Technical filed:
This invention relates to process for synthesis of N-(4-fluorobenzyl)-N-(1-
methylpiperidin-4-yl) -N′-(4-(2-methylpropyloxy)-phenylmethyl)carbamide,
known as Pimavanserin(INN), and novel intermediate thereof.
Background and Prior art:
Pimavanserin constitute a new class of compounds, viz., N-azacycloalkyl-N-aralkyl carbamides which are first disclosed in WO 01/66521. These compounds are effective in inhibiting an activity of monoamine receptors, including the serotonin receptor of the 5-HT2A subclass. These compounds can be used for disease conditions selected from the group consisting of neuropsychiatric diseases such as schizophrenia, Alzheimer's, depression, anxiety, sleep disorders, appetite disorders, affective disorders such as major depressions, bipolar, depression with psychotic features, Tourette's Syndrome, hypertension, migraine, etc.
Pimavanserin is a non-dopaminergic atypical antipsychotic, having the following structure.

Pimavanserin is currently marketed under the trade name ‘Nuplazid’, developed by Acadia Pharmaceuticals for the treatment of Parkinson's disease psychosis and schizophrenia.
US8377959 discloses a method of treating Lewy Body Dementia in a patient, which comprises administering to a patient a therapeutically effective amount of Pimavanserin.

US20130143901 disclose combination of Pimavanserin and risperidone for the treatment of psychosis.
US8618130, US8921393 and US9211289 describe selective serotonin 2A/2C receptor inverse agonists such as Pimavanserin for neurodegenerative diseases.
Co-administration of with an agent to ameliorate one or more cholinergic abnormalities is disclosed in US20140349976.
US2015313888 describes methods for the treatment of disease psychosis using Pimavanserin.
US2015231126 reports combinations of 5-HT2A inverse agonists and antagonists with antipsychotics.
US20060111399 discloses salts of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and their preparation. However, there are very few reports available on the synthesis of Pimavanserin. One such synthetic method is reported in US8236960, which discloses synthesis of Pimavanserin, by reacting (4-fluorobenzyl)-(1-methylpiperidin-4-yl) amine of formula II
with 4-(2-methylpropyloxy)phenylmethyl-isocyanate of formula III


An article titled “On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson’s Psychosis” by Uli Hacksell published in Neurochem Research (DOI 10.1007/s11064-014-1293-3) reports a synthetic method for the production of Pimavanserin, as shown in scheme 1. Scheme 1

The prior art schemes, as mentioned above involves 4-(2-methylpropyloxy)phenylmethyl-isocyanate, the handling of which on industrial scale is not easy as the same is hazardous to humans and the environment causing irritation to eyes, respiratory system and skin. Also, 4-(2-methylpropyloxy)phenylmethyl-isocyanate may emit toxic gasses like carbon monoxide, carbon dioxide, nitrogen oxides upon thermal decomposition.
In view of the Pimavanserin having been tested and indicated for various disease conditions, there is a need in the art to provide Pimavanserin using a simple, environmentally safe and cost-effective process, by avoiding the use of 4-(2-methylpropyloxy) phenylmethyl-isocyanate.
Therefore, the objective of the present invention is to provide a novel and cost-effective synthetic route for the production of Pimavanserin involving novel intermediate using green solvents.
Summary of the invention:
In line with the above objective, the present invention provides a process for
preparation of Pimavanserin of formula I which process comprises;
a) reacting N-(4-fluorobenzyl)-1-methylpiperidin-4-amine of formula II with urea or Potassium isocyanate to obtain 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea of formula IV; and
b) condensing 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea of formula IV with 4-isobutoxybenzaldehyde of formula V to obtain Pimavanserin of formula I.
The reaction of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine and urea for preparation of 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea is carried out in presence of an acid catalyst in a polar medium. The acid catalyst may be selected from HCl, H2SO4, HNO3, H3PO4 etc. The polar medium comprises an aqueous medium or an organic medium or aqueous organic medium.

In one preferred aspect, the polar medium is aqueous medium. In another preferred aspect, the aqueous organic medium comprises polar organic solvent selected from polar solvents that is miscible with water, for example, solvents selected from the group consisting of Methanol, Ethanol, 1-Propanol, 2-Propanol, Dimethylformamide, Dimethylsulfoxide, Dioxane, Acetone, Acetic acid, Acetonitrile, etc.
Further, the condensation of 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea with 4-isobutoxybenzaldehyde can also be conveniently carried out in presence of a Lewis acid catalyst and a reducing agent in an organic solvent at room temperature for 3 to 5 hrs.
In another aspect, the invention provides 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea of formula IV, a novel and hitherto unexploited intermediate for the production of Pimavanserin.
In another aspect, the invention provides a novel process for preparation of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine which comprises reaction of 4-fluorobenzylamine and 1-methyl-4-piperidone in presence of a Lewis acid and reducing agent in an organic solvent at room temperature for 12 to 15 hrs.
4-isobutoxybenzaldehyde is prepared by a conventional method which includes reaction of isobutyl bromide with 4-hydroxy benzaldehyde in a polar aprotic solvent such as DMF or DMSO in presence of an alkali and a catalyst such as Sodium iodide at 80°C for 2 to 4hrs.

The process of the invention is broadly depicted in scheme 2.

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Accordingly, the present invention provides a process for preparation of Pimavanserin of formula I which process comprises;

a) reacting N-(4-fluorobenzyl)-1-methylpiperidin-4-amine of formula II with urea or Potassium cyanate to obtain 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea of formula (IV); and
b) condensing 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea with 4-isobutoxybenzaldehyde formula V to obtain Pimavanserin of formula I.
The process of the present invention is shown in scheme 3 as below:
The reaction of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine of formula II with Urea for preparation of 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea of formula IV is carried out in presence of an acid catalyst in a polar medium. The acid catalyst may be selected from HCl, H2SO4, HNO3 or H3PO4 etc. The polar medium comprises an aqueous medium or an aqueous organic medium.
In one preferred aspect, the polar medium is aqueous medium, Water. In another aspect, the aqueous organic medium comprises polar organic solvent selected from polar solvents that are miscible with Water, for example, solvents selected from the group consisting of Methanol, Ethanol, 1-Propanol, 2-Propanol, Dimethylformamide, Dimethylsulfoxide, Dioxane, Acetone, Acetic acid,

Acetonitrile, etc. The reaction is carried out at a temperature of 50-110°C for 8 to 10 hrs, followed by cooling to 0 to 5°C. The pH of the reaction mass is adjusted to 8-9 by the addition of alkali, followed by extraction of the 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea with an organic solvent, such as Ethyl acetate, Methyl tert-butyl ether (MTBE), Dichloromethane (DCM), Ethylene dichloride (EDC) etc.
The molar ratio of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine to urea is in the range of 1:1 to 1:8. Preferably, the molar ration is 1:4.
In another embodiment, the reaction of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine of formula II with Potassium cyanate for preparation of 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea of formula IV is carried out in presence of an acid catalyst in a polar medium. The acid catalyst may be selected from HCl and Acetic acid. The polar medium comprises an aqueous medium or an aqueous organic medium comprises polar organic solvent selected from organic solvents consisting of EDC, DCM Ethanol, Isopropyl alcohol and DMF.
The invention further relates to a novel intermediate, 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea of formula IV having the following structure.

The novel intermediate, 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea of formula IV, is characterized by NMR and Mass.
In an additional embodiment, the invention provides a novel process for the preparation of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine, which process comprises, reacting 4-fluorobenzylamine with 1-methyl-4-piperidone in presence of Lewis acid and reducing agent in an organic solvent at room temperature for 3

to 5 hrs. The reaction mixture is acidified to pH 6-5 with acetic acid, concentrated and basified with Na2CO3 solution to pH 8-9. The aqueous layer is extracted with an organic solvent and concentrated to obtain N-(4-fluorobenzyl)-1-methylpiperidin-4-amine.
The Lewis acids may be selected from Titanium (IV) isopropoxide and Titanium tetrachloride. The Lewis acid may preferably be used in the range of about 0.5 to 2 equivalents. The organic solvents for this reaction may be selected from Ethyl acetate, THF, DMF, MeOH etc.
Further, the condensation of 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea with 4-isobutoxybenzaldehyde can also be conveniently carried out in presence of a Lewis acid catalyst and a reducing agent in an organic solvent for 12 to 15hrs under stirring. The reaction may be carried out from at room temperature to 80°C. The organic solvents for this reaction may be selected from Ethyl acetate, THF, DMF etc. The reaction mass is quenched with 1N HCl at 0°C, and the residue is taken in Water and basified with an alkali solution to pH 8-9 and the product is further extracted with an organic solvent, such as n-Butanol, Isopropyl alcohol, Dichloromethane or combinations thereof to obtain Pimavanserin, which is further purified using chromatography or crystallization using suitable solvents such as Ethyl acetate- Hexane. Preferably, Pimavanserin may be extracted with 10 to 50% mixture of IPA and DCM.
The Pimavanserin thus obtained according to the process of present invention has a purity of >99%.
The reducing agent is Sodium borohydride. In a preferred embodiment, the reducing agent is 0.5 equivalents to 2equivalents of Sodium borohydride and the addition of the reducing agent is carried out under cold conditions. The alkali used for basification is selected from the group consisting of Sodium bicarbonate,

Potassium bicarbonate, Sodium carbonate, Potassium carbonate and Sodium hydroxide etc.
The molar ratio of 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea to 4-isobutoxybenzaldehyde is in the range of 0.5:1 to 1:1.2. The reaction may be conducted using variable molar ratios like 0.5:1: 0.7:1; 1:1 and 1: 1.2, to obtain Pimavanserin in good yield.
In yet another embodiment, the invention provides process for preparation of 4-isobutoxy benzaldehyde, which method comprises reaction of Isobutyl bromide with 4-hydroxy benzaldehyde in a polar aprotic solvent such as DMF or DMSO in presence of an alkali and a catalyst such as Sodium iodide at 80°C for 2 to 8hrs. After completion of the reaction the reaction mass is cooled to room temperature and extracted with an organic solvent to obtain 4-isobutoxybenzaldehyde in good yield. The alkali may be selected from Sodium or Potassium carbonates or bicarbonates.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Examples Example 1 Stage 1
Preparation of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine: 4-fluorobenzylamine (2g, 0.0159mol.) and 1-methyl-4-piperidone (1.826g, 0.0161mol.) were charged in a RBF at RT. Ethyl acetate (8mL) was charged in the reaction mixture at RT followed by the dropwise addition of Titanium (IV) isopropoxide (4.54g, 0.0159mol) at RT for 10-15minutes. Reaction mixture was stirred for 3hrs at RT and then cooled to 0-5°C. Ethanol (20mL) and NaBH4 (0.6g,

0.0159mol.) were added portion wise to this at 0-5°C and then stirred for 3-4hrs at RT. The reaction mixture was acidified to pH 6-5 with acetic acid and concentrated. The crude was taken in water (20mL) and basified with Na2CO3 solution to pH 8-9. Aqueous layer was extracted with Ethyl acetate and concentrated. Product was purified by column chromatography to obtain 2.4g of product with 68% yield.
Stage 2
Preparation of 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea: N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (0.5g, 2.2mmol.), Urea (0.53g, 8.83mmol.), Water (6mL) and conc. HCl (0.27mL) were taken in a 100mL flask. The reaction mixture was refluxed at 100-110°C for 8hrs. Reaction mixture was cooled to 0-5°C. pH was adjusted to 8-9 by adding 30% NaOH solution. Reaction mixture was further diluted with Water (6mL) and extracted with Ethyl acetate (8mL). Organic layer was separated and concentrated to obtain 360mg of the product with 60% yield.
The 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea thus obtained is further characterized.by NMR and Mass.
1H NMR (300MHz, CDCl3); δ 1.48-1.52(m,2H),1.87-1.91(m,2H),1.98-2.06(t,2H), 2.27(s,3H),2.81-2.85(m, 3H), 4.12-4.38(t,1H), 4.37(s,2H), 4.56-4.65(bs,2H), 6.96-7.02(t,2H),7.25-7.30(dd,2H). Mass; M+267.
Preparation of 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea using Potassium cyanate:
N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (0.5g, 2.2mmol.), Potassium cyanate (0.46g, 5.67mmol.), Water (16mL) and conc. HCl (0.34mL) were taken in a 100mL flask. The reaction mixture was stirred for 18hrs at ambient temperature. Reaction mixture was cooled to 0-5°C. pH was adjusted to 8-9 by adding 30% NaOH solution. Reaction mixture was further diluted with Water (6mL) and

extracted with Ethyl acetate (8mL). Organic layer was separated and concentrated to obtain 320mg of the product with 54% yield.
Stage-3
Preparation of 4-isobutoxybenzaldehyde:
Isobutyl bromide (4.49g, 32.7mmol.) and DMF (10mL) were charged in a 100mL
flask. 4-hydroxy benzaldehyde (2g, 16.3mmol.) in DMF (8mL) was added to the
reaction mixture followed by K2CO3 (6.79g, 49.12mmol.) and Sodium iodide
(0.240g, 1.63mmol). The reaction mixture was heated at 80°C for 2hrs. It was
cooled to room temperature. The reaction mixture was filtered and washed with
Ethyl acetate (20mL). Organic layer was washed with water (100mL) and
concentrated to get 2.6g of the product with 92% yield.
Stage-4
Preparation of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-
methylpiperidin-4-yl)urea:
4-isobutoxybenzaldehyde (130mg, 0.72mmol.), 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea (0.29g, 1.09mmol.), THF (1.352mL) were charged in a 25mL flask Titanium(IV) isopropoxide (0.338g, 1.19mmol.) was added and the reaction mixture was stirred for 3hrs. Reaction mixture was cooled to 0°C, Sodium borohydride (0.020g, 0.54mmol.) was added portion wise. The reaction mixture was stirred for 12hrs at room temperature. The reaction mass was quenched with 1N HCl at 0°C, concentrated to remove THF. The residue was taken in Water (4mL) and basified with Na2CO3 solution to pH 8-9. It was extracted twice with 20% IPA/DCM (5mL) and concentrated to obtain 369mg of crude product which was purified by column chromatography to obtain 360mg of the compound with 79% yield. Purity: > 99%.

We claim,
1. A process for preparation of Pimavanserin comprising;
a) reacting N-(4-fluorobenzyl)-1-methylpiperidin-4-amine of formula II with Urea or Potassium cyanate to obtain 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea of formula IV; and
b) condensing 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea of formula IV with 4-isobutoxybenzaldehyde of formula V to obtain Pimavanserin of formula I.

2. The process according to claim 1, wherein, the process of step a) is carried out in presence of an acid catalyst in a polar medium.
3. The process according to claim 2, wherein, the acid catalyst is selected from HCl, H2SO4, HNO3 or H3PO4 etc.
4. The process according to claim 2, wherein, the polar medium comprises an aqueous medium or an aqueous organic medium.
5. The process according to claim 2, wherein, the polar medium comprises solvents selected from the group consisting of Water, Methanol, Ethanol, 1-Propanol, 2-Propanol, Dimethylformamide, Dimethylsulfoxide, Dioxane, Acetone, Acetic acid, Acetonitrile, or mixtures thereof.
6. The process according to claim 1, wherein, the reaction in step a) is carried out at a temperature of 50-110°C.
7. The process according to claim 1, wherein, the molar ratio of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine to Urea will be 1:1 to 1:8.

8. The process according to claim 7, wherein, the molar ratio of N-(4-
fluorobenzyl)-1-methylpiperidin-4-amine to urea Urea 1:8.
9. The process according to claim 1, wherein, in step b) the condensation of 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea with 4-isobutoxybenzaldehyde is carried out in presence of a Lewis acid catalyst and a reducing agent in an organic solvent.
10. The process according to claim 9, wherein, the reaction is carried out from room temperature to 80° C.
11. The process according to claim 9, wherein, the organic solvent is selected from Ethyl acetate, THF, DMF etc.
12. The process according to claim 9, wherein, the reducing agent is Sodium borohydride.
13. The process according to claim 12, wherein, the reducing agent is 0.5 to 2
equivalents of Sodium borohydride.
14. The process according to claim 1, wherein, the molar ratio of 1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl) urea to 4-isobutoxybenzaldehyde is in the range of 0.5:1 to 1:1.2.
15. The process according to claim 1, wherein, the N-(4-fluorobenzyl)-1-methylpiperidin-4-amine is prepared by a process comprising reacting 4-fluorobenzylamine with 1-methyl-4-piperidone in presence of Lewis acid and reducing agent in an organic solvent at room temperature.

16. The process according to claim 15, wherein, the Lewis acid is selected from Titanium (IV) isopropoxide and Titanium tetrachloride, in an amount of about 0.5 to 2 equivalents.
17. The process according to claim 15, wherein, the organic solvent is selected from Ediyl acetate, THF, DMF etc.
18. The process according to claim 15, wherein, the reducing agent is Sodium borohydride or Lithium aluminium hydride.
19. The process according to claim 18, wherein, the reducing agent is 0.5 to 2 equivalence of Sodium borohydride.
20. l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl) urea of formula IV.

21. l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl) urea according to claim 20
prepared by a process comprising reacting N-(4-fluorobenzyl)-l-
methylpiperidin-4-amine of formula II with urea or Potassium cyanate to
obtain l-(4-fluorobenzyl)-l-(l-methylpiperidin-4-yl) urea of formula -IV.