanserin (Scheme V).


However, the first two processes (Schemes I and II) suffer from use of hazardous reagents such as phosgene derivatives or diphenylphosphoryl azide for the preparation of l-isobutoxy-4-(isocyanatomethyl)benzene, a benzyl isocyanate intermediate. Processes for preparing benzyl isocyanate derivatives are generally associated with the use of hazardous reagents as described above. Schemes III and IV utilize expensive reagents such as carbonyldiimidazole or 4-nitrophenyl chloroformate for the coupling of secondary amine to afford Pimavanserin followed by tedious purification procedures. The above-described processes involve the use of hazardous reagents or expensive reagents or involve purification by column chromatography with low yields.
Recently two patent applications, WO2017/15272A (Acadia) and WO20I7/036432A (Zentiva), reported almost similar concepts for making Pimavanserin free base (1) using a substituted urea such as l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)urea (8). Both the applications follow a 'one-pot process of reductive amination' by first condensing 4-isobutoxy benzaldehyde with 8 followed by reduction using NaBKU, to afford Pimavanserin free base (1).
However, the patent application WO2017/15272A disclosed only an outline of the synthetic process for the free base without giving details of compounds and their purities. The elevated temperature and use of slightly excess urea, result in the backward path to form the starling material, besides the formation of a 'defluorinated' product, drastically reducing the yield. In addition to this, the combined operation of reductive amination involves cumbersome and tedious workup procedure. The combined step led to the formation of product with number of impurities, which impact the quality and yield of the final product (Scheme-VI).


The later application WO2017/036432A describing the formation of urea using metal isocyanate (Scheme VII) has the disadvantage of formation of 'diurea' impurity (formula 2) due to instant reactivity. The process of purification to remove the formed diurea impurity, leads to considerable yield loss. The later step of reductive amination carries the impurity from the initial stage and results in low yield of 61% and purity of 98.3% only (our results, as per patent application example 14, product contains 51% of Pimavanserin, 4% of 8 and 3% of 10).

All the impurities formed were not disclosed. However, on repeating the experiments as described, we observed a major impurity along with the product. The impurity was isolated and identified as C-alkylated impurity of formula 4. This substance is hitherto unreported and unknown. The formation of 4 might be explained as follows. During the imine formation using Lewis acid the benzylidene impurity of formula 3 might have been generated, which subsequently underwent reduction to form 4. Because of structural similarities between the final free base of formula 1 and the reduced impurity of formula 4, it is very difficult to eliminate the undesirable impurity without the loss of the required product.


Furthermore, the reduction step performed by using NaBhUas per the patent application, not only resulted in
the formation of product (Scheme-VII) with low yield, but also generated an interesting borane complex of
formula (5). with piperidine moiety as quaternary salt. It was also observed that the formation of this complex
depends upon the solvent in which the reaction was performed. The complex was quite stable and was isolated !
through column chromatography in good yield and well characterized. This substance is also hitherto j
unreported and unknown. !

Thus the above two patent applications suffer from drawbacks such as low pharmaceutical grade purity of the final compound (API) and low yields due to purification procedures required to eliminate the formed impurities during early stages. Therefore there is a need for an improved process for efficient synthesis of Pimavanserin of high purity.
Summary of the Invention:
By considering the drawbacks discussed above in prior art processes, it was planned to develop a simple process for preparation of Pimavanserin (1) avoiding hazardous reagents and conditions besides suppressing formation of undesirable impurities. This objective could be achieved in three steps:

(a) reaction between the known starting material l-(l-methylpiperidinyl)-4-fluorobenzylamine (6) and urea at a low temperature in acetic acid media to provide l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)urea (8);
(b) condensing the product (8) and 4-isobutyloxy benzaldehyde (10) in the presence of titanium tetraisopropoxide and isolating the novel intermediate l-(4-fluorobenzyl)-3-(4-isobutoxybenzylidene)-l-(l-methylpiperidin-4-yl)urea of formula 9 (iminourea), with high chemical purity in good yield and
(c) subsequently reducing the iminourea (9) with hydrogen in presence of metal catalyst to afford Pimavanserin free base (1), with chemical purity of pharmaceutical grade in a facile manner.
(d) The process makes use of eco-friendly urea as the carbamoylating reagent to prepare highly pure l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)urea (8).
The present inventive process has the advantage of not only getting high purity of the compound, but is also free from critical impurities 6 and 7, which are unavoidable in the prior art processes, or the newly identified impurities 4 and 5 described earlier.

Detailed disclosure of the Invention :
The present invention relates to the synthesis of Pimavanserin free base(l) as depicted in Scheme VIII below.


While trying to repeat prior art processes for preparing the key intermediate 8, we had noticed low yields and unwanted :diurea' impurity when using isocyanates. On the other hand the reaction with urea and 6 seemed to result in low 'diurea' impurity although with low yield of the product (8). In the prior art process the reaction between 6 and urea was conducted at a high temperature of 150°C without any solvent. We argued that the reaction if conducted at lower temperatures in a solvent might help. To our surprise and satisfaction, we found that use of acetic acid as medium and at a temperature of about 80°C resulted not only in excellent yield of 90% but also of purity of over 99% of product. Other solvents may also be tried at lower temperatures but ■ acetic acid was found preferable.
Thus one embodiment of the present invention consists of condensing N-(4-fluorobenzyl)-l-methylpiperidine-4-amine (6) with urea in acetic acid medium at a temperature of less than 100°C, preferably about 80°C, for a period of 10-20 hours, preferably about 15 hours.


The reaction labeled as 'reductive animation' as described in prior art is actually a :one-pot' process consisting of two steps, involving the formation of an 'imine1 intermediate, which is then reduced to the 'amine'. In 'one-pot' processes the reagents used for all the involved steps remain in the reaction media and can bring about undesirable side reactions, although in several such processes beneficial results have been reported. However, we wanted to study this reaction in greater detail and attempted to isolate the 'imine' intermediate before subjecting it to the reduction step. To our great surprise and satisfaction, we found that both the yield and quality of the intermediate were excellent.
Thus another embodiment of the present invention refers to the process for preparing l-(4-fluorobenzyl)-3-(4-isobutoxybenzylidene)-l-(l-methylpiperidin-4-yl)urea, compound of formula (9), simply referred as 'iminourea'. The iminourea forming reaction may be carried out in the presence of any Lewis acid, preferably titanium tetraisopropoxide, in a suitable solvent such as dichloromethane. The preferred temperature to conduct the reaction is within the range of 20-l00°C, preferably at 25-50°C fora period of 7-20 h and in particular 12-16 h.
Another embodiment of the present invention refers to the process for preparing Pimavanserin (1), by reducing the novel intermediate 'iminourea' (9) using gaseous hydrogen in presence of a metal catalyst. The reaction should be conducted at a temperature of 0-40°C, preferably at 25°C, for a period of2-20 h, preferably 12-16 h. The metal catalyst may be selected from any well-known complexes of metals such as Ni, Ru, Pd or Pt, preferably Pd. The reduction reaction can be carried out in a suitable solvent, selected for example from the
group comprising polar protic solvents, such as methanol, ethanol, isopropanol and tertiary butyl alcohol, preferably methanol.
Examples:
Example-1 : Preparation of l-(4-Fluorobenzyl)-l-(l-methylpiperidin-4-yl)urea (8):
To a solution of N-(4-fluorobenzyl)-l-methylpiperidine-4-amine (30.0 g, 0.13 mol) in acetic acid (150 ml) urea (162.0 g, 2.7 mol) was added and the mixture stirred at 80-85°C for 15-20 h. Acetic acid was completely evaporated and residue dissolved in minimum amount of water. The pH was adjusted to 9.5-10.0 using aqueous ammonia solution. After complete dissolution, the reaction mixture was extracted with dichloromethane (3 X 100 ml). The extract was washed with water followed by brine and dried over NaiSCXThe vitreous product was triturated with methyl tertiary butyl ether (MTBE, 100 ml), which after aspiration and washing with MTBE provided 32.0 g (90%) of a white solid substance containing 99.7% of l-(4-Fluorobenzyl)-l-(I-methylpiperidin-4-yl)urea of formula (8) according to HPLC with melting point of I26-129°C. lH NMR

(CDCb, 300.13 MHz): 7.27-7.21 (m, 2H, ArH), 7.03 (t, 2H, AvH), 4.46 (brs, 2H, UH2)t 4.38 (s, 2H, Ar-CH2-N), 4.26-4.20 (m, IH, N-C//), 2.87 (d, 2H, (Cfl»2-N-CH3), 2.26 (s, 3H, N-C/fc), 2.06 (td, 2H, (C/fc)2-N-CH3), 1.71-1.62 (m, 4H, CH-(C//>)2). I3C NMR (CDCI3, 75.47 MHz) 163.53, 160.27.. 159.42, 134.05, 127.73, 115.77, 55.16, 52.45, 46.02, 45.46, 30.02. MS (M+H)+: 266.0. Elemental analysis: Found C, 63.74; H, 7.32; N, 16.52.
Example-2 :Preparation of l-(4-Fluorobenzyl)-3-(4-isobutoxybenzylidene)-l-(l-methylpiperidin-4-yl)urea (9):
To a solution of4-isobutoxy benzaldehyde(22.15 g, 0.12 mol) in dichloromethane (60 ml) l-(4-fluorobenzyl)-]-(l-methylpiperidin-4-yl)urea (30.0 g, 0.1 I mol) was added and the resulting suspension was stirred under nitrogen for 15 minutes. Then Ti(0-/Pr)4 (48.0 g, 0.17 mol) was added and the mixture was stirred at ambient temperature for 15 h. After addition of saturated aqueous solution ofNaHCO3(300 ml) and ethyl acetate (300 ml), the insoluble fraction was aspirated and washed with ethyl acetate (2 X 100 ml). The combined extracts were washed with water followed by brine, dried over NaiSCU and after evaporation 53.0 g of a colorless product was obtained, which on trituration with hexanes (200 ml) provided 42.0 g (87%) of a white substance, which contained 99.5% of l-(4-ftuorobenzyl)-3-(4-isobutoxybenzylidene)-l-(l-methylpiperidin-4-yl)urea of formula (9) and 0.2% of benzylidene impurity, (RRT: 0.95) of formula 3 according to HPLC with melting point of94-97°C.lHNMR(CDCI3) 300.13MHz): 9.06 (d, 1H, N=Ctf-Ar), 7.89 (d, 1H, F-Ar-//), 7.77 (d, 1H, F-Ar-//), 7.30-7.18 (m, 2H, Ar-//), 7.00-6.89 (m, 4H5Ar-/f)> 4.83&4.63
(s, 2H, N-C/fc-Ar-F), 4.6-4.39 (m, IH, N-Ctf-(CH2)2), 3.82-3.75 (m, 2H, (CH3)2-CH-Ctf >), 2.80(d, 2H, CH3-N-(C//>)2), 2.26 (s, 3H, C/fc-N), 2.15-1.96 (m, 3H,C/6-N-(CH2)2&CH2-C//-(CH3)2, 1.80-1.61 (m, 4H5 N-CH-(C^)2), 1.06-1.01 (m, 6H, (C//j)2-CH-CH2).l3C NMR (CDCb, 75.47 MHz) : 168.16, 167.81, 164.22, 163.45, 160.12, 135.95, 135.26, 132.24, 128.7, 128.3, 127.45, 115.27, 114.8,74.55,55.30,53.50,46.02,45.43, 30.94, 30.00, 28.17, 19.16.MS (M+H)*:426.I3. Elemental analysis: Found C, 70.65; H, 7.51; N, 9.82.

Example-3 : Preparation of l-(4-Fluorobenzyl)-3-(4-isobutoxybenzyIidene)-l-(I-methylpiperidin-4-yl)urea (9):
To a solution of 4-isobutoxy benzaldehyde (3.6 g, 0.02 mol) in tetrahydrofuran (60 ml) l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)urea (5.0 g, 0.02 mol) was added and the resulting suspension was stirred under nitrogen for 15 minutes. Then Ti(0-/'Pr)4 (10.4 g. 0.036 mol) was added and the mixture was stirred at the ambient temperature for 24 h. After addition of saturated aqueous solution ofNaHCO3(30ml)andethyl acetate (60 ml), the insoluble fraction was aspirated and washed with ethyl acetate (2 X 30 ml).The combined extracts were washed with water followed by brine, dried with NaiS04 and after evaporation 8.6 g of a colorless product contained 83.0% of l-(4-fluorobenzyl)-3-(4-isobutoxybenzylidene)-l-(l-methylpiperidin-4-yl)urea of formula (9) and 10% of benzylidene impurity, (RRT: 0.95) of formula 3 according to HPLC.
Example-4 : (Reduction using 10% Pd-C): Preparation of N-(4-Fluorobenzyl)-N-(l-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy) phenyl methyl) carbamide (1 , Pimavanserin):
l-(4-Fluorobenzyl)-3-(4-isobutoxybenzylidene)-l-(l-methylpiperidin-4-yl) urea (9; 30.0 g, 0.07 mol) from example 2 was added to methanol (600 ml) at ambient temperature. The heterogeneous catalyst 10% Pd-C (3.0 g) was added to the mixture. Hydrogen gas at a pressure of 50 psi was then applied to the vessel containing the mixture. The mixture was then stirred under 50 psi for 15 h at ambient temperature. The catalyst was separated by aspiration and after evaporation 30.0 g of a colorless evaporation product was obtained, which on trituration with hexanes (200 ml) provided 28.6 g (95%) of a white substance containing 99.7% of Pimavanserin according to HPLC with melting point of 124-128°C.iHNMR(CDCb, 300.13 MHz): 7.20-7.15 (m,2H,F-Ar-H), 7.03-6.96 (m, 4H, Ar-ff), 6.78 (d, 2H, Ar-//), 4.48 (t, 1H, N-C//-(CH2)2), 4.46 (m,lH, Hff), 4.37 (s, 2H, N-Ctfj-Ar-F), 4.28 (d, 2H, C/fc-NH), 3.67 (d, 2H, (CH3)2-N-(Ctf:>)2)} 2.86 (d, 2H, CH3-N-(C//j)2)3 2.26 (s,3H, CZ/j-N), 2.11-2.01 (m)3H)CWj-N-(CH2)2&CH2-C^-(CH3)2,); 1.73-1.61
(m,4H,N-CH-(C//>)2, 1.02 (d, 6H, (C//j)2-CH-CH2).l3CNMR (CDCI3, 75.47 MHz): 163.6, 160.32, 158.43, 158.05, 134.2, 131.2, 128.6, 127.7, 115.6, 114.5,74.44,55.25,52.22,46.04,45.06,44.39,30.15,28.23,19.23. MS (M+H)+:428.21.; Elemental analysis: Found C, 70.15; H, 8.09; N; 9.76.

Example-5 (Reduction using Raney Ni): Preparation of N-(4-Fluorobenzyl)-N-(l-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyI)carbamide (1 , Pimavanserin):
l-(4-Fluorobenzyl)-3-(4-isobutoxybenzylidene)-l-(l-methylpiperidin-4-yl) urea (9; 10.0 g. 0.024 mol) was added to methanol (200 ml) at ambient temperature. The heterogeneous catalyst Raney Ni (2 g) was added to the mixture. Hydrogen gas at a pressure of 50 psi was then applied to the vessel containing the mixture. The mixture was then stirred under 50 psi for 10 h at ambient temperature. The catalyst was separated by aspiration and after evaporation 10.0 g of a colorless product was obtained, which on trituration with hexanes (100 ml) provided 7.05 g (70%) of a white substance with melting point of 123-I26°C.
Example-6(Reduction using 5% Ru-C): Preparation of N-(4-Fluorobenzyl)-N-(l-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide (1 , Pimavanserin) :
l-(4-Fluorobenzyl)-3-(4-isobutoxybenzylidene)-l-(l-methylpiperidin-4-yl) urea (9; I0.0g, 0.024 mol) was added to methanol (200 ml) at ambient temperature. The heterogeneous catalyst 5% Ru-C (2.5 g) was added to the mixture. Hydrogen gas at a pressure of 50 psi was then applied to the vessel containing the mixture. The mixture was then stirred under 50 psi for 10 h at ambient temperature. The catalyst was separated by aspiration and after evaporation 10.0 g of a colorless product was obtained, which on trituration with hexanes (100 ml) provided 6.5 g (65%) of a white substance with melting point of 124-127°C.
Comparative examples: : Example-A (Ref: WO2017/036432; Example 1) : Preparation of l-(4-Fluorobenzyl)-l-(l-methylpiperidin-4-yl)urea (8)
To a solution of N-(4-fluorobenzyl)-l-methylpiperidine-4-amine (5.0 g: 0.02 mol) in acetic acid (45 ml) NaNCO (3.65 g. 0.05 mol) was added and the mixture stirred at 30°C for 24 h. The reaction mixture was quenched using aqueous 2M NaOH solution and extracted into dichloromethane (2 X 30 ml). The extract was washed with water followed by brine and dried over NaiSCXThe vitreous product was triturated with diethyl ether (20 ml), which after aspiration and washing with diethyl ether provided 4.89 g (80%) of a white solid substance with melting point of 116-119°C and contained 93.8% of l-(4-fluorobenzyl)-l-(l-

methylpiperidin-4-yl)urea of formula (8) and 5.8% of diurea impurity (RRT: 1.33) of formula 2 according to HPLC.
Example-B(Ref: WO2017/036432; Example 5): Preparation of l-(4-FIuorobenzyl)-l-(l-methy]piperidin-4-yl)urea(8) :
To a solution of N-(4-fluorobenzyl)-l-methylpiperidine-4-amine dihydrochloride (5.4 g, 18 mmol) in water (75 ml) a solution of KNCO (2.4 g, 30 mmol) in 75 ml of water was added. The mixture (pH 7.6) was stirred for 24 h at the ambient temperature. Then additional KNCO (0.8 g, 10 mmol) was added and the mixture (pH 7.9) stirred for another 15 h. After the adjustment of pH with I M NaOH to about pH 9, solid NaCI (15 g) was added to the reaction mixture. After complete dissolution the reaction mixture was extracted with dichloromethane (10 x 50 ml). The extract was washed with brine and dried over MgSCX The vitreous evaporation product was triturated with Et:0 (50 ml) and after aspiration and washing with EtiO, 3.9 g (80%) of a white solid substance with the melting point of 1 I8-I21°C, containing 97% of l-(4-Fluorobenzyl)-l-(l-methylpiperidin-4-yl)urea of formula (8) and 2.4% of diurea impurity (RRT: 1.33) of formula2 as per HPLC.
Example-C (Ref: WO2017/015272: as per an outline of the synthetic process on page 63, para [260]) : Preparation of l-(4-Fluorobenzyl)-l-(l-methylpiperidin-4-yl)urea (8) :
To N-(4-fluorobenzyl)-l-methylpiperidine-4-amine (5.0 g, 0.02 mol), urea (2.7.0 g, 0.04 mol) was added and the mixture was stirred at 150°C for 15 h. Then the reaction mixture was gradually cooled to 25-30°C, water (50.0 ml) was added and the mixture extracted with dichloromethane (3 X 50 ml). The extract was washed with water followed by brine and dried over Na2S04. The vitreous evaporation product was triturated with diethyl ether (20.0 ml), which after aspiration and washing with diethyl ether provided 1.40 g (23%) of a white solid substance with melting point of 120-I24°C, that contained 98.6% of l-(4-Fluorobenzyl)-l-(l-methylpiperidin-4-yl)urea of formula (8)3 0.3% of diurea impurity (RRT: 1.33) of formula 2 and 0.9% of other unknown impurities as per HPLC. The reaction appears to be incomplete because of about 23% of the starting material. The crude isolate also contained impurities: defluoro impurity (2.7%), diurea impurity (6.0%) and other unknown impurities (20.7%). During purification all impurities and unreacted SM were reduced. The impurities are due to high temperature whereby reaction mass became dark brown color.

Example-D (Reductive amination)(Ref: WO2017/0I5272; as per an outline of the synthetic process on [264] page 65. para [264]) : Preparation of N-(4-Fluorobenzyl)-N-(l-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide (1 , Pimavanserin):
To a solution of 4-isobutoxy benzaldehyde (3.7 g, 0.02 mol) in tetrahydrofuran (25 ml) l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)urea(5.0 g, 0.034 mol, from example I above) was added and the resulting suspension was stirred under nitrogen for 15 minutes. Then Ti(0-/Pr)4 (5.9 g, 0.02 mol) was added and the mixture was stirred at 60-65°C temperature for 6 h. Then the mixture was gradually cooled to 25-30°C, NaBhU (l.43g, 0.038 mol) was added at ambient temperature and continued stirring for further 2 h at the same temperature. Water (70 ml) was added and pH adjusted to about 2 using 2N HCI. Then ethyl acetate (100.0 ml) was added followed by filtration. Separated organic layer was washed with water followed by brine and finally dried over Na2SC>4. The vitreous evaporation product was triturated with hexane (50.0 ml), which after aspiration and washing with hexane provided 6.1 g (76%) of product containing 8.6% of Pimavanserin and 84.72%ofaborane complex of formula 5 (RRT: 1.47), 0.9% of C-alkylated impurity of formula 4 (RRT: 0.95) as per HPLC.
Example-E (Reductive animation) (Ref: WO2017/036432; Example 14) : Preparation of N-(4-
Fluorobenz>'l)-N-(l-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide
(1, Pimavanserin):
To a solution of 4-isobutoxy benzaldehyde (5.0 g, 0.03 mol) in tetrahydrofuran (50 ml) l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)urea (9.0 g, 0.034 mol) was added and the resulting suspension was stirred under nitrogen for 15 minutes. Then Ti(0-/Pr)4 (14.0 g, 0.05 mol) was added and the mixture was stirred at the ambient temperature for 24 h. NaBrU (2.77 g, 0.07 mol) was added to the reaction mixture at ambient temperature and continued stirring for further 2 h at the same temperature. Water (70 ml) was added and pH was adjusted to 7 using 2N HCI. The aqueous layer was extracted with ethyl acetate (3 X 50 ml). The combined extracts were washed with water followed by brine and then dried over Na2S04. After evaporation 11.5 g(79%) of a colorless product was obtained containing 20.0% of Pimavanserin, 75% of borane complex of formula 5 (RRT: 1.47) and 2% of C-alkylated impurity of formula 4 (RRT: 0.95) according to HPLC.

Example-F(Carbamoylation & Reductive amination) :(Ref: WO2017/036432; Example 25; Triethyl silane used as reducing agent instead ofTMDS): Preparation of N-(4-Fluorobenzyl)-N-(l-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide (1 , Pimavanserin) :
To a suspension of a N-(4-fluorobenzyl)-l-methylpiperidine-4-amine dihydrochloride (7.4 g, 0.025 mol) in methanol (50 ml) KNCO(4g, 0.049 mol) was added and the mixture was stirred for 4 h at ambient temperature. The insoluble fraction was aspirated, washed with methanol (10 ml) and the filtrate was concentrated to a quarter of the volume. Then, acetonitrile (25 ml) was added and 15 ml of mixture was removed by distillation. After addition of acetonitrile (15 ml) about 15 ml of the solvent was removed by distillation. To the obtained concentrated product acetonitrile (50 ml) was added and the turbid solution was filtered. 4-Isobutoxybenzaldehyde (6.25. 0.035 mol) and trifluoroacetic acid (15 ml) were added to the clear solution. Triethyl silane (9.3 g. 0.08 mol) was then added to the obtained solution and the mixture was refluxed for 4 h. During the last hour of the reflux a part of the solvent (35 ml) was removed from the reaction mixture by distillation. Then methanol (20 ml) was added to the reaction mixture, the mixture was refluxed for 1 h and then was subjected to evaporation in vacuum. Saturated solution of'NaiCCh was added to the mixture to achieve pH about 10 (50 ml) and stirred for 30 minutes. After addition of ethyl acetate (50 ml) the mixture was vigorously stirred for 1 h and after separation the aqueous layer was extracted with ethyl acetate (5 x 25 ml). The combined extracts were dried over MgSOa. The obtained evaporation product (11.0 g) contained 20% of Pimavanserin along with number of unknown impurities according to HPLC.

We Claim:
1. An improved process for the preparation of Pimavanserin free base of the compound of formula (1), comprising

(a) reacting l-(l-methylpiperidinyl)-4-fluorobenzylamine (6)

with urea in acetic acid at 80-85°C to provide l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)urea (8)

(b) reacting the product (compound of formula 8) with 4-isobutoxy benzaldehyde (compound of formula 10)
in the presence of titanium tetra isopropoxide in dichloromethane solvent at about 25 to 50°C for about 12 to
16 hours to provide 1 -(4-fluorobenzyl)-3-(4-isobutoxybenzylidene)-1 -(I -methy!piperidin-4-yl)urea
(compound of formula 9) and


(c) reducing the novel compound (9) with hydrogen in the presence of a metal catalyst in a protic polar solvent, preferably methanol, to obtain Pimavanserin free base of formula (1).
2) According to claim 1, the metal catalyst is selected from the group comprising metal complexes of nickel,
palladium, platinum, ruthenium, and rhodium, preferably of palladium.
3) Novel compound I -(4-fluorobenzyl)-3-(4-isobutoxybenzylidene)-1 -(I -methylpiperidin-4-yl)urea of
formula 9:

4) A process for the preparation of l-(4-fluorobenzyl)0-(4-isobutoxybenzylidene)-l-(l-methylpiperidin-4-yl)urea, compound of formula 9, comprising the step of reacting l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)urea (compound of formula 8) with 4-isobutoxy benzaldehyde (compound of formula 10) in the presence of titanium tetra isopropoxide in dichloromethane solvent.
5) A process for the preparation of l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl)urea(8) comprising reacting I -(I -methylpiperidinyl)-4-fluorobenzylamine (compound of formula 6)

with urea in acetic acid at 80-85°C.

The present invention relates to an improved process for the preparation of N-(4-fluorobenzyl)-N-(l-methy!piperidinyl)-N'-(4-(2-methylpropyloxy)-phenylmethyl carbamide (Formula 1), also known as Pimavanserin, with excellent yield and high degree of chemical purity.