DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Prucalopride of formula (I) and salts thereof.

BACKGROUND OF THE INVENTION
Prucalopride, gastroprokinetic agent acting as a selective serotonin agonist is developed by the Belgian Movetis NV Company. It is clinically used for the treatment of chronic constipation and it is sold under the trade name RESOLOR™. This product is the first new type of dihydrobenzofuran carboxylic acid derivative to stimulate the 5-HT4a and 5-HT4b receptors efficiently and selectively, increase gastrointestinal motility, and improve the symptoms of constipation. The chemical name of Prucalopride is 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurocarboxamide. It is represented by the following structural formula (I):

U.S. Patent No. 5,854,260 (hereinafter referred to as the US '260 patent) describes several synthetic routes for preparing prucalopride. According to one synthetic process, Prucalopride was prepared by the condensation of 4-amino-5-chloro-2,3-dihydro-7- benzofurancarboxylic acid with l-(3-methoxypropyl)-4-piperidinamine in the presence of 1,1'-carbonylbis-1H-imidazole in THF followed by treatment with water to produce Prucalopride monohydrate. Further, Prucalopride succinate is prepared by dissolving prucalopride monohydrate in warm ethanol, followed by the addition of a solution of succinic acid in aqueous ethanol.

Considering the importance of Prucalopride in the pharmaceutical field, there is a need that remains for an improved and commercially viable process of preparing pure prucalopride.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides an improved process for preparation of Prucalopride as represented schematically in general scheme 1 as below.
Scheme 1
In another aspect, the present invention provides an improved process of preparation of Prucalopride of Formula (I), comprising the steps of:
a) reacting compound of Formula (II) with 1,2- dibromo ethane in presence of suitable catalyst to obtain compound of Formula (III);
b) cyclizing compound of Formula (III) to obtain compound of Formula (IV);
c) hydrolyzing the compound of Formula (IV) to obtain compound of Formula (V); and
d) reacting compound of Formula (V) with 1-(3-methoxypropyl)-4-piperidinamine or its hydrochloride salt to obtain compound of Formula (I).
In another aspect, the present invention provides process of preparation of Prucalopride of formula (I), comprising reacting the compound of Formula (Va) wherein M is selected from alkaline metal or alkaline earth metal, with an acid under suitable reaction temperature and suitable reaction time to obtain compound of Formula (V), wherein the content of compound of Formula (VII) in Formula (V) is less than 1% by HPLC,

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides an improved process of preparation of prucalopride, comprising the steps of:
a) reacting compound of Formula (II) with 1,2- dibromoethane in presence of suitable catalyst, base and solvent to obtain compound of Formula (III);

b) cyclizing compound of Formula (III) using zinc and suitable solvent to obtain compound of Formula (IV);

c) hydrolyzing the compound of Formula (IV) using suitable base and water to obtain compound of Formula (V); and

d) reacting compound of Formula (V) with carbonyl di-imidazole (CDI) and suitable solvent to obtain compound of formula (VI) and further treating with 1-(3-methoxypropyl)-4-piperidinamine or its hydrochloride salt to obtain compound of Formula (I).

In one embodiment of the present invention, step (a) is carried out by reacting compound of Formula (II) with 1,2-dihaloketone like 1,2- dibromoethane to get compound of Formula (III). The reaction is carried out in presence of suitable base such as inorganic base selected from potassium carbonate (K2CO3), sodium carbonate (Na2CO3), sodium hydroxide (NaOH), potassium hydroxide (KOH), ammonium hydroxide (NH4OH) and the like. Alternatively an organic base may also be employed.
In another embodiment the reaction is carried out in the presence of suitable catalyst such as phase transfer catalyst selected from tetrabutyl ammonium bromide, tetrabutyl ammmonium chloride and methyltributyl ammonium chloride and the like. The reaction is carried out in the presence of suitable solvent such as an inert organic solvent including but not limited to solvent such as N, N’-dimethylacetamide, N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, diglyme, sulfolane and the like. The reaction may be carried out at a temperature of about 0°C to about boiling point of the solvent used. Preferably, the reaction is carried out at 50-55°C.
In one embodiment, compound of Formula (III) is isolated and purified if required from the reaction mixture by any known technique in the art or the compound can be subjected to next reaction without isolation and/or purification. In one embodiment, compound of Formula (III) may be isolated by stirring with water and/or organic solvent such as MTBE, toluene and like.
In another embodiment of the present invention, step (b) is carried out by cyclizing compound of Formula (III) to compound of Formula (IV). The reaction is performed using zinc (Zn). The reaction is carried out in the presence of suitable solvent such as an inert organic solvent including but not limited to N,N’-dimethyl acetamide (DMAc), N-methyl pyrolidine (NMP), N,N-dimethylformamide (DMF), N-methylmorpholine (NMM) and mixtures thereof. The reaction is carried out at a temperature of about 0 °C to about boiling point of the solvent used. Preferably, the reaction is carried out at 50-70°C. After completion of the reaction, it may be quenched with an acid to get solid. Preferable acid is hydrochloric acid.
In one embodiment, compound of Formula (IV) is isolated and purified if required from the reaction mixture by any known technique in the art or the compound can be subjected to next reaction without isolation and/or purification. In another embodiment, compound of Formula (IV) may be crystallized in inert organic solvent such as ethyl acetate, propylene glycol monomethyl ether.
In another embodiment of the present invention, step (c) is carried out by hydrolyzing the compound of Formula (IV) under suitable conditions to obtain compound of Formula (V), wherein the compound of Formula (VII) is less than 1% by HPLC in the compound of Formula (V). Compound of Formula (VII) is a possible impurity in compound of Formula (V);

In another embodiment of the present invention, step (c) is carried out by hydrolysis of compound of Formula (IV) using suitable base such as sodium hydroxide (NaOH), potassium hydroxide (KOH), ammonium hydroxide (NH4OH), Lithium hydroxide (LiOH), Calcium hydroxide (Ca(OH)2) and the like In another embodiment, compound of Formula (V) may optionally be isolated as its salt, represented as compound of Formula (Va), wherein M is selected from alkaline metal or alkaline earth metal in which alkaline metal is selected from sodium, potassium and cesium and alkaline earth metal is selected from magnesium and calcium.
In another embodiment of the present invention, involves reacting the compound of Formula (Va) wherein M is selected from alkaline metal or alkaline earth metal with an acid under suitable conditions to obtain compound of Formula (V), wherein the content of compound of Formula (VII) in Formula (V) is less than 1% by HPLC,

In another embodiment of the present invention, obtained salt (in-situ or isolated) is treated with acid such as hydrochloric acid (HCl), sulfuric acid (H2SO4), acetic acid (CH3COOH). The reaction is carried out in presence of water and/or inert organic solvent. The inert organic solvent including but not limited to methanol, ethanol, isopropanol, n-butanol. The reaction mass can be homogeneous or heterogeneous. The reaction is carried out at a temperature of about 0 °C to about boiling point of the solvent used. Preferably, the reaction can be carried out at 50 °C to 80 °C temperature. The time period of reaction may be monitored in such a way that impurity of compound of Formula (VII) formed should not be more than 1%. Preferable time period of the reaction may be 25 to 35 minutes.
Impurity (VII) is formed due to decarboxyation during reaction of alkali/alkali earth metal salt of compound of formula (V) with an acid. The formation of this impurity during reaction is undesired as it results in decreased yield and purity. The formation of impurity of formula (VII) can be controlled by limiting the reaction time to about 15 minutes to 60 minutes, preferably about 30 minutes when the reaction is carried out at 50°C to 80°C as is evident from the below table-1 which compares the formation of impurity of formula (VII) at different time intervals of reaction. The reaction time might vary depends on reaction temperature.
Table-1
time Compound (V) Compound (VII)
0.5 hrs 99.7 0.023
3 hrs 92.9 6.7
6 hrs 85.3 14.3

In one embodiment, compound of Formula (V) may be isolated and purified if required from the reaction mixture by any known technique in the art or the compound can be subjected to next reaction without isolation and/or purification.
In another embodiment of the present invention, step (d) is carried out by reacting compound of Formula (V) with 1-(3-methoxypropyl)-4-piperidinamine to get compound of Formula (I). The reaction is carried out in presence of acid activating agent such as N,N,carbonyldiimidazole (CDI). During first step compound of Formula (V) reacts with CDI in presence of suitable solvent to form intermediate of compound of Formula (VI) which is isolated by filtration or without isolation is further reacted with 1-(3-methoxypropyl)-4-piperidinamine in the presence of suitable solvent to form Prucalopride of Formula (I). The suitable solvent including but not limited to THF, toluene, methanol, ethanol, N N-dimethylformamide, water and mixture thereof. The first reaction is carried out at about 0°C to about boiling point of the solvent used. Preferably, the reaction can be carried out at 10°C to 20°C. The second reaction is carried out at about 0°C to about boiling point of the solvent used. Preferably, the reaction can be carried out at 50°C to 60°C.
Further, obtained compound of Formula (VI) if isolated may optionally purified if required by any known technique in the art or the compound can be subjected to next reaction without isolation. In another embodiment, compound of Formula (VI) may be crystallized in inert organic solvent such as ethyl acetate, ethanol, tetrahydrofuran.
One more embodiment is to provide process for preparing pure compound of Formula (I) comprising isolating compound of Formula (VI) and then condensing with 1-(3-methoxypropyl)-4-piperidinamine.

In another embodiment the compound of Formula (I) obtained is substantially free of impurities compound of Formula (VIII) and compound (IX).

In another embodiment, compound of Formula (I) can be converted into its succinate salt by employing conventional methods known in the art.
In one embodiment, the present invention provides a process for the preparation of compound of Formula (I) as represented schematically in scheme 2 as below.

Scheme 2
In one embodiment, the present invention provides a process for the preparation of 1-(3-methoxypropyl)-4-piperidinamine as represented schematically in scheme 3 as below.

In another embodiment process of preparation of 1-(3-methoxypropyl)-4-piperidinamine involves condensation of 4-Boc-amino piperidine with bromo-3-methoxy propane in presence of potassium carbonate and acetonitrile to give Boc-protected compound, which is further treated with conc. HCl in n-butanol to obtain 1-(3-methoxypropyl)-4-piperidinamine which is further purified with toluene.
Wherever applicable in the example of the present invention, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material like N-acetyl-L-cysteine, SilaMetS thiol to remove metallic impurity, color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
The isolated compound according to the present invention may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100° C., less than about 80° C., less than about 60° C., less than about 50° C., less than about 30° C., or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the compound is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
Examples:
Example-1: Preparation of methyl 4-(acetylamino)-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate.
1,2- dibromoethane (465.89 g,) was added to a solution of methyl 4-(acetylamino)-3-bromo-5-chloro-2-hydroxybenzoate (100.0 g), potassium carbonate (51.41 g), and tetra-butyl ammonium bromide (10.0 g) in N, N’-dimethyl acetamide (450 mL) at room temperature. The resulting reaction mixture was heated to 50-55 °C and stirred until completion of the reaction. After completion of reaction, MTBE and water were added to reaction mixture and stirred. The obtained precipitate was filtered and dried to get methyl 4-(acetylamino)-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate. Yield 78%.

Example-2: Preparation of (methyl-4-acetylamino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylate
A solution of methyl 4-(acetylamino)-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (100.0 g) in N,N’-dimethyl acetamide (225 mL) was slowly added to a solution of freshly activated zinc (22.0 g) in N,N’-dimethyl acetamide (100 mL) at 50-70 ?C under nitrogen atmosphere and . The resulting reaction mixture was stirred. After completion of the reaction, reaction mass was quenched by HCl then cooled to room temperature. Obtained solid was filtered and was recrystallized in ethyl acetate to get (methyl-4-acetylamino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylate. Yield 58%.

Example-3: Preparation of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid
Methyl-4-acetylamino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylate was lot wise added to the solution of sodium hydroxide (74.0 g) in water (600 mL) at 70-90°C. The resulting mixture was stirred at 70-90?C till completion of reaction. After completion of reaction, reaction mass was cooled to room temperature to obtained sodium salt of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid. Sodium salt of compound was filtered and obtained solid was treated with dilute HCl at 70-80° for 30 minutes. Reaction mass was cooled to room temperature and stirred for 2-3 hours. The obtained solid was filtered and dried to afford the 4-amino-5-chloro-2, 3-dihydro-7-benzofurancarboxylic acid. Yield 90%. Content of compound of Formula (VII) is 0.023 (HPLC condition- column: Inertsil ODS 3V (250x4.6)mm 5µ; Ghost buster-II (50 x 3.0 mm); UV at 220 nm; eluent: buffer, acetonitrile). The other alkali/alkaline earth metal salt can be prepared by reacting Methyl-4-acetylamino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylate with appropriate base.

Example-4: Preparation of 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide monohydrate
Carbonyl di-imidazole (CDI) (10.62 g, 1.4 eq. mole) was added to the solution of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (10.0 g) in THF (150 mL) at room temperature and resulting reaction mixture was stirred at 10-20°C . Obtained precipitate was filtered to get an intermediate (4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-yl)(1H-imidazol-1-yl)methanone. Solution of 1-(3-methoxypropyl)-4-piperidinamine in THF was added to the solution of (4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-yl)(1H-imidazol-1-yl)methanone in THF at 25-35 °C. The resulting reaction mixture was stirred for at 50-60 °C until the completion of reaction. After completion of reaction, reaction mass was partially distilled to remove THF then water was added and distilled out the organic solvent and cooled to room temperature to obtain crude compound which was recrystallised in ethyl acetate to obtain pure 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide monohydrate. Yield 88%.
Example-5: preparation of 4-amino-5-chloro-2, 3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide butanedioic acid (1:1) salt (Prucalopride succinate):
Solution of succinic acid (35.18 g) in ethanol (70 mL) and water (70 mL) was added to the solution of 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofuran carboxamide monohydrate (100 g) in ethanol (600 ml) at 50-55°C. The resulting reaction mixture was stirred at 50-55°C. Reaction mass was cooled to room temperature and stirred. Obtained solid was filtered and dried to get Prucalopride succinate. Yield >86%.

Dated this: Feb. 24th, 2023 Dr. S. Ganesan
Alembic Pharmaceutical Ltd.
,CLAIMS:1. A process of preparation of Prucalopride of formula (I), comprising reacting the compound of Formula (Va) wherein M is selected from alkaline metal or alkaline earth metal, with an acid under suitable reaction temperature and suitable reaction time to obtain compound of Formula (V), wherein the content of compound of Formula (VII) in Formula (V) is less than 1% by HPLC.

2. The process as claimed in claim 1, wherein acid is selected from hydrochloric acid, sulfuric acid and acetic acid.

3. The process as claimed in claim 1, wherein alkaline metal is selected from sodium, potassium and cesium.

4. The process as claimed in claim 1, wherein alkaline earth metal is selected from magnesium and calcium.

5. The process as claimed in claim 1, wherein suitable reaction temperature is at 0°C to 100°C.

6. The process as claimed in claim 5, wherein suitable reaction temperature is at 50°C to 80°C.

7. The process as claimed in claim 1, wherein suitable reaction time is 25 to 35 minutes.

8. The process as claimed in claim 1, further comprising of converting compound of formula (V) into Prucalopride of Formula (I).

Dated this: Feb. 24th, 2023 Dr. S. Ganesan
Alembic Pharmaceutical Ltd.