DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of Samidorphan and its L-malate salt (1).

(1)
The present invention also relates to novel intermediates of Samidorphan, its preparation and use for preparation of Samidorphan and salts thereof
BACKGROUND OF THE INVENTION
Samidorphan L-malate is marketed under brand name “LYBALVI” (combination of Olanzapine and Samidorphan) for treatment of schizophrenia and bipolar disorder. Samidorphan L-malate is chemically known as 17-(Cyclopropylmethyl)-4, 14-dihydroxy-6-oxomorphinan-3-carboxamide; (2S)-2-hydroxybutanedioic acid and is represented by following general formula (I).

(1)
US7262298B2 discloses process for preparation of Samidorphan and its pharmaceutically acceptable salts thereof by the following scheme:

This patent discloses use of carbon monoxide which requires special handling, high pressure experiments and most serious issue is toxicity. Most gases including CO used in organic synthesis are toxic to human even at very low concentration their exposure and leakage must be strictly suppressed during the reaction to ensure user safety. Therefore, difficulties associated with the handling of toxic gases that have unfavorable chemical and physical properties have significantly hampered their use in synthesis.
US10155772B2 discloses a process for preparation of Samidorphan as follows:

This patent disclosed a process which involves use of zinc cyanide, which is not only a hazardous substance but also produce lot of waste. Furthermore, it is difficult to handle and store.
US9119848B2 discloses Samidorphan L-malate salt and its process for preparation.
The present invention provides efficient and economical process for the preparation of Samidorphan L-malate by the use of novel intermediates which overcome drawbacks of reagents used in prior art processes.
OBJECTS OF THE INVENTION
The main object of the present invention relates to an improved process for preparation of Samidorphan and its L-malate salt (1).
Another object of the present invention relates to novel intermediates for preparation of Samidorphan malate.
Yet another object is to provide process for preparation of novel intermediates.
SUMMARY OF THE INVENTION
In an aspect the present invention provides process to prepare Samidorphan malate using novel intermediates.
In an aspect the process for preparation of Samidorphan and its salts can be represented as following scheme 1 and 1A:
Scheme 1

Wherein R1, R2, R3, R4 is selected from hydrogen, halo, C1-C8 alkyl chain, nitro and CN substituents.
Scheme 1A

In another aspect present invention provides process for preparation of Samidorphan and its salts as represented in scheme 2
Scheme 2

Wherein R is same as above.
In yet another aspect present invention provide process for preparation of Samidorphan and its salts as represented in scheme 3:
Scheme 3

Wherein X1 and X2 are selected from O, S and may be same or different;
In another aspect present invention provides process for preparation of Samidorphan and its salts as represented in scheme 4:
Scheme 4


Wherein X1 and X2 are selected from same as above.
In an aspect present invention provides novel intermediates of following structural formula:

Wherein R, X1 and X2 are same as above.
DETAILED DESCRIPTION OF THE INVENTION
The present invention focus on ameliorating problems associated with prior art processes and provide an improved process for preparation of Samidorphan and its salt and its intermediates.
In an embodiment present invention provides a process for preparation of samidorphan and its salts thereof according to Scheme 1 or 1A comprising steps of:
Step 1: converting naltrexone to compound of Formula 4, a number of methods are known to convert carbonyls to dioxalanes by using reagents such as 1,2-ethanediol or 1,3-propane diols or like thereof in the presence of a bronsted or lewis acid catalyst, optionally using base, in the presence of solvent.
Step 2: relates to conversion of compound of Formula 4 to 5 by preparing triflates in presence of base and solvent.
Step 3: relates to conversion of compound of Formula 5 to 8 or 8A by first treating compound of Formula 5 with palladium catalyst in presence of phosphine reagent, solvent and optionally using base, followed by coupling with compound of Formula A or B or C or I or II or III or IV.

Step 4: compound of Formula 8 or 8A is converted to compound of Formula 7 by using amidation reagent in the presence of suitable solvent.
Step 5: conversion of compound of Formula 7 to 3 by using mineral acid, optionally using solvent.
Step 6: converting compound of Formula 3 to Samidorphan and its salts thereof.
Process as per scheme 1 and 1A comprise novel intermediates of compound of Formula 8 and 8A and its use for preparation of Samidorphan and its salts thereof.
In another embodiment the present invention provides process for preparation of Samidorphan and its salts thereof as per scheme 2, which comprises novel intermediate of formula 9. The process according to scheme 2 comprises following steps:
Step 1: converting naltrexone to compound of Formula 2 by preparing triflates in presence of the base and solvent.
Step 2: comprises conversion of compound of Formula 2 to 9 by first treating compound of Formula 2 with palladium catalyst in presence of phosphine reagent and solvent, optionally using base. Followed by coupling with compound of formula I or II or III or IV or A or B or C.
Step 3: comprises conversion of compound of Formula 9 to 3 by using amidation reagent in the presence of suitable solvent.
Step 4: comprises conversion of compound of Formula 3 to Samidorphan and its salts thereof.
In another embodiment present invention comprises preparing Samidorphan and its salts thereof according to scheme 3 and also includes novel intermediate of formula 10, 11, 12 and 13 and their use in preparation of Samidorphan and its salts thereof. Scheme 3 comprises following steps:
Step 1: converting naltrexone to compound of Formula 10 by using reagents selected from alkyl thiol such as 1,2-ethanedithiol, 2-mercaptoethan-1-ol and like thereof in the presence of a bronsted or lewis acid catalyst, optionally using base, in the presence of solvent.
Step 2: compound of Formula 10 is converted to Formula 11 by preparing triflates in the presence of the base and solvent.
Step 3: relates to conversion of compound of Formula 11 to 12 by treating with suitable cyanide reagent, optionally using base, in the presence of solvent.
Step 4: amidation of compound of Formula 12 to obtain compound of Formula 13 by treating with suitable amidation agent.
Step 5: hydrolyzing compound of Formula 13 by using base in the presence of solvent to form compound of Formula 3.
Step 6: finally, converting compound of Formula 3 to Samidorphan and its salts thereof.
In another aspect the present invention provides a process to prepare Samidorphan and its salts thereof according to scheme 4, this comprises novel intermediates of Formula 14, 15, 16 and 17 and their use in preparation of Samidorphan and its salts thereof. Process according to scheme 4 includes following steps:
Step 1: converting naltrexone to compound of Formula 14 by using reagents selected from alkyl thiol such as 1,2-ethanedithiol, 2-mercaptoethan-1-ol and like thereof in the presence of a bronsted or lewis acid catalyst, optionally using base, in the presence of solvent.
Step 2: relates to conversion of compound of Formula 14 to 15 by using triflating agents in the presence of the base and solvent.
Step 3: relates to conversion of compound of Formula 15 to 16 by treating with suitable cyanide reagent, optionally using base, in the presence of solvent.
Step 4: amidation of compound of Formula 16 to obtain compound of Formula 17 by treating with suitable amidation agent.
Step 5: hydrolyzing compound of Formula 17 by using base in the presence of solvent to form Formula 3.
Step 6: converting compound of Formula 3 to Samidorphan and its salts thereof.
In process of preparation according to present invention bronsted or Lewis acid catalyst can be selected from p-toluensulfonic acid, hydrofluoric acid, phosphoric acid, polystyrene sulfonate, hetero poly acids, zeolites, tetra butyl ammonium bromide, tetra butyl ammonium chloride, aluminium chloride, zirconium chloride, boron trihalides, titanium chloride, SnCl4 and like thereof.
The triflates can be prepared by using triflating agents selected from 4-Nitrophenyltriflate, N-phenyl bis (trifluoromethanesulfonimide), trifluoro methane -sulfonic anhydride (triflic anhydride) and tritlyl chloride and like thereof.
The base can be selected from inorganic or organic base such as hydroxides, carbonates, bicarbonates, hydrides of alkali or alkaline earth metals, triethyl amine, diisopropylethylamine, pyridine, N, N-dimethylaminopyridine, morpholino, and 2, 6-di-t- butyl-4-methylpyridine and like thereof.
The solvent can be selected from aliphatic or aromatic hydrocarbons, alcohols, halogenated hydrocarbons, ethers, nitriles, ester, amide, sulfoxides, polar solvents, polar aprotic solvents, water or mixture thereof.
The mineral acid can be selected from the hydrochloric acid, hydro bromic, hydrofluoric acid, nitric acid, sulfuric acid, acetic acid and like thereof.
The catalyst such as palladium catalyst is selected from tetrakis (triphenylphosphine)palladium, Tris(dibenzylidene acetone) dipalladium (Pd2(dba)3), palladium acetate (Pd(OAc)2) or palladium dichloride (PdCl2) and the like; and phosphine reagent is selected 1,l'-bis(diphenylphosphino)ferrocene (DPPF), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos), l,3-bis(diphenylphosphino)propane (DPPP), triphenylphosphine, 1,3- bis(diphenylphosphino)propane and 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl (BINAP) and like thereof.
The amidation reagent can be selected from ammonia, ammonium hydroxides and like thereof.
The cyanide reagent can be selected from zinc cyanide (Zn(CN)2), copper cyanide and like thereof.
The compound of Formula 3 is converted to Samidorphan by any of the method known in the art, one of the method is reported in US7262298 which involves use of zinc dust, hydrochloric and acetic acid.
Samidorphan is converted to salts such as malate salt by any of the known method. One of the method is reported in US9119848B2 which involves treating Samidorphan with malic acid using solvents methanol and ethanol.
Generally all the steps for preparation of Samidorphan and its salts thereof is conducted at a temperature range between -30 °C to reflux temperature.
The following intermediates are formed in scheme 3 and 4, when X1 and X2 are selected from O and S:

Although following examples illustrated in the present invention in more detail, but the examples are not intended in any way to limit the scope of the present invention. It will thus be readily apparent to the one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modifications and variation of the concepts herein disclosed may be resorted to by those skilled in the art and that such modifications and variations are considered to be falling within the scope of the invention.
EXAMPLES
Example 1
Synthesis of 4-Chlorophenyl formate
A mixture of formic acid (146 ml) and acetic anhydride (300 ml) was heated at 60 to 65°C and stirred for 1 hour under nitrogen atmosphere. The reaction mass cooled to 0 to 5°C, charged sodium acetate (60.4 gm) and stirred for 10 to 15 minutes at the same temperature. To the reaction mass, a solution of 4-chloro phenol (100 gm in toluene 1500 ml) was added dropwise at 0 to 5°C. The resulting reaction mass was heated to 25 to 35°C and stirred for 3 to 4 hours. After completion of reaction, purified water (500 ml) was added to the reaction mass and stirred for 20 to 30 minutes. The layers were separated and organic layer was washed with purified water (3 X 500 ml) and brine solution (2 X 500 ml). The organic layer distilled out under vacuum below 50°C to obtained light yellow colored title compound (Yield 120 gm).
Example 2
Preparation of 4-chlorophenyl (4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[[1,3]dioxolane-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinoline]-9'-carboxylate
A mixture of (4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[[1,3]dioxolane-2,7'-[4,12]methano- benzofuro[3,2-e]isoquinolin]-9'-yl trifluoromethanesulfonate (20 gm), zinc dust (0.504 gm), dimethylformamide (100 ml) and triethyl amine (10 ml) was prepared and to this palladium acetate (0.43 gm) , diphenylphosphino ferrocene (DPPF) (2.14 gm) were added. Resulting reaction mass was heated at 80 to 90°C. Then, 4-chlorophenyl formate (12.1 gm) was added and reaction mixture was further stirred for 2 hours at 80 to 90°C under nitrogen atmosphere. After completion of reaction, reaction mass was cooled to room temperature and purified water (600 ml) was added. The organic layer was separated and distilled out to give brown colored titled compound. (Yield 15 gm).
Example 3
Synthesis of (4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[[1,3]dioxolane-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinoline]-9'-carboxamide
A mixture of 4-chlorophenyl (4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[[1,3]dioxolane-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinoline]-9'-carboxylate (15 gm) in tetrahydrofuran (150 ml) were stirred under pressure at 25 to 35°C and ammonia was added, reaction mixture was heated at 60-75°C for 6 to 8 hr. After completion of reaction, solvent was distilled out to give title compound. (Yield (14 gm)

Example 4
Synthesis of 4-Chlorophenyl formate
The mixture Formic acid (38 gm) and acetic anhydride (79 gm) was stirred at 25 to 35°C, heated to 60 to 65°C and maintained for 60 to 70 minutes under nitrogen atmosphere. The reaction mixture was cooled 25 to 35°C. Separately, a mixture of 4-chloro phenol (30 gm), toluene (450 ml) was cooled to 0 to 10°C and anhydrous sodium acetate (20 gm) was added at same temperature. To this mixture, was added previously prepared reaction mixture drop wise at 0 to 10°C under nitrogen atmosphere and stirred at 25 to 35 °C for 3 to 4 hours. After completion of the reaction water (150 ml) was added, stirred, separate the layers, organic layer washed with water (2 X 150 ml) and brine solution. The solvent of organic layer was distilled out to obtain the title compound. (Yield 36 gm)
Example 5
Synthesis of (4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H-spiro[[1,3]dioxolane-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinoline]-4a',9'-diol (compound 4)
To the mixture of toluene (240 ml) and Ethylene glycol (105 gm) was added Naltrexone hydrochloride (30 gm) and 4-Methylbenzenesulfonic acid monohydrate (7.5gm) at 25 to 35°C. The reaction mixture was stirred, heated up to 110 to 120°C, remove water using dean stark apparatus and maintained till reaction completion. The reaction mixture was cooled to 25 to 35°C and separated both layers. The lower product containing layer was cooled to 10 to 20°C, aqu. sodium carbonate solution (450 ml) was added and stirred the reaction mass for 1 hour at 25 to 35°C. Filtered, wash solid with purified water (2 x 30 ml) and dried under vacuum to get title compound. (Yield 32.5 gm)
Example 6
Synthesis of (4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[[1,3]dioxolane-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-9'-yl trifluoromethanesulfonate (compound 5)

The stirred mixture of Methylene chloride (125 ml) under Nitrogen atmosphere (4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-1',2',3',4',5',6'-hexahydro-4a'H,7a'H -spiro[[1,3]dioxolane-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinoline]-4a',9'-diol (25 gm) was cooled to -15 to -5°C , Di isopropyl ethylamine (12.5 gm) and Trifluoromethane sulfonic anhydride (22 gm) was added. The reaction mixture was maintained at -10 to -0 °C for 1 hour. After the completion of reaction aqu. ammonium chloride solution (125 ml) and methyl tertiary butyl ether (250ml) were added and stirred at room temperature. Further, separating the layers and organic layer again washed with aqu. ammonium chloride solution (125 ml) at 25-35°C. The organic layer was washed with water (125 ml) and brine solution (125 ml). The organic layer was distilled completely under vacuum, Methyl tertiary-butyl ether (25 ml) was added, stirred at 40 to 45°C for 10 to 15 minutes and distilled out the solvent. To the reaction mass Methyl tertiary butyl ether (25 ml) was added, stirred the reaction mass at 40-45°C for 10 to 15 minutes and added n-heptane (200 ml) and stirred the reaction mass at 40 to 45 °C for 15 to 20 minutes. Distilled out solvent (75 ml) and stirred for 60 to 70 minutes at 25 -35°C. Filtered, wash the solid with n-Heptane (25 ml), dried under vacuum to obtain the tilted compound. (Yield 31.7 gm)
Example 7
Synthesis of 4-chlorophenyl (4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[[1,3]dioxolane-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinoline]-9'-carboxylate (compound 8A)
To the stirred mixture of acetonitrile (320 ml), (4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[[1,3]dioxolane-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinolin]-9'-yl trifluoromethanesulfonate (160 gm) under nitrogen, di isopropyl ethyl amine (80 gm), zinc dust (4 gm), palladium acetate (3 gm) and Diphenyl phosphino ferrocene (13.5 gm) were added at 25-35°C . The reaction mixture was heated to 70 to 75°C and slowly added dropwise 4-Chlorophenylformate solution (4-Chlorophenylformate (121 gm) in acetonitrile (320 ml)), maintained at same temperature till reaction completion. After the completion of the reaction, the solvent was distilled out, toluene (1600 ml), water (800 ml) were added and stirred the reaction mass for 20 to 30 minutes at 25 to 35°C. The reaction mass through hyflow bed and wash hyflow with toluene (160 ml). The layers of filtrate were separated and upper organic layer was washed with aqu. brine solution (800 ml) in RBF at 25-35°C. The solvent was distilled out, methanol (160ml) was added into the reaction mass and stirred the reaction mass for 10 to 15 minutes at 50-55 °C, and distilled out the solvent again. Further, Methanol (8000 ml) was added into the reaction mass and stirred for 60 to 70 minutes at 50 to 55°C, cooled, filtered, washed the solid with methanol (2x 160 ml) and dried under vacuum to obtained the title compound. (Yield 136 gm)
Example 8
Synthesis of (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide (Compound 3)
In an autoclave, the mixture of tetrahydrofuran (1000 ml) and 4-chlorophenyl (4'R,4a'S,7a'R,12b'S)-3'-(cyclopropylmethyl)-4a'-hydroxy-2',3',4',4a',5',6'-hexahydro-1'H,7a'H-spiro[[1,3]dioxolane-2,7'-[4,12]methanobenzofuro[3,2-e]isoquinoline]-9'-carboxylate (100 gm) was flushed with nitrogen pressure, stirred and ammonia (g) is purged with pressure up to 4 to 5 kg/cm2 at 25 to 35 °C. The reaction mixture was stirred for 20 to 30 minutes at 25 to 35 °C to stabilize the ammonia pressure 4 to 5 kg/cm2, heated the reaction mass at 65 to 70 °C and maintained till completion of the reaction. Further, the reaction mass was cooled to at 25 to 35 °C, release the ammonia pressure. The solvent was distilled out, tetrahydrofuran (400 ml), water (400 ml), conc. hydrochloric acid (400 ml) was added and stirred the reaction mass at 50 to 55 °C till completion of the reaction. The reaction mass was cooled to 25 to 35 °C, toluene (400 ml) was added, stirred and separate the layers. To the aqueous layer, methylene chloride (2000 ml) was added, cooled at 10 to 20 °C, adjusted pH 9 to 10 using aqueous ammonia and stirred for 20 to 30 minutes at 25 to 30 °C. The layers were separated, organic layer washed with brine solution (500 ml) and distill out solvent. To the reaction mass, isopropyl alcohol (100 ml) was added, stirred for 15 to 20 minutes at 50 to 55 °C, distilled out solvent, again isopropyl alcohol (300 ml) was added, stirred the reaction mass for 30 to 40 minutes at 60 to 65 °C. The reaction mixture was cooled, filtered, washed with Isopropyl alcohol and dried under vacuum to obtained titled compound. (Yield 60 gm)
Example 9
Synthesis of Samidorphan free base
To the mixture of aqu. ethanol sol. (water 25 ml; ethanol 430 ml), (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide (30 gm) was added ammonium chloride (26 gm), stirred, heated at 80 to 85oC and added zinc dust (187 gm) lot wise. The reaction mixture was maintained at 80 to 85oC till completion of the reaction. Filtered, washed with aqu. ethanol solution (60 ml) and distill out solvent. To the reaction mass water (300 ml), methylene chloride (300 ml) were added, stirred, cooled to 15 to 20 °C and pH was adjusted 9-10 by liq. ammonia. The reaction mixture was stirred for 10 to 15 minutes at room temperature, separate the layers, organic layer washed with 15% brine solution (300 ml) and distill out the solvent. To the reaction mass ethanol (90 ml) was added, stirred at room temperature, cooled, filtered, washed with ethanol (15 ml) and dried under vacuum to obtained titled compound. (Yield 30 gm)
Example 10
Synthesis of Samidorphan L-malate salt
The mixture of samidorphan free base (75 gm), methanol (225 ml), ethanol (225 ml) was stirred and heated at 65 to 70 °C. The reaction mixture was filtered through hyflo bed, filtrate was heat to 65 to 70°C and L- Malic acid solution (L-Malic acid (32.5 gm) in ethanol (225 ml)) was added slowly. The reaction mixture was stirred for 60 minutes at 65 to 70 °C, cooled, filtered, washed with ethanol (75 ml) to obtain the title compound. (Yield 97.5 gm) ,CLAIMS:We Claim:
1. A process for preparation of Samidorphan and its salts thereof comprising use of novel intermediates of Formula 8 or 8A and steps of :
a) converting naltrexone to compound of Formula 4 using 1,2-ethanediol, bronsted or lewis acid catalyst, optionally using base, in the presence of solvent;
b) reacting compound of Formula 4 with triflating agents using base in the presence of solvent to form compound of Formula 5;
c) reacting compound of Formula 5 with compound of Formula A or B or C or I or II or III or IV using palladium catalyst, phosphine reagent, optionally using base, in the presence of solvent to form compound of Formula 8 or 8A;
d) converting compound of Formula 8 or 8A to compound of Formula 7 by using amidation reagent in the presence of solvent;
e) converting of compound of Formula 7 to 3 using mineral acid, optionally in the presence of solvent; and
f) converting compound of Formula 3 to Samidorphan and its salts thereof.
2. The process as claimed in claim 1, for preparation of Samidorphan and its salts comprising use of novel intermediate of Formula 8A and steps of:
a) converting naltrexone to compound of Formula 4 using 1,2-ethanediol, bronsted or lewis acid catalyst, optionally using base, in the presence of solvent;
b) reacting compound of Formula 4 with triflating agents using base in the presence of solvent to form compound of Formula 5;
c) reacting compound of Formula 5 with compound of Formula IV using palladium catalyst, phosphine reagent, optionally using base, in the presence of solvent to form compound of Formula 8A;
d) converting compound of Formula 8A to compound of Formula 7 by using amidation reagent in the presence of solvent;
e) converting of compound of Formula 7 to 3 using mineral acid, optionally in the presence of solvent; and
f) converting compound of Formula 3 to Samidorphan or its salts thereof.
3. A process for preparation of Samidorphan and its salts thereof comprising use of novel intermediate of formula 9 and steps of:
a) converting naltrexone to compound of Formula 2 by using triflating agents in presence of the base and solvent;
b) reacting compound of Formula 2 with compound of Formula A or B or C or I or II or III or IV using palladium catalyst, phosphine reagent, optionally using base, in the presence of solvent to form compound of Formula 9;
c) converting compound of Formula 9 to 3 by using amidation reagent in the presence of suitable solvent; and
d) conversion of compound of Formula 3 to Samidorphan or its salt thereof.
4. A process for preparation of Samidorphan or its salts thereof comprising use of novel intermediates of formula 10, 11, 12 and 13 and steps of:
a) converting naltrexone to compound of Formula 10 by using alkyl thiol or alkyl diol selected from group comprising of 1,2-ethanedithiol, 2-mercaptoethan-1-ol 1,2-ethanediol or like, , bronsted or lewis acid catalyst, optionally using base, in the presence of solvent;
b) converting compound of Formula 10 to 11 by using triflating agent, base in the presence of solvent;
c) converting compound of Formula 11 to 12 by treating with cyanide reagent, optionally using base, in the presence of solvent;
d) amidating compound of Formula 12 to obtain compound of Formula 13 by treating with amidation agent;
e) hydrolyzing compound of Formula 13 using base in the presence of solvent to form compound of Formula 3; and
f) converting compound of Formula 3 to Samidorphan or its salts.
5. A process for preparation of Samidorphan or its salts thereof comprising use of novel intermediates of Formula 14, 15, 16, 17 and steps of:
a) converting naltrexone to compound of Formula 14 by using reagents selected from alkyl thiol or alkyl diol such as 1,2-ethanedithiol, 2-mercaptoethan-1-ol 1,2-ethanediol or like in the presence of a bronsted or lewis acid catalyst, optionally using base, in the presence of solvent;
b) converting compound of Formula 14 to 15 using triflating agents, base and solvent;
c) converting compound of Formula 15 to 16 by treating with cyanide reagent, optionally using base, in the presence of solvent;
d) amidating compound of Formula 16 to obtain compound of Formula 17 by treating with amidation agent;
e) hydrolyzing compound of Formula 17 using base in the presence of solvent to form Formula 3; and
f) converting compound of formula 3 to Samidorphan or its salts thereof.
6. The process as claimed in claim 1 to 5, for preparation of Samidorphan and its salts thereof, wherein bronsted or lewis acid catalyst is selected from group comprising of from p-toluensulfonic acid, hydrofluoric acid, phosphoric acid, polystyrene sulfonate, hetero poly acids, zeolites, tetra butyl ammonium bromide, tetra butyl ammonium chloride, aluminium chloride, zirconium chloride, boron trihalides, titanium chloride, SnCl4 or like thereof; triflating agents is selected from group comprising of 4-Nitrophenyltriflate, N-phenyl bis (trifluoromethanesulfonimide), trifluoro methane -sulfonic anhydride (triflic anhydride), tritlyl chloride or like thereof; palladium catalyst is selected from group comprising of tetrakis (triphenylphosphine)palladium, Tris(dibenzylidene acetone) dipalladium (Pd2(dba)3), palladium acetate (Pd(OAc)2) or palladium dichloride (PdCl2) or like; phosphine reagent is selected from group comprising 1,l'-bis(diphenylphosphino)ferrocene (DPPF), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos), l,3-bis(diphenylphosphino)propane (DPPP), triphenylphosphine, 1,3- bis(diphenylphosphino)propane and 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl (BINAP) or like; amidation reagent is selected from group comprising of ammonia, ammonium hydroxides or like thereof; mineral acid is selected from group comprising of hydrochloric acid, hydro bromic acid, hydrofluoric acid, nitric acid, sulfuric acid, acetic acid or like; cyanide reagent is be selected from group comprising of zinc cyanide (Zn(CN)2), copper cyanide or like thereof.
7. The process as claimed in claim 1 to 5, for preparation of Samidorphan and its salts thereof, wherein solvent is selected from group comprising of aliphatic or aromatic hydrocarbons, alcohols, halogenated hydrocarbons, ethers, nitriles, ester, amide, sulfoxides, polar solvents, polar aprotic solvents, water or mixture thereof; and base is selected from group comprising inorganic or organic base such as hydroxides, carbonates, bicarbonates, hydrides of alkali or alkaline earth metals, triethyl amine, diisopropylethylamine, pyridine, N, N-dimethylaminopyridine, morpholino and 2, 6-di-t- butyl-4-methylpyridine or like thereof
8. Compounds of formula 8, 8A, 9 and their use for preparation of Samidorphan and its salts thereof:

Wherein R is selected from compound of Formula A, B, C and R1, R2, R3, R4 is selected from hydrogen, halo, C1-C8 alkyl chain, nitro and CN substituents

9. Compounds of formula 10, 11, 12, 13, 14, 15, 16, 17 and their use for preparation of Samidorphan and its salts thereof:

Wherein X1 and X2 are selected from O, S and may be same or different.
10. Compounds, their use for preparation of Samidorphan and its salts thereof: