Related Applications:

This application claims the benefit of priority of our Indian patent application number 201641008709 filed on 14 ^th March 2016, which are incorporated herein by reference.

Field of the Invention:

The present invention relates to an improved process for the preparation of [[2(S)-

[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidinyl]me thyl]-l-oxo-3-phenylpropyl] amino]acetic acid d ula:

Formula- la

Background of the Invention :

Alvimopan dihydrate, chemically known as [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4- dimethyl-l-piperidinyl]methyl]-l-oxo-3-phenylpropyl]amino]ac etic acid dihydrate is indicated to accelerate the time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis.

CN101967118 patent application discloses process for the preparation of ethyl 2-((S)- 2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl)piperid in-l-yl)propanamido)acetate hydrochloride compound of formula-5a by reacting 3-((3R,4R)-3,4-dimethylpiperidin-4-yl) phenol with (S)-isobutyl 2-(2-benzyl-3-(methylsulfonyloxy)propanamido)acetate in presence of triethyl amine and toluene to provide compound of formula-4 with low yield and purity.

There remains an unmet need for a process for preparation of Alvimopan dihydrate which provides high yield, purity and also applicable for multi-kilogram production. Brief description of the Invention:

The first aspect of the present invention is to provide a process for the preparation of acid addition salts of ethyl 2-((S)-2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl piperidin-l-yl)propanamido)acetate compound of compound of general formula-5.

The second aspect of the present invention is to provide a process for the purification of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l]methyl]-l-oxo-3-phenyl propyl]amino]acetic acid compound of formula- 1.

The third aspect of the present invention is to provide an improved process for the preparation of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l]methyl]-l-oxo -3-phenylpropyl]amino]acetic acid dihydrate compound of formula- 1 a.

The fourth aspect of the present invention is to provide a process for the preparation of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l]methyl]-l-oxo-3-phenyl propyl]amino]acetic acid dihydrate compound of formula- la, comprising of:

a) Treating [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l]methyl]-l- oxo-3-phenylpropyl]amino]acetic acid compound of formula- 1 with a suitable base in a suitable solvent,

b) optionally, filtering the reaction mixture,

c) adding a suitable solvent to the reaction mixture,

d) acidifying the reaction mixture with a suitable acid and stirring the reaction mixture, e) filtering the solid and drying to provide [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4- dimethyl-I-piperidinyl]methyl]-l-oxo-3-phenylpropyl]amino]ac etic acid dihydrate compound of formula- la. Detailed description of the Invention:

As used herein the term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; "ether solvents" such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethyl acetamide (DMA), dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), N- methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2- fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 1,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; "polar solvents" such as water or mixtures thereof. As used herein the present invention the term "suitable base" refers to "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylamino pyridine (DMAP), N-methylmorpholine (NMM), 2,6-lutidine, lithium diisopropylamide; organo silicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof. As used herein the term "HA" refers to acid such as hydro bromic acid, hydrochloric acid, hydro iodic acid, phosphoric acid, sulfuric acid, nitric acid, oxalic acid, tartaric acid, fumaric acid, dibenzoyl tartaric acid, maleic acid, succinic acid, acetic acid, malic acid and formic acid. The first aspect of the present invention provides a process for the preparation of acid addition salts of ethyl 2-((S)-2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl piperidin-l-yl)propanamido)acetate compound of general formula-5, comprising of reacting 3-((3R,4R)-3,4-dimethylpiperidin-4-yl)phenol compound of formula-2 with (S)-ethyl 2-(2- benzyl-3-(methylsulfonyloxy)propanamido)acetate compound of formula-3 in presence of a suitable base in a suitable solvent to provide ethyl 2-((S)-2-benzyl-3-((3R,4R)-4-(3-hydroxy phenyl)-3,4-dimethylpiperidin-l-yl)propanamido)acetate compound of formula-4, which on further treating with a suitable acid in a suitable solvent to provide compound of general formula-5. Wherein, the suitable base is selected from organic and inorganic base; preferably inorganic base; and suitable solvent is selected from alcohol solvent such as tertiary butanol;

Wherein, the suitable acid is selected from HC1 gas, aqueous HC1, dry HC1, ethyl acetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl; preferably ethyl acetate-HCl, hydro bromic acid, hydro iodic acid, phosphoric acid, sulfuric acid, nitric acid, acetic acid, oxalic acid, tartaric acid, fumaric acid, dibenzoyl tartaric acid, maleic acid, succinic acid, malic acid and formic acid.

The preferred embodiment of the present invention provides a process for the preparation of ethyl 2-((S)-2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylp iperidin- 1-yl) propanamido)acetate hydrochloride compound of formula-5a, comprising of reacting 3- ((3R,4R)-3,4-dimethylpiperidin-4-yl)phenol compound of formula-2 with (S)-ethyl 2-(2- benzyl-3-(methylsulfonyloxy)propanamido)acetate compound of formula-3 in presence of sodium bicarbonate in tertiary butanol to provide ethyl 2-((S)-2-benzyl-3-((3R,4R)-4-(3- hydroxyphenyl)-3,4-dimethylpiperidin-l-yl)propanamido)acetat e compound of formula-4, which on further treating with ethyl acetate-HCl in ethyl acetate to provide compound of formula-5a.

CN 102127005 patent application discloses process for the preparation of ethyl 2-((S)- 2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl)piperid in-l-yl)propanamido)acetate compound of formula-4 by reacting 3-((3R,4R)-3,4-dimethylpiperidin-4-yl)phenol compound of formula-2 with (S)-ethyl 2-(2-benzyl-3-(methylsulfonyloxy)propanamido)acetate compound of formula-3 in the presence of triethyl amine and acetonitrile to provide compound of formula-4 with low yield and purity.

CN102757379 patent discloses process for the preparation of ethyl 2-((S)-2-benzyl-3- ((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl)piperidin-l-yl)pro panamido)acetate compound of formula-4 by reacting 3-((3R,4R)-3,4-dimethylpiperidin-4-yl)phenol compound of formula-2 with (S)-ethyl 2-(2-benzyl-3-(4-nitrophenylsulfonyloxy)propanamido)acetate in the presence of triethyl amine, ethylene glycol dimethyl ether or diethyl ether or methyl tert- butyl ether or tetrahydrofuran to provide compound of formula-4 with low yield and purity.

The prior art process for the preparation of compound of formula-4 involves reacting the compound of formula-2 with formula-3 in the presence of various pharmaceutical solvents such as acetonitrile, dimethyl formamide, n-butanol, ethylene glycol dimethyl ether, diethyl ether, methyl tert-butyl ether, tetrahydrofuran and toluene to provide compound of formula-4 with low yield and purity, which was further purified for several times to achieve pure compound. The inventors of the present invention have also repeated the reaction by utilizing the same solvents. It was observed that in most of the cases the reaction was not initiated and in some cases the yields of the desired compound was very low. The results were summarized in the following table.

Hence, there was a need to overcome this drawback. After a lot of experimentation and research this problem was overcame. It was found that when the reaction solvent was replaced by tertiary butanol, it was observed that the yield of the desired compound was increased drastically. The result was illustrated in the following table:

Usage of organic base like triethyl amine needed tedious workup, which has been overcome by the use of inorganic bases like sodium bicarbonate which made the process more conducive. Hence, the present process is more advantageous, cost effective, eco-friendly and commercially viable when compared over the prior known processes.

The second aspect of the present invention provides a process for the purification of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l]methyl]-l-oxo-3-phenyl propyl]amino]acetic acid compound of formula-1, comprising of the following steps:

a) Adding a suitable solvent to [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l- piperidinyl]methyl]-l-oxo-3-phenylpropyl]amino]acetic acid compound of formula-1, b) adding a suitable base to the reaction mixture,

c) acidifying the reaction mixture using a suitable acid,

d) cooling the reaction mixture to a suitable temperature,

e) stirring the reaction mixture,

f) filtering the solid and drying to get the pure [[2(S)-[[4(R)-(3-hydroxyphenyl)-3 (R),4- dimethyl- 1 -piperidinyl]methyl]- 1 -oxo-3-phenylpropyl] amino] acetic acid compound of formula-1.

Wherein, in step-a) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, chloro solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, polar solvents like water and acids like acetic acid, formic acid and mixtures thereof;

in step-c) the suitable acid is selected from mineral acids or organic acid selected from acetic acid, oxalic acid, formic acid, methane sulfonic acid, ethane sulfonic acid, paratoluene sulfonic acid;

in step-b) the suitable base is selected from organic or inorganic base; preferably inorganic base such as ammonia;

in step-d) the suitable temperature is ranging from 0°C to 30°C.

The preferred embodiment of the present invention provides a process for the purification of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l]methyl]-l - oxo-3-phenyl propyl]amino]acetic acid compound of formula-1, comprising of the following steps: a) Adding methanol to [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l] methyl]-l-oxo-3-phenylpropyl]amino]acetic acid compound of formula-1, b) adding ammonia to the reaction mixture and stirring the reaction mixture,

c) acidifying the reaction mixture using acetic acid,

d) cooling the reaction mixture to 10-15°C,

e) stirring the reaction mixture,

f) filtering the solid and drying to get the pure [[2(S)-[[4(R)-(3-hydroxyphenyl)-3 (R),4- dimethyl-l-piperidinyl]methyl]-l-oxo-3-phenylpropyl]amino]ac etic acid compound of formula-1.

The [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l]methyl]-l-oxo-3- phenylpropyl]amino]acetic acid dihydrate compound of formula- la obtained according to the present invention having the olefin acid impurity less than 0.1%; preferably less than 0.05%; more preferably less than 0.02% as measured by HPLC.

Further, the compound of formula- la obtained according to the present invention having the piperidinyl phenol impurity, DMP ester impurity, des-methyl impurity and metabolite impurity (acid impurity) less than 0.1%; preferably less than 0.06%; more preferably less than 0.02% as measured by HPLC.

The third aspect of the present invention provides an improved process for the preparation of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l]methyl]-l-oxo -3-phenylpropyl] amino]acetic acid dihydrate compound of formula- la, comprising of the following steps:

a) Reacting 3-((3R,4R)-3,4-dimethylpiperidin-4-yl)phenol compound of formula-2

Formula-2

with (S)-ethyl 2-(2-benzyl-3-(methylsulfonyloxy)propanamido)acetate compound of formula-3

Formula-3

in presence of a suitable base in a suitable solvent to provide ethyl 2-((S)-2-benzyl-3- ((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-l-yl)prop anamido)acetate compound of fo

Formula-4

which on further treating with a suitable acid in a suitable solvent to provide acid addition salts of ethyl 2-((S)-2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl piperidin-l-yl)propanamido)acetate compound of general formula-5,

Formula-5

wherein, HA = acid such as HC1, HBr, HI, phosphoric acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, tartaric acid, fumaric acid, dibenzoyl tartaric acid, maleic acid, succinic acid, malic acid and formic acid

b) treating the compound of general formula-5 with a suitable base in a suitable solvent to provide [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l]methyl]- l-oxo-3-phenylpropyl]amino]acetic acid compound of formula- 1,

Formula-1

c) purifying the compound of formula- 1 by treating it with a suitable base and a suitable acid in a suitable solvent to provide pure [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4- dimethyl-l-piperidinyl]methyl]-l-oxo-3-phenylpropyl]amino]ac etic acid compound of formula- 1,

d) treating the compound of formula-1 with a suitable base and a suitable acid in a suitable solvent to provide [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l- piperidinyl]methyl]-l-oxo-3-phenylpropyl]amino]acetic acid dihydrate compound of formula- la.

Formula- la

Wherein, in step-a) to d) the suitable base is selected from organic or inorganic base, preferably inorganic base;

in step-a) the suitable acid is same as defined in the first aspect of the present invention; in step-a) to d) the suitable solvent is selected from hydrocarbon solvents, ketone solvents, ester solvents, alcohol solvents, chloro solvents, ether solvents, polar aprotic solvents and polar solvent like water, acid like acetic acid, formic acid or there mixture thereof;

in step-c) & d) the suitable acid is selected from mineral acids or organic acid selected from acetic acid, oxalic acid, formic acid, methane sulfonic acid, ethane sulfonic acid, para toluene sulfonic acid.

The preferred embodiment of the present invention provides an improved process for the preparation of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l]methyl]-l- oxo-3-phenylpropyl]amino]acetic acid dihydrate compound of formula-la, comprising of the following steps:

a) Reacting 3-((3R,4R)-3,4-dimethylpiperidin-4-yl)phenol compound of formula-2 with (S)-ethyl 2-(2-benzyl-3-(methylsulfonyloxy)propanamido)acetate compound of formula-3 in presence of sodium bicarbonate in tertiary butanol to provide ethyl 2-((S) -2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperid in-l-yl)propanamido) acetate compound of formula-4, which on further treating with ethyl acetate-HCl in ethyl acetate to provide ethyl 2-((S)-2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4- dimethylpiperidin-l-yl)propanamido)acetate hydrochloride compound of formula-5a, b) treating the compound of formula-5a with aqueous sodium hydroxide in a mixture of isopropanol and water to provide [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l- piperidinyl]methyl]-l-oxo-3-phenylpropyl]amino]acetic acid compound of formula-1, c) purifying the compound of formula-1 by treating it with ammonia and acetic acid in methanol to provide pure [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l- piperidinyl]methyl]-l-oxo-3-phenylpropyl]amino]acetic acid compound of formula-1, d) treating the compound of formula-1 with ammonia and acetic acid in a mixture of methanol and water to provide [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l- piperidinyl]methyl]-l-oxo-3-phenylpropyl]amino]acetic acid dihydrate compound of formula- la. [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l]methyl]-l-oxo-3- phenylpropyl]amino]acetic acid dihydrate compound of formula-la obtained according to the present invention is having purity more than 99.9% as measured by HPLC.

The starting material (S)-ethyl 2-(2-benzyl-3-(methylsulfonyloxy)propanamido) acetate compound of formula-3 used in the present invention can be prepared according to the process disclosed in our PCT publication WO2016/038622 A2 or any of the process known in the art.

The starting material 3-((3R,4R)-3,4-dimethylpiperidin-4-yl)phenol compound of formula-2 used in the present invention can be prepared according to the any of the process disclosed in the art.

The fourth aspect of the present invention provides a process for the preparation of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l]methyl]-l-oxo-3-phenyl propyl]amino]acetic acid dihydrate compound of formula- la, comprising of:

a) Treating [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l]methyl]-l- oxo-3-phenylpropyl]amino]acetic acid compound of formula-1 with a suitable base in a suitable solvent,

b) optionally, filtering the reaction mixture,

c) adding a suitable solvent to the reaction mixture,

d) acidifying the reaction mixture with a suitable acid and stirring the reaction mixture, e) filtering the solid and drying to provide [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4- dimethyl-l-piperidinyl]methyl]-l-oxo-3-phenylpropyl]amino]ac etic acid dihydrate compound of formula- la.

Wherein step-a) the suitable base is selected from inorganic base and in step-a) & b) the suitable solvent is selected from alcohol solvents, chloro solvents, ester solvents, ether solvents, hydrocarbon solvents, ketone solvents, polar aprotic solvents and polar solvent like water or mixture thereof,

in step-d) suitable acid is selected from mineral acid or organic acid such as oxalic acid, acetic acid, formic acid, malic acid, maleic acid, fumaric acid and tartaric acid.

The preferred embodiment of the present invention provides a process for the preparation of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l -piperidinyljmethyl]- 1 - oxo-3-phenylpropyl]amino]acetic acid dihydrate compound of formula-la, comprising of: a) Treating [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l]methyl]-l- oxo-3-phenylpropyl]amino]acetic acid compound of formula-1 with aqueous ammonia in methanol,

b) filtering the reaction mixture,

c) adding water to the reaction mixture, d) acidifying the reaction mixture with acetic acid and stirring the reaction mixture, e) filtering the solid and drying to provide [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4- dimethyl- 1 -piperidinyl]methyl]- 1 -oxo-3 -phenylpropyl] amino] acetic acid dihydrate compound of formula- la.

[[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperid inyl]methyl]-l-oxo-3- phenylpropyl] amino] acetic acid dihydrate compound of formula- la produced by the present invention can be further micronized or milled in a conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.

P-XRD Method of Analysis: PXRD analysis of compounds produced by the present invention were carried out using BRUKER D8 ADVANCE/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03 min.

PSD method of Analysis: Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.

The process of the present invention can be represented schematically as follows:

FormuIa-5

Formula-5a = HC1 1. NaOH, IPA, Water

2. MeOH, Aqu. NH ₃

Acetic acid

Formula-la Formula-1 The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples

Example-1:

Preparation of ethyl 2-((S)-2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl piperidin-l-yl)propanamido)acetate hydrochloride: (FormuIa-5a)

A mixture of 3-((3R,4R)-3,4-dimethylpiperidin-4-yl)phenol (50 gms), (S)-Ethyl-2-(2- benzyl-3-(methylsulfonyloxy)propanamido)acetate (50.18 gms) and tertiary butanol (600 ml) were stirred for 10 minutes at 25-30°C. Sodium bicarbonate (40.92 gms) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 10 hours at the same temperature. Cooled the reaction mixture to 50-55°C. (S)-Ethyl-2-(2-benzyl-3- (methylsulfonyloxy)propanamido)acetate (33.45 gms) was added to the reaction mixture at 50-55°C. Heated the reaction mixture to 80-85°C and stirred for 12 hours at the same temperature. Cooled the reaction mixture to 50-55°C. (S)-Ethyl-2-(2-benzyl-3 -(methyl sulfonyloxy)propanamido)acetate (37.6 gms) was added to the reaction mixture at 50-55°C. Heated the reaction mixture to 80-85°C and stirred for 26 hours at the same temperature. Cooled the reaction mixture to 40-45°C. Filtered the reaction mixture and washed with tertiary butanol. To the obtained filtrate, sodium bicarbonate (40.9 gms) was added at 25- 30°C. Heated the reaction mixture to 80-85°C and stirred for 12 hours at the same temperature. Cooled the reaction mixture to 40-45°C. Filtered the reaction mixture and washed with tertiary butanol. Distilled off the solvent completely form the filtrate under reduced pressure. Ethyl acetate and water were added to the obtained compound at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated and organic layer was washed with 10% aqueous citric acid solution. Water was added to the organic layer. Basifying the reaction mixture using aqueous ammonia solution at 25-30°C and stirred for 20 minutes at the same temperature. Both the organic and aqueous layers were separated and organic layer was washed with aqueous sodium chloride solution. Acidifying the organic layer using ethyl acetate-hydrochloric acid at 25-30°C and stirred for I hour at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound.

Yield: 100 gms; M.R: 90-97°C. Purity by HPLC: 94.70%; Piperidinyl phenol impurity: 0.02%; Sulfonyl ester impurity: 0.38%; Olefin ester impurity: 1.24%; Desmethyl ester impurity: 0.08%; HIUI: 0.60%.; Unknown impurities: 2.98%. Example-2:

Preparation of [[2(S)-[[4(R)-(3-hydroxyphenyI)-3(R),4-dimethyl-l-piperidiny l]methyl-l- oxo-3-phenyIpropyl]amino]acetic acid: (Formula-l)

Isopropanol (3 Its) and ethyl 2-((S)-2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4- dirriethylpiperidin-l-yl)propanamido)acetate hydrochloride (200 gms) were stirred for 10 minutes at 25-30°C. Basified the reaction mixture using aqueous sodium hydroxide solution at 25-30°C and stirred for 60 minutes at the same temperature. Carbon (10 gms) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with isopropanol. Acidifying the obtained filtrate using aqueous hydrochloric acid solution at 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with isopropanol and dried at 70-75°C.

Methanol (1200 ml) and aqueous ammonia solution (100 ml) were added to the obtained compound at 25-30°C and stirred for 10 minutes at the same temperature. Acidifying the reaction mixture using acetic acid at 25-30°C. Cooled the reaction mixture to 10-15°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound.

Yield: 88.6 gms; M.R: 196-200°C.

Purity by HPLC: 99.65%; Purity by Chiral HPLC: 99.91%; Piperidinyl phenol impurity: Not detected; Sulfonyl ester impurity: Not detected; Olefin acid impurity: Not detected; Desmethyl ester impurity: 0.03%; DMP ester impurity: Not detected; HIUI: 0.06%; Enantiomer impurity: 0.03; RRR-Diastereomer impurity: 0.06%; SSS-Diastereomer impurity: Not detected Unknown impurities: 0.26%.

Example-3:

Preparation of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l]methyl]- l-oxo-3-phenylpropyI] amino] acetic acid dihydrate: (Formula-la)

Methanol (120 ml) was added to [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l- piperidinyl]methyl]-l-oxo-3-phenylpropyl]amino]acetic acid (60 gms) at 25-30°C and stirred for 10 minutes at the same temperature. Aqueous ammonia solution (120 ml) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with a mixture of methanol and aqueous ammonia solution. Water was added to the obtained filtrate at 25-30°C and stirred for 10 minutes at the same temperature. The pH of the reaction mixture was adjusted using acetic acid at 25-3G°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with water and dried to get the title compound.

Yield: 55.9 gms; M.R: 201-206°C; Water content: 7.8% (w/w).

Purity by HPLC: 99.92%; Purity by Chiral HPLC: 99.96%; Olefin acid impurity: Not detected; Pipefidinyl phenol impurity: Not detected; Des-methyl impurity: 0.03%; Metabolite impurity: 0.01%; DMP ester impurity: Not detected; Enantiomer impurity: 0.04; RRR- Diastereomer impurity: Not detected; SSS-Diastereomer impurity: Not detected; Unknown impurities: 0.04%; Particle size distribution: Di ₀ : 2.38 μπι; D ₅₀ : 6.80 μιη; D9 ₀ : 13.57 μιη.

Example-4:

Preparation of (S)-ethyl 2-(2-benzyl-3-(methylsulfonyIoxy)propanamido)acetate: (Formula-3)

A mixture of 1-phenylethanamine (S)-2-benyzl-3-hydroxypropanoate (7.0 kg), water (21.0 Its) and ethyl acetate (14.0 Its) was stirred for 10 minutes at 25-30°C. Acidified the reaction mixture using aqueous hydrochloric acid solution (3.5 Its). Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with , water and distilled off the solvent completely from the organic layer. Dichloromethane (42.0 Its) and ethyl 2-aminoacetate hydrochloride (4.2 kgs) was added to the obtained compound at 25-30°C and stirred for 10 minutes at the same temperature. Triethyl amine (3.5 kgs), followed by N,N'-Dicyclohexylcarbodiimide (115 gm) and dichloromethane (7.0 Its) were slowly added to the reaction mixture at 25 to 30°C and stirred for 10 hours at the same temperature. Aqueous hydrochloric acid solution was added to the reaction mixture. Cooled the reaction mixture to 0 to 5°C and stirred for 1 ½ hour at the same temperature. Filtered the unwanted by-product, washed with dichloromethane. Both the organic and aqueous layers were separated and organic layer was washed with water. Distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate was added to the obtained compound at 25-30°C. Cooled the reaction mixture to 0 to 5°C and stirred for 1 ½ hour at the same temperature. Filtered the reaction mixture and washed with ethyl acetate. Cooled the reaction mixture to 10-15°C. Triethylamine (4.7 kgs) and methanesulfonyl chloride (4.0 kgs) were added to the reaction mixture at 10-15°C and stirred for 2 hours at the same temperature. Water was added to the reaction mixture and stirred for 15 minutes. Both the organic and aqueous layers were separated. Aqueous layer was extracted with ethyl acetate. Combined the organic layers and organic layer was washed with aqueous sodium carbonate solution, followed by aqueous hydrochloric acid solution and finally with water. Distilled off the solvent completely under reduced pressure and co-distilled with toluene. To the obtained compound, toluene (14.0 Its) was added at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 45 minutes at the same temperature. Further, cooled the reaction mixture to 0-5 °C and stirred for 1 ½ hour at the same temperature. Filtered the reaction mixture to get the title compound.

Yield: 5.6 kgs.

Example-5:

Preparation of ethyl 2-((S)-2-benzyI-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyI piperidin-l-yl)propanamido)acetate hydrochloride: (Formula-5a)

A mixture of 3-((3R,4R)-3,4-dimethylpiperidin-4-yl)phenol (1.0 kg), (S)-Ethyl-2-(2- benzyl-3-(methylsulfonyloxy)propanamido)acetate (1.0 kg) and tertiary butanol (12.0 Its) were stirred for 10 minutes at 25-30°C. Sodium bicarbonate (0.82 kg) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 10 hours at the same temperature. Cooled the reaction mixture to 50-55°C. (S)-Ethyl-2-(2-benzyl-3- (methylsulfonyloxy)propanamido)acetate (0.67 kg) was added to the reaction mixture at 50- 55°C. Heated the reaction mixture to 80-85°C and stirred for 12 hours at the same temperature. Cooled the reaction mixture to 50-55°C. (S)-Ethyl-2-(2-benzyl-3 -(methyl sulfonyloxy)propanamido)acetate (0.75 kg) was added to the reaction mixture at 50-55°C. Heated the reaction mixture to 80-85°C and stirred for 26 hours at the same temperature. Cooled the reaction mixture to 40-45°C. Filtered the reaction mixture and washed with tertiary butanol. To the obtained filtrate, sodium bicarbonate (0.82 gms) was added at 25- 30°C. Heated the reaction mixture to 80-85°C and stirred for 12 hours at the same temperature. Cooled the reaction mixture to 40-45°C. Filtered the reaction mixture and washed with tertiary butanol. Distilled off the solvent completely form the filtrate under reduced pressure. Ethyl acetate and water were added to the obtained compound at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated and organic layer was washed with 10% aqueous citric acid solution. Water was added to the organic layer. Basifying the reaction mixture using aqueous ammonia solution at 25-30°C and stirred for 20 minutes at the same temperature. Both the organic and aqueous layers were separated and organic layer was washed with aqueous sodium chloride solution. Acidifying the organic layer using ethyl acetate-hydrochloric acid at 25-30°C and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound.

Yield: 1.99 kgs.

Example-6:

Preparation of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l]methyl-l- oxo-3-phenylpropyl]amino]acetic acid: (Formula-1)

Isopropanol (22.5 Its) and ethyl 2-((S)-2-benzyl-3-((3R,4R)-4-(3-hydroxyphenyl)-3,4- dimethylpiperidin-l-yl)propanamido)acetate hydrochloride (1.5 kg) were stirred for 10 minutes at 25-30°C. Basified the reaction mixture using aqueous sodium hydroxide solution (0.45 kgs of sodium hydroxide in 4.5 Its of water) at 25-30°C and stirred for 1 hour at the same temperature. Carbon (0.075 kgs) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with isopropanol. Acidifying the filtrate using aqueous hydrochloric acid solution (0.75 Its) at 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with isopropanol and dried at 70-75°C. Methanol (9.0 Its) and aqueous ammonia solution (0.75 Its) were added to obtained compound at 25-30°C and stirred for 10 minutes at the same temperature. Acidifying the reaction mixture using acetic acid at 25-30°C. Cooled the reaction mixture to 10-15°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound.

Yield: 0.66 kgs.

Example-7:

Preparation of [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l-piperidiny l]methyl]- l-oxo-3-phenylpropyl]amino]acetic acid dihydrate: (Formula-la)

Methanol (1.0 Its) was added to [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl-l- piperidinyl]methyl]-l-oxo-3-phenylpropyl]amino]acetic acid (0.5 kg) at 25-30°C and stirred for 10 minutes at the same temperature. Aqueous ammonia solution (1.0 Its) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with a mixture of methanol and aqueous ammonia solution. Water (10.0 Its) was added to the obtained filtrate at 25-30°C and stirred for 10 minutes at the same temperature. Acidifying the reaction mixture using acetic acid at 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with water and dried to get the title compound.

Yield: 0.46 kgs; M. : 201-206°C; Water content: 8.35% (w/w); Purity by HPLC: 99.89%. Olefin acid impurity: Not detected; Piperidine phenol impurity: Not detected; Des methyl impurity: 0.05%; DMP impurity: Not detected; Metabolite impurity: Not detected; HIUI: 0.06%. Enantiomer impurity: 0.01%; RRR Diastereomers impurity: 0.06%; SSS Diastereomer impurity: Not detected.

Particle size distribution: Di ₀ : 4.16 μπι; D ₅ o: 14.1 μηι; D90: 38.1 μιη.