WO2019058387A1

WO2019058387A1 - An improved process for the preparation of (5α,6α)-17-allyl-6-(2,5,8,11,14,17,20- heptaoxadocosan-22-yloxy)-4,5-epoxymorphinan-3,14-diol and its pharmaceutically acceptable salts

Info

Publication number: WO2019058387A1
Application number: PCT/IN2018/050607
Authority: WO
Inventors: Thirumalai Rajan Srinivasan; Eswaraiah Sajja; Satyanarayana Revu; Rajeshwar Reddy Sagyam; Srinivasulu Rangineni; Prabhakar Macharla; Srinivasa Rao AMBATI; Ramakrishna BOMMIDI
Original assignee: Msn Laboratories Private Limited, R&D Center
Priority date: 2017-09-19
Filing date: 2018-09-19
Publication date: 2019-03-28

Abstract

The present invention relates to an improved process for the preparation of (5α, 6α)-17-allyl-6-(2, 5, 8, 11, 14, 17, 20- heptaoxadocosan-22-yloxy)-4, 5-epoxymorphinan-3, 14-diol which is represented by the following structural formula-1 or its pharmaceutically acceptable salts and also provides an improved process for the purification of the compound of formula-1 and its oxalate salt.

Description

An improved process for the preparation of (5a,6a)-17-allyl-6-(2,5,8,ll, 14,17,20- heptaoxadocosan-22-yloxy)-4,5-epoxymorphinan-3,14-diol and its pharmaceutically acceptable salts

Related Applications:

This application claims priority to Indian patent application numbers 201741033100 filed on September 19, 2017 and 201841005468 filed on February 13, 2018; the disclosure of which are incorporated herein by reference in its entirety.

Field of the invention:

The present invention relates to an improved process for the preparation of (5α,6α)- 17-allyl-6-(2,5,8, l 1,14, 17,20- heptaoxadocosan-22-yloxy)-4,5-epoxymorphinan-3,14-diol which is represented by the following structural formula- 1 or its pharmaceutically acceptable salts.

Formula- 1

Background of the invention:

(5a,6a)-17-allyl-6-(2,5,8, 11, 14, 17, 20-heptaoxadocosan-22-yloxy)-4,5- epoxymorphinan-3,14-diol oxalate is generally known as Naloxegol oxalate which was approved in US and Europe under the brand name of Movantik^® is an opioid antagonist indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain. The structural formula of (5a,6a)-17-allyl-6-(2,5,8,ll,14,17,20- heptaoxadocosan-22-yloxy)-4,5-epoxymorphinan-3,14-diol oxalate compound of formula-la is given below:

Formula- 1 a

US patent number 7,786, 133 (herein described as US'133) first discloses the process for the preparation of (5a,6a)-17-allyl-6-(2,5,8,ll,14,17,20-heptaoxadocosan-22- yloxy)-4,5-e oxymoφhinan-3,14-diol with low yield.

US9012469 describes the crystalline form- A & form-B of the compound of formula- la.

US'133 disclose the deprotection of MEM from (4R,4aS,7aR,12bS)-7- (2,5,8, 11 , 14, 17,20-heptaoxadocosan-22-yloxy)-3-allyl-9-((2-methoxyethoxy)methoxy)-2,3,4, 4a,5,6,7,7a-octahydro-lH-4, 12-methanobenzofuro[3,2-e]isoquinolin-4a-ol using trifluoro acetic acid. The said process was disadvantageous because it is also removes the side chain along with MEM protecting group. It leads to the formation of diol impurity, which was difficult to remove the impurities from the final API. Hence there is a need to the development of deprotection of protecting group without disturbing the side chain.

The present invention overcomes the above drawback by using titanium reagent which removes the protecting group without disturbing a side chain.

US' 133 discloses the process for the preparation of compound of general formula-6 from compound of general formula-4 using sodium hydride which is very unstable, prone to explosion, highly inflammable especially when coming into contact with moisture. The reaction must therefore be performed under conditions completely devoid of water; this is very difficult to achieve on an industrial scale. In order to overcome this draw back in the present invention, sodium hydride has been replaced by alkoxide such as potassium-t- butoxide. The use of which is completely safe on an industrial scale and also provides the compound with high purity and good yield. Further the obtained compound is well suitable in the preparation of the pure (5a,6a)-17-allyl-6-(2,5,8,ll,14,17,20-heptaoxadocosan-22- yloxy)-4,5-epoxymorphinan-3, 14-diol oxalate compound of formula-la. Further the compound of formula- la obtained according to the prior art literature provides low yield and less purity. Prior disclosed processes for the preparation of the compound of formula- la involved the use of hazardous and highly expensive reagents which were difficult to handle in the laboratory as well as industry. The present inventors have developed an improved process for the preparation of the compound of formula- la by using easily available reagents. The compound of formula- la obtained according to the present invention with higher yield and high purity.

Brief description of the invention:

The first aspect of the present invention is to provide an improved process for the preparation the compound of formula- 1 or its pharmaceutically acceptable salts.

The second aspect of the present invention is to provide an improved process for the preparation of compound of formula-1 or pharmaceutically acceptable salts.

The third aspect of the present invention is to provide amorphous solid dispersion comprising the compound of formula- la and at least one pharmaceutically acceptable excipient and its process for the preparation.

The fourth aspect of the present invention is to provide an improved process for the purification the compound of formula- 1 a.

Brief description on drawings:

Figure 1: Illustrates the PXRD pattern of amorphous solid dispersion comprising the compound of formula- 1 a and Copovidone.

Figure 2: Illustrates the PXRD pattern of amorphous solid dispersion comprising the compound of formula- 1 a and Cross povidone.

Figure 3: Illustrates the PXRD pattern of amorphous solid dispersion comprising the compound of formula- la and HPMC-E5.

Figure 4: Illustrates the PXRD pattern of amorphous solid dispersion comprising the compound of formula- la and HPMC-AS.

Figure 5: Illustrates the PXRD pattern of amorphous solid dispersion comprising the compound of formula- la and colloidal silicon dioxide. Detailed description of the invention:

As used herein the term "pharmaceutically acceptable salts" or "salts" or "acid addition salts" in the present invention refers to acid addition salts selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; organic acids such as acetic acid, maleic acid, malic acid, oxalic acid, succinic acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid; chiral acids such as S-(+) mandelic acid, R-(-) mandelic acid, L-(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D- malic acid, D-maleic acid, (-)-naproxen, (-i-)-naproxen, (lR)-(-)-camphor sulfonic acid, (IS)- (+)-camphor sulfonic acid (lR)-(+)-bromocamphor-10-sulfonic acid, (lS)-(-)- bromocamphor- 10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L- tartaricacid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -tartaric acid monohydrate, (+)-dipara-tolyl- D-tataric acid, (-)-dipara-tolyl-L-tataricacid, L(-)- pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid, L-lysine, D-lysine etc., and like.

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, benzene, toluene, pentane, cycloheptane, methyl cyclohexane, ethylbenzene, m-, o-, or p-xylene, or naphthalene 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 dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (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; "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t- butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1,2- propanediol (propylene 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 inorganic bases like "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 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, tertiary butyl amine, benzyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; "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; organosihcon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.

The term "hydroxy protecting group" used herein the present invention is selected from, but not limited to "substituted or unsubstituted arylcarbonyl" such as benzoyl, p- methoxy benzoyl, p-phenyl benzoyl and the like; "straight chain or branched chain alkyl and alkenyl" such as tertiary butyl, allyl and the like; "substituted or unsubstituted acyl" such as acetyl, chloro acetyl, dichloro acetyl, trichloro acetyl, trifluoro acetyl, pivaloyl and the like; "substituted or unsubstituted arylalkyl" such as p-methoxy benzyl, p-nitrobenzyl, benzyl, p- bromo benzyl and the like; "(alkyl)m (aryl)3-m silyl" wherein, 'm' represents 0, 1, 2 and 3, such as trimethyl silyl, triethyl silyl, triisopropyl silyl, tributyl silyl, dimethylisopropyl silyl, diisopropyl silyl, tert-butyldimethyl silyl, tert-butyl diphenyl silyl and the like; "alkoxyalkyl" such as methoxymethyl, 2-methoxyethoxymethyl and the like; "aryloxy alkyl" such as benzyloxymethyl and the like; "substituted or unsubstituted tetrahydro-2H-pyran-2-yl"; "substituted or unsubstituted trityl" such as trityl, 4-methyltrityl and the like; "alkyl sulfonyl" such as methane sulfonyl, ethane sulfonyl and the like; "substituted or unsubstituted aryl sulfonyl" such as tosyl, nosyl and the like; protecting groups of the formula "-CO-O-Ri" wherein represents CI -4 alkyl or aryl or arylalkyl such as methoxy carbonyl, ethoxy carbonyl, benzyloxy carbonyl, 9-(fluorenylmethyloxy)carbonyl, tertiary butyloxy carbonyl and the like;

The term "suitable protecting agent" is selected such that it is capable of protecting the oxygen atom with any of the above mentioned hydroxy protecting groups.

The term "suitable protecting agent" is selected from, but not limited to substituted or unsubstituted trityl halides such as trityl chloride, 4-methyl trityl chloride; alkoxy carbonyl halide and anhydrides such as methoxy carbonyl halide, ethoxy carbonyl halide, tert^Abutoxy carbonyl halides, di-tert.butyl dicarbonate (DIBOC); aryloxy carbonyl halides; arylalkoxy carbonyl halides such as benzyl chloroformate, fluorenylmethyloxy carbonyl chloride (FMOC chloride); straight chain or branched chain alkyl halides such as methyl halides; straight chain or branched chain alkenyl halides such as allyl halides, substituted or unsubstituted acids, acid halides and acid esters such as acetyl halide, chloro acetyl halide, pivaloyl halides, trichloroacetyl halides, trifluoro acetyl halides, alkyl trifluoroacetates; substituted or unsubstituted acid anhydrides such as acetic anhydride, chloro acetic anhydride, trifluoro acetic anhydride, aryl alkyl halides, alkoxyalkyl halide, aryloxy alkyl halide, (alkyl)m (aryl)3__m silyl halides and triflates; alkyl or aryl sulfonyl halides or anhydrides such as mesyl halides, mesyl anhydride, tosyl halides, tosyl anhydrides, benzyl halides, benzoyl halides.

The suitable "deprotecting agent" is selected from titanium reagents such as titanium tetrachloride; "acids" such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, acetic acid, trifluoro acetic acid, formic acid, benzene sulfonic acid, trifluoromethane sulfonic acid, toluene sulfonic acid, pyridinium p-toluene sulfonic acid etc; and "hydrogen fluoride (HF) sources" such as ammonium fluoride, tetrabutyl ammonium fluoride, pyridine-HF, Et₃N-3HF etc; Zn/Acetic acid, DDQ; "base" such as alkali metal carbonate and alkali metal hydroxides, sodium in liquid ammonia, organic base etc; metal catalysts in presence of hydrogen source.

The first aspect of the present invention provides an improved process for the preparation the compound of formula- 1 or its pharmaceutically acceptable salts comprising: a) reacting the compound of formula-2 or its salts with a suitable protecting agent in presence of a suitable base in a suitable solvent to provide the compound of general formula-3,

b) reducing the compound of general formula-3 with a suitable reducing agent in a suitable solvent to provide the compound of general formula-4,

c) reacting the compound of general formula-4 with the compound of general formula-5 in the presence of a suitable base in a suitable solvent to provide the compound of general formula-6,

d) deprotecting the compound of formula-6 with suitable deprotecting agent in a suitable solvent to give the compound of formula- 1 ,

e) optionally converting the compound of formula- 1 into its pharmaceutically acceptable salts.

Wherein in steps-a) to d) the suitable solvent is selected from alcohol solvents, chloro solvents, ether solvents, ester solvents, polar aprotic solvents, hydrocarbon solvents, ketone solvents and polar solvents or mixtures thereof;

in step-a) the suitable protecting agent is same as defined above;

in step-b) the suitable reducing agent is selected from Lithium borohydride, Sodium borohydride and Potassium borohydride in presence of an acid; wherein acid is selected from acetic acid, propionic acid, butanoic acid and like; MB(R₇)pH(4_p), wherein M is selected from the group consisting of lithium ("Li"), sodium ("Na") and potassium ("K"), R₇ (in each occurrence) is independently selected from the group consisting of straight alkyl having 1-10 carbon atoms, branched alkyl having 1-10 carbon atoms, substituted aryl, unsubstituted aryl, straight alkoxy having 1-10 carbon atoms, branched alkoxy having 1-10 carbon atoms, and R₈C(0)0- wherein R$ is an organic radical (typically having 1-10 carbon atoms), and (p) is an integer selected from the group consisting of 1, 2 and 3; L-selectride; and like

in step-c) the suitable base is selected from organic or inorganic base;

in step-d) the suitable deprotecting agent is same as defined above.

Preferred embodiment of present invention provides an improved process for the preparation of formula- la comprising: a) reacting the hydrochloride salt compound of formula-2a with benzyl bromide in presence of potassium carbonate in dimethyl formamide to provide the compound of formula-3a, b) reducing the compound of formula-3a with lithium borohydride in presence of acetic acid in a solvent selected from methanol, tetrahydrofuran and mixtures thereof to provide the compound of formula-4a,

c) reacting the compound of formula-4a with 22-bromo-2, 5, 8, 11, 14, 17, 20- heptaoxadocosane compound of formula-5a in presence of sodium hydride in dimethyl formamide to provide the compound of formula-6a,

d) deprotecting the compound formula-6a with titanium tetrachloride in dichloromethane to provide the compound of formula- 1 ,

e) treating the compound of formula- 1 with oxalic acid or its hydrates in acetonitrile and methyl tertiarybutyl ether provide the compound of formula- 1 a.

The second aspect of the present invention provides an improved process for the preparation (5a,6a)-17-allyl-6-(2,5,8,l l,14,17,20-heptaoxadocosan-22-yloxy)-4,5-epoxy morphinan-3, 14-diol compound of formula- 1 or its pharmaceutically acceptable salts comprising:

a) reacting the compound of general formula-4 with the compound of general formula- 11 in the presence of a suitable base in a suitable solvent to provide the compound of general formula-6,

b) deprotecting the compound of formula-6 with suitable deprotecting agent in a suitable solvent to give the compound of formula- 1 ,

c) optionally converting the compound of formula- 1 into its pharmaceutically acceptable salts.

Wherein in steps-a) & b) the suitable solvent is selected from alcohol solvents, chloro solvents, ether solvents, ester solvents, polar aprotic solvents, hydrocarbon solvents, ketone solvents and polar solvents or mixtures thereof;

in step-a) the suitable base is selected from organic or inorganic base; preferably alkoxides; the reaction can be carried out at below 30°C; preferably 15 to 25 °C.

in step-b) the suitable deprotecting agent is same as defined above. Prior art literature discloses the process for the preparation of the compound of formula-6 involves the use of sodium hydride which is hazardous and difficult to handle. The present inventors developed a process using alalimetal alkoxides specifically potassium tertiary butoxide which is easy to handle and use. The present inventors also observed that by using potassium tertiary butoxide in the process to get highly pure compound with higher yields.

The preferred embodiment of present invention provides an improved process for the preparation of (5a,6a)-17-allyl-6-(2,5,8,l l,14,17,20-heptaoxadocosan-22-yloxy)-4,5-epoxy- morphinan-3, 14-diol oxalate compound of formula-la comprising:

a) reacting the compound of formula-4b with 2,5,8, 11,14,17,20-heptaoxadocosan -22-yl 4- methylbenzenesulfonate compound of formula- l ib in presence of potassium tertiary butoxide in dimethyl sulfoxide at 15 to 25 °C to provide the compound of formula-6b, b) deprotecting the compound formula-6b with titanium tetrachloride in dichloromethane to provide the compound of formula- 1 ,

c) treating the compound of formula- 1 with oxalic acid or its hydrates in a suitable solvent to provide the compound of formula- 1 a.

Further aspect of the present invention provides an improved process for the preparation of the compound of formula- la comprising:

a) adding a suitable solvent to the compound of formula- 1 ,

b) adding oxalic acid or its hydrates to a solution obtained in step-a),

c) isolating the solid to provide substantially pure compound of formula- la.

Wherein solvent in step-a) selected from alcohol solvents, nitrile solvents, polar solvents such as water, polar aprotic solvents, ether solvents, ester solvents and/or mixtures thereof; optionally heating the reaction mixture to a suitable temperature ranges from 35°C to reflux of the solvent used; in step-c) isolating refers to by adding a suitable anti-solvent or cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction; wherein anti-solvent selected from ether solvents, ester solvents. The present invention is schematically represented as follows:

Scheme-1:

Formula-6

Formula-la Formula-1

6a:P=Benzyl

6b:P=MEM

Wherein P is hydroxy protecting group; X is halogen; L is Mesyl or Tosyl

Scheme-2:

lib: L=Ts

Wherein L is selected from leaving group such as tosyl, mesyl and like..; X is selected from halogen

The third aspect of the present invention provides amorphous solid dispersion comprising (5a,6a)-17-allyl-6-(2,5,8,l l,14,17,20-heptaoxadocosan-22-yloxy)-4,5-epoxy morphinan-3, 14-diol oxalate compound of formula- la and at least one pharmaceutically acceptable excipient. As used herein, the term "solid dispersion" means any solid composition having at least two components. In certain embodiments, a solid dispersion as disclosed herein includes an active ingredient (compound of formula- la) dispersed among at least one other component, for example an excipient.

In general, the excipient is selected from but not limited to colloidal silicon dioxide, polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K-15, K-30, K-60, K- 90 and K-120 may be used), polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), copovidone, Eudragit, polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, α-, β-, γ-cyclodextrins, sulfobutylether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like.

The pure amorphous form as well as amorphous solid dispersion of compound of formula- la of the present invention are having purity of greater than 98%, preferably greater than 99% by HPLC and is useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula- la is present in the composition in particular polymorphic form mentioned. Such pharmaceutical compositions may comprise compound of formula- 1 a present in the composition in a range of between 0.005% and 100% (wt/wt), with the balance of the pharmaceutical composition comprising additional substances such as excipients, diluents, lubricants, binders, wetting agents, disintegrating agents, glidants, sweetening agents, flavoring agents, emulsifying agents, solubilizing agents, pH buffering agents, perfuming agents, surface stabilizing agents, suspending agents and other conventional pharmaceutically inactive agents.

The amorphous solid dispersion of the present invention is stable at room temperature under normal stability conditions and does not convert to any other solid state form.

Further aspect of the present invention provides a process for the preparation of amorphous solid dispersion comprising compound of formula- la and at least one pharmaceutically acceptable excipient, comprising of;

a) dissolving the compound of formula- la in a suitable solvent,

b) adding at least one excipient at a suitable temperature,

c) stirring the reaction mixture,

d) removing the solvent from the reaction mixture and drying the material to provide amorphous solid dispersion comprising compound of formula- la and excipient.

Wherein, in step-a) the suitable solvent is selected from but not limited to alcohol solvents, chloro solvents, polar-aprotic solvents or their mixtures; and the suitable temperature ranges from 25 °C to reflux temperature of the solvent used;

in step (b) the excipient is same as defined above in the fourth aspect;

After dissolving the compound of formula- la and excipient in the solvent system, the solution may optionally be treated with charcoal or any other suitable material to remove color and/or to clarify the solution and the solution may optionally be filtered to make it particle free.

In step (d) the suitable techniques which may be used for the removal of solvent from the reaction mixture includes but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction or by any other suitable techniques known in the art.

In the present invention, the ratio of the amount by weight of compound of formula- 1 a within the solid dispersion to the amount by weight of the excipient therein ranges from but not limited to about 1 :0.05 to about 1:5.

The fourth aspect of the present invention provides the process for the purification of (5a,6a)-17-allyl-6-(2,5,8, ll,14,17,20-heptaoxadocosan-22-yloxy)-4,5-epoxymorphinan-3,14- diol oxalate compound of formula- la comprising the following steps:

a) dissolving the compound of formula- la in a suitable solvent at a suitable temperature, b) stirring the reaction mixture,

c) isolating the solid to get substantially pure compound of formula- la.

Wherein in step-a) the suitable solvent is selected from alcohol solvents, nitrile solvents, polar solvents such as water, polar aprotic solvents, ether solvents, ester solvents and/or mixtures thereof; the suitable temperature ranges from 25°C to reflux of the solvent used; in step-c) isolating refers to by adding a suitable anti-solvent or cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction or by any other suitable techniques known in the art.

After dissolving the compound of formula- la in the said solvent system, the solution may be optionally treated with charcoal or any other suitable material to remove color and/or to clarify the solution and the solution may optionally be filtered to make it particle free.

Preferred embodiment of the present invention provides the process for the purification of the compound of formula- la comprising the following steps:

a) dissolving the compound of formula- la in a mixture of water and acetonitrile at 25 °C to reflux temperature, b) adding ethyl acetate to the solution obtained in step-a) at below 25°C, c) filtering the solid to get pure compound of formula- la.

The compound of formula-2, compound of formula-7 and compound of formula-9 which are utilized in the present invention can be synthesized by any of the known processes or they can be procured from any of the commercial sources.

Further aspect of the present invention provides a process for the preparation of substantially pure compound of formula- 1 or its pharmaceutically acceptable salts comprising of:

a) providing a solution containing the compound of formula- 1 in the mixture of water and water immiscible organic solvent;

b) acidifying the reaction mixture using a suitable acid,

c) separating both the organic and aqueous layers,

d) adding the aqueous solution of base to the aqueous layer,

e) adding water immiscible organic solvent to the reaction mixture obtained in step-d) f) separating both the organic and aqueous layers,

g) washing the organic layer using aqueous solution of base,

h) adding water to the organic layer and adjusting the pH of the reaction mixture using a suitable acid,

i) separating both the organic and aqueous layers,

j) optionally washing the organic layer using aqueous sodium chloride solution, k) concentrating the organic layer to get pure compound of formula- 1 ,

1) optionally converting the compound of formula- 1 into its pharmaceutically acceptable slats.

Wherein in steps -b) and h) the suitable acid is selected from organic or inorganic acids; preferably organic acids;

in steps-d) and g) the base is selected from organic bases or inorganic bases;

in steps-a) and e) the suitable water immiscible organic solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents; preferably chloro solvents. Further aspect of the present invention provides a process for the preparation of substantially pure compound of formula- 1 or its pharmaceutically acceptable salts comprising of:

a) providing a solution of acid addition salts of compound of formula- 1 in water, b) optionally washing with water immiscible organic solvent,

c) adjusting the pH of the solution obtained in step-a) or step-b) to 4.5-5 with a suitable base,

d) extracting the substantially pure compound of formula- 1 into a suitable water immiscible organic solvent,

e) washing the solution of compound of formula- 1 obtained in step-d) with an aqueous base,

f) isolating substantially pure compound of formula- 1 ,

g) optionally converting the compound of formula- 1 into its substantially pure pharmaceutically acceptable slats.

Wherein in step-a) "providing a solution of acid addition salts of compound of formula- 1 "can be directly obtained from the reaction mixture or it can be obtained by treating the compound of formula- 1 with a suitable acid in a suitable solvent;

the suitable water immiscible organic solvent in step-b) and step-d) is selected from chloro solvent, ester solvent, ether solvent and hydrocarbon solvent; suitable base is selected from organic or inorganic base.; "isolating" refers to the solution obtained in step-e) washing with an aqueous acid followed by distilling off the solvent completely from the organic layer.

Preferred embodiment of the present invention provides a process for the preparation of substantially pure compound of formula- la comprising:

a) providing a solution of the oxalic acid salt compound of formula- 1 in water

b) washing the solution with dichlorome thane,

c) adjusting the pH to 4.5 to 5 with aqueous sodium carbonate solution,

d) extracting the compound of formula- 1 into dichloromethane,

e) washing the organic layer obtained in step-d) with aqueous sodium hydroxide solution, f) washing the organic layer with aqueous acetic acid solution,

g) removing the solvent from the organic layer to provide substantially pure compound of formula- 1.

"Substantially pure" means compound of formula- 1 or its pharmaceutically acceptable salts prepared by the process of the present invention is substantially free from the impurities. The compound of formula- 1 or formula- la obtained according to the present invention is substantially pure having a purity >95%, preferably >97%, more preferably >99%.

The following impurities are observed during the synthesis of the compound of formula- la as per the present invention. Along with these impurities, the starting materials are well controlled as per ICH guide lines in the compound of formula- la.

HPLC Method of Analysis:

(5a,6a)-17-allyl-6-(2,5,8, ll,14,17,20-heptaoxadocosan-22-yloxy)-4,5-epoxy morphinan- 3,14-diol oxalate and its related substances were analyzed by HPLC with the following chromatographic conditions:

Apparatus: A liquid chromatograph is equipped with dual wavelength UV Detector and integrator. Column: YMC-Pack Pro C18, 150 x 4.6 mm, 3 μπι, 12 nm (or) Equivalent; Wavelength: 210 nm; Column temperature: 10°C; Injection volume: 5 μΕ; Elution: Gradient; Diluent: Acetonitrile: Water (20:80) v/v; Needle wash: Diluent.

Buffer Preparation:

i) Accurately transfer 1000 ml of milli-Q water into a suitable cleaned and dry beaker.

ii) Weigh accurately 2.72 g of potassium di hydrogen phosphate and mix well with above 1000 ml of milli-Q-water; add about 1.0 ml of Triethyl amine and mix well.

iii) Adjust the pH 3.5±0.05 with diluted ortho phosphoric acid solution.

iv) Filter the obtained solution through 0.22 μπι nylon membrane filter paper and sonicate about 10 minutes to degas it.

Mobile phase-A: Buffer 100%; Mobile phase-B: Acetonitrile: Buffer: Methanol (55:37:8 v/v)

(5a,6a)-17-allyl-6-(2,5,8, ll,14,17,20-heptaoxadocosan-22-yloxy)-4,5-epoxy morphinan-3, 14-diol oxalate compound of formula- la produced by the present invention can be further micronized or milled in a conventional techniques. 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.

(5α,6α)- 17-allyl-6-(2,5,8, 11,14, 17,20-heptaoxadocosan-22-yloxy)-4,5-epoxy morphinan-3, 14-diol oxalate compound of formula- la obtained according to the present invention having particle size about less than 500μπι, preferably <300 μπι, most preferably <200 nm.

The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provides as illustration only and hence should not be construed as limitation of the scope of the invention.

Examples:

Example-1: Preparation of compound of formula-3a

A mixture of compound of formula-2a (10 g) and dimethylformamide (100 ml) was stirred for 15 minutes at 30-35°C and cooled to 0-5°C. Potassium carbonate (6.91 gms) was added to the reaction mixture at 0-5°C and stirred for 15 minutes at the same temperature. Benzyl bromide (6.41 gms) was slowly added to the reaction mixture at 0-5°C, raised the temperature of the reaction mixture to 25-30°C and stirred for 6 hours at the same temperature. To the above reaction mixture potassium carbonate (1.72 gms) followed by benzyl bromide (2.13 gms) was slowly added at 25-30°C. Stirred the reaction mixture for 30 minutes at 25-30°C. Ethyl acetate and water were added to the obtained compound and stirred for 15 minutes. Both the organic and aqueous layers were separated; and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure and co-distilled with cyclohexane. Cyclohexane (20 ml) was added to the obtained compound at 25-30°C and stirred for 45 minutes at the same temperature. Filtered the solid, washed with cyclohexane and dried to get the title compound. Yield: 8.4 gms

Example-2: Preparation of (4R,4aS,7aR,12bS)-3-allyl-4a-hydroxy-9-((2-methoxy ethoxy)methoxy)-2,3,4,4a,5,6-hexahydro-lH-4,12-methanobenzofuro[3,2-e]isoquinolin- 7(7aH)-one [Formula-3b]

A mixture of the compound of formula-2a (50 gms), dichloromethane (300 ml) and water was stirred for 10 minutes at 25-30°C and basified the reaction mixture using triethylamine. Separated the both organic and aqueous layers and the aqueous layer was extracted with dichlorome thane. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. Dichloromethane followed by N,N-diisopropylethylamine (85.3 ml) were added to the obtained compound at 25-30°C and cooled the reaction mixture to 5-10°C. 2- methoxyethoxymethyl chloride [MEM-C1] (56.6 gms) was added to the reaction mixture at 5-10°C and stirred for 2 hours at the same temperature. Water was added to the reaction mixture at 5-10°C and raised the temperature of the reaction mixture to 25-30°C. Separated the both organic and aqueous layers. The organic layer was washed with aqueous sodium bicarbonate solution followed by aqueous sodium chloride solution. Distilled of the solvent completely from the organic layer to get the title compound. Yield: 48.5 gms.

Example-3: Preparation of compound of formula-4a

A mixture of compound of formula-3a (8 gms), tetrahydrofuran (80 ml) and methanol (80 ml) was stirred for 15 minutes at 30-35°C under nitrogen atmosphere and cooled to 0-5°C. To this reaction mixture sodium triacetoxyborohydride (6.14 gms) and acetic acid (1.14 gms) were added, raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Sodium triacetoxyborohydride (20.4 gms) and acetic acid (4.56 gms) were added to the reaction mixture in the lot-wises. After completion of the reaction, the reaction was quenched with water at 25-30°C and neutralized the reaction mixture using aqueous sodium carbonate solution. Distilled off the solvent from the reaction mixture under reduced pressure. Ethyl acetate was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Separated both the organic and aqueous layers and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 7.34 gms.

Example-4: Preparation of compound of formula-4a

Cooled the mixture of acetic acid (10 ml) and tetrahydrofuran (4 ml) to 0-5°C. 0.52 gm of 2M lithium borohydride was slowly added to the reaction mixture at 0-5 °C and stirred the reaction mixture for 3 hours at the same temperature. This reaction mixture was added to the solution of the compound of formula-3a (2 gms) in tetrahydrofuran (16 ml) at 25-30°C and stirred for 8 hours at the same temperature. Quenched the reaction mixture with water and neutralized the reaction mixture using aqueous sodium carbonate solution. Ethyl acetate was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Separated both the organic and aqueous layers and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 1.8 gms.

Example-5: Preparation of compound of formula-4b

7.2 ml of 2M lithium borohydride was added to pre-cooled tetrahydrofuran (10 ml) at 0-5°C and stirred for 5 minutes. Acetic acid (2.9 ml) was slowly added to the reaction mixture at 0- 5°C and stirred the reaction mixture for 30 minutes at the same temperature. This reaction mixture was added to the solution of the compound of formula-3b (2 gms) in tetrahydrofuran (10 ml) at 0-5°C and stirred for 35 minutes at the same temperature. Quenched the reaction mixture with water and basified the reaction mixture using aqueous ammonia. Ethyl acetate was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Separated both the organic and aqueous layers and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 1.7 gms.

Example-6: Preparation of compound of formula-4b

7.2 ml of 2M lithium borohydride was added to pre-cooled tetrahydrofuran (10 ml) at 0-5°C and stirred for 5 minutes. Propionic acid (2.9 ml) was slowly added to the reaction mixture at 0-5 °C and stirred the reaction mixture for 30 minutes at the same temperature. This reaction mixture was added to the solution of the compound of formula-3b (2 gms) in tetrahydrofuran (10 ml) at 0-5°C and stirred for 35 minutes at the same temperature. Quenched the reaction mixture with water and basified the reaction mixture using aqueous ammonia. Ethyl acetate was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Separated both the organic and aqueous layers and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 1.6 gms.

Example-7: Preparation of compound of formula-6a

Sodium hydride (2.8 gms) was added to the mixture of compound of formula-4a (7.0 gms) and dimethylformamide (70 ml) at 25-30°C under nitrogen atmosphere and stirred for 15 minutes at the same temperature. To this reaction mixture 22-bromo-2,5, 8, 11, 14,17,20- heptaoxadocosane compound of formula-5a (23.5 gms) was slowly added, heated the reaction mixture to 40-45°C and stirred for 8 hours. Cooled the reaction mixture to 25-30°C. Quenched the reaction mixture with aqueous ammonium chloride solution at 25-30°C and ethyl acetate was added to it. Separated both the organic and aqueous layers and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure. Purified the obtained compound using column chromatography by eluting with 5% methanol in dichloromethane. Yield: 4.6 gms.

Example-8: Preparation of (4R,4aS,7aR,12bS)-7-(2,5,8,ll,14,17,20-heptaoxadocosan-22- yloxy)-3-allyl-9-((2-methoxyethoxy)methoxy)-2,3,4,4a,5,6,7,7a-octahydro-lH-4,12- methanobenzofuro[3,2-e]isoquinolin-4a-ol [Formula-6b]

The compound of formula-4b (40 gms) was added to the mixture of the compound of formula-5b (100.2 gms) and toluene (800 ml) at 25-30°C and stirred for 5 minutes. Distilled off the solvent from the reaction mixture under reduced pressure and co-distilled with toluene. Cooled the reaction mixture to 25-30°C and to this toluene (1600 ml), dimethylformamide (60 ml) and sodium hydride (25.6 gms) were added at the same temperature. Heated the reaction mixture to 50-55 °C and stirred for 7 hours at the same temperature. Cooled the reaction mixture to 25-30°C and quenched the reaction mixture with aqueous sodium chloride solution. Water was added to the reaction mixture. Separated the both organic and aqueous layers and aqueous layer was extracted with toluene. Combined the organic layers and water was added. The reaction mixture pH was adjusted with 50% of acetic acid to 4 and stirred for 15 minutes. Separated the both organic and aqueous layers and aqueous layer was washed with toluene. Neutralized the aqueous layer using aqueous sodium bicarbonate solution and washed with methyl tertiary butyl ether. The reaction mixture pH was adjusted to 8 using aqueous potassium carbonate solution and added aqueous sodium chloride solution. The reaction mixture was extracted with methyl tertiary butyl ether. Combined methyl tertiary butyl ether layers, dried over anhydrous sodium sulphate and distilled off the solvent completely to get the title compound. Yield: 41 gms

Example-9: Preparation of compound of formula-1

A solution of titanium tetrachloride (3.39 gms) in dichloromethane (67.5 ml) was slowly added to mixture of compound of formula-6a (4.5 gms) and dichloromethane (67.5 ml) at 25- 30°C. Stirred for 2 hours at 25-30°C and quenched with water. Neutralized the reaction mixture using aqueous sodium carbonate solution, filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Separated both the organic and aqueous layers and aqueous layer was extracted with ethyl acetate. Distilled off the solvent completely under reduced pressure and purified the obtained compound using column chromatography by eluting with 5% methanol in dichloromethane. Yield: 1.5 gms.

Example-10: Preparation of the compound of formula-1

A mixture of titanium tetrachloride (86 ml) and dichloromethane (36 ml) was slowly added to the pre-cooled solution of the compound of formula-6b (18 gms) in dichloromethane (360 ml) at 15-20°C and stirred for 15 minutes at the same temperature. Quenched the reaction mixture with water at 15-20°C. Both the organic and aqueous layers were separated and the aqueous layer was basified by using ammonia solution. The aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with water followed by aqueous sodium chloride solution. Distilled off the solvent completely to from the organic layer under the reduced pressure to get the title compound. Yield: 15 gms

Example-11: Preparation of the compound of formula-la

The solution of oxalic acid ( 2.89 gms) in methyl tertiary butyl ether (175 ml) was slowly added to the pre-cooled mixture of (4R,4aS,7aR,12bS)-7-(2,5,8,l l,14,17,20-hepta oxadocosan-22-yloxy)-3-allyl-2,3,4,4a,5,6,7,7a-octahydro-lH-4,12-methanobenzofuro[3,2-e] isoquinoline-4a,9-diol (17.5 gms), ethanol (35 ml) and methyl tertiary butyl ether (140 ml) at the 15-20°C and stirred for 2 hours. Filtered the precipitated solid, washed with methyl tertiary butyl ether and dried to get the title compound. Yield: 17.1 gms.

Example-12: Preparation of 2-(2-(2-methoxyethoxy)ethoxy)ethyl methanesulfonate [Formula-8a]

Cooled the mixture of 2-(2-(2-methoxyethoxy)ethoxy)ethanol (20 gms), triethylamine (23.7 ml) and dichloromethane (100 ml) to 5 to 10°C. Slowly added the solution of methanesulfonyl chloride (11.3 ml) in dichloromethane (20 ml) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 10 minutes at the same temperature. Filtered the reaction mixture and washed with dichloromethane. Water was added to the filtrate and stirred for 15 minutes at the 25-30°C. Separated both the organic and aqueous layers and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer to get the title compound. Yield: 20.1 gms.

Example-13: Preparation of 2,5,8,ll,14,l'7,20-heptaoxadocosan-22-ol [Formula-10]

The solution of the compound of formula-9 (54.5 gms) in 34 ml of tetrahydrofuran was slowly added to pre-cooled mixture of sodium hydride (5.6 gms) and tetrahydrofuran (170 ml) at 0-5 °C under nitrogen atmosphere and stirred the reaction mixture for 45 minutes at the same temperature. To this reaction mixture, the solution of the compound of formula-8a (34 gms) in tetrahydrofuran (34 ml) was added. Heated the reaction mixture to 40-45 °C and stirred for 12 hours at the same temperature. Cooled the reaction mixture to 25-30°C and acidified the reaction mixture using aqueous hydrochloric acid solution. Distilled off the solvent completely from the reaction mixture. To this reaction mixture aqueous sodium chloride solution was added and washed with ethyl acetate. Extracted the compound into dichloromethane from the reaction mixture. Combined the dichloromethane layers and washed with aqueous sodium solution and distilled off the solvent completely from the organic layer to get the title compound. Yield: 30 gms.

Example-14: Preparation of 2,5,8,H,14,17,20-heptaoxadocosan-22-ol [Formula-10]

Potassium tertiary butoxide (20.3 gms) was slowly added to the solution of the compound of formula-9 (64.1 gms) in tetrahydrofuran (280 ml) at 25-30°C and stirred for 2 hours at the same temperature. To this reaction mixture the compound of formula-8a (40 gms) was slowly added at 25-30°C. The reaction mixture was heated to 55-60°C and stirred at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture and cooled to the 25-30°C. Water was added and acidified the reaction mixture using hydrochloric acid and the reaction mixture was washed with ethyl acetate. The aqueous sodium chloride solution was added to the reaction mixture and extracted with dichlorome thane. Organic layers were dried over anhydrous sodium sulphate. Distilled off the solvent completely under reduced pressure to get the title compound. Yield: 29 gms

Example-15: Preparation of 2,5,8,ll,14,17,20-heptaoxadocosan-22-yl methanesulfonate [Formula-lla]

Cooled the mixture of the compound of formula-10 (35 gms), triethylamine (21.5 ml) and dichloromethane (175 ml) to 0-5°C and the solution of methanesulfonyl chloride (11.9 ml) in dichloromethane (35 ml) was slowly added to the reaction mixture at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 10 minutes at the same temperature. To the reaction mixture water was added and stirred for 15 minutes at 25- 30°C. Both the organic and aqueous layers were separated. The organic layer washed with aqueous sodium bicarbonate solution followed by water. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 32.8 gms. Example-16: Preparation of 22-bromo-2,5,8,ll,14,17,20-heptaoxadocosane [Formula- 5a]

A mixture of the compound of formula-lla (10 gms), lithium bromide (4.1 gms) and tetrahydrofuran (100 ml) was heated to 50-55°C and stirred it for 11 hours at the same temperature. Cooled the reaction mixture to 25-30°C. To this reaction mixture water and ethyl acetate were added at 25-30°C and stirred for 15 minutes. Both organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 6 gms.

Example-17: Preparation of 2,5,8,11,14,1 ,20-heptaoxadocosan-22-ol

Slowly added the solution of methanesulfonyl chloride (83.7 gms) in dichloromethane (500 ml) to pre-cooled mixture of 2-(2-(2-methoxyethoxy)ethoxy)ethanol (100 gms), triethylamine (98.5 gms) and dichloromethane (100 ml) at 5-10°C and stirred the reaction mixture for 3 hours at the same temperature. Raised the temperature of the reaction mixture to 25-30°C. To this reaction mixture water was added and stirred for 20 minutes. Separated the both organic and aqueous layers and the aqueous layer was extracted with dichlorome thane. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer under reduced pressure to get 2-(2-(2- methoxyethoxy)ethoxy)ethyl methane sulfonate. To this obtained compound toluene (1500 ml) was added at 25-30°C and stirred for 15 minutes at the same temperature. Potassium tertiary butoxide (74 gms) was added in lot-wise to 2, 2'-(ethane- 1 ,2-diylbis(oxy))diethanol (235 gms) at 25-30°C and stirred for 4 hours at the same temperature. To this reaction mixture, above obtained 2-(2-(2-methoxyethoxy)ethoxy)ethyl methane sulfonate solution was slowly added at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 12 hours at the same temperature. Cooled the reaction mixture to 25-30°C, water was added and acidified the reaction mixture using hydrochloric acid. Stirred the reaction mixture for 20 minutes at the same temperature and separated the both organic and aqueous layers. The aqueous layer was washed with ethyl acetate. Aqueous sodium chloride solution and dichloromethane were added to the aqueous layer and stirred for 10 minutes. Separated the both organic and aqueous layers and the aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer. Methyl tertiary butyl ether ( 1500 ml) was added to the obtained compound at 25-30°C and stirred for 60 minutes at the same temperature. Slowly cooled the reaction mixture to -50°C to -55°C and stirred for 4 hours at the same temperature. Settled the reaction mixture and decanted the upper layer and raised the temperature the reaction mixture to 30-35 °C. Distilled off the solvent completely from reaction mixture under the reduced pressure to get the title compound.

Yield: 125 gms; Purity by GC: 93.24%.

Example-18: Preparation of 2,5,8,11,14,1 ,20-heptaoxadocosan-22-yl 4-methylbenzene sulfonate [Formula-lib]

Tetrahydrofuran (75 ml) and 2,5,8, ll,14,17,20-heptaoxadocosan-22-ol (50 gms) were added to the aqueous sodium hydroxide solution (14.68 gms of sodium hydroxide dissolved in 75 ml of water) at 25-30°C and cooled the reaction mixture to 0-5°C. The solution of 33.59 gms of para toluene sulfonyl chloride in tetrahydrofuran (75 ml) was slowly added to the reaction mixture at 0-5 °C and stirred for 4 hours at the same temperature. To this reaction mixture water and ethyl acetate were added, raised the temperature of the reaction mixture to 25-30°C and stirred for 20 minutes at the same temperature. Separated the both organic and aqueous layers and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under the reduced pressure to get the title compound.

Yield: 58 gms; Purity by HPLC: 96.95%.

Example-19: Preparation of compound of formula-3b

A mixture of Naloxone hydrochloride dihydrate compound of formula-2a (100 gms) and water (500 ml) was stirred for 15 minutes at 25-30°C. Basified the reaction mixture using aqueous sodium carbonate solution and stirred for 60 minutes at 25-30°C. Filtered the solid and washed with water. Dichloromethane (600 ml) was added to the compound at 25-30°C and stirred for 10 minutes. Separated the both organic and aqueous layer. Collected the water from the organic layer under azeotropic conditions. Cooled the reaction mixture to 0-5°C, diisopropylethyl amine (218 ml) was added to the reaction mixture and stirred for 10 minutes at the same temperature. 2-methoxyethoxymethyl chloride (113 ml) was slowly added to the reaction mixture at 0-5 °C and stirred for 4 hours at the same temperature. Water was added to the reaction mixture and stirred for 15 minutes at 0-5°C. Separated the both organic and aqueous layers and the aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with cyclohexane. Purity by HPLC: 95.07%. Cyclohexane (500 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 2 hours at the same temperature. Slowly cooled the reaction mixture to 10-15°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with cyclohexane and dried to get title compound. Yield: 78.4 gms; MR: 60-65°C.

Purity by HPLC: 96.79%.

Example-20: Preparation of (4R,4aS,7aR,12bS)-3-allyl-9-((2-methoxyethoxy)methoxy)- 2,3,4, 4a,5,6, 7,7a-octahydro-lH-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,7-diol compound of formula-4b

The compound of formula-3b (100 gms) was dissolved in methanol (400 ml) at 25-30°C. To this reaction mixture acetic acid (220 ml) and followed by 2M lithium borohydride (601 ml) were slowly added at 25-30°C and stirred for 3 hours at the same temperature. Quenched the reaction mixture with water and basified the reaction mixture using aqueous potassium carbonate solution. Distilled off the solvent completely from the reaction mixture under reduced pressure. Toluene was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Separated the both organic and aqueous layers and the aqueous layer was extracted with toluene. Combined the organic layers and washed with aqueous sodium hydroxide solution, followed by water and aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 94.1 gms; Purity by HPLC: 93.55%.

Example-21: Preparation of the compound of formula-6b

A mixture of the compound of formula-4b (50 gms), 2,5,8,ll,14, 17,20-heptaoxadocosan-22- yl-4-methylbenzenesulfonate compound of formula- l ib (71 gms) and dimethyl sulfoxide (200 ml) was cooled to 10-15°C. To this reaction mixture potassium tertiary butoxide (13.41 gms) was added at 10-15°C, raised the temperature of the reaction mixture to 20-25°C and stirred the reaction mixture for 45 minutes at the same temperature. Another lot of potassium tertiary butoxide (10.06 gms) was added to the reaction mixture at 20-25 °C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 10-15°C and quenched the reaction mixture with water. Raised the temperature of the reaction mixture to 25-30°C and extracted the reaction mixture with toluene. Combined the organic layers and washed with water. Water was added to the organic layer and acidified the reaction mixture using acetic acid at 25-30°C. Separated the both organic and aqueous layers and the aqueous layer was washed with toluene. Aqueous layer was neutralized with aqueous sodium carbonate solution at 25-30°C and washed with methyl tertiary butyl ether. The aqueous layer was basified using aqueous ammonia and followed by extracted with toluene. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.

Yield: 60 gms; Purity by HPLC: 92.46%.

Example-22: Preparation of the compound of formula-6b

The solution of compound of formula-4b (100 gms) in toluene (400 ml) was added to the mixture of sodium hydride (23.9 gms) and toluene (600 ml) at 25-30°C under nitrogen atmosphere. The solution of compound of formula- lib (142 gms) in toluene (200 ml) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 60-65 °C and stirred the reaction mixture for 5 hours at the same temperature. Cooled the reaction mixture to 20- 25 °C and quenched the reaction mixture with acetic acid. Aqueous sodium chloride solution was added to the reaction mixture at 20-25 °C and stirred for 10 minutes. Separated the both organic and aqueous layers and the aqueous layer was extracted with toluene. Combined the organic layers, water was added to the organic layer and acidified the reaction mixture using acetic acid at 25-30°C. Separated the both organic and aqueous layers and the aqueous layer was washed with toluene. Aqueous layer was neutralized with aqueous sodium carbonate solution at 25-30°C and washed with methyl tertiary butyl ether. The aqueous layer was basified using aqueous ammonia and followed by extracted with toluene. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 101 gms; Purity by HPLC: 92%.

Example-23: Preparation of the compound of formula-la

A mixture of titanium tetrachloride (66.8 ml) and dichloromethane (300 ml) was slowly added to the mixture of compound of formula-6b (150 gms) and dichloromethane (2700 ml) at 20-25°C and stirred the reaction mixture for 2 hours at the same temperature. Quenched the reaction mixture with aqueous sodium sulfite solution. Raised temperature of the reaction mixture to 25-30°C and stirred for 30 minutes at the same temperature. Separated the both organic and aqueous layers and the aqueous layer was extracted with dichloromethane. Combined the organic layers and water was added to it. Acidified the reaction mixture using aqueous oxalic acid solution at 25-30°C and stirred for 15 minutes at the same temperature. Separated the both organic and aqueous layers and the aqueous layer was washed with dichloromethane. The aqueous layer pH was adjusted to 4.6 using aqueous sodium carbonate solution and stirred the reaction mixture for 15 minutes at the same temperature. Dichloromethane was added to the reaction mixture and separated the both organic and aqueous layers. The aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with aqueous sodium hydroxide solution. Stirred the reaction mixture for 45 minutes at 25-30°C and separated the both organic and aqueous layers. Water was added to the organic layer and pH of the reaction mixture was adjusted to 8.5 using acetic acid. Stirred the reaction mixture for 15 minutes and separated the both organic and aqueous layers. Organic layer was washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with methyl tertiary butyl ether. Acetonitrile (225 ml) was added to the obtained compound at 15-20°C. To this mixture oxalic acid dihydrate (21.6 gms) was slowly added at 15-20°C and stirred for 20 minutes at the same temperature. Methyl tertiary butyl ether (1350 ml) was added to the reaction mixture at 15-20°C and stirred for 5 hours at the same temperature. Filtered the precipitated solid, washed with methyl tertiary butyl ether and dried to get the title compound. Yield: 93.0 gms; M.R: 90-95°C.

Example-24: Preparation of the compound of formula-la

The preparation of the compound of formula- la is similar to the example-7 except ethyl acetate was used instead of methyl tertiary butyl ether for the isolation of compound of formula- la. Yield: 68.9%.

Example-25: Preparation of the compound of formula-la

The preparation of the compound of formula- 1 a is similar to the example-7 except Isopropyl acetate was used instead of methyl tertiary butyl ether for the isolation of compound of formula- la. Yield: 72.1%.

Example-26: Preparation of the compound of formula-la

A mixture of titanium tetrachloride (66.8 ml) and dichloromethane (300 ml) was slowly added to the mixture of compound of formula-6b (150 gms) and dichloromethane (2700 ml) at 20-25 °C and stirred the reaction mixture for 2 hours at the same temperature. Quenched the reaction mixture with aqueous sodium sulfite solution. Raised temperature of the reaction mixture to 25-30°C and stirred for 30 minutes at the same temperature. Separated the both organic and aqueous layers and the aqueous layer was extracted with dichloromethane. Combined the organic layers and water was added to it. Acidified the reaction mixture using aqueous oxalic acid solution at 25-30°C and stirred for 15 minutes at the same temperature. Separated the both organic and aqueous layers and the aqueous layer was washed with dichloromethane. The aqueous layer pH was adjusted to 4.6 using aqueous sodium carbonate solution and stirred the reaction mixture for 15 minutes at the same temperature. Dichloromethane was added to the reaction mixture and separated the both organic and aqueous layers. The aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with aqueous sodium hydroxide solution. Stirred the reaction mixture for 45 minutes at 25-30°C and separated the both organic and aqueous layers. Water was added to the organic layer and pH of the reaction mixture was adjusted to 8.5 using acetic acid. Stirred the reaction mixture for 15 minutes and separated the both organic and aqueous layers. Organic layer was washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with ethyl acetate. To the above obtained compound acetonitrile (225 ml), water (7.2 ml) and oxalic acid (15.5 gms) were added at 15-20°C and stirred for 20 minutes at the same temperature. To this reaction mixture ethyl acetate (1350 ml) was added at 15-20°C and stirred for 5 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 93.0 gms. Purity by HPLC: 98.79%.

Example-27: Process for the purification of the compound of formula-la

Dissolved the compound of formula- la (80 gms) in the mixture of acetonitrile (160 ml) and water (4 ml) at 25-30°C. Carbon (1.6 gms) was added to the reaction mixture at 25-30°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with the mixture of acetonitrile and water. Cooled the filtrate to 15-20°C and ethyl acetate (960 ml) was slowly added to it at the same temperature. Stirred the reaction mixture for 4 hours at 15-20°C. Filtered the precipitated solid and washed with ethyl acetate. Ethyl acetate (80 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 70-75 °C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture slowly to 5-10°C and stirred for 4 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get pure title compound. Yield: 65 gms; Purity by HPLC: 99.63%.

Example-28: Process for the purification of the compound of formula-la

Dissolved the (5a,6a)-17-allyl-6-(2,5,8,l l,14,17,20-heptaoxadocosan-22-yloxy)-4,5-epoxy morphinan-3, 14-diol oxalate compound of formula-la (25 gms) in the mixture of acetonitrile (50 ml) and water (1.25 ml) at 25-30°C. Carbon (0.5 gms) was added to the reaction mixture at 25-30°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with the mixture of acetonitrile and water. Cooled the filtrate to 15-20°C and ethyl acetate (300 ml) was slowly added to it at the same temperature. Stirred the reaction mixture for 4 hours at 15-20°C. Filtered the precipitated solid, washed with ethyl acetate and dried to get pure title compound. Yield: 25 gms

Example-29: Process for the purification of the compound of formula-la

Dissolved the compound of formula-la (10 gms) in ethanol (60 ml) at 55-60°C. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with ethanol and dried to get the title compound.

Yield: 5.6 gms; purity by HPLC: 99.34%.

Example-30: Process for the purification of the compound of formula-la

Dissolved the compound of formula- la (10 gms) in the mixture of N-methyl-2-pyrrolidone (20 ml) and isopropyl acetate (120 ml) at 60-65°C. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with isopropyl acetate and dried to get the title compound.

Yield: 5.6 gms; Purity by HPLC: 98.71%.

Example-31: Process for the purification of the compound of formula-la

A mixture of the compound of formula- la (10 gms) and n-propanol (50 ml) was stirred for 1 hour at 25-30°C same temperature. Filtered the solid, washed with n-propanol and dried to get the title compound. Yield: 7.3 gms; Purity by HPLC: 99.45%.

Example-32: Process for the purification of the compound of formula-la

Dissolved the compound of formula-la (50 gms) in acetonitrile (150 ml) at 25-30°C. Isopropyl acetate (360 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 5 minutes at the same temperature. Heated the reaction mixture to 50-55 °C and stirred for 10 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with isopropyl acetate and dried to get the title compound. Yield: 42 gms; Purity by HPLC: 99.21%.

Example-33: Process for the purification of the compound of formula-la

Dissolved the compound of formula-la (10 gms) in N-methyl-2-pyrrolidone (60 ml) at 55- 60°C. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 6.2 gms; Purity by HPLC: 99.07%.

Example-34: Process for the purification of the compound of formula-la

Dissolved the compound of formula- la (10 gms) in dimethylformamide (25 ml) at 25-30°C.

Isopropyl acetate (120 ml) was added to the reaction mixture at 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 5.1 gms; Purity by HPLC: 98.99%.

Example-35: Process for the purification of the compound of formula-la

Dissolved the compound of formula- la (10 gms) in dimethyl sulfoxide (30 ml) at 25-30°C.

Isopropyl acetate (120 ml) was added to the reaction mixture at 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with isopropyl acetate and dried to get the title compound. Yield: 4.8 gms; Purity by HPLC: 98.92%.

Example-36: Preparation of compound of formula-la

The mixture of the compound of formula- 1 (70 gms), isopropanol (350 ml) and oxalic acid dihydrate (14.9 gms) was heated to 40-45°C and stirred for 10 minutes at the same temperature. Cooling the reaction mixture to 25-30°C and seeded with the compound of formula- la. Stirred the reaction mixture for 2 hours at 25-30°C. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound. Yield: 58.1 gms.

Example-37: Preparation of compound of formula-la

The mixture of the compound of formula- 1 (50 gms), acetone (250 ml) and oxalic acid dihydrate (10.6 gms) was heated to 40-45°C and stirred for 10 minutes at the same temperature. Cooling the reaction mixture to 25-30°C and seeded with the compound of formula- la. Stirred the reaction mixture for 2 hours at 25-30°C. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound. Yield: 28 gms.

Example-38: Preparation of amorphous solid dispersion comprising compound of formula-la and Copovidine

Copovidine (1 gm) was added to the solution of the compound of formula- la (1 gm) in methanol (20 ml) at 25-30°C and stirred for 20 minutes at the same temperature. Distilled off the solvent completely under reduced pressure and dried to get the title compound.

Yield: 1.2 gms. The PXRD pattern of the obtained compound is shown in figure- 1.

Example-39: Preparation of amorphous solid dispersion comprising compound of formula-la and Cross povidone

A mixture of the compound of formula- la (1 gm), cross-povidone (1 gm) and methanol (20 ml) was stirred for 30 minutes at 25-30°C. Distilled off the solvent completely under reduced pressure and dried to get the title compound. Yield: 1.8 gm. The PXRD pattern of the obtained compound is shown in figure-2.

Example-40: Preparation of amorphous solid dispersion comprising compound of formula-la and HPMC-E5

HPMC (1 gm) was added to the solution of the compound of formula- la (1 gm) in methanol (20 ml) at 25-30°C and stirred for 35 minutes at the same temperature. Distilled off the solvent completely under reduced pressure and dried to get the title compound.

Yield: 1.5 gms. The PXRD pattern of the obtained compound is shown in figure-3.

Example-41: Preparation of amorphous solid dispersion comprising compound of formula-la and HPMC-AS

HPMC- AS (1 gm) was added to the solution of the compound of formula- la (1 gm) in methanol (20 ml) at 25-30°C and stirred for 30 minutes at the same temperature. Distilled off the solvent completely under reduced pressure and dried to get the title compound.

Yield: 1.5 gms. The PXRD pattern of the obtained compound is shown in figure-4.

Example-42: Preparation of amorphous solid dispersion comprising compound of formula-la and colloidal silicon dioxide

Colloidal silicon dioxide ( 1 gm) was added to the solution of the compound of formula- 1 a ( 1 gm) in methanol (20 ml) at 25-30°C and stirred for 30 minutes at the same temperature. Distilled off the solvent completely under reduced pressure and dried to get the title compound. Yield: 1.6 gms. The PXRD pattern of the obtained compound is shown in figure - 5.

Example-43: Preparation of amorphous solid dispersion comprising compound of formula-la and Povidone K-30

A mixture of the compound of formula- la (1 gm), Povidone K-30 (1 gm) and methanol (20 ml) was stirred for 30 minutes at 25-30°C. Distilled off the solvent completely under reduced pressure and dried to get the title compound. Yield: 1.6 gms.

Example-44: Preparation of amorphous solid dispersion comprising compound of formula-la and HPMC

A mixture of the compound of formula- la (5 gm), HPMC (5 gm) and methanol (200 ml) was stirred for 30 minutes at 25-30°C. Spray dried the reaction mixture to provide the title compound. Yield: 5.0 gm.

Example-45: Preparation of amorphous solid dispersion comprising compound of formula-la with HPMC-E5 (1:1)

Dissolved (5a,6a)-17-allyl-6-(2,5,8, ll, 14,17,20-heptaoxadocosan-22-yloxy) - 4,5-epoxy morphinan-3, 14-diol oxalate compound of formula-la (75 gms) in the mixture of methanol (540 ml) and dichloromethane (810 ml) at 25-30°C. Filtered the reaction mixture for particle free and washed the mixture of methanol and dichloromethane. HPMC-E5 (75 gms) was added to the obtained filtrate and stirred for 20 minutes at the same temperature. Spray dried the obtained solution using spray dryer as following conditions:

Internal temperature: 60-65°C; Feed rate: 10 ml/min; Aspirator flow rate: 70%; N2 Pressure: 2 Kg. Obtained material was dried to get the title compound. Yield: 60 gms. Purity by HPLC: 99.37%. PXRD of the obtained compound shown in figure-3.

Claims

We Claim:

1. A process for the preparation of the (5a,6a)-17-allyl-6-(2,5,8, l l,14, 17,20-hept docosan-22-yloxy)-4,5-epoxymorphinan-3,14-diol compound of formula-1 or pharmaceutically acceptable salts,

Formula- 1

comprising:

a) reacting the compound of formula-2 or its salts

Formula-2

with a suitable protecting agent in presence of a base in a suitable solvent to provide the compound of general formula-3,

Formula-3

Wherein P is hydroxy protecting group;

b) reducing of the compound of general formula-3 with a suitable reducing agent in a suitable solvent to provide the compound of general formula-4,

Formula-4 c) reacting the compound of general formula-4 with the compound of general formula-5 (or) compound of general formula- 11

Formula-5 Formula- 11

Wherein X is halogen; L is leaving group such as Mesyl or Tosyl

in the presence of a suitable base in a suitable solvent to provide the compound of general formula-6,

Formula-6

d) deprotecting the compound of formula-6 with a suitable deprotecting agent in a suitable solvent to provide the compound of formula- 1,

2. The process according to claim 1, wherein suitable reducing agent is selected from Lithium borohydride, Sodium borohydride and Potassium borohydride in presence of acid; wherein acid is selected from acetic acid, propionic acid and butanoic acid; the suitable base is selected from organic or inorganic base; suitable deprotecting agent is selected from titanium reagent such as titanium tetrachloride; "acid" such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, acetic acid, trifluoro acetic acid, formic acid, benzene sulfonic acid, trifluoromethane sulfonic acid, toluene sulfonic acid, pyridinium p-toluene sulfonic acid etc; and "hydrogen fluoride (HF) sources" such as ammonium fluoride, tetrabutyl ammonium fluoride, pyridine-HF, Et₃N-3HF etc; Zn/Acetic acid, DDQ; "base" such as alkali metal carbonate and alkali metal hydroxides, sodium in liquid ammonia, organic base etc; metal catalysts in presence of hydrogen source;

suitable solvent in steps-a) to d) is selected from alcohol solvents, chloro solvents, ether solvents, ester solvents, polar aprotic solvents, hydrocarbon solvents, ketone solvents and polar solvents or mixtures thereof.

3. A process for the preparation of the compound of formula- 1 a

Formula- la

comprising:

a) treating the compound of formula-2a with a suitable base followed by reacting with 2- methoxyethoxymethyl chloride in presence of diisopropylethyl amine in dichloromethane to provide the compound of formula-3b,

b) reducing of the compound of formula-3b with lithium borohydride in presence of acetic acid in a solvent selected from methanol, tetrahydrofuran or mixtures thereof to provide the compound of formula-4b,

c) reacting the compound of formula-4b with the 2,5, 8, 11, 14, 17,20-heptaoxadocosan-22- yl 4-methylbenzenesulfonate compound of formula- l ib in presence of potassium tertiary butoxide in dimethyl sulfoxide to provide the compound of formula-6b, d) deprotecting the compound of formula-6b with titanium tetrachloride in dichloromethane to provide the compound of formula- 1,

e) treating the compound of formula- 1 with oxalic acid dihydrate in a suitable solvent to provide the compound of formula- la.

4. A process for the preparation of the compound of formula- la comprising:

a) treating the compound of formula-2a with a suitable base followed by reacting with benzyl bromide in presence of potassium carbonate in dimethyl formamide to provide the compound of formula-3a,

b) reducing of the compound of formula-3a with lithium borohydride in presence of acetic acid in a solvent selected from methanol, tetrahydrofuran or mixtures thereof to provide the compound of formula-4a,

c) reacting the compound of formula-4a with the compound of formula-5a in presence of sodium hydride in dimethyl formamide to provide the compound of formula-6a, d) deprotecting the compound of formula-6a with titanium tetrachloride in dichloromethane to provide the compound of formula- 1,

e) treating the compound of formula- 1 with oxalic acid in a suitable solvent to provide the compound of formula- la.

5. A process for the purification of (5a,6a)-17-allyl-6-(2,5,8,l l, 14,17,20-heptaoxadocosan- 22-yloxy)-4,5-epoxymorphinan-3, 14-diol oxalate compound of formula-la comprising: a) dissolving the compound of formula- la in a suitable solvent at a suitable temperature,

b) isolating the solid to provide substantially pure compound of formula- la.

6. The process according to claim 5, wherein suitable solvent in step-a) is selected from alcohol solvents, nitrile solvents, polar solvents such as water, polar aprotic solvents, ether solvents, ester solvents and/or mixtures thereof; the suitable temperature ranges from 25°C to reflux of the solvent used;

in step-b) isolating refers to by adding a suitable anti-solvent or cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction.

7. A process for the purification of the compound of formula- la comprising:

a) dissolving the compound of formula- la in a mixture of water and acetonitrile at 25-

35°C,

b) combining the solution obtained in step-a) with ethyl acetate at below 25°C, c) filtering the solid to provide substantially pure compound of formula- la.

8. A process for the preparation of the compound of general formula-4 comprising reduction of the compound of general formula-3 with lithium borohydride in presence of an acid in a suitable solvent to provide the compound of general formula-4; wherein acid is selected from acetic acid, propionic acid and butanoic acid.

9. A process for the preparation of the compound of formula-4b comprising reduction of the compound of general formula-3b with lithium borohydride in presence of acetic acid in a solvent selected from methanol, tetrahydrofuran or mixtures thereof to provide the compound of formula-4b.

10. A process for the preparation of the compound of general formula-6 comprising reacting the compound of general formula-4 with compound of general formula- 11 in presence of alkali metal alkoxides in a suitable solvent to provide the compound of general formula- 6.

11. A process for the preparation of compound of formula-6b comprising reacting compound of formula-4b with 2,5,8, l l,14, 17,20-heptaoxadocosan-22-yl 4-methylbenzenesulfonate compound of formula- l ib in presence of potassium tertiary butoxide in dimethyl sulfoxide to provide compound of formula-6b.

12. A process for the preparation of the compound of formula- 1 comprising deprotecting the compound of formula-6 with titanium reagents such as titanium tetrachloride in a suitable solvent to provide the compound of formula- 1.

13. A process for the preparation of the compound of formula-1 comprising deprotecting the compound of formula-6b with titanium tetrachloride in dichloromethane to provide the compound of formula-1.

14. A process for the preparation of substantially pure compound of formula-1 or its pharmaceutically acceptable salts comprising of:

a) providing a solution of acid addition salts of compound of formula-1 in water, b) optionally washing with water immiscible organic solvent,

c) adjusting the pH to 4.5 to 5 with a suitable base,

d) extracting substantially pure compound of formula-1 into a suitable water immiscible organic solvent,

e) washing the solution of compound of formula-1 obtained in step-d) with an aqueous base,

f) isolating substantially pure compound of formula-1,

g) optionally converting the compound of formula-1 into its substantially pure pharmaceutically acceptable slats.

15. The process according to claim 14, wherein suitable water immiscible organic solvent in step-b) and step-d) is selected from chloro solvent, ester solvent, ether solvent and hydrocarbon solvent; suitable base is selected from organic or inorganic base.

16. A process for the preparation of substantially pure compound of formula-la comprising: a) providing a solution of the oxalic acid salt compound of formula-1 in water b) washing the solution with dichloromethane,

c) adjusting the pH to 4.5 to 5 with aqueous sodium carbonate solution, d) extracting the compound of formula- 1 into dichlorom ethane,

e) washing the organic layer obtained in step-d) with aqueous sodium hydroxide solution,

f) washing the organic layer with aqueous acetic acid solution,

g) removing the solvent from the organic layer to provide substantially pure compound of formula- 1,

h) treating the compound of formula- 1 with oxalic acid or its hydrates in a suitable solvent to provide the compound of formula- la.

17. A process for the preparation of the compound of formula-la comprising:

a) adding a suitable solvent to the compound of formula- 1,

b) adding oxalic acid or its hydrates to a solution obtained in step-a),

c) isolating the solid to provide substantially pure compound of formula- la.

18. The process according to claim 17, wherein solvent in step-a) selected from alcohol solvents, nitrile solvents, polar solvents such as water, polar aprotic solvents, ether solvents, ester solvents and/or mixtures thereof; optionally heating the reaction mixture to a suitable temperature ranges from 35°C to reflux of the solvent used;

in step-c) isolating refers to by adding a suitable anti-solvent or cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction; wherein anti-solvent selected from ether solvents, ester solvents.

19. A process for the preparation of the compound of formula-la comprising:

a) adding acetonitrile to the compound of formula- 1,

b) adding oxalic acid dihydrate to the mixture obtained in step-a),

c) combining methyl tertiary butyl ether to a solution obtained in step-b),

d) filtering the solid obtained in step-c) to provide the compound of formula- la.

20. The compound of formula-la having particle size distribution of D₉₀ less than 250 μπι, preferably less than 150 μπι.