DESC:RELATED PATENT APPLICATION
This application claims the priority to and benefit of Indian Provisional Patent Application No. 202141016880 filed on April 10, 2021; the disclosure of which are incorporated herein by reference.

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Prucalopride succinate (1) having purity greater than 99.0%.

BACKGROUND OF THE INVENTION
Prucalopride is a serotonin-4 (5-HT4) receptor agonist indicated for the treatment of chronic idiopathic constipation (CIC) in adults. It is chemically known as 4-amino-5-chloro-N-[1-(3-methoxypropyl) piperidin-4-yl]-2,3-dihydrobenzofuran-7-carboxamide succinate marketed by Shire development LLC under the brand name Motegrity.

The synthesis of Prucalopride succinate (1) has been reported in few patents the contents of which are hereby incorporated as reference in their entirety.

US5854260 patent discloses process for the preparation of Prucalopride succinate (1) by condensation of 4-amino-5-chloro-2,3-dihydro-7- benzofuran carboxylic acid with l-(3-methoxypropyl)-4-piperidinamine under nitrogen atmosphere in the presence of 1,1'-carbonyl bis-1H-imidazole. The obtained Prucalopride free base was then treated with water to afford Prucalopride monohydride which is then converted to its succinate salt by treating with succinic acid in ethanol.

The above disclosed process suffers from several disadvantages such as the use of column chromatographic purifications, tedious work-up procedures using excess amounts of solvents and low yields, low purity. To overcome the disadvantages associated with the above prior art process, the present inventors hereby developed an improved process for the preparation of Prucalopride succinate (1) with simple work-up procedures which results in high yield and high purity.

OBJECTIVE OF THE INVENTION
Accordingly, one objective of the present invention is to provide an improved process for the preparation of Prucalopride succinate (1).

Another objective of the present invention is to provide Prucalopride Succinate (1) with purity greater than 99.0% by High-performance liquid chromatography (HPLC).

SUMMARY OF THE INVENTION
Accordingly, in one embodiment, the present invention provides an improved process for the preparation of Prucalopride succinate (1) with purity greater than 99.0% by HPLC.

In another embodiment the steps involved in the preparation of Prucalopride succinate (1) comprising of
a) hydrolyzing methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate (7) in the presence of a base to obtain 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid (6);
b) coupling of 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid (6) with 4-amino-1-(3-methoxypropyl) piperidine (5) in the presence of a coupling agent and a base to afford 4-acetamido-5-chloro-N-(1-(3-methoxypropyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (4);
c) deacetylating of 4-acetamido-5-chloro-N-(1-(3-methoxypropyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (4) in the presence of a base in a protic solvent to obtain 4-amino-5-chloro-N-(1-(3-methoxypropyl) piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (3); and
d) converting 4-amino-5-chloro-N-(1-(3-methoxypropyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (3) to 4-amino-5-chloro-N-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydrobenzofuran-7-carboxamide succinate (Prucalopride succinate) (1) by reacting with succinic acid (2).

In another embodiment, the present invention provides a process for the preparation of intermediate compound methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate (7) comprising of
i. esterification of 4-amino-2-hydroxybenzoic acid (14) in the presence of an acid in a protic solvent to obtain methyl 4-amino-2-hydroxybenzoate (13);
ii. acetylating methyl 4-amino-2-hydroxybenzoate (13) with suitable acetylating agent to obtain methyl 4-acetamido-2-hydroxybenzoate (12);
iii. reacting methyl 4-acetamido-2-hydroxybenzoate (12) with thionyl chloride in a protic solvent to afford methyl 4-acetamido-5-chloro-2-hydroxybenzoate (11);
iv. brominating methyl 4-acetamido-5-chloro-2-hydroxybenzoate (11) with bromine to obtain methyl 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoate (10);
v. reacting methyl 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoate (10) with 1,2-dibromoethane (9) to obtain methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (8); and
vi. reductive cleavage of methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (8) in the presence of a suitable metal catalyst in a protic solvent to afford methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate (7).

In another embodiment the present invention provides a process for the preparation of intermediate compound 4-amino-1-(3-methoxypropyl) piperidine (5) comprising of:
I. reacting methyl acrylate (19) with 3-methoxypropan-1-amine (18) to obtain dimethyl 3,3'-(3-methoxypropylazanediyl) dipropanoate (17);
II. cyclization of dimethyl 3,3'-(3-methoxypropylazanediyl)dipropanoate (17) to obtain methyl 1-(3-methoxypropyl)-4-oxopiperidine-3-carboxylate (16) ;
III. deprotection of methyl 1-(3-methoxypropyl)-4-oxopiperidine-3-carboxylate (16) to obtain 1-(3-methoxypropyl) piperidin-4-one (15); and
IV. reductive amination of 1-(3-methoxypropyl) piperidin-4-one (15) to obtain
4-amino-1-(3-methoxypropyl)piperidine (5).

In another embodiment, optionally in-situ the intermediates dimethyl 3,3'-(3-methoxypropylazanediyl)dipropanoate (17) and methyl 1-(3-methoxypropyl)-4-oxopiperidine-3-carboxylate (16) are used in the preparation of intermediate compound 4-amino-1-(3-methoxypropyl)piperidine (5).

BRIEF DESCRIPTION OF DRAWINGS
Figure 1 illustrates the X-ray powder diffraction pattern (XRPD) of Prucalopride succinate (1).

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides an improved process for the preparation of Prucalopride Succinate (1) with purity greater than 99.0% by HPLC as illustrated in Scheme 1

Scheme 1

In another embodiment the steps involved in the preparation of Prucalopride succinate (1) comprising of
Step a) proceeds with hydrolyzing methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate (7) in the presence of a base in a protic solvent to obtain 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid (6). The reaction temperature was maintained at 0-45 °C. preferably 40-45 °C.

Step b) involves coupling of 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid (6) with 4-amino-1-(3-methoxypropyl) piperidine (5) in the presence of a coupling reagent and a base to afford 4-acetamido-5-chloro-N-(1-(3-methoxypropyl) piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (4).

Step c) involves deacetylating of 4-acetamido-5-chloro-N-(1-(3-methoxypropyl) piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (4) in the presence of a base in a protic solvent to obtain 4-amino-5-chloro-N-(1-(3-methoxypropyl) piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (3).

Step d) proceeds with converting 4-amino-5-chloro-N-(1-(3-methoxypropyl) piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (3) to 4-amino-5-chloro-N-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydro benzofuran-7-carboxamide succinate (Prucalopride succinate) (1) by reacting with succinic acid (2).

In another embodiment the present invention provides process for the preparation of intermediate compound methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate (7) as shown in scheme 2:

Scheme 2

The process comprises:
i. esterification of 4-amino-2-hydroxybenzoic acid (14) in the presence of an acid in a protic solvent to obtain methyl 4-amino-2-hydroxybenzoate (13);
ii. acetylating methyl 4-amino-2-hydroxybenzoate (13) with suitable acetylating agent to obtain methyl 4-acetamido-2-hydroxybenzoate (12);
iii. reacting methyl 4-acetamido-2-hydroxybenzoate (12) with thionyl chloride in a protic solvent to afford methyl 4-acetamido-5-chloro-2-hydroxybenzoate (11);
iv. brominating methyl 4-acetamido-5-chloro-2-hydroxybenzoate (11) with bromine to obtain methyl 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoate (10);
v. reacting methyl 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoate (10) with 1,2-dibromoethane (9) to obtain methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (8); and
vi. reductive cleavage of methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (8) in the presence of a suitable metal catalyst in a protic solvent to afford methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate (7).

In another embodiment the present invention provides a process for the preparation of intermediate compound 4-amino-1-(3-methoxypropyl) piperidine (5) comprising of:
I. reacting methyl acrylate (19) with 3-methoxypropan-1-amine (18) in a protic solvent to obtain dimethyl 3,3'-(3-methoxypropylazanediyl) dipropanoate (17);
II. cyclization of dimethyl 3,3'-(3-methoxypropylazanediyl)dipropanoate (17) in the presence of a base in aprotic solvent to obtain methyl 1-(3-methoxypropyl)-4-oxopiperidine-3-carboxylate (16) ;
III. deprotection of methyl 1-(3-methoxypropyl)-4-oxopiperidine-3-carboxylate (16) in a suitable acid and followed by add base to adjust the pH in a aprotic solvent to obtain 1-(3-methoxypropyl) piperidin-4-one (15); and
IV. reductive amination of 1-(3-methoxypropyl) piperidin-4-one (15) in the presence of a base in a protic solvent and suitable metal catalyst to obtain 4-amino-1-(3-methoxypropyl)piperidine (5).

Scheme 3
The base used in the present invention is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium methoxide, ammonia, triethyl amine, diisopropyl ethyl amine and the like, preferably using sodium hydroxide or potassium carbonate.

The protic solvents used in the present invention is selected form the group consisting of water or C1-C4-alkanols such as methanol, ethanol, propanol, isopropanol, butanol, C2-C4-alkandiols, such as ethylene glycol or propylene glycol, and ether alkanols such as diethylene glycol, and mixtures thereof. Particularly preferred are water or C1-C4-alkanols, e.g., methanol, ethanol, isopropanol, butanol, or mixtures thereof, methanol, ethanol, or water.

The aprotic solvents used in the present invention is selected from the group consisting of tetrahydrofuran, dichloromethane, dichloroethane, acetone, diethyl ether, toluene, ethyl acetate, dimethyl acetamide, dimethylformamide, acetonitrile and the like, preferably using tetrahydrofuran, toluene, dimethyl acetamide or dimethylformamide.

The coupling reagent used in the present invention is selected from the group consisting of diisopropylcarbodiimide (DIC), Dicyclohexylcarbodiimide (DCC), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl), 1,1’-Carbonyldiimidazole (CDI), 1-Hydroxybenzotriazole (HOBt) and the like, preferably using 1,1’-Carbonyldiimidazole (CDI).

The acid used in the present invention is selected from the group consisting of hydrochloric acid, acetic acid, sulphuric acid, trifluoro acetic acid and the like, preferably using hydrochloric acid or sulphuric acid.

The acetylating agent used in the present invention is selected from the group consisting of acetyl chloride, acetic anhydride, acetic acid and the like or mixture thereof, preferably using mixture of acetic acid and acetic anhydride.

The metal catalyst used for the reductive cleavage/ reductive amination is selected from the group consisting of palladium, zinc, platinum (IV) oxide, iron, Raney nickel, sodium and the like, preferably using zinc or Raney nickel.

In another embodiment, optionally in-situ the intermediates dimethyl 3,3'-(3-methoxypropylazanediyl)dipropanoate (17) and methyl 1-(3-methoxypropyl)-4-oxopiperidine-3-carboxylate (16) are used in the preparation of intermediate compound 4-amino-1-(3-methoxypropyl)piperidine (5).

In another embodiment, the present invention further relates to certain intermediates formed in the aforementioned processes. One novel intermediate is a compound of general formula (16a) or salt.

wherein R1, R2 are independently selected from alkyl group..

In another embodiment the present invention further relates to novel intermediate (16a) in the preparation of Prucalopride succinate (1).

In another embodiment the present invention further relates to the pure Prucalopride succinate (1) is having purity greater than 99.0 % (w/w) by HPLC and each impurity is controlled less than 0.15%.

In another embodiment the present invention provides Prucalopride succinate (1) having characteristic X-Ray powder diffraction is as shown in Figure-1, may have 2(?) values (±0.2) as tabulated in Table-1 below:

Two theta (2T) values Relative Intensity (I/Io)
2.72 12.2
3.95 7.6
5.18 7.2
6.56 7.9
7.59 31.7
8.99 24.5
9.8 33.8
11.0 7.3
12.32 8.9
12.56 7.6
12.98 8.6
13.63 46
15.39 66.4
17.52 13.1
18.16 26.7
18.93 12.8
20.0 55.3
20.64 30.5
21.97 100
23.17 29.5
23.96 43.8
24.44 33.1
24.7 20.9
26.2 13.4
27.51 22.1
28.19 19.4
28.72 20.8
29.81 16.7
30.4 10.6
30.96 12.5
32.24 10.5
32.81 7.1
35.47 9.0
36.48 9.0
38.86 9.0
41.52 13.3
42.64 10.2
42.94 11.2

The following examples further illustrate the present invention but should not be construed in any way as to limit its scope.

EXAMPLES
EXAMPLE 1: Preparation of 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid (6)
To 100 g of methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate (7), 500 mL of methanol, 500 mL of tetrahydrofuran were added at 25-30 0C. The reaction mixture was cooled to 15-20 0C and 44.5 g of sodium hydroxide in 500 mL of water was added. The reaction mass was heated to 40-45 0C and stirred for 2-3 h at 40-45 0C. The reaction mass was cooled to 0-5 0C and pH was adjusted to 1-2 by using 100 mL of hydrochloric acid, stirred for 1 h and filtered. The obtained solid was washed with water and dried under vacuum at below 55 0C to afford 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid (6).
Yield: 85%; Purity: 96%

EXAMPLE 2: Preparation of 4-acetamido-5-chloro-N-(1-(3-methoxypropyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (4)
To 100 g of 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid (6), 400 mL of dimethyl formamide was added at 25-30 0C. 95.1 g of 1,1’-carbonyldimidazole was slowly added and stirred for 10-20 min at 25-30 0C.The reaction mass was heated to 50-55 0C, stirred for 1-2 h and 71 g of 1-(3-methoxypropyl)piperidin-4-amine (5) was added slowly at 50-55 0C and stirred for 4-5 h. cold water was added, stirred for 1h and filtered. The obtained solid was washed with water and dried under vacuum at below 55 0C to afford 4-acetamido-5-chloro-N-(1-(3-methoxypropyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (4). Yield: 65%; Purity: 95%

EXAMPLE 3: Preparation of 4-amino-5-chloro-N-(1-(3-methoxypropyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (3)
100 g of 4-acetamido-5-chloro-N-(1-(3-methoxypropyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (4) was taken in 700 mL of ethanol at 25-30 0C. 29.2 g of sodium hydroxide dissolved in 300 mL of water was slowly added and the reaction mass was heated to 80-85 0C. . The solvent was removed completely under vacuum and the obtained residue was cooled to 25-30 0C and filtered. The obtained solid was washed with water and dried under vacuum for 6-7 h to afford 4-amino-5-chloro-N-(1-(3-methoxypropyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (3).Yield: 85%; Purity: 96%

EXAMPLE 4: Preparation of 4-amino-5-chloro-N-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydrobenzofuran-7-carboxamide succinate (Prucalopride succinate) (1)
To 100 g of 4-amino-5-chloro-N-(1-(3-methoxypropyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (3), 800 mL of ethanol was added at 25-30 0C. The reaction mass was heated to 50-55 0C, 10 g of activated carbon was added and stirred for 20-30 min. The reaction mass was filtered. To the obtained filtrate, 32 g of succinic acid was added at 50-55 0C. The reaction mass was heated to 80-85 0C, stirred for 1-2 h and gradually cooled to 25-30 0C. The reaction mass was filtered and the solid was washed with ethanol and then under vacuum to afford 4-amino-5-chloro-N-[1-(3-methoxy propyl)piperidin-4-yl]-2,3-dihydrobenzofuran-7-carboxamide succinate (Prucalopride succinate) (1).Yield: 95%; Purity: >99.0%

EXAMPLE 5: Preparation of methyl 4-amino-2-hydroxybenzoate (13)
To 100 g of 4-amino-2-hydroxybenzoic acid, 700 mL of methanol was added at 25-30 0C. The reaction mass was cooled to 0-5 0C, 140 mL of concentrate sulphuric acid was added and stirred for 15-20 min at 0-5 0C. The reaction mass was heated to 65-70 0C and stirred for 12-14 h. The reaction mass was cooled to 0-5 0C and stirred for 1-2 h then filtered. The obtained solid was washed with cold methanol at 0-5 0C and dried under vacuum to afford methyl 4-amino-2-hydroxybenzoate (13) as sulphate salt. Yield: 92%; Purity: 97%

EXAMPLE 6: Preparation of methyl 4-acetamido-2-hydroxybenzoate (12)
To 100 g of methyl 4-amino-2-hydroxybenzoate (13), 500 mL of water, 400 ml of ethyl acetate were added at 25-30 0C. The reaction mass was cooled to 0-5 0C and 163 g of sodium bicarbonate was added portion wise. The reaction mass was warmed to 25-30 0C, stirred for 15-30 min and the layers were separated. The organic layer was taken, and 163 g of sodium carbonate was added. The reaction mass was cooled to 0-5 0C and 140 g of acetyl chloride was added, stirred for 15-30 min. The reaction mass was warmed to 25-30 0C and stirred for 2-3 h. 500 mL of water was added and stirred for 15-20 min and layers were separated. The organic layer was taken and 80% of the solvent was distilled off under vacuum. The obtained compound was dried under vacuum for 10-12 h to afford methyl 4-acetamido-2-hydroxybenzoate (12). Yield: 80%; Purity: 98%.

EXAMPLE 7: Preparation of methyl 4-acetamido-5-chloro-2-hydroxybenzoate (11)
To 100 g of methyl 4-acetamido-2-hydroxybenzoate (12), 1200 mL of dichloromethane was added at 25-30 0C. The reaction mass was cooled to -5 to 0 0C, 90 g of sulfuryl chloride in 300 mL of dichloromethane was added dropwise and stirred for 30-45 min. 500 mL of water was added and pH was adjusted to 4-5 by sodium hydroxide at 0-5 0C. The solvent was removed under vacuum and filtered. The obtained solid was washed with water and dried under vacuum to afford methyl 4-acetamido-5-chloro-2-hydroxybenzoate (11). Yield: 88%; Purity: 75%.

EXAMPLE 8: Preparation of methyl 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoate (10).
To 100 g of methyl 4-acetamido-5-chloro-2-hydroxybenzoate (11), 600 mL of acetic acid, 600 mL of water were added at 25-30 0C. 98 g of bromine was added dropwise and stirred for 14-15 h at 25-30 0C. The reaction mass was cooled to 10-15 0C and 500 mL of 50% aqueous sodium sulphite solution was added and filtered. The obtained solid was washed with water and dried under vacuum to afford methyl 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoate (10). Yield: 90%; Purity: 98%

EXAMPLE 9: Preparation of methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (8)
To 100 g of methyl 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoate (10), 600 mL of dimethyl acetamide, 44 g of potassium carbonate were added at 25-30 0C. The reaction mass was heated to 50-55 0C and 115 g of 1,2-dibromoethane was slowly added for a period of 45-60 min at 50-55 0C, stirred for 8-9 h. 500 mL of water was added, stirred for 1h at 50-55 0C. The reaction mass was cooled to 25-30 0C, stirred for 6-7 h and filtered. To the obtained solid 1200 mL of toluene, 10 g of hyflo were added at 25-30 0C. The reaction mass was heated to 110-120 0C and stirred for 30-40 min and filtered. The obtained solid was washed with toluene and dried under vacuum to afford methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (8). Yield: 75%; Purity: 96%

EXAMPLE 10: Preparation of methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate (7)
To 100 g of methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (8), 250 ml of dimethyl acetamide was added at 25-30 0C. The reaction mass was degassed with nitrogen gas for 1-2 h and 30 g of zinc was added under nitrogen atmosphere. The reaction mass further degassed with nitrogen gas for 1-2 h at 25-30 0C. The reaction mass was heated to 50-55 0C and stirred for 10-12 h. 80 ml of water, 70 ml of concentrated hydrochloric acid and 50 mL of isopropyl alcohol were added dropwise at 50-55 0C and stirred for 1h. The reaction was further heated to 75-80 0C, 1000 mL of water was added and stirred for 1h. The reaction mass was cooled to 25-30 0C, stirred for 4-5 h and filtered. The obtained solid was washed with water and dried under vacuum. To the obtained residue, toluene was added and heated to 60-65 0C. And tetrahydrofuran was added and stirred for 30-45 min, filtered. The obtained solid was washed with toluene and dried under vacuum to afford methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate (7). Yield: 50%; Purity: 98%

EXAMPLE 11: Preparation of 1-(3-methoxypropyl) piperidin-4-one (15)
To 214 g of methyl acrylate (19), 500 ml of methanol was added at 25-30 0C. Cool the reaction mass and slowly added 100 g of 3-methoxypropan-1-amine (18), maintained the reaction mass for certain time. The reaction mass (crude) was degassed with nitrogen gas for 20-30 minutes. Take another round bottom flask, then charge 400ml of toluene and 230 ml of sodium methoxide at 25-30 °C, raise the reaction mass temperature to 75-80oC and slowly added reaction mass in 400 ml of toluene. Maintained the reaction mass for 5-6 hr at 110-115oC and cooled the reaction mass to 10 to 15oC. Take another RB flask to this added 800 mL of 25% hydrochloric acid at 25-30 °C, cooled the reaction mass and slowly add above reaction mass at 0 to 5oC. Stirred for 15 to 30 min and separated aqueous and organic layer, adjust the reaction mass pH to 11.0-12.0 by added slowly 400 ml of 30% aqueous sodium hydroxide. And dichloromethane was added and stirred for 10-30 min, filtered. The obtained organic layer dried with sodium sulphate to afford 1-(3-methoxypropyl) piperidin-4-one (15). Yield: 68-75%; Purity: 98%

EXAMPLE 12: Preparation of 4-amino-1-(3-methoxypropyl) piperidine (5).
To 100 g of 1-(3-methoxypropyl) piperidin-4-one (15), 1000 ml of methanolic ammonia was added and stirred for 1-2 hrs. 40 g of Raney Nickel was added and hydrogenated for 16 to 16 hrs at 25-30°C. The reaction mass was filtered through hyflo bed and distilled off under vacuum to obtain solid 4-amino-1-(3-methoxypropyl) piperidine (5).
,CLAIMS:1. A process for the preparation of Prucalopride succinate of formula (1) with purity greater than 99.0% by HPLC, comprising the steps of:
a) hydrolyzing methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate (7) in the presence of a base to obtain 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid (6);

b) coupling of 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid (6) with 4-amino-1-(3-methoxypropyl) piperidine (5) in the presence of a coupling reagent and a base to afford 4-acetamido-5-chloro-N-(1-(3-methoxypropyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (4);

c) deacetylating of 4-acetamido-5-chloro-N-(1-(3-methoxy propyl) piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (4) in the presence of a base to obtain 4-amino-5-chloro-N-(1-(3-methoxypropyl) piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (3); and

d) converting 4-amino-5-chloro-N-(1-(3-methoxypropyl) piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide (3) to 4-amino-5-chloro-N-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydro benzofuran-7-carbox amide succinate (Prucalopride succinate) (1) by reacting with succinic acid (2).

2. The process as claimed in claim 1, wherein, the compound of formula-7

is prepared by the process comprising the step of:
a) esterification of 4-amino-2-hydroxybenzoic acid (14) in the presence of an acid in a protic solvent to obtain methyl 4-amino-2-hydroxybenzoate (13);

b) acetylating methyl 4-amino-2-hydroxybenzoate (13) with suitable acetylating agent to obtain methyl 4-acetamido-2-hydroxybenzoate (12);

c) reacting methyl 4-acetamido-2-hydroxybenzoate (12) with thionyl chloride in a protic solvent to afford methyl 4-acetamido-5-chloro-2-hydroxybenzoate (11);

d) brominating methyl 4-acetamido-5-chloro-2-hydroxybenzoate (11) with bromine to obtain methyl 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoate (10);

e) reacting methyl 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoate (10) with 1,2-dibromoethane (9) to obtain methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (8); and

f) reductive cleavage of methyl 4-acetamido-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoate (8) in the presence of a suitable metal catalyst in a protic solvent to afford methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate (7).

3. The process as claimed in claim 1, wherein, the compound of formula 5

is prepared by the process comprising the step of:
a) reacting methyl acrylate (19) with 3-methoxypropan-1-amine (18) in a protic solvent to obtain dimethyl 3,3'-(3-methoxypropylazanediyl) dipropanoate (17);

b) cyclization of dimethyl 3,3'-(3-methoxypropylazanediyl)dipropanoate (17) in the presence of a base in aprotic solvent to obtain methyl 1-(3-methoxypropyl)-4-oxopiperidine-3-carboxylate (16) ;

c) deprotection of methyl 1-(3-methoxypropyl)-4-oxopiperidine-3-carboxylate (16) in a suitable acid and followed by add base to adjust the pH in aprotic solvent to obtain 1-(3-methoxypropyl) piperidin-4-one (15); and

d) reductive amination of 1-(3-methoxypropyl) piperidin-4-one (15) in the presence of a base in a protic solvent and suitable metal catalyst to obtain 4-amino-1-(3-methoxypropyl)piperidine (5).

4. The process as claimed in claims 1, 2 and 3, wherein, suitable bases used in present invention is selected from the group consisting of lithium hydroxide, sodium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, ammonia, triethyl amine, diisopropyl ethyl amine, and the like; suitable acids used in the present invention is selected from the group consisting of hydrochloric acid, acetic acid, sulphuric acid, trifluoro acetic acid and the like.

5. The process as claimed in claims 1, 2 and 3, wherein, suitable solvents used in the present invention is selected from protic solvents and aprotic solvents, wherein, protic solvents selected from ethanol, methanol, isopropanol, n-butanol, water, and the like; aprotic solvents selected from tetrahydrofuran, dichloromethane, dichloroethane, acetone, diethyl ether, toluene, ethyl acetate, dimethyl acetamide, dimethylformamide, acetonitrile and the like.

6. The process as claimed in claim 1, wherein, coupling reagent used in the present invention is selected from the group consisting of diisopropylcarbodiimide (DIC), Dicyclohexylcarbodiimide (DCC), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl), 1,1’-Carbonyldiimidazole (CDI), 1-Hydroxybenzotriazole (HOBt) and the like.

7. The process as claimed in claim 2, wherein, acetylating agent used in the present invention is selected from the group consisting of acetyl chloride, acetic anhydride, acetic acid and the like or mixture thereof.

8. The process as claimed in claims 2 and 3, wherein, metal catalyst used in the present invention is selected from the group consisting of palladium, zinc, platinum (IV) oxide, iron, Raney nickel, sodium, and the like.

9. A novel process for the preparation of 4-amino-1-(3-methoxypropyl)piperidine (5), comprising the steps of:
a) cyclization of dimethyl 3,3'-(3-methoxypropylazanediyl) dipropanoate (17) in the presence of base in a aprotic solvent to obtain methyl 1-(3-methoxypropyl)-4-oxopiperidine-3-carboxylate (16);

b) deprotection of methyl 1-(3-methoxypropyl)-4-oxopiperidine-3-carboxylate (16) in a suitable acid to obtain 1-(3-methoxypropyl) piperidin-4-one (15); and

c) reductive amination of 1-(3-methoxypropyl) piperidin-4-one (15) in the presence of a base and suitable metal catalyst to obtain 4-amino-1-(3-methoxypropyl)piperidine (5).

10. A compound, methyl 1-(3-methoxypropyl)-4-oxopiperidine-3-carboxylate of formula (16):