DESC:Technical Field of the Invention:
The present invention relates to a novel process for the preparation of a compound of formula (I) and to novel intermediates which are produced during the course of carrying out the novel process.

Background of the Invention:
Psychotic symptoms, particularly visual hallucinations and paranoid delusions, occur in up to 40% of patients with Parkinson's disease (PD) who receive dopamine (DA) replacement therapy. Clozapine and quetiapine, two atypical antipsychotic drugs, at doses markedly lower than those effective in schizophrenia, which, nevertheless, still cause sedation, hypotension, and other side effects, are widely used to treat psychotic symptoms in patients with PD psychosis (PDP).

Pimavanserin is a novel selective serotonin 5-HT2A receptor inverse agonist, which has shown antipsychotic activity in animal models, including blockade of amphetamine- or the N-methyl--aspartate receptor noncompetitive antagonist 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate; MK-801)-induced locomotor activity, conditioned avoidance response, head twitch, and the deficit in prepulse inhibition produced by the 5-HT2A agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) in rats (Vanover et al, 2006).

Pimavanserin tartrate was developed by Acadia Pharmaceuticals and was approved under the, trade, name, NUPLAZID. Pimavanserin tartrate, 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1- methylpiperidin-4-yl)urea, L-hemi-tartrate, has the following chemical structure A :

Pimavanserin free base (referred to as “compound I”), its salts namely hydrochloride and tartrate salts and synthesis are disclosed in US 7,601,740 (referred to herein as, the '740 patent) and US 7,790,899 (referred to herein as the '899 patent).

The '740 patent discloses a process for the preparation of Pimavanserin tartrate.

N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (compound III) obtained by the reductive amination of N-methyl piperidine-4-one ( VII) with 4-fiuorobenzylamine (VI) in the presence of a metal hydride such as NaBH3CN, acetic acid, and methanol.

Whereas methyl ester of 4-hydroxy phenyl acetic acid (XI) is subjected to electrophilic substitution reaction with isobutyl bromide and potassium carbonate in dimethyl formamide (DMF) at about 80° C to give 4-isopropyloxy benzylamine (compound X), followed by hydrolysis with potassium hydroxide in ethanol/water to give 2-(4-isobutoxyphenyl) acetic acid (compound IX). Curtius rearrangement of compound IX with diphenylphosphonyl azide (DPPA) and a proton sponge in tetrahydrofuran (THF) under reflux produces 1-isobutoxy-4-(isocyanomethyl)benzene ( compound VIII).

Finally, coupling reaction of the compound (VIII) with the compound (III) in methylene chloride produces pimavanserin (I). The tartrate salt of the compound of formula (I) may be produced by mixing with L-( +)-Tartaric acid in ethanol.

The process is illustrated by the following Scheme 1
Scheme 1
This process suffers from low process safety, and utilizes the hazardous reagent, diphenylphosphoryl azide (DPPA).
US '899'describes another process, which includes O-alkylation of 4-hydroxybenzaldehyde (XV) with isobutylhalogenide (e.g.,isobutyl bromide) to give 4-isobutoxybenzaldehyde (XIV) which may be converted with hydroxylamine to the aldoxime (XIII). This oxime may be catalytically hydrogenated with a palladium catalyst to the corresponding 4- isobutoxy benzylamine (IV), from which the isocyanate of formula (VIII) may be obtained by reaction with phosgene; while (4-fluorobenzyl)-(1-methylpiperidin-4-yl) amine (III) was obtained from 4-fluorobenzylamine ( VI) and N-methyl-4-piperidone (VII) via reductive amination; finally (VIII) and (III) were subjected to coupling reaction to give pimavanserin (I).

This process is illustrated by the following Scheme 2:
Scheme 2

Both of the, above processes for the preparation of Pimavanserin include a reaction between 1-isobutoxy-4-(isocyanatomethyl)benzene ( VIII), a benzyl isocyanate intermediate, and N-
(4-fluorobenzyl)-I-methylpiperidin-4-amine (III). These processes often use the, hazardous reagents like phosgene derivatives or diphenylphosphoryl azide (DPPA) for conversion to key intermediate benzyl isocyanate. DPPA is very toxic and a potential explosive like most other azide compounds. Whereas Phosgene is an insidious poison and highly toxic. Owing to the hazards and high toxicity associated with DPPA and phosgene, the production of isocyanates intermediate requires special precautions. Further, isocyanates are potentially dangerous irritants to the eyes and respiratory tract, despite their relatively low acute toxicities. Hence, handling and storage on large scale is not viable. Further, use of expensive proton sponge (1, 8-bis (dimethylamino) naphthalene) to prepare isocyanate intermediate and the chromatographic purification of the obtained pimavanserin making it not feasible for industrial-scale production.

A refinement of the process for the preparation of Pimavanserin tartrate is disclosed in WO 2016/141003 A1; which involves use of various intermediates. This process is illustrated by the following Scheme 3:

Scheme 3

Thus, it would be a significant contribution to the art to provide a process for large scale synthesis of Pimavanserin or salts thereof having high degree of chromatographic and optical purity and low residual solvent content, which is consistent and to provide industrially viable methods of preparation, pharmaceutical formulations, and methods of use thereof. This provides a new opportunity to improve and facilitate the handling and storage of Pimavanserin tartrate as active ingredients.

OBJECT OF THE INVENTION:
The object of the present invention is to provide novel processes for the synthesis of Pimavanserin and salts thereof.

Yet another object of the present invention is to provide novel processes which proceed via new chemical intermediates for the synthesis of Pimavanserin and salts thereof .

Yet another object of the present invention is to provide processes which avoids the use of hazardous agents phosgene and DPPA and subsequently simplifies work up procedure.

Yet another object of the invention is to provide an industrially-advantageous, cost-effective and environmentally-friendly processes for preparing highly-pure Pimavanserin and salts thereof in high yields.

SUMMARY OF THE INVENTION:
According to a first aspect of the present invention, there is provided a process for preparing Pimavanserin ( I) and salts thereof

which comprises converting 2,5-dioxopyrrolidin-1-yl-(4-isobutoxybenzyl)carbamate (compound II)

to Pimavanserin ( I) or salts thereof.

In an embodiment, the process of conversion comprises reacting 2,5-dioxopyrrolidin-1-yl-(4-isobutoxybenzyl)carbamate (compound II) with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (compound III) or salt thereof

to obtain Pimavanserin, or a salt thereof.

In another aspect, the present invention provides hitherto unreported novel intermediate i.e., 2,5-dioxopyrrolidin-1-yl-(4-isobutoxybenzyl)carbamate, a compound of formula (II).

In another aspect, the present invention provides a process for preparing 2,5-dioxopyrrolidin-1-yl-(4-isobutoxybenzyl)carbamate (compound II) comprising, reacting a 4-isobutoxy benzylamine (compound IV) or a salt thereof;

with N,N- disuccinimidyl carbonate ( compound V).

According to another aspect of the present invention, there is provided a process for preparing Pimavanserin (I) or salts thereof

which comprises converting 2,5-dioxopyrrolidin-1-yl-(4-fluorobenzyl )-(4-methylcyclohexyl)carbamate (compound IIIA)

to Pimavanserin (I) and salts thereof.

In an embodiment, the conversion comprises reacting 2,5-dioxopyrrolidin-1-yl-(4-fluorobenzyl )-(4-methylcyclohexyl)carbamate (compound IIIA) with 4-isobutoxy benzylamine (compound IV) or a salt thereof

to obtain Pimavanserin (I) or a salt thereof.

In another aspect, the present invention provides hitherto unreported novel intermediate i.e., 2,5-dioxopyrrolidin-1-yl-(4-fluorobenzyl )-(4-methylcyclohexyl)carbamate ( compound IIIA).

In another aspect, the present invention provides a process for preparing 2,5-dioxopyrrolidin-1-yl-(4-fluorobenzyl )-(4-methylcyclohexyl)carbamate (compound IIIA) comprising, reacting N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (compound III) or salt thereof ;

with N,N- disuccinimidyl carbonate ( compound V).

The prior art processes disclosed in the citations listed above involve the use of toxic reagents such as phosgene and DPPA. The inventors have devised a highly-advantageous process which avoids the use of toxic reagents. The process of the present invention instead involves the use of simple reagents and solvents. The inventors have surprisingly found that the use of the simple reagents and solvents reduces the number of steps involved in the preparation of Pimavanserin or salt thereof. Thus, the process of the present invention is cost-effective and highly-suitable for industrial scale-up.

According to yet another aspect of the present invention there is provided novel compounds II and IIIA. The compounds may be prepared according to the processes described above.

There is also provided by the present invention ,Pimavanserin (I) or salt thereof, prepared by a process as described above, having a purity of more than about 99% by HPLC.

The present invention also provides a pharmaceutical composition comprising Pimavanserin (I) or salt thereof, prepared according to the process of the present invention, and a pharmaceutically acceptable excipient.

The present invention also provides a method for the treatment of neuropsychiatric diseases, comprising administering to the patient in need thereof a therapeutically effective amount of Pimavanserin (I) or salt thereof, prepared according to the process of the present invention.

The present invention also provides a methods of treating a disease treatable by administration of a 5-HT2A receptor inverse agonist which method comprises administrating to the patient Pimavanserin (I) or salt thereof, prepared according to the process of the present invention. That is, the present invention provides a method of treating a disease treatable by administration of a 5-HT2A receptor inverse agonist which method comprises administrating to a patient in need thereof a therapeutically effective amount of Pimavanserin (I) or salt thereof, prepared according to the process of the present invention.

The invention is directed to the use of Pimavanserin (I) or salt thereof, prepared according to the process of the present invention, to treat a disease treatable by administration of a 5-HT2A receptor inverse agonist as disclosed herein, that is, the use of Pimavanserin (I) or salt thereof, prepared according to the process of the present invention for the manufacture of a medicament to treat diseases treatable by administration of a 5-HT2A receptor inverse agonist as disclosed herein.

DETAILED DESCRIPTION :
In an embodiment of the present invention, there is provided an improved synthesis of Pimavanserin (I) or salt thereof, as depicted below in reaction scheme 4.

Scheme 4

2,5-dioxopyrrolidin-1-yl-(4-isobutoxybenzyl)carbamate (Compound II) is one of the hitherto unreported intermediates useful in the process for the preparation of Pimavanserin or salt thereof as described herein. Compound II may in some embodiments be isolated prior to the reaction with compound III or a salt thereof, while in other embodiments, compound II is used as such without isolation directly in the next step, i.e. in a "one-pot" reaction, with compound III, or a salt thereof, to, obtain Pimavanserin or salt thereof or the corresponding precursor of Pimavanserin or salt thereof.

In one embodiment of the invention, 4-isobutoxy benzylamine ( compound IV) is reacted with N,N'-disuccinimidyl carbonate ( compound V) in the presence of a suitable base.

Suitable base includes organic and inorganic bases. The base can be selected from the group consisting of one or more of alkali metal hydroxide, metal amides, metal alkoxides, alkyllithiums, amine bases, and alkali metal hydrides. Examples of suitable bases are: sodium hydroxide, potassium hydroxide, triethylamine, diisopropylamine, Hunig’s base, sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide, potassium t-butoxide, BuLi, and 1 ,8-diazabicyclo[ 5.4.0]undec-7-ene. Most preferably, the base is selected from the group consisting of amine bases. In a particularly preferred embodiment the base is triethylamine.

Preferably, the reaction is carried out in the presence of water and an organic solvent, wherein the organic solvent is preferably selected from the group consisting of C6-C10 substituted / unsubstituted aromatic hydrocarbons, C4-C8 cyclic ethers and C3-C8 acyclic ethers, and C1-C5 halogenated hydrocarbons. Preferably, the organic solvent is selected from the group consisting of dichloromethane (MDC), chloroform, tetrachloroethane, chlorobenzene, dimethylformamide (DMF), acetonitrile, N-methyl-2-pyrrolidone (NMP), dimethylformamide (DMA), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-Me-THF), petroleum ether, pentane, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene; and mixtures thereof as well as mixtures of at least one of the abovementioned solvents with water. In a particularly preferred embodiment the organic solvent is MDC, DMF, acetonitrile and toluene.

The reaction is typically carried out at a temperature in the range of from about 70°C to reflux temperature of the solvent used. Preferably, the reaction is carried out at a temperature in the range of from about -10°C to about 55°C. In still other embodiments, it is carried out at a temperature in the range of from about 10°C to about 30°C. In a particularly preferred embodiment the reaction is carried out at a temperature of about 15° C to about 20°C.

The reaction is carried out for about 30 minutes to about 10 hours, more preferably for about 1 hours to about 10 hours, most preferably for about 1 hour to about 5 hours.

The prior art processes disclosed in the citations listed above involve the use of toxic reagents such as phosgene gas and DPPA . The inventors have devised a highly-advantageous process in that it avoids the use of toxic reagents. Further, N,N'-disuccinimidyl carbonate (compound V) is commercially available, or it can be conveniently prepared from N-hydroxysuccinimide. The ready availability of N,N'-disuccinimidyl carbonate (compound V), the stability of the organic carbamate (compound II), and the mildness of the reaction procedure render this method a reliable route to organic carbamates. This forms one aspect of the present invention.

Further, in the preparation of isocyanate, when phosgene is used, the reaction is carried out under extremely dry condition. Addition of the phosgene gas either at low temperature of about -5°C to about 5°C or at high temperature of 60°C to about 100°C is a time consuming process. Further, these reactions are conducted at high temperature and absence of phosgene need to be monitored. The excess phosgene gas is then degassed by bubbling nitrogen through it. After this operation, the bulk is checked to confirm the absence of residual phosgene. All these operations make the process unsuitable for industrial scale up. The advantage of the present invention is use of solid N,N- disuccinimidyl carbonate, low reaction temperature of 10°C to about 30°C. Further, the reaction time is reduced drastically to 2 hours from 4 hours stirring, as reported in the prior art. In the process of the present invention, the work up procedure may be simplified. In the present process, after completion of reaction, the carbamate (II) is easily isolatable by quenching the reaction mass in water and concentrating the organic filtrate to obtain a residue. This process avoids tedious work up procedure as reported in the prior art, and this forms another aspect of the present invention.

Further, the use of triethylamine as a promoter has a notable effect on the yield and the rate of the alkoxycarbonylation process. The process of the present invention involves the use of simple reagents and solvents. The inventors have surprisingly found that the use of the simple reagents and solvents reduces the number of steps involved in the preparation of Pimavanserin or salt thereof. Thus, the process of the present invention is highly-suitable for industrial scale-up. This forms yet another aspect of the present invention.

The compound 2,5-dioxopyrrolidin-1-yl-(4-isobutoxybenzyl)carbamate (compound II) obtained by the process of the present invention is then reacted with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (compound III) or salt thereof in the presence of a suitable base and suitable organic solvent to obtain Pimavanserin or salt thereof.

Suitable base includes organic and inorganic bases. The base can be selected from the group consisting of one or more of alkali metal hydroxide, metal amides, metal alkoxides, alkyllithiums, amine bases, and alkali metal hydrides. Examples of suitable bases are: sodium hydroxide, potassium hydroxide, triethylamine, diisopropylamine, Hunig’s base, sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide, potassium t-butoxide, BuLi, and 1 ,8-diazabicyclo[ 5.4.0]undec-7-ene. Most preferably, the base is selected from the group consisting of amine bases. In a particularly preferred embodiment the base is triethylamine.

Suitable solvents are organic solvents and ionic liquids, especially polar organic solvents or mixtures of at least two solvents. In particular, examples of suitable solvents include hydrocarbons such as petroleum ether, pentane, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene; halogenated hydrocarbons such as dichloromethane, chloroform, tetrachloroethane, chlorobenzene; ethers such as diethyl ether, dibutyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl, diethyl ether; carbonic esters and lactones such as methyl acetate, ethyl acetate, isopropyl acetate, methyl propionate, valerolactone; N,N-substituted carboxamides and lactams such as dimethylformamide, dimethylacetamide, N-methyl pyrrolidinone; ketones such as acetone, methylisobutylketone, cyclohexanone; sulfoxides and sulfones such as dimethylsulfoxide, dimethylsulfone, tetramethylene sulfone; nitriles such as acetonitrile, propionitrile; tertiary amines such as trimethylamine, triethylamine, tripropylamine, tributylamine, pyridine, N-methylpiperazine, N-methylmorpholine; ionic liquids; and mixtures thereof.

The reaction may be carried out under inert atmosphere, such as under nitrogen or argon.

The reaction is typically carried out at a temperature in the range of from about 70°C to about 75°C. Preferably, the reaction is carried out at a temperature in the range of from about -10°C to about 55°C. In still other embodiments, the reaction is carried out at a temperature in the range of from about 20°C to about 45°C. In a particularly preferred embodiment the reaction is carried out under ambient conditions.

In another embodiment, the present invention encompasses an alternative route for preparing Pimavanserin (I) or salt thereof which proceeds essentially as shown in the following scheme 5.

Scheme 5

2,5-dioxopyrrolidin-1-yl-(4-fluorobenzyl)-(4-methylpiperidin-4-yl)carbamate (compound IIIA) is one of the hitherto unreported intermediates useful in the process for the preparation of Pimavanserin or salt thereof as described herein. Compound IIIA may in some embodiments be isolated prior to the reaction with compound IV or a salt thereof, while in other embodiments, compound IIIA is used as such without isolation directly in the next step, i.e. in a "one-pot" reaction, with compound IV, or a salt thereof, to, obtain Pimavanserin or salt thereof or the corresponding precursor of Pimavanserin or salt thereof.

In one embodiment of the invention, N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (compound III) or salt thereof is reacted with N,N'-disuccinimidyl carbonate (compound V) in the presence of a suitable base and suitable solvent to obtain 2,5-dioxopyrrolidin-1-yl-(4-fluorobenzyl )-(4-methylpiperidin-4-yl))carbamate (compound IIIA).

2,5-dioxopyrrolidin-1-yl-(4-fluorobenzyl )-(4-methylpiperidin-4-yl) carbamate (compound IIIA) is then reacted with 4-isobutoxy benzylamine (IV) or salt thereof in the presence of a suitable base and suitable organic solvent to obtain Pimavanserin or salt thereof.

In yet another embodiment, the present invention encompasses an alternative route for preparing Pimavanserin (I) or salt thereof which proceeds essentially as shown in the following scheme 6.

Scheme 6

4-nitrophenyl(4-isobutoxybenzyl) carbamate (compound XIII) is one of the important intermediates useful in the process for the preparation of Pimavanserin or salt thereof as described herein.

In one embodiment of the invention, bis-(4-nitrophenyl) carbonate (compound XII) is reacted with 4-isobutoxy benzylamine (IV) or salt thereof in the presence of a suitable base and suitable organic solvent to obtain 4-nitrophenyl(4-isobutoxybenzyl) carbamate (compound XIII).

4-nitrophenyl(4-isobutoxybenzyl) carbamate (compound XIII) is then reacted with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (compound III) or salt thereof in the presence of a suitable base and suitable organic solvent to obtain Pimavanserin or salt thereof.

Preferably the reaction steps may be carried out in accordance with any of the embodiments and preferred embodiments discussed above.

Pimavanserin (I) prepared by the process of the present invention is in the form of its free base or a pharmaceutically acceptable salt thereof. Examples of suitable salts include addition salts with inorganic acids such as hydrochloride acid, hydrobromic acid, phosphoric acid, di phosphoric acid, sulfuric acid and nitric acid, or organic acids such as carboxylic acids, e.g. fumaric acid, oxalic acid, acetic acid, Clavulanic acid, citric acid, tartaric acid, maleic acid, malic acid, succinic acid, mandelic acid, lauric acid, oleic acid, ascorbic acid, tannic acid, valeric acid, nicotinic acid, benzoic acid, salicylic acid, stearic acid, and glutamic acid, or sulfonic acids, e.g. methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 2-ethane disulfonic acid, naphthalenesulfonic acid. Pimavanserin or the pharmaceutically acceptable salts thereof can be prepared in a non-crystalline, i.e. amorphous, form or a crystalline form including any polymorphic or pseudopolymorphic forms such as solvates like hydrates. Most preferably, Pimavanserin (I) is prepared in the form of its hemi-tartrate salt.
Preferably, the obtained Pimavanserin (I) or salt thereof has a purity of at least 99.5 %.

The process of invention may be used as a method for purifying any form of pimavanserin (I) or salt thereof , as well as for the preparation of the new polymorphic forms.

Pimavanserin (I) or salt thereof; more particularly pimavanserin tartrate ( Compound A ) , an atypical antipsychotic has been found to be effective for the treatment of neuropsychiatric diseases including psychosis, affective disorders, dementia, neuropathic pains, hypertensions, hallucinations and delusions associated with Parkinson’s disease psychosis. Pharmaceutical compositions according to the present invention comprise pimavanserin tartrate as an active ingredient together with one or more pharmaceutically acceptable carriers, excipients or diluents. Any conventional technique may be used for the preparation of pharmaceutical compositions according to the invention.

Pharmaceutical compositions may be formulated for oral delivery in the form solid formulations such as capsules, tablets, pills and troches of tablets or in the form liquid formulations such as aqueous suspensions. elixirs and syrups. Pharmaceutical compositions according to the present invention may preferably comprise two 17 mg strength tablets once daily of active ingredient along with a pharmaceutically acceptable carrier. Pimavanserin tartrate tablets of the present invention may be taken with or without food on the same time each day to maintain proper blood levels.

The invention is further described by reference to the following examples, which set forth in detail certain aspects and embodiments of the preparation of compounds and compositions of the present invention. It will be apparent to those skilled in the art, that many modifications, both to materials and methods, can be practiced without departing from the purpose and intent of this invention. While each step of the reaction sequence can be carried out by first isolating the product of the preceding step, some of the reaction steps may be carried out sequentially, in one reaction vessel, without isolation of the intermediate formed by the preceding step, thus reducing costs associated with vessel time, clean-up, and labour. The examples that follow are not intended to limit the scope of the invention as described herein above or as claimed below.

Examples

Example 1
Preparation of 2,5-dioxopyrrolidin-1-yl-(4-isobutoxybenzyl)carbamate ( compound II)
4-isobutoxy benzylamine (compound IV) (100 g, 0.558 mole) stirred in dichloromethane (1000 ml) at room temperature. To the above clear solution was added N,N- disuccinimidyl carbonate (compound V) (185 g, 0.722 mole) at room temperature. The reaction mass cooled to 10-15°C and triethyl amine (84.6 g, 0.831 mole) was added dropwise maintaining the temperature below 20°C. The reaction mass was stirred at 15-20°c for 2 hrs. The reaction mass was quenched in 10% NaHCO3 solution (500 ml). The organic layer was separated and washed with 10% NaHCO3 solution (500 ml). The organic layer was evaporated and compound II isolated.
Yield : 140 g

Example 2
Preparation of pimavanserin (I)
2,5-dioxopyrrolidin-1-yl-(4-isobutoxybenzyl)carbamate ( compound II) (100 g, 0.3125 mol) stirred in dichloromethane ( 1000 ml) at room temperature. N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (compound III) (57.8 g, 0.260mol) was added to the above reaction mass. The reaction mass cooled to 10-15°C and triethyl amine (42.2 g, 0.416 mol) was added dropwise maintaining the temperature below 10°C. The reaction mass was stirred at 10-15°c temperature for 3 hrs. The reaction mass was quenched in 10% NaHCO3 solution (500 ml). The organic layer was separated and washed with 10% NaHCO3 solution (500 ml). The organic layer was evaporated and compound I was isolated.
Yield: 110 gm

Example 3
Preparation of pimavanserin oxalate
Pimavanserin base (100 g, 0.234 mole) stirred in ethyl acetate (1000 ml) at 55-60°C. To the resulting solution was added oxalic acid dihydrate (32.3 g, 0.256 mol) at 55-60°C. The reaction mass was stirred at 60-65°C for 1 hr, cooled to room temperature and stirred further for 3 hrs. The solid was isolated by filtration and dried to obtain pimavanserin oxalate.
Yield : 105 g

Example 4
Preparation of pimavanserin tartrate from pimavanserin oxalate
Pimavanserin oxalate (100 g, 0.1934 mol) was stirred in a solution of liq ammonia (50 ml) and water (500 ml) at 25-30°C. To the stirred solution was added dichloromethane (500 ml) and stirred for 15 minutes at 25-30°C. The organic layer was separated and evaporated to obtain solid.
Yield: 82 g

The solid (82 g) was stirred in a solution of ethanol ( 1558 ml) and toluene (82 ml) at 25-30°C. The reaction mass was heated to 55-60°C. To the clear solution was added L(+) tartaric acid (12.37 g ) at 55-60°C. The reaction mass was stirred at 55-60°C for about 5-10 minutes, cooled to room temperature and chilled further to 0°C. The reaction mass was stirred further at 0°C for 1 hour. The solid was isolated by filtration, washed with ethanol (1 vol) and dried to obtain pimavanserin tartrate.
Yield: 59 g

Example 5
Preparation of pimavanserin tartrate
2,5-dioxopyrrolidin-1-yl-(4-isobutoxybenzyl)carbamate ( compound II) (50 g, 0.1562mol) stirred in dichloromethane ( 1000 ml) at room temperature. N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (compound III) (28.9 g, 0.130mol) was added to the above reaction mass. The reaction mass cooled to 10-15°C and triethyl amine (21.1 g, 0.208 mol) was added dropwise maintaining the temperature below 20°C. The reaction mass was stirred at room temperature for 5 hrs. The reaction mass was quenched in 10% NaHCO3 solution (250 ml). The organic layer was separated and washed with 10% NaHCO3 solution (250 ml). The organic layer was evaporated and compound I was isolated.
Yield : 55 g

The solid (55 g) was stirred in a solution of ethanol (1045 ml) and toluene (55 ml) at 25-30°C. The reaction mass was heated to 55-60°C. To the clear solution was added L (+) tartaric acid (8.29 g) at 55-60°C. The reaction mass was stirred at 55-60°C for about 5-10 minutes, cooled to room temperature and chilled further to 0°C. The reaction mass was stirred further at 0°C for 1 hour. The solid was isolated by filtration, washed with ethanol (1 vol) and dried to obtain pimavanserin tartrate.
Yield: 40 g

,CLAIMS:1. Process for preparing pimavanserin of formula (I) or a pharmaceutically acceptable salt thereof

comprising, converting a compound (II)

to compound (I)

2. The process according to claim 1, wherein the conversion comprises; reacting compound (II) with compound (III)

in the presence of a suitable base.

3. The process according to claim 2, wherein the base is an organic base or inorganic base.

4. The process according to claim 3, wherein the inorganic base comprises one or more of alkali metal hydroxide, metal amides, metal alkoxides, alkyllithiums or alkali metal hydrides.

5. The process according to claim 3, wherein the organic base comprises one or more of
amine bases.

6. The process according to any one of the preceding claim, wherein the reaction is carried out in the presence of an organic solvent and ionic liquids or mixtures of at least two solvents, preferably selected from hydrocarbons, halogenated hydrocarbons, ethers, carbonic esters and lactones, N,N-substituted carboxamides and lactams, ketones, sulfones, nitriles, tertiary amines, and mixtures thereof.

7. The process according to claim 6, wherein, the solvents are selected from petroleum ether, pentane, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, dichloromethane, chloroform, tetrachloroethane, chlorobenzene, diethyl ether, dibutyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl, diethyl ether, methyl acetate, ethyl acetate, isopropyl acetate, methyl propionate, valerolactone, dimethylformamide, dimethylacetamide, N-methyl pyrrolidinone, acetone, methylisobutylketone, cyclohexanone, dimethylsulfoxide, dimethylsulfone, tetramethylene sulfone, acetonitrile, propionitrile, trimethylamine, triethylamine, tripropylamine, tributylamine, pyridine, N-methylpiperazine, N-methylmorpholine; ionic liquids and mixtures thereof.

8. The process according to any one of the preceding claim, wherein the reaction is carried out at a temperature range of 10°C to about 30°C.

9. A compound of formula (II).

10. A process for preparing a compound (II), comprising reacting compound (IV)

or a salt thereof; with compound (V)

in the presence of a suitable base.

11. The process according to claim 10, wherein the base is an organic base or inorganic base.

12. The process according to claim 11, wherein the inorganic base comprises one or more of alkali metal hydroxide, metal amides, metal alkoxides, alkyllithiums or alkali metal hydrides.

13. The process according to claim 11, wherein the organic base comprises one or more of
amine bases.

14. The process according to any one of the claims 10 to 13, wherein the reaction is carried out in the presence of water and an organic solvent selected from the group consisting of C6-C10 substituted / unsubstituted aromatic hydrocarbons, C4-C8 cyclic ethers and C3-C8 acyclic ethers, and C1-C5 halogenated hydrocarbons and mixtures thereof as well as mixtures of at least one of the abovementioned solvents with water.

15. The process according to claim 14, wherein the organic solvent is selected from the group consisting of dichloromethane (MDC), chloroform, tetrachloroethane, chlorobenzene, dimethylformamide (DMF), acetonitrile, N-methyl-2-pyrrolidone (NMP), dimethylformamide (DMA), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-Me-THF), petroleum ether, pentane, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene; and mixtures thereof as well as mixtures of at least one of the abovementioned solvents with water.

16. The process according to any one of the claims 10 to 15, wherein the reaction is carried out at a temperature range of 10°C to about 30°C.

17. A process for preparing pimavanserin of formula (I) or a pharmaceutically acceptable salt thereof

comprising converting a compound (IIIA)

to compound (I).
18. The process according to claim 17, wherein the conversion comprises; reacting 2,5-dioxopyrrolidin-1-yl-(4-fluorobenzyl )-(4-methylcyclohexyl)carbamate of compound (IIIA) with 4-isobutoxy benzylamine of compound (IV) in the presence of a suitable base and suitable solvent.

19. The process according to any one of the claims 17 or 18 , wherein the reaction is carried out at a temperature range of -75°C to the boiling temperature of the solvent.

20. A compound of formula (IIIA)

21. A process for preparing a compound (IIIA), comprising reacting N-(4-fluorobenzyl)-1-methylpiperidin-4-amine of compound (III) or salt thereof; with N,N- disuccinimidyl carbonate of compound (V).

22. Use of a compound according to any one of the claims 9 or 20 for preparing pimavanserin of formula (I) or a pharmaceutically acceptable salt thereof.

23. Process for preparing pimavanserin of formula (I) or a pharmaceutically acceptable salt thereof using at least one compound according to any one of the claims 9 or 20.