A process for the preparation of samidorphan and its intermediates

Abstract

The present application relates to a process for preparation of the compound of Formula-5 which is a key intermediate in the production of Samidorphan. Samidorphan is chemically known as 17-(cyclopropylmethyl)-4,14-dihydroxy-6-oxomorphinan-3- carboxamide or morphinan-3-carboxamide, 17-(cyclopropylmethyl)-4,14-dihydroxy-6-oxo, is represented by the structural formula-1. Formula-1 Formula-5. wherein n is 1, 2, 3, 4 or 5; R is hydrogen, methyl, and allyl. The present invention also provides a process for the preparation of Samidorphan or a salt thereof.

Description

[0001] A PROCESS FOR THE PREPARATION OF SAMIDORPHAN AND ITS INTERMEDIATES

[0002] Related Applications:

[0003] This application claims the benefit of priority to our Indian patent application number 202341078373 filed on Nov 17, 2023, the disclosures of all of which is incorporated by reference in their entirety.

[0004] Field of the invention:

[0005] The present application relates to a process for preparation of the compound of Formula-5, a key intermediate in the production of Samidorphan. Samidorphan, also identified as 17-(cyclopropylmethyl)-4,14-dihydroxy-6-oxomorphinan-3- carboxamide or morphinan-3-carboxamide, 17-(cyclopropylmethyl)-4,14-dihydroxy- 6-oxo, is represented by the structural formula- 1.

[0006] Formula- 1 Formula-5. wherein n is 1, 2, 3, 4 or 5; R is hydrogen, methyl, and allyl.

[0007] The present invention also provides a process for the preparation of Samidorphan or its salts.

[0008] Background of the invention:

[0009] Morphinan-3 -carboxamide , 17 -(cycloprop ylmethyl)-4 , 14-dihydroxy 6-oxo- , (2S)-2-hydroxybutanedioate of formula- la is commonly known as Samidorphan L- malate. It is approved by the USFDA under the brand name of LYBALVI. LYBALVI is a combination of Olanzapine, an atypical antipsychotic, and Samidorphan, an opioid antagonist, indicated for the treatment of Schizophrenia in adults and Bipolar I disorder in adults, acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate and maintenance monotherapy treatment.

[0010] Formula- la.

[0011] US Patent number 7262298 describes certain methods for making Samidorphan and its intermediates. The patent also discloses column chromatographic purification for the Samidorphan, which is tedious and lengthy process.

[0012] W02012005795A1 describes the process for the preparation of Samidorphan and its intermediate compounds by protecting the carbonyl group to a 1,3-dioxalane group and the scheme is depicted as follows:

[0013]

[0014] In the above process, zinc cyanide is used to prepare the cyanide intermediate. However, zinc cyanide has several disadvantages, including toxicity, volatility, corrosiveness and issues with waste disposal. The present invention addresses these concerns by replacing zinc cyanide with N-hydroxysuccinamide (NHS), a flexible, efficient, and reasonably safe coupling agent.

[0015] However, there is always a need exist for alternative routes, which for example involves fewer steps, use reagents that are less expensive and / or easier to handle, consumes smaller amounts of reagents, provide a higher yield of product, have smaller and / or more ecofriendly waste products, and / or provide a higher purity of the final compound of Formula- 1. Hence, the inventors of the present invention has developed a process for the preparation of compound of formula-5 which is a key intermediate used in the preparation of Samidorphan and its salts.

[0016] Brief summary of the invention:

[0017] First embodiment of the present invention is to provide a process for the preparation of compound of formula-5, which is a key intermediate of Samidorphan.

[0018] Second embodiment of present invention is to provide a process for the purification of Samidorphan or a salt thereof. Third embodiment of the present invention is to provide a novel compound of formula-7 or a salt thereof.

[0019] Fourth embodiment of the present invention is to provide a pure Samidorphan or a salt thereof having purity of greater than about 99.5% measured by HPLC.

[0020] Fifth embodiment of the present invention is to provide a crystalline form of Samidorphan L-malate.

[0021] Sixth embodiment of the present invention is to provide Samidorphan L- malate having a particle size distribution of at least one of: a) DIO value is less than about 10 pm; b) D50 value is less than about 30 pm; and c) D90 value is less than about 100 pm.

[0022] Brief description of the drawings:

[0023] Figure 1 : Illustrates Powder X-Ray Diffraction [PXRD] pattern of crystalline form of Samidorphan L-malate obtained according to the present invention.

[0024] Detailed description of the Invention:

[0025] The “solvent” used in the present invention can be selected from but not limited to “hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and mixtures thereof; “ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and mixtures thereof; “ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, tert-butyl acetate and mixtures thereof; “polar-aprotic solvents” such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N- methylpyrrolidone (NMP) and mixtures thereof; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and mixtures thereof; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and mixtures thereof; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and mixtures thereof; “alcohol solvents” such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, 2-butanol, tert-butanol, ethane- 1,2- diol, propane- 1,2-diol and mixtures thereof; water; formic acid, acetic acid and the like or mixture of any of the afore mentioned solvents.

[0026] As used herein the term “base” used in the present invention refers to inorganic bases selected from “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkaline earth metal carbonates” such as calcium carbonate, magnesium carbonate, barium carbonate, strontium carbonate; “alkaline earth metal bicarbonates” such as calcium bicarbonate, magnesium bicarbonate, barium bicarbonate, strontium bicarbonate; “alkaline earth metal hydroxide” such as calcium hydroxide, magnesium hydroxide, barium hydroxide, strontium hydroxide;“alkyl metals” such as n-butyl lithium and like; “metal hydrides” such as lithium hydride, sodium hydride, potassium hydride and the like; “alkali metal phosphates” such as disodium hydrogen phosphate, dipotassium hydrogen phosphate; ammonia such as aqueous ammonia, ammonia gas, methanolic ammonia and like and “organic bases” selected from but not limited to methyl amine, ethyl amine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6- lutidine, n-methyl pyridine (NMP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo [4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; “alkali metal amides” such as sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA), “organosilicon bases” such as sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide, lithium bis(trimethysilyl)amide (LiHMDS), potassium hexamethyldisilazide (KHMDS) and the like; or mixtures thereof.

[0027] The term “salts” or “pharmaceutically acceptable salts” used 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, 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, (+)-naproxen, (lR)-(-)-camphor sulfonic acid, (IS)- (+)-camphor sulfonic acid (lR)-(+)-bromocamphor-10-sulfonic acid, (IS)-(-)- bromocamphor- 10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)- Dibenzoyl-L- tartaric acid 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 and like.

[0028] As used herein, the term “about” means within a statistically meaningful range of a value, such as a stated concentration range, time frame, molecular weight, particle size, temperature or pH. Such a range can be within an order of magnitude, typically within 20%, more typically within 10%, and even more typically within 5% of the indicated value or range. Sometimes, such a range can be within the experimental error typical of standard methods used for the measurement and / or determination of a given value or range. The allowable variation encompassed by the term “about” will depend upon the particular system under study, and can be readily appreciated by one of ordinary skill in the art. Whenever a range is recited within this application, every whole number integer within the range is also contemplated as an embodiment of the invention.

[0029] "Substantially pure" or “pure” as used herein refers to the purity of the material which is at least about 98.0 %, at least about 98.5 %, at least about 99.0 %, at least about 99.1 %, at least about 99.2 %, at least about 99.3 %, at least about 99.4 %, at least about 99.5 %, at least about 99.6 %, at least about 99.7 %, at least about 99.8 %, at least about 99.9 % or 100 % as measured by a liquid chromatography method.

[0030] "Substantially free of" as used herein refers to the level of impurity present in the material which is less than about 0.10 % or less than about 0.05 % or less than about 0.01 %.

[0031] First embodiment of the present invention provides a process for the preparation of compound of formula-5

[0032] Formula-5 wherein X is halogen or triflate; n is 1, 2, 3, 4 or 5; R is hydrogen, methyl, and allyl comprises: a) reacting the compound of formula-2

[0033] Formula-2 wherein X is halogen or triflate; n is 1, 2, 3, 4 or 5; R is hydrogen, methyl, and allyl; with carbon monoxide and the compound of formula-3

[0034]

[0035] Formula-3 wherein Ri & R2 are selected from H, alkyl, aryl or Riand R2 together form a cyclic compound, in a solvent in the presence of a palladium catalyst and a base to obtain compound of formula-4,

[0036] Formula-4 b) converting the compound of formula-4 to compound of formula-5; wherein, palladium catalyst is selected from palladium complexed with a ligand chosen from l,l’-bis(diphenylphosphino) ferrocene (DPPF), 1,3- bis(diphenylphosphino)propane (DPPP), triphenylphosphine, l,3-bis(diphenyl- phosphino) propane, 2,2’-bis(diphenylphosphino)-l,l'-binaphthyl (BINAP) and 4,5- Bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos); base is selected from organic bases or inorganic bases; the solvent is selected from from alcohol solvents, ether solvent, ketone solvents, nitrile solvent, ester solvents, chloro solvents, polar- aprotic solvents, water and / or mixtures thereof; the conversion of compound of formula-4 to formula-5 in step-b) by doing amidation; wherein the amidating agent is selected from ammonia, including aqueous ammonia, ammonia gas, methanolic ammonia, and formamide. Alternatively, sodium methoxide in formamide can be employed, optionally in the presence of another base or similar compounds. In first aspect of the first embodiment, the compound of formula-4 optionally isolated or proceeds to next step without isolation.

[0037] In the second aspect of the first embodiment, wherein R is triflate and n is 1.

[0038] In the third aspect of the first embodiment, compound of formula-5 is converted to compound of formula- 1 or compound of formula- A by the process described in Bioorganic & Medicinal Chemistry Letters 2001, 11, 1717-1721, Bioorganic & Medicinal Chemistry Letters 2005, 15, 2107-2110 or

[0039] W02012005795A1 or any other process known in the art or a process described in the present invention.

[0040] Compound of formula-2 used in the present invention is prepared according to process described in W02012005795A1 or any other process known in the art or the process described in the present invention. Second embodiment of the present invention provides a process for the purification of Samidorphan or a salt thereof comprising the steps of: a) treating Samidorphan with a base, b) isolating a pure Samidorphan or a salt thereof .

[0041] In the first aspect of the second embodiment, wherein the base in step-a) is selected from inorganic base or organic base.

[0042] In the second aspect of the second embodiment, wherein the isolation of pure Samidorphan or its acid addition salt in step-b) can be carried by treating with an acid or Lewis acid.

[0043] In the third aspect of the second embodiment, the reaction in step-a) and step- fa) can be carried out in a solvent selected from alcohol solvents, ether solvent, ketone solvents, nitrile solvent, ester solvents, chloro solvents, polar-aprotic solvents, water and / or mixtures thereof.

[0044] In the fourth aspect of the second embodiment, wherein the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfuric acid; organic acids such as acetic acid, maleic acid, malic acid, L-malic acid, D-malic acid, oxalic acid, succinic acid, fumaric acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid; Lewis acid is selected from aluminum trihalides such as A1CL, AIBn and the like, boron trihalides such as BCL and the like, TiCL, FeCh, ZnCh and the like.

[0045] In the fifth aspect of the second embodiment, wherein the mixture obtained in step-a) contains base addition salt which can be optionally isolated.

[0046] Third embodiment of the present invention provides a novel compound of formula-7 or a salt thereof

[0047]

[0048] Formula-7

[0049] In the first aspect of the third embodiment, Samidorphan or a salt thereof substantially free of compound of formula-7 herein also referred as amine impurity.

[0050] In the second aspect of the third embodiment, pure Samidorphan or a salt thereof substantially free of compound of formula-7.

[0051] In the third aspect of the third embodiment, wherein substantially free of compound of formula-7 (amine impurity) as used herein refers to the level of amine impurity in Samidorphan or a salt thereof which is less than about 0.05 % or less than about 0.03 % or less than about 0.01 % or less than about 0.008 % or less than about 0.007% or less than about 0.006 % or less than about 0.005 % or less than about 0.004 % or less than about 0.003 % or less than about 0.002 % or less than about 0.001 % or in below the detection limit or entirely absent.

[0052] Fourth embodiment of the present invention provides a pure Samidorphan or a salt thereof having purity of greater than about 99.5% measured by HPLC {High Performance Liquid Chromatography}. This high level of purity is critical for pharmaceutical applications, ensuring minimal impurities for enhanced safety and efficacy.

[0053] In the first aspect of the fourth embodiment provides a pure Samidorphan or a salt thereof, wherein compound of formula-7 (amine impurity) is less than about 0.15%, compound of formula-8 (amide impurity) is less than about 0.15% or compound of formula-9 (ketal amide impurity) is less than about 0.15% as measured by HPLC. In the second aspect of the fourth embodiment provides a pure Samidorphan or a salt thereof wherein the amine impurity is less than about 0.10%, a ketal amide impurity is less than about 0.10% or amide impurity is less than about 0.10% measured by HPLC.

[0054] In the third aspect of the fourth embodiment provides a pure Samidorphan or a salt thereof wherein the amine impurity is less than about 0.05%, a ketal amide impurity is less than about 0.05% or amide impurity is less than about 0.05% as measured by HPLC.

[0055] In the fourth aspect of the fourth embodiment provides a pure Samidorphan or a salt thereof, wherein the amine impurity, ketal amide impurity, or amide impurity is below the detection limit or entirely absent.

[0056] In the fifth aspect of fourth embodiment, pure Samidorphan or its salts is stable which is suitable for pharmaceutical preparations with having greater stability.

[0057] The following impurities are observed during the synthesis of the compound of formula- 1 or a salt thereof obtained according to the present invention. Along with these impurities, the starting materials are well controlled as per ICH guidelines in the compound of formula- 1 or a salt thereof.

[0058]

[0059] Fifth embodiment provides a crystalline form of Samidorphan L-malate of formula-la characterized by its PXRD peaks at about 9.0°, 13.2° and 23.1° ± 0.2° 20.

[0060] In the first aspect of the fifth embodiment provides a crystalline form of Samidorphan L-malate further characterized by its PXRD peaks at about 9.0°, 12.7°, 13.2°, 13.8°, 15.1°, 16.5°, 21.5°, 22.0° and 23.1° ± 0.2° 29.

[0061] In the second aspect of the fifth embodiment provides the crystalline form of Samidorphan L-malate of formula- la characterized by its PXRD pattern as illustrated in figure- 1.

[0062] In third aspect of fifth embodiment provides an accelerated and long-term stability data of crystalline form of Samidorphan L-malate of formula- 1 a is outlined in Table- 1 as follows:

[0063] PXRD Method of Analysis:

[0064] The PXRD analysis of compounds of the present invention was carried out by using BRUKER / D8 ADVANCE X-Ray diffractometer using CuKa radiation of wavelength 1.5406A0and at a continuous scan speed of 0.03° / min. HPLC Method of Analysis:

[0065] Samidorphan or a salt thereof and its related substances were analyzed by HPLC with the following chromatographic conditions:

[0066] Apparatus: A liquid chromatograph is equipped with variable wavelength UV / PDA detector; Column: Kinetex C8, 150 x 4.6 mm, 2.6 pm, 100A; (or) Equivalent; Ghost Buster Column; Wavelength: 215 nm; Column temperature: 50°C; Elution: Gradient; Diluent: 0.1% perchloric acid: acetonitrile

[0067] Needle wash: 0.5% perchloric acid in 1000 mL methanol

[0068] Solvents: Acetonitrile, Methanol; Reagents: Perchloric acid

[0069] Buffer: Add 5 mL of Perchloric acid (70%) in 1.0 Ltr of Milli-Q-water, mix and filter through 0.22 pm PVDF membrane filter.

[0070] Mobile phase- A: Buffer; Mobile phase-B: Methanol and buffer

[0071] In general, the Samidorphan L-malate obtained according to the present invention having the particle size distribution as characterized by 90% particles having particle size (D90) less than about 500 pm, preferably less than about 400 pm; 50% particles having particle size (D50) less than about 250 pm, preferably less than about 200 pm and 10% particles having particle size (D10) less than about 100 pm, preferably less than about 50 pm.

[0072] Samidorphan or its pharmaceutically acceptable salts produced by the processes of the present invention can be further micronized or milled to get desired particle sizes to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include but not limited to a single or multi-stage micronization using cutting mills, pin / cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling or micronization may be performed before drying or after drying of the product. Sixth embodiment of the present invention provides Samidorphan L-malate having particle size distribution of at least one of: a) DIO value is less than about 10 pm; b) D50 value is less than about 30 pm; and c) D90 value is less than about 100 pm.

[0073] In the first aspect of the sixth embodiment, wherein Samidorphan L-malate having a particle size distribution of DIO value is less than about 10 pm; a D50 value is less than about 30 pm; and a D90 value is less than about 100 pm is obtained by the micronization of Samidorphan L-malate.

[0074] In the second aspect of the sixth embodiment, wherein Samidorphan L-malate having a particle size distribution of D10 value is less than about 5 pm; a D50 value is less than about 20 pm; and a D90 value is less than about 50 pm is obtained by the micronization of Samidorphan L-malate.

[0075] Seventh embodiment of the present invention provides the use of Samidorphan or a salt thereof obtained according to the present invention for the preparation of various pharmaceutical formulations.

[0076] Eighth embodiment of the present invention provides a pharmaceutical composition comprising Samidorphan or a salt thereof obtained according to the present invention and at least one pharmaceutically acceptable excipient.

[0077] As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

[0078] The term “pharmaceutically acceptable excipients” selected from but not limited to binders, diluents, disintegrants, surfactants and lubricants. Suitable binders that can be include polyvinylpyrolidone, copovidone, starches such as pregelatinized starch, cellulose derivatives such as hydroxypropylmethyl cellulose, ethylcellulose, hydroxypropylcellulose and carboxymethylcellulose, gelatine, acacia, agar, alginic acid, carbomer, chitosan, dextrates, cyclodextrin, dextrin, glycerol dibehenate, guargum, hypromellose, maltodextrin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, sodium alginate, sucrose, mixtures thereof; suitable diluents that can be include anhydrous lactose, lactose monohydrate, modified lactose, dibasic calcium phosphate, tribasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, maize starch, pregelatinized starch, calcium carbonate, sucrose, glucose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol starch, calcium lactate or mixtures thereof; suitable disintegrants that can be include magnesium aluminometa silicate (or magnesium aluminum silicate), starch, pregelatinized starch, sodium starch glycolate, crospovidone, croscarmellose sodium, low- substituted hydroxypropyl cellulose, alginic acid, carboxy methyl cellulose sodium, sodium alginate, calcium alginate and chitosan; suitable lubricants that can be include (but are not limited to) magnesium stearate, stearic acid, palmitic acid, talc, and aerosil. Suitable surfactants that can be include (but are not limited to) polysorbate 80, polyoxyethylene sorbitan, polyoxyethylene -polyoxy-propylene copolymer and sodium lauryl sulphate; beta-cyclodextrin include (but are not limited to) sulfobutylalkyl ether-beta-cyclodextrin, betadex-sulfobutylether sodium, or hydroxypropyl-beta-cyclodextrin.

[0079] Ninth embodiment of the present invention provides a pharmaceutical composition comprising a combination of Olanzapine and Samidorphan or its salts obtained according to the present invention, indicated for the treatment of Schizophrenia in adults and Bipolar I disorder in adults, acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate and maintenance monotherapy treatment. The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

[0080] Examples:

[0081] Example-1: Preparation of compound of formula-5a

[0082] Under the inert atmosphere, dimethyl sulfoxide (150 ml), compound of formula-2a (30 g), Pd(PPh3)C12 (191 g), triethylamine (8.7 g) and N-hydroxy succinamide of formula-3a (9.3 g) at 25-30°C were charged into autoclave and stirred at the same temperature. Carbon monoxide gas pressure applied into reaction mixture at 25-30°C, heated the reaction mixture to 70-80°C and stirred at the same temperature. Cooled the reaction mixture to 25-30°C and released the pressure. Degassed the reaction mixture with nitrogen gas. Applied the ammonia gas pressure to the reaction mixture at 25-30°and stirred at the same temperature. Filtered the reaction mixture and it is slowly added to pre-cooled water at 10-15°C and stirred at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Further slurried the obtained compound in ethanol get the pure title compound.

[0083] Yield: 12.2 g.

[0084] Example-2: Preparation of compound of formula-6a

[0085] A mixture of compound of formula-5a (0.5 g), ethanol (3.5 ml), hydrochloric acid (0.90 ml) and water (1.70 ml) heated to 75-80°C and stirred at the same temperature. The reaction mixture is cooled to 25-30°C, water added and stirred the reaction mixture. Aqueous Ammonia solution is added to the mixture at 25-30°C. Ethyl acetate added to the mixture, separated the organic from the mixture. The aqueous layer is extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer to get the title compound.

[0086] Yield: 337 mg.

[0087] Example-3: Preparation of compound of formula-1

[0088] Zinc (0.065 g) added to the mixture of compound of formula-6a (0.1 g), ammonium chloride (0.060 g) and ethanol (2 ml) at 25-30°C, heated to 60-70°C and stirred at the same temperature. Reaction mixture was cooled to 25-30°C and stirred at the same temperature. The reaction mixture was quenched with water, aqueous ammonia solution was added to this mixture and followed by ethyl acetate added to it. Separated the both organic from the mixture and the aqueous layer is extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer to get the title compound. Yield: 90 mg.

[0089] Example-4: Preparation of compound of formula-la

[0090] The compound of formula- 1 (0.08 g) is dissolved in the mixture of methanol (2 ml) and ethanol (2 ml). The mixture is heated to 60 to 70°C, an ethanolic solution of L- malic acid (0.043 g of malic acid in 0.5 ml of ethanol) is added to this mixture and stirred at the same temperature. Reaction mixture slowly cooled to 20-30°C and stirred at the same temperature. Filtered the solid, washed with ethanol and dried to get the title compound. Yield: 120 mg.

[0091] Example-5: Preparation of compound of formula-la

[0092] A mixture of compound of formula-1 (3.5g), methanol (10.93 ml) and ethanol (10.93 ml) heated to 60-70°C and stirred the same temperature. An ethanolic solution of malic acid (1.5 g of L-malic acid in 4.3 mL of ethanol) was added to the reaction mixture at 60 to 70°C and stirred at the same temperature. Reaction mixture slowly cooled to 20-30°C and stirred at the same temperature. Filtered the solid, washed with ethanol and dried to get the title compound.

[0093] Yield: 4 g. PXRD of the obtained compound is illustrated in figure- 1.

[0094] Example-6: Preparation of (4R,4aS,7aR,12bS)-3-(Cyclopropylmethyl)- l,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2'- [l,3]dioxolane]-4a,9-diol

[0095] Ethylene glycol (406.25 ml) added to the mixture of Naltrexone hydrochloride (125 g), toluene (1250 ml), para-toluenesulfonic acid (10.32 g) at 25-35°C, heated to 105- 115°C and stirred at the same temperature. Cooled the reaction mixture to 25-35°C and stirred at the same temperature. Separated the layers. Water added to the bottom layer and basified by using aqueous sodium carbonate solution. Filtered the solid, washed with water and dried to get the title compound.

[0096] Yield: 106 g.

[0097] Example-7: Preparation of compound of formula-2a

[0098] 1,1,1 -Trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (32.45 g) added to the pre-cooled mixture of (4R,4aS,7aR,12bS)-3-(Cyclopropylmethyl)- l,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2'- [l,3]dioxolane]-4a,9-diol (25 g), dichloromethane (125 ml), trimethylamine (10.50 g) at 0-10°C, raised the temperature to 25-35°C and stirred at the same temperature. Water added to the reaction mixture and separated the both organic and aqueous layers. Organic layer washed with water and followed by aqueous sodium chloride solution. Carbon treatment given to the organic layer. Distilled off the solvent completely from obtained organic layer and followed by co-distilled with n-heptane. Slurried the obtained compound in aqueous ammonia solution. Filtered the solid, washed with water and dried to get the title compound.

[0099] Yield: 29.7 g

[0100] Example-8: Preparation of compound of formula-5a

[0101] A mixture of compound of formula-2a (100 g), acetonitrile (2000 ml), triethylamine (29.54 g), ammonium acetate (22.33 g), N-hydroxysuccinamide of formula-3a (33.35 g), Pd(dppf)C12.dichloromethane (4.94 g) in autoclave applied the carbon monoxide gas pressure at 25-35°C, heated to 65-75°C and stirred at the same temperature. Cooled the reaction mixture to 15-25°C, applied the argon gas pressure and released. Then ammonia gas pressure applied and stirred at the same temperature. Distilled off the solvent completely from the reaction mixture. Water added to the obtained compound at 25-35°C and stirred at the same temperature. Filtered the solid and washed with water to get the title compound.

[0102] Example-9: Preparation of compound of formula-6a

[0103] Water (50 ml) and trifluoroacetic acid (375 ml) were added to the compound of formula-5a obtained in example-8 at 25-35°C, heated to 35-45°C and stirred at the same temperature. Distilled off the solvent completely from reaction mixture. Water added to the obtained compound at 25-35°C and carbon treatment given to it. Filtered the mixture through the hyflow bed, washed the bed with aqueous hydrochloric acid. Ethyl acetate added to the obtained filtrate, cooled to 0-100C, neutralized with aqueous sodium hydroxide solution, and followed by basified with aqueous sodium carbonate solution. Filtered the solid, washed with aqueous ethyl acetate and dried to get the title compound. Yield: 52 g

[0104] Example-10: Preparation of Samidorphan of formula-1

[0105] Dissolved the compound of formula-6a (75 g) in ethanol (2250 ml) at 75-85°C and cooled to 55-65°C. Zinc dust (46.58 g) and ammonium chloride (37.89 g) added to reaction mixture at 55-65°C and stirred at the same temperature. Cooled the reaction mixture to 25-35°C, filtered and washed with ethanol. Distilled off the solvent from the completely from the filtrate.

[0106] Purity by HPLC: 85.35%; Amine impurity: 0.56%, Amide impurity: 0.06%, Ketal amide impurity: Not detected as measured by HPLC.

[0107] Example-11: Purification of Samidorphan

[0108] Aqueous sodium hydroxide solution ( 15 g in 300 ml) added to the solution of Crude Samidorphan obtained in example- 10 in dichloromethane (300 ml) and at 25-35°C and stirred at the same temperature. Separated the both the layers, organic layer extracted with aqueous sodium hydroxide solution. Combined the aqueous layers, neutralized with aqueous hydrochloric acid at 25-35°C and stirred at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 59.7 g.

[0109] Example-12: Preparation of Samidorphan L-malate of formula-la

[0110] Aqueous ammonia solution (75 ml) added to the mixture of Samidorphan (59.7 g), water (375 ml) and dichloromethane (375 ml) at 25-35°C and stirred at the same temperature. Separated the both organic and aqueous layer and the aqueous layer extracted with dichloromethane. Combined the organic layers and washed with aqueous sodium chloride solution. Carbon treatment given to the organic layer. Distilled off the solvent completely from the organic layer and co-distilled with methanol. Dissolved the obtained compound in methanol (210 ml) at 25-35°C and ethanol (150 ml) added to it. Heated the mixture to 55-65°C and stirred at the same temperature. A solution of L-malic acid (24.57 g) in ethanol (81 ml) added to the above mixture at 55-65°C and stirred at the same temperature. Cooled the mixture to 25-35°C and stirred at the same temperature. Filtered the solid, washed with a mixture of methanol and ethanol and dried to get the title compound.

[0111] Yield: 65.5 g; PXRD of the obtained compound is similar to figure-1; Purity by HPLC: 99.81%; Amine impurity: Not detected, Amide impurity: not detected, Ketal amide impurity: Not detected as measured by HPLC.

[0112] Example-13: Preparation of compound of formula-7

[0113] A mixture of Samidorphan (50 g), methanol (500 ml), hydroxylamine hydrochloride (14.07 g) and aqueous ammonia (10 ml) stirred at the 25-35°C. Obtained mixture transferred into the autoclave, Raney nickel (2 g) added to it, applied hydrogen pressure at 25-35 ° C, and stirred at the same temperature. Heated the reaction mixture to 55-65°C and stirred at the same temperature. Cooled the reaction mixture to 25-35°C, fdtered through the hyflow bed and washed the bed with methanol. Distilled off the solvent completely from the filtrate. Methanol added to the obtained compound at 25-35°C and stirred it. Cooled the mixture to -5 to 5°C and stirred at the same temperature. Filtered the solid, washed with methanol and dried to get the title compound.

[0114] Yield: 20 g.

Claims

Claims1. A pure Samidorphan of formula- 1 or a salt thereofFormula- 1 having a purity greater than about 99.5% as measured by HPLC.

2. A pure Samidorphan of formula- 1 or a salt thereofFormula- 1 wherein the compound of formula-7 is less than about 0.15%, compound of formula-8 is less than about 0.15% or compound of formula-9 is less than about 0.15% as measured3. The compound according to claim 2, wherein the compound of formula-7 is less than about 0.10%, the compound of formula-8 is less than about 0.10% and the compound of formula-9 is less than about 0.10% by HPLC.

4. The compound according to claim 2, wherein the compound of formula-7 is less than about 0.05%, the compound of formula-8 is less than about 0.05% or the compound of formula-9 is less than about 0.05% as measured by HPLC.

5. A process for the purification of Samidorphan or a salt thereof comprising the steps of: a) treating Samidorphan with a base, b) isolating a pure Samidorphan or a salt thereof .

6. The process according to claim 5, wherein base in step-a) is selected from inorganic base or organic base.

7. The process according to claim 5, wherein the isolation of pure Samidorphan or a salt thereof in step-b) can be carried by treating with an acid or Lewis acid.

8. The process according to claim 7, wherein the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfuric acid; organic acids such as acetic acid, maleic acid, L-malic acid, oxalic acid, succinic acid, fumaric acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid; Lewis acid is selected from A1C13, AlBr3, BC13, TiCl4, FeCl3and ZnCh.

9. The compound according to any one of the preceding claims, wherein Samidorphan salt is Samidorphan L-malate of formula- la10. A process for the preparation of compound of formula-5Formula-5wherein n is 1, 2, 3, 4 or 5; R is hydrogen, methyl,and allyl comprises: a) reacting the compound of formula-2wherein X is halogen or triflate; a is 1, 2, 3, 4 or 5; R is hydrogen, methyl,and allyl with carbon monoxide and the compound of formula-3wherein R1 & R2 are selected from H, alkyl, aryl or Rland R2 together form a cyclic compound, to obtain compound of formula-4,b) converting the compound of formula-4 to compound of formula-5 ;11. The process according to claim 10, wherein the reaction in step-a) is carried out in a solvent, in the presence of a palladium catalyst and a base.

12. The process according to claim 10, wherein the conversion of compound of formula-4 to formula-5 in step-b) by doing amidation; wherein the amidating agent is selected from ammonia, including aqueous ammonia, ammonia gas, methanolic ammonia, and formamide, sodium methoxide in formamide, optionally in the presence of another base.

13. The process according to claim 10, wherein palladium catalyst is selected from palladium complexed with a ligand chosen from l,l’-bis(diphenylphosphino) ferrocene (DPPF), l,3-bis(diphenylphosphino)propane (DPPP), triphenylphosphine, 1,3- bis(diphenyl-phosphino) propane, 2,2’-bis(diphenylphosphino)-l,r-binaphthyl (BINAP) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos); base is selected from organic bases or inorganic bases; the solvent is selected from from alcohol solvents, ether solvent, ketone solvents, nitrile solvent, ester solvents, chloro solvents, polar-aprotic solvents, water and / or mixtures thereof.

14. The process according to claim 10, the compound of formula-5 is converted to Samidorphan or a salt thereof.

15. A crystalline form of Samidorphan L- malate of formula- laFormula- la characterized by its PXRD peaks at about 9.0°, 13.2° and 23.1° ± 0.2° 20.

16. The crystalline form according to claim 15, wherein of crystalline form of Samidorphan L-malate further characterized by its PXRD peaks at about 9.0°, 12.7°, 13.2°, 13.8°, 15.1°, 16.5°, 21.5°, 22.0° and 23.1° ± 0.2° 20.

17. The crystalline form according to claim 15, wherein crystalline form Samidorphan L- malate characterized by its PXRD pattern as illustrated in figure- 1.A compound of formula-7 or a salt thereofFormula-7.

19. A Samidorphan or a salt thereof is substantially free of compound of formula-7.

20. A Samidorphan L-malate having a particle size distribution of at least one of: a) DIO value is less than about 10 pm; b) D50 value is less than about 30 pm; and c) D90 value is less than about 100 pm.

21. A pharmaceutical composition comprising a combination of Olanzapine and Samidorphan or its salts obtained according to preceding claims, indicated for the treatment of Schizophrenia in adults and Bipolar I disorder in adults, acute treatment of manic or mixed episodes as monotherapy and as adjunct to lithium or valproate and maintenance monotherapy treatment.(1 / 1)Figure- 1

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