DESC:FIELD OF INVENTION
The present invention provides novel intermediate for preparation of pimavanserin and its salts and also provides one pot process for preparation of pimavanserin tartrate. The present invention further provides process for preparation of amorphous form of pimavanserin tartrate.
BACKGROUND OF THE INVENTION
Pimavanserin (I) which is marketed under the brand name Nuplazid ® contains the active ingredient pimavanserin tartrate. It is an atypical antipsychotic drug with chemical name Urea,N-[(4-fluorophenyl)methyl]-N-(1-methyl-4-piperidinyl)-N'-[[4-(2-methylpropoxy) phenyl]methyl] and structure as mentioned below.

The patent US 7601740 discloses pimavanserin and its salts. The patent also discloses process for their preparation of pimavanserin which includes reaction of 1-isobutoxy-4-(isocyanatomethyl)benzene and N- (4-fluorobenzyl)-1-methylpiperidin-4-amine. The preparation of 1-isobutoxy-4-(isocyanatomethyl) benzene intermediate involves use of hazardous reagents like phosgene derivatives or diphenylphosphoryl azide. Another patent US 7790899 discloses similar process for preparation. The PCT applications WO 2016141003 and WO 2017015272 disclose alternate process for preparations of pimavanserin tartrate.
The present invention provides process for preparation of pimavanserin and its salt and novel intermediate for preparation of pimavanserin and its salt. The present invention also provides process for preparation of amorphous form of pimavanserin tartrate.

SUMMARY OF THE INVENTION
The present invention provides process for preparation of pimavanserin (I) or its salt, comprising reacting (4-isobutoxy phenyl) methanamine (IV) and disuccinimidyl carbonate (V) to obtain novel intermediate, compound (III) and converting compound (III) to pimavanserin (I) or salt thereof. The present invention provides one pot preparation of pimavanserin tartrate. The present invention also provides process for preparation of amorphous form of pimavanserin tartrate.
DETAILED DESCRIPTION OF THE INVENTION
In the first embodiment, the present invention provides process for preparation of pimavanserin (I) or its salt comprising:
i. reacting compound (III) and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (VI) to obtain pimavanserin (I), and

ii. optionally converting pimavanserin (I) to its salt.
In the second embodiment, the present invention provides process for preparation of compound (III), comprising reacting (4-isobutoxy phenyl) methanamine (IV) and disuccinimidyl carbonate (V).

In the third embodiment, the present invention provides compound (III) as novel intermediate for preparation of pimavanserin (I) or its salt. Compound (III) is characterized by NMR 1H (CDCl3) d:6.8-7.2,dd (4H), j=8.5; d:6.0, s (1H); d:4.2-4.3, s (2H); d:3.6-3.7, d (2H); d:2.6-2.8 m (4H); d:2.1 m (1H); d:2.0-2.1 m (6H), and MS/LC; m/z=338.2 (m+NH4 Adduct).

In the fourth embodiment, the present invention provides one pot process for preparation of pimavanserin (I) tartrate comprising:

i. reacting (4-isobutoxy phenyl) methanamine (IV) and disuccinimidyl carbonate (V) to obtain compound (III),
ii. reacting compound (III) and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (VI) to obtain pimavanserin (I), and
iii. reacting pimavanserin (I) with tartaric acid.

Reaction of (4-isobutoxy phenyl) methanamine (IV) with disuccinimidyl carbonate (V) and reaction of compound (III) with N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (VI) can be carried out in an non-polar organic solvent such as hydrocarbon solvent selected from benzene, toluene, hexane, cyclohexane heptane and the like; chlorinated solvent selected from dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like and mixtures thereof. The reactions can be carried out optionally in presence of base. The base can be selected from organic or inorganic base; organic base can be selected from alkyl amines such as triethyl amine, tributyl amine, diisopropylethylamine and the like; inorganic bases include hydroxide, alkoxides or carbonates, bicarbonates of alkali or alkaline earth metal such as sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium carbonate, potassium carbonate, sodium bicarbonate and the like and mixtures thereof.
The reactions can be carried out at a temperature of 25-30°C to reflux temperature of the solvent. Reactants can be employed in molar equivalents of 1 to 3. After the reaction, compound (III) and pimavanserin (I) can be isolated from the reaction mixture by techniques known in art like filtration, concentration, removal of solvent by evaporation, distillation, centrifugation, cooling, flash evaporation, drying on rotavapor. The compounds (4-isobutoxy phenyl) methanamine (IV), disuccinimidyl carbonate (V) and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (VI) can be prepared by processes known in the literature.
In the present invention pimavanserin (I) salt can be selected from inorganic salts such as hydrochloric, hydrobromic, sulfuric, phosphoric and the like; organic salt such as tartrate, succinate, lactate, maleate, citrate, ascorbate and the like. Pimavanserin (I) can be converted to its salt by reacting Pimavanserin (I) with the respective inorganic acid such as hydrochloric acid, hydrobromic acid , sulfuric acid, phosphoric acid and the like and respective organic acid such as tartaric acid, succinic acid, lactic acid, maleic acid, citric acid, ascorbic acid and the like; preferred salt is hemi-tartrate. The preparation of salt can be carried in solvent selected from polar organic solvent, water or mixture thereof. Polar organic solvent can be selected from alcohol such as methanol, ethanol, propanol, propanediol, butanol, butanediol and the like; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone; ethers like dioxane, tertrahydrofuran and the like and mixtures thereof.

In the fifth embodiment, the present invention provides process for preparation of amorphous pimavanserin tartrate comprising dissolving pimavanserin tartrate in a solvent and removing the solvent.

Solvent can be selected from water or mixture of water and polar organic solvent selected from alcohol such as methanol, ethanol, propanol, propanediol, butanol, butanediol and the like; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone; ethers like dioxane, tertrahydrofuran and the like and mixtures thereof. Pimavanserin tartrate can be dissolved in the solvents by techniques known in art like stirring, heating the mixture etc. Solvent can be removed by techniques known in art like concentration, evaporation, agitated thin film drying, distillation, centrifugation, cooling, flash evaporation, drying on rotavapor etc.

The present invention is further illustrated by the following representative examples and does not limit the scope of the invention.
EXAMPLES
Example 1: preparation of compound (III)
A mixture of (4-isobutoxy phenyl) methanamine (IV) (20.0 g, 0.111 moles), disuccinimidyl carbonate (V) (40 g, 0.156 mole), diisopropylethylamine (36.0 g, 0.277 mole) and dichloromethane (200 ml) was heated to reflux for 4 hours. The reaction mixture was cooled to 25-30°C and water (140 ml) was added to it. The organic layer was separated and washed with water and with brine solution. The organic layer was distilled and cyclohexane (120 ml) was added to the residue. The solid was filtered and dried under vacuum. Yield: 9.5 g.
Example 2: preparation of pimavanserin (I).
A mixture of compound (III) (8.0 g, 0.0249 mole), N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (VI) (6.1 g, 0.0273 mole), diisopropylethyl amine (6.5 g, 0.0498 mole) and dichloromethane (40 ml) was heated to reflux for 10 hours. The reaction mixture was cooled to 25-30°C and water (48 ml) and dichloromethane (32 ml) was added to it. The organic layer was separated and distilled off. Cyclohexane (48 ml) and n-heptane (48 ml) was added to the residue. The solid was filtered and dried under vacuum. Yield: 9.5 g.
Example 3: preparation of pimavanserin (I) tartrate.
A mixture of pimavanserin (I) (7 g, 0.0163 mole) and ethanol (56 ml) was heated to 50-55°C, a solution of L(+) tartaric acid (1.47 g, 0.098 moles) in ethanol (42 ml) was added to it and stirred for 20 minutes at 50-55°C. The reaction mixture was cooled to 20-25°C. The solid was filtered and dried under vacuum. Yield: 2.7 g.
Example 4: One pot preparation of pimavanserin (I) tartrate.
A mixture of (4-isobutoxy phenyl) methanamine (5.0 g, 0.027 moles), disuccinimidyl carbonate (10 g, 0.0390 mole), diisopropylethylamine (9.0 g, 0.0067 mole) and dichloromethane (50 ml) was heated to reflux for 160 minutes, N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (6.5 g, 0.0297 mole) was added to it and reaction mixture was heated to reflux for 6 hours. The reaction mixture was cooled to 25-30°C and water (50 ml) was added to it. The organic layer was separated and washed with water and with dried over sodium sulphate. The organic layer was distilled and ethanol (ml) was added to the residue. The mixture was heated to 50-55°C, a solution of L (+) tartaric acid (2.5 g) in ethanol (25 ml) was added to it and stirred for 4 hours at 50-55°C. The reaction mixture was cooled to 20-25°C. The solid was filtered and dried under vacuum. Yield: 5.3 g.
Example 5: preparation of amorphous pimavanserin tartrate.
A mixture of pimavanserin tartrate (55 g) and water (385 ml) was heated to 45°C to obtain a clear solution. Water was distilled out at about 55°C under reduced pressure and the residue was degassed. Amorphous solid was obtained.
Example 6: preparation of amorphous pimavanserin tartrate.
A mixture of pimavanserin tartrate (3 g), acetone (10 ml) and water (10 ml) was stirred to obtain a clear solution. Solvent was distilled out at 52°C under reduced pressure and the residue was degassed. Amorphous solid was obtained.
Example 7: preparation of amorphous pimavanserin tartrate.
A mixture of pimavanserin tartrate (3 g), tetrahydrofuran (10 ml) and water (10 ml) was stirred to obtain a clear solution. Solvent was distilled out at 48°C under reduced pressure and the residue was degassed. Amorphous solid was obtained.
Example 8: preparation of amorphous pimavanserin tartrate.
A mixture of pimavanserin tartrate (5 g), ethanol (20 ml) and water (20 ml) was stirred to obtain a clear solution. Solvent was distilled out at 50°C under reduced pressure and the residue was degassed. Amorphous solid was obtained.
Example 9: preparation of amorphous pimavanserin tartrate.
A mixture of pimavanserin tartrate (5 g), methanol (20 ml) and water (20 ml) was stirred to obtain a clear solution. Solvent was distilled out at 50°C under reduced pressure and the residue was degassed. Amorphous solid was obtained.
,CLAIMS:1. A process for preparation of pimavanserin (I) or its salt comprising:
i. reacting compound (III) and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (VI) to obtain pimavanserin (I), and

ii. optionally converting pimavanserin (I) to its salt.

2. The process of claim 1, further comprising preparation of compound (III) by reacting (4-isobutoxy phenyl) methanamine (IV) and disuccinimidyl carbonate (V).

3. The process according to claims 1 and 2, wherein reactions are carried out in presence of solvent.
4. The process according to claim 3, wherein solvent is selected from hydrocarbon solvent and chlorinated solvent.

5. The process according to claim 4, wherein hydrocarbon solvent is selected from benzene, toluene, hexane, cyclohexane, heptane and mixtures thereof.

6. The process according to claim 4, wherein chlorinated solvent is selected from dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and mixtures thereof.

7. A compound of formula (III) of claim 1.

8. A one pot process for preparation of pimavanserin (I) tartrate comprising:

i. reacting (4-isobutoxy phenyl) methanamine (IV) and disuccinimidyl carbonate (V) to obtain compound (III),
ii. reacting compound (III) and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (VI) to obtain pimavanserin (I), and
iii. reacting pimavanserin (I) with tartaric acid.

9. A process for preparation of amorphous pimavanserin tartrate comprising dissolving pimavanserin tartrate in a solvent and removing the solvent.

10. The process according to claim 9, wherein solvent is alcohol, nitrile, ketone or ether.