WO2019008595A1

WO2019008595A1 - Process for the preparation of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1- methylpiperidin-4-yl)urea and salts thereof

Info

Publication number: WO2019008595A1
Application number: PCT/IN2018/050053
Authority: WO
Inventors: Shailendra Kumar Dubey; Vaibhav MISHRA; Jai Prakash VERMA; Rajendra Singh SHEKHAWAT; Sujay Biswas; Dharam Vir
Original assignee: Jubilant Generics Limited (Formerly A Division Of Jubilant Life Sciences Limited)
Priority date: 2017-07-03
Filing date: 2018-02-02
Publication date: 2019-01-10

Abstract

The present invention relates to an efficient process for the preparation of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1- methylpiperidin-4-yl)urea and pharmaceutically acceptable salts thereof involving use of novel intermediates.

Description

PROCESS FOR THE PREPARATION OF l-(4-FLUOROBENZYL)-3-(4- ISOBUTOXYBENZYL)-l-(l- METHYLPIPERIDIN-4-YL)UREA AND SALTS

THEREOF

Field of the Invention

The present invention relates to an efficient process for the preparation of l-(4- fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(l-methylpiperidin-4-yl)urea and pharmaceutically acceptable salts thereof involving use of novel intermediates.

Background of the Invention l-(4-Fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(l-methylpiperidin-4-yl)urea is known as pimavanserin and has been developed as pimavanserin tartrate salt by Acadia Pharmaceuticals which has been approved for use in patients for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. Pimavanserin tartrate is represented structurally as Formula I,

I

Pimavanserin synthesis is disclosed in US 7,601,740 and US 7,790,899, wherein the process involves the reaction of N-(4-fluorobenzyl)-l-methylpiperidine-4-amine with 1- isobutoxybenzyl isocyanate. The patents disclose the preparation of intermediate 1- isobutoxybenzyl isocyanate via two processes wherein one process involves reaction of 2- (4-isobutoxyphenyl)acetic acid with diphenyl phosphoryl azide and the other process involves reaction of 4-isobutoxybenzylamine with phosgene or its equivalents. The methods mentioned in the patents suffer a number of disadvantages, the main disadvantage involves use of 4-isobutoxybenzyl isocyanate, as isocyanates are known toxic and are highly reactive compounds and thus are very unsafe to handle at industrial scale. Another disadvantage pertains to use of highly toxic reagents such as phosgene and diphenyl phosphoryl azide, which are again toxic and explosive in nature, thereby are highly unsafe to be used at industrial level. The process disclosed not only suffers working incapability but the product obtained i.e. pimavanserin is also not of very high purity as per the required standards and need undue multiple purifications, which leads to loss of yield and thus makes processes highly incapable for industrial application.

WO2017015272 discloses a process for the preparation of pimavanserin via preparation of variously substituted carbamate intermediates, which are further condensed with another intermediate to obtain pimavanserin. Of the various processes disclosed, the process using dimethyl carbonate for the preparation of carbamate is carried out in the presence of zirconium catalyst for about 72 hours at high temperature with a proximal yield of 20%. The process involving use of diphenyl carbonate for the preparation of carbamate takes place in about 24 hours. In another process, the preparation of carbmate using methyl chloroformate involved column chromatography for the purification of carbamate intermediate to achieve required purity standards. In yet another disclosure, the pimavanserin was obtained by trituration with only 70.5% purity, wherein the carbamte intermediate was prepared using bis(2,2,2-trifluroethyl)carbonate of 2,2,2-trifluoroethyl chloroformate. Thus, the processes disclosed involve major challenges to be easily applicable on industrial scale such as use of an expensive catalyst, long reaction time increases energy consumption, which increases overall production cost. The process providing pimavanserin with purity of 70% will attract additional purifications, thereby leading to loss of yield and increase in cost. The procedure of trituration is not at all advisable at industrial scale. Thus, it is evident that the disclosed processes suffer a number of disadvantages to be successfully implemented on industrial scale. Thus, there remains an urgent need for the development of a process, which not only overcome one or more problems of the prior art processes as mentioned above, but also is an efficient, safe and convenient process for the preparation of pimavanserin and pharmaceutically acceptable salts thereof.

Object and Summary of the Invention

The principal object of present invention relates to novel, efficient and safe processes for the preparation of l-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-l-(l-methylpiperidin-4- yl)urea and pharmaceutically acceptable salts thereof in high yield and purity involving novel intermediates, which alleviates one or more drawbacks of prior art processes. embodiment, the present invention relates to the compound of formula IV

In another embodiment, the present invention provides a process for the preparation of compound of formula IV

comprising reacting compound of formula II or its salt with a compound of formula III.

In yet another embodiment, the present invention provides use of compound of formula IV for the preparation of pimavanserin and pharmaceutically acceptable salts thereof, comprising the reaction of formula II or its salt with the compound of formula III to give a compound of formula IV. The next step involves reaction of compound of formula IV with compound of formula V to give pimavanserin of formula IA, according to Scheme 1, which is optionally converted to its pharmaceutically acceptable salts.

IA

Scheme 1

In another embodiment, the present invention relates to the compound of formula VI

VI In yet another embodiment, the present invention provides a process for the preparation of compound of formula VI

VI

comprising reacting compound of formula V with a compound of formula III.

III

In another embodiment, the present invention provides use of compound of formula VI for the preparation of pimavanserin and pharmaceutically acceptable salts thereof, comprising the reaction of compound of formula V with compound of formula III to give a compound of formula VI. The next step involves reaction of compound of formula VI with compound of formula II or its salt to give pimavanserin of formula IA, according to Scheme 2, which is optionally converted to its pharmaceutically acceptable salts.

IA

Scheme 2

Detailed description of the Invention

The well-known intermediates of formula II and V used for the preparation of pimavanserin are reported in literature and that used in the present invention are very much prone to the formation of multiple impurities such as dimer impurity of formula VII.

The formation of impurities or the control on formation of impurities is dependent upon the reagents, solvents and conditions used for carrying out various reactions, therefore it is a challenge for the present inventors to reach at such reaction conditions, selection of solvents and reagents such that they provide pimavanserin with required purity standards, wherein the process should not involve working difficulties, involve high costs, expensive techniques/reagents, rather the process should be simple, convenient, easy to operate, environment friendly and economical.

In view of above requirements, the present invention provides processes that are simple, convenient, environment friendly and economical for industrial application. The method utilizes use of safer reagents, conditions and novel intermediates that avoids formation of multiple impurities and thereby reduces the additional requirements of purifying intermediates at various stages and accordingly reduces the use of solvents and reagents, which results in decrease in costs attributed to a more efficient use of reagents and solvents and at the same time makes process more environment friendly.

In an embodiment, the present invention relates to the compound of formula IV:

IV

In an embodiment, the present invention provides a process for the preparation of compound of formula IV:

IV

II III

According to present invention, the compound of formula II or its salt is reacted with compound of formula III to give compound of formula IV. Whenever a salt of compound of formula II is used it is selected from the group comprising of hydrochloride, hydrobromide, acetate and the like. The salt is neutralized to compound of formula II by use of base in a solvent, wherein the base used is selected from the group comprising organic and inorganic. The organic base used is selected from the group comprising of trimethylamine and the like. The inorganic base used is selected from alkali and alkaline earth metal carbonates, bicarbonates and the like. The alkali and alkaline earth metal is selected from the group comprising of sodium, potassium, calcium, barium and the like. The solvent used in the liberation of free base of compound of Formula II and further reaction with compound of Formula III can be same or different and is selected from the group comprising of halogenated hydrocarbons such as dichloromethane, chlorobenzene and the like, hydrocarbons such as cyclohexane, heptane, octane, toluene, xylene and the like, esters such as ethyl acetate, propyl acetate and the like, nitrile such as acetonitrile, propionitrile and the like, DMSO, DMF, water and mixtures thereof. The reaction provides compound of formula

IV.

In yet another embodiment, the present invention provides a process for the preparation of pimavanserin involving use of compound of formula IV, comprising the reaction of formula II or its salt with the compound of formula III to give a compound of formula IV. The next step involves reaction of compound of formula IV with compound of formula V to give pimavanserin of formula IA, according to Scheme 1, which is optionally converted to its pharmaceutically acceptable salts.

IA

Scheme 1

According to present invention, compound of formula II or its salt reacts with compound of formula III to give compound of formula IV. Whenever a salt of compound of formula II is used it is selected from the group comprising of hydrochloride, hydrobromide, acetate and the like. The salt is neutralized to compound of formula II by use of base in a solvent, wherein the base used is selected from the group comprising organic and inorganic. The organic base used is selected from the group comprising of trimethylamine and the like. The inorganic base used is selected from alkali and alkaline earth metal carbonates, bicarbonates and the like. The alkali and alkaline earth metal is selected from the group comprising of sodium, potassium, calcium, barium and the like. The solvent used in the liberation of free base of compound of Formula II and further reaction with compound of Formula III can be same or different and is selected from the group comprising of halogenated hydrocarbons such as dichloromethane, chlorobenzene and the like, hydrocarbons such as cyclohexane, heptane, octane, toluene, xylene and the like, esters such as ethyl acetate, propyl acetate and the like, nitrile such as acetonitrile, propionitrile and the like, DMSO, DMF, water and mixtures thereof. The compound of formula II is optionally isolated after neutralization and is further reacted with compound of formula III to obtain compound of formula IV, which is isolated or is used in-situ for further reaction. According to present invention, the compound of formula IV is treated with compound of formula V, wherein the reaction is carried out in solvent in presence of base. The solvent used is selected from the group comprising of halogenated hydrocarbons such as dichloromethane and the like, esters such as ethyl acetate, isopropyl acetate and the like, nitrile such as acetonitrile, propionitrile and the like, aromatic hydrocarbons such as toluene, chlorobenzene and the like, DMSO, DMF, water and mixtures thereof. The base used is selected from organic and inorganic, wherein organic base used is selected from the group comprising of triethylamine and the like. The inorganic base used is selected from alkali and alkaline earth metal carbonates, bicarbonates and the like. The alkali and alkaline earth metal is selected from the group comprising of sodium, potassium, calcium, barium and the like. The reaction give pimavanserin of formula IA, which is optionally converted to its pharmaceutically acceptable salts. embodiment, the present invention relates to the compound of formula VI

VI

In another embodiment, the present invention provides a process for the preparation of compound of formula VI

VI

comprising reacting compound of formula V with a compound of formula III.

V III According to present invention, the compound of formula V reacts with compound of formula III in solvent to obtain compound of formula VI. The solvent used is selected from the group comprising of halogenated hydrocarbons such as dichloromethane and the like, esters such as ethyl acetate and the like, nitrile such as acetonitrile, propionitrile and the like, water and mixtures thereof.

IA

Scheme 2

According to present invention, the N-(4-fluorobenzyl)-l-methylpiperidine-4-amine of formula V reacts with compound of formula III. The reaction is carried out in solvent optionally in presence of base. The solvent used is selected from the group comprising of halogenated hydrocarbons such as dichloromethane and the like, esters such as ethyl acetate and the like, nitrile such as acetonitrile and the like, water and mixtures thereof. The base used is selected from organic and inorganic, wherein organic base used is selected from the group comprising of trimethylamine and the like. The inorganic base used is selected from alkali and alkaline earth metal carbonates, bicarbonates and the like. The alkali and alkaline earth metal is selected from the group comprising of sodium, potassium, calcium, barium and the like. The reaction give compound of formula VI which is optionally isolated and is further used in next step.

According to present invention, the compound of formula VI is then treated with 4- isobutoxybenzylamine or its salt of formula II, wherein the 4-isobutoxybenzylamine salt used is selected from the group comprising of hydrochloride, hydrobromide, acetate and the like. The salt is neutralized to compound of formula II by use of base in a solvent, wherein the base used is selected from the group comprising organic and inorganic. The organic base used is selected from the group comprising of trimethylamine and the like. The inorganic base used is selected from alkali and alkaline earth metal carbonates, bicarbonates and the like. The alkali and alkaline earth metal is selected from the group comprising of sodium, potassium, calcium, barium and the like. The reaction is carried out in solvent selected from the group comprising of halogenated hydrocarbons such as dichloromethane and the like, esters such as ethyl acetate and the like, nitrile such as acetonitrile and the like, water and mixtures thereof. The reaction of compound of formula VI with compound of formula II is carried out in presence of solvent, optionally in the presence of a catalyst such as dimethylaminopyridine and the like. The solvent used is selected from the group comprising of esters such as ethyl acetate, isopropyl acetate and the like, aromatic hydrocarbons such as toluene, chlorobenzene and the like, DMSO, DMF, water and mixtures thereof. The pimavanserin of formula IA so obtained is optionally converted to pharmaceutically acceptable salts.

According to present invention, the pharmaceutically acceptable salt of pimavanserin is selected from the group comprising of hydrochloride, hydrobromide, tartrate, oxalate and the like. According to the present invention, the compound of formula IV, VI and pimavanserin or its pharmaceutically acceptable salt are isolated using one or more work-up processes such as extraction, washing, filtration and the like. The pimavanserin or its pharmaceutically acceptable salt obtained is then optionally crystallized from suitable organic solvent to get pure pimavanserin. The suitable organic solvent for crystallization is selected from the group comprising of alcohols, esters, ketones, ethers, water or mixtures thereof; particularly methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert- butanol, methyl acetate, ethyl acetate, isopropyl acetate, tertiary butyl acetate, acetone, methyl ethyl ketone, di-isopropyl ether, tetrahydrofuran, water or mixtures thereof.

According to present invention, pimavanserin or its pharmaceutically acceptable salts obtained is having purity not less than 99.5%, preferably not less than 99.8%.

The process for the preparation of pimavanserin or salts thereof described in the present invention is demonstrated in the examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. Examples

Example 1: Preparation of compound of formula IV

To a solution of (4-isobutoxyphenyl) methanamine acetate (II) (1.34 g) in dichloromethane (5 ml), added saturated solution of sodium bicarbonate at room temperature and stirred the reaction mixture for about 1 hour. The layers were separated and to the organic layer, added bis(2,5-dioxopyrrolidin-l-yl) carbonate (III) (1.57 g). The reaction mixture was stirred at room temperature for 1-2 h. On completion of reaction, the solvent was distilled off to obtain compound of formula IV as solid residue.

1H-NMR (400 MHz, DMSO, δ): 8.778 (1H, t, H), 7.16-7.18 (2H, d, CH), 6.89-6.91 (2H, d, CH), 4.17-4.19 (2H, d, CH₂), 3.71-3.72 (2H, d, CH₂), 2.762 (4H, s, CH₂), 1.96-2.09 (1H, m, CH), 0.95-0.97 (6H, d, CH₃)

Mass [M+H⁺]: 321.3, [M⁺+NH₃]: 338.4

Example 2: Preparation of pimavanserin using compound of formula IV

To a solution of compound of formula IV (as obtained in Example 1) in toluene (20 ml), added potassium carbonate (0.77 g) and N-(4-fluorobenzyl)-l-methylpiperidin-4-amine (V) (1.48 g) at room temperature. The temperature of reaction mixture was raised to 70-80 °C and stirred for 1-2 hours. On completion of reaction, the solvent was distilled off and ethyl acetate (30 ml) was charged to the residue. The solution was washed with water and the solvent was evaporated. The solid residue so obtained was treated with ethyl acetate/n- heptane and cooled to precipitate out pimavanserin, which was filtered and dried.

Example 3: Preparation of pimavanserin using compound of formula IV

To a solution of compound of formula IV (as obtained in Example 1) in isopropyl acetate (25 ml), added potassium carbonate (1.16 g) and N-(4-fluorobenzyl)-l- methylpiperidin-4-amine (V) (1.36 g) at room temperature. The temperature of reaction mixture was raised to 50-60 °C and stirred for about 6 hours. On completion of reaction, water (125 ml) was added to reaction mixture and stirred for another 1 hour at 50-60 °C, cooled the reaction mixture and separated layers. The solvent was distilled off from organic solvent to obtain residue. To the residue, n-heptane (25 ml) was added slowly and stirred for about 3 hours at about 40 °C. The solid pimavanserin so obtained was filtered and dried. Yield: 82%

HPLC purity: 99.4%

Example 4: Preparation of compound of formula VI

To a solution of N-(4-fluorobenzyl)-l-methylpiperidin-4-amine (V) (1.34 g) in dichloromethane (5 ml), added bis(2,5-dioxopyrrolidin-l-yl) carbonate (III) (1.57 g). The reaction mixture was stirred at room temperature for 2 h. On completion of reaction, the solvent was distilled off to obtain compound of formula VI as solid residue.

1H-NMR (400MHz, CDC1_3, δ): 7.39 (1H, m, CH), 7.22 (1H, m, CH), 7.00-7.06 (2H, m, CH), 4.51-4.59 (2H, d, CH₂), 2.84 (6H, brs, CH₂), 3.89-3.95 (1H, m, CH), 2.23 (3H, s, CH₃), 1.93-1.98 (2H, m, CH₂), 1.66-1.80 (4H, m, CH₂)

Mass [M+H⁺]: 364.1

Example 5: Preparation of pimavanserin using compound of formula VI

To a solution of compound of formula VI (as obtained in Example 3) residue in toluene (75 ml), added 4-isobutoxy benzylamine (4.0 g) and catalytic amount of dimethylamino pyridine (0.05 g) at 20-25 °C. The temperature of reaction mixture was raised to 85-90 °C and stirred for 18 hours. Thereafter the solvent was distilled off to obtain desired pimavanserin.

Example 6: Preparation of pimavanserin tartrate

To solution of pimavanserin (1.5 g) in ethanol (18 ml) slowly added a solution of L- (+)-tartaric acid (0.263 g) in ethanol (12 ml) at 60-65 °C. The resulting clear mixture is slowly cooled to room temperature. The solid so obtained is filtered and dried to obtain pimavanserin tartrate.



Claims

Claims:

1. A com ound of formula IV

IV

2. A rocess for the preparation of compound of formula IV

II III

The process according to claim 2, wherein salt of compound of formula II is selected from the group comprising of hydrochloride, hydrobromide and acetate.

The process according to claim 2, wherein the reaction is carried out in solvent selected from the group comprising of halogenated hydrocarbons, hydrocarbons, esters, nitrile, DMSO, DMF, water and mixtures thereof.

Use of compound of formula IV for the preparation of pimavanserin and its pharmaceutically acceptable salts.

A process for the preparation of pimavanserin comprising:

(i) reacting compound of formula II or its salt with the compound of formula III to give a compound of formula IV;

II III

IV

(ii) reacting compound of formula IV with compound of formula V to give pimavanserin of formula IA; and

IA

(iii) optionally, converting compound of formula IA to its pharmaceutically acceptable salts.

7. The process according to claim 6, wherein the reaction of step (i) is carried out in solvent selected from the group comprising of hydrocarbons, halogenated hydrocarbons, esters, nitriles, DMSO, DMF, water and mixtures thereof.

8. The process according to claim 6, wherein the reaction of step (ii) is carried out in solvent and in presence of base.

9. The process according to claim 8, wherein solvent is selected from the group comprising of hydrocarbons, halogenated hydrocarbons, esters, nitriles, DMSO, DMF, water and mixtures thereof.

10. The process according to claim 8, wherein base used is selected from the group comprising of organic and inorganic.

11. The process according to claim 10, wherein organic base used is trimethylamine.

12. The process according to claim 10, wherein the inorganic base used is selected from alkali and alkaline earth metal carbonates and bicarbonates.