WO2024150250A1

WO2024150250A1 - A process for the preparation of atogepant and its intermediates

Info

Publication number: WO2024150250A1
Application number: PCT/IN2024/050024
Authority: WO
Inventors: Thirumalai Rajan Srinivasan; Eswaraiah Sajja; Rajeshwar Reddy Sagyam; Venkata Reddy SHERI; Venkata Subbaiah BATCHANABOINA
Original assignee: Msn Laboratories Private Limited, R&D Center
Priority date: 2023-01-10
Filing date: 2024-01-10
Publication date: 2024-07-18

Abstract

The present application provides a process for the preparation of (3'S)-N-[(3S,5S,6R)- 6-methyl-2-oxo-1-(2,2,2-trifluoro ethyl)-5-(2,3,6-trifluoro phenyl)piperidin-3- yl]-2'-oxo- 1',2',5,7-tetrahydro spiro [cyclopenta[b] pyridine-6,3'-pyrrolo [2,3-b] pyridine]-3- carboxamide of formula-1. This patent also provides a process for the preparation of pure compound of formyula-1 having less than about 0.15% of diasteromer impurity determined by HPLC and its process for the preparation.

Description

A process for the preparation of Atogepant and its intermediates

Related Application:

This application claims the benefit of priority to our Indian patent application numbers 202341002069 filed on Jan 10, 2023 and 202341056370 filed on Aug 23, 2023, the disclosures of all of which are incorporated by reference in their entirety.

Field of the invention:

The present application relates to a novel crystalline form of Atogepant and its process for the preparation thereof. Atogepant represented by the following structural formula- 1.

Formula- 1.

This patent also provides a process for the preparation of pure Atogepant having less than about 0.15% of diasteromer impurity by HPLC.

Background of the invention:

(3'S)-N-[(3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluoro phenyl)piperidin-3-yl]-2'-oxo-l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'- pyrrolo[2,3-b]pyridine]-3-carboxamide compound of formula-1 is commonly known as Atogepant, which was approved for the indication of a calcitonin gene-related peptide receptor antagonist indicated for the preventive treatment of episodic migraine in adults with the brand name of Qulipta®.

Atogepant or its pharmaceutically acceptable salts described in US8754096B2. This patent also describes the process for the preparation of Atogepant. US9174989B2 patent describes the various polymorphic forms of Atogepant such as Atogepant monohydrate, Atogepant trihydrate, Atogepant methanol solvate, Atogepant methanol-water solvate, Atogepant acetonitrile solvate and Atogepant L- tartaric acid co-crystal and amorphous Atogepant.

Discovering new solid-state forms/ polymorphic forms, solvates of a pharmaceutical product can provide materials having desirable physicochemical properties. New polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product.

US9174989B2 patent discloses the process for the preparation of Atogepant. US’989B2 did not disclose any purity of Atogepant obtained according to the disclosed process. The present inventors have developed an improved process for obtaining high-purity Atogepant, which contains less than about 0.15% of all possible isomers, as determined by HPLC/Chiral HPLC.

Summary of the invention:

First embodiment of the present invention provides a novel crystalline form of Atogepant of formula- 1.

Second embodiment of the present provides a process for the preparation of novel crystalline form of Atogepant of formula- 1.

Third embodiment of the present invention provides a process for the preparation of Atogepant monohydrate.

Fourth embodiment of the present invention provides a pure Atogepant.

Fifth embodiment of the present invention provides a process for the preparation of pure Atogepant.

Sixth embodiment of the present invention provides a process for the purification of ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluoro phenyl)piperidin-3-aminium (S)-2-acetamido-3-phenylpropanoate of formula- 10.

Seventh embodiment of the present invention provides a process for the preparation compound of formula-8.

Eighth embodiment of the present invention provides a process for the preparation of Amorphous Atogepant.

Brief description of the drawings:

Figure-1: Illustrates the powder X-Ray diffraction {PXRD} pattern of form-M of Atogepant.

Figure-2: Illustrates the PXRD pattern of amorphous form of Atogepant.

Detailed description of the Invention:

The “suitable 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; “polar solvents” such as water; formic acid, acetic acid and the like or mixture of any of the afore mentioned solvents.

The term “contacting” as used herein, refers to dissolving, slurrying, stirring, suspending, or combinations thereof.

As used herein, the term “solution” or “reaction mixture” does not limit to a clear solution only and includes any hazy or opaque mass obtained. All ranges recited herein include the endpoints and the terms “about”, “from”, “to” are to be construed as modifying a value they are applied to such that it is not absolute and includes, to the very least, the degree of expected experimental error, limitation of method or instrument error for a given technique used to measure the value.

The first embodiment of the present invention provides a novel crystalline form of Atogepant compound of formula- 1, herein after designated as crystalline form-M.

The first aspect of first embodiment provides a crystalline form-M of Atogepant of formula- 1 characterized by its PXRD (Powder X-Ray Diffraction) pattern having peaks at about 5.3°, 7.9°, 9.8°, 12.8° and 17.3° ± 0.2° 20.

The second aspect of first embodiment provides a crystalline form-M of Atogepant of formula- 1 characterized by PXRD pattern as illustrated in figure- 1.

The third aspect of the first embodiment provides crystalline form-M of Atogepant used in the preparation of Atogepant monohydrate.

The fourth aspect of the first embodiment provides a Atogepant monohydrate prepared from crystalline form-M of Atogepant having the purity greater than 99.5% or more by HPLC (High performance liquid chromatography).

Second embodiment of the present invention provides a process for the preparation of crystalline form-M of Atogepant of formula- 1 comprising: a) contacting or dissolving Atogepant in a solvent or a mixture of solvents and b) isolating crystalline form-M of Atogepant of formula- 1.

Wherein, contacting or dissolving Atogepant in step-a) can be done at a temperature ranging from about 20°C to reflux temperature of the solvent used. The solvent in step-a) is selected from nitrile solvent, alcohol solvents, ether solvent, ketone solvents, ester solvents, water and/or mixtures thereof; isolating crystalline form-M of Atogepant in step-b) is by solvent removal by known techniques which are selected from distillation, filtration, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, crystallization or by combining with an anti-solvent.

Third embodiment of the present invention provides a process for the preparation of Atogepant monohydrate comprising: a) dissolving Atogepant in a solvent or a mixture of solvents and b) isolating Atogepant monohydrate.

Wherein, dissolving Atogepant in step-a) can be done at a temperature ranging from about 25°C to reflux temperature of the solvent used; the solvent in step-a) is selected from alcohol solvents, ether solvent, ketone solvents, ester solvents, water and/or mixtures thereof; isolating Atogepant monohydrate in step-b) is by solvent removal by known techniques which are selected from distillation, filtration, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, crystallization or by combining with an anti-solvent.

An aspect of the third embodiment, the process carried out optionally in presence of moisture or in water.

Fourth embodiment of the present invention provides a pure Atogepant of formula- 1 having less than about 0.15% of diasteromer impurity by HPLC {High- performance liquid chromatography}. “Pure Atogepant” is defined herein having purity of greater than about 99.5% measured by HPLC {High Performance Liquid Chromatography} .

In first aspect of the fourth embodiment provides a pure Atogepant having a diasteromer impurity less than about 0.15%, having an acid impurity less than about 0.15% and amine impurity having less than about 0.15%.

In second aspect of the fourth embodiment provides a pure Atogepant preferably having a diasteromer impurity less than about 0.10%, having an acid impurity less than about 0.05% and amine impurity having less than about 0.05%.

In third aspect of the fourth embodiment provides a pure Atogepant having less than about 0.15% of all possible isomers or diasteromers, as determined by HPLC/Chiral HPLC.

In fourth aspect of fourth embodiment, pure Atogepant is stable which is suitable for pharmaceutical preparations with having greater stability.

In fifth aspect of fourth embodiment provides an accelerated and long-term stability data of Atogepant of formula- 1 is outlined in Table- 1 as follows:

The following impurities are observed during the synthesis of the compound of formula- 1 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.

Fifth embodiment of the present invention provides a process for the preparation of pure Atogepant comprising: a) contacting Atogepant with isopropanol and acetonitrile, b) isolating a pure Atogepant; wherein contacting Atogepant in step-a) can be carried out by combining Atogepant with a mixture isopropanol and acetonitrile at a suitable temperature ranging from about 25°C to reflux temperature; Atogepant in step-a) is obtained from the synthetic process in which Atogepant is prepared; isolating pure Atogepant in step-b) by cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture and crystallization.

In an aspect of the fifth embodiment, Atogepant having less than about 0.15% of all possible isomers, as determined by HPLC/Chiral HPLC.

Sixth embodiment of the present invention provides a process for the purification of ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluoro phenyl)piperidin-3-aminium (S)-2-acetamido-3-phenylpropanoate of formula- 10 having purity greater than about 99% by HPLC

comprising: a) contacting ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluoro phenyl)piperidin-3-aminium (S)-2-acetamido-3-phenylpropanoate of formula-10 with methanol, b) combining with isopropanol to the obtained mixture in step-a), c) isolating a pure ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-aminium (S)-2-acetamido-3-phenylpropanoate of formula- 10; wherein contacting compound of formula- 10 in step-a) can be carried out by combining compound of formula- 10 with methanol at a suitable temperature ranging from about 25 °C to reflux temperature; isolating pure compound of formula- 10 in step-c) by optionally cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture.

Seventh embodiment of the present invention provides a process for the preparation compound of formula-8 comprising reacting the compound of formula-6 with compound of formula-7 in presence of a base selected is from lithium tert- butoxide, lithium tert-pentoxide or lithium tert-amoxide in a solvent and in the presence of dimethylformamide as an additive.

Formula-6 Fonnula-7 Fonnula-8

In the literature, the process for the preparation of tert-butyl ((5S,6R)-6- methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl) carbamate of formula-4 involves the use of N,N’ -dimethylpropyleneurea. The present inventors replaces this with dimethylformamide, which is a cheaper and more readily available alternative.

The eighth embodiment of the present invention provides a process for the preparation of amorphous form of Atogepant of formula- 1

Formula- 1 comprising: a) contacting Atogepant of formula- 1 with a solvent, b) isolating amorphous form of Atogepant; wherein, ‘contacting Atogepant of formula- 1 with a solvent’ means bringing the Atogepant and the solvent into contact with each other, or obtaining Atogepant from the synthetic process in which it is prepared. This can be done by mixing the Atogepant and solvent together or dissolving the Atogepant in the solvent; the solvent in step-a) is selected from ester solvent, alcohol solvent, ketone solvent, polar-aprotic solvents; isolating amorphous form of Atogepant in step-b) by known techniques which are selected from removing of the solvent, spray drying, agitated thin film drying, lyophilization, combining with an anti-solvent, distillation, decanting, filtration, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture. The anti-solvent is a selected from ether solvents, hydrocarbon solvents water or mixture thereof.

The term “polymorphs” as used herein, refers to any of the solid state form of Ateogepant obtained according to the present invention i.e., crystalline form-M, Monohydrate or amorphous form and like. The term “Atogepant of formula- 1” can be any of the solid state forms obtained according to the present invention.

Atogepant obtained according to the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include but not limited to single or multistage 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.

In general, the Atogepant obtained according to the present invention has particle size distribution as characterized by 90% particles having particle size (D90) less than about 100 pm, 50% particles having particle size (D50) less than about 50 pm and 10% particles having particle size (D10) less than about 30 pm.

An embodiment of the present invention provides the use of Atogepant of formula- 1 obtained according to the present invention for the preparation of various pharmaceutical formulations.

Another embodiment of the present invention provides pharmaceutical composition comprising Atogepant of formula- 1 obtained according to the present invention and at least one pharmaceutically acceptable excipient.

Another embodiment of the present invention provides pharmaceutical composition comprising Atogepant monohydrate obtained according to the present invention and at least one pharmaceutically acceptable excipient. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

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 hydroxyl propyl-beta-cyclodextrin. Atogepant obtained according to the present invention and one or more pharmaceutically acceptable carriers used for indication of is a calcitonin gene-related peptide receptor antagonist indicated for the preventive treatment of episodic migraine in adults.

Atogepant prepared in the present invention is depicted in the following scheme- 1.

Scheme- 1

(6S)-2'-oxo-l',2',5,7-tetrahydrospiro[cyclopenta [b]pyridine-6,3'-pyrrolo[2,3- b]pyridine] -3 -carboxylic acid of formula- 11 used in the preparation of Atogepant can be prepared according to process described in US8754096B2 and US9174989B2 or any other literature. HPLC Method of Analysis:

Atogepant and its related substances were analyzed by HPLC with the following chromatographic conditions:

Apparatus: A liquid chromatograph is equipped with variable wavelength UV. Column: Kinetex Biphenyl, 250 x 4.6 mm, 5u; (or) Equivalent; Wavelength: 210 nm; Column temperature: 35°C; Elution: Gradient; Diluent: Acetonitrile: Water; Needle wash: Diluent.

Buffer: Aqueous perchloric acid solution.

Mobile phase-A : Buffer; Mobile phase-B : Acetonitrile : Buffer.

PXRD Method of Analysis:

The PXRD analysis of compound of the present invention was carried out by using BRUKER-Axis/D8 ADVANCE (DAVINCI) X-Ray diffractometer using CuKa radiation of wavelength 1.5406A⁰.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions and Formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

Examples:

Example-1: Preparation of Isopropyl 2-((tert-butoxycarbonyl)amino)-5-oxo-4- (2,3,6-trifluoro phenyl)hexanoate of formula-5

Methane sulfonyl chloride (120.45 g) was slowly added to the pre-cooled mixture of isopropyl 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoate of formula-2 (200 g) and dimethylformamide (1600 ml) at 0-5°C and followed by triethylamine (204.6 g) slowly added. Raised the reaction mixture temperature to 25-30°C and stirred at the same temperature. Methyl tertiary butyl ether added to the reaction mixture and cooled to 10-15°C. Water added to the reaction mixture, separated the both organic and aqueous layers and aqueous layer extracted with methyl tertiary butyl ether. Organic layer washed with aqueous citric acid solution and followed by with aqueous sodium chloride solution. Distilled off the solvent from organic layer under reduced pressure. Dimethyl sulfoxide (400 ml) added to the above obtained compound. This solution in slowly added to the mixture of dimethylsulfoxide (1600 ml), cesium carbonate (184.48 g) and l-(2,3,6-trifluorophenyl) propan-2-one of formula-4 (152.19 g) at 25-30°C and stirred at the same temperature. Methyl tertiary butyl ether added to the reaction mixture, filtered and washed with methyl tertiary butyl ether. The obtained filtrate washed with aqueous sodium chloride solution. Distilled off solvent completely from the organic layer to get the title compound.

Yield: 255 g

Example-2: Preparation of tert-butyl ((5S,6R)-6-methyl-2-oxo-5-(2,3,6-trifluoro phenyl)piperidin-3-yl)carbamate formula-6

Isopropylamine (258 ml) added to the mixture of water (900 ml) and disodium tetraboratedecahydrate (49.34 g) at 0-5°C and pH is adjusted to 10-11 using aqueous hydrochloric acid solution. Pyrdioxial phosphate monohydrate (4.97 g), enzyme (1500 g) and followed by isopropyl 2-((tert-butoxycarbonyl)amino)-5-oxo-4-(2,3,6- trifluoro phenyl) hexanoate of formula-5 (300 g) in dimethyl sulfoxide (900 ml) were added to the above mixture at 0-5 °C, heated to 50-60°C and stirred at the same temperature. Aqueous isopropylamine solution (1050 ml) was lot wise added to the reaction mixture at 55-60°C and stirred at the same temperature. Cooled the reaction mixture to 25-30°C, dichloromethane and followed by isopropanol added and stirred at the same temperature. Cooled the reaction mixture to 10-15°C and slowly added aqueous sodium hydroxide solution to the above mixture. Raised the temperature of the reaction mixture to 25-30°C and hyflow added. Filtered the mixture and washed with dichloromethane. The obtained filtrate was washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer. Methyl tertiary butyl ether and water added to the obtained compound. Separated the both organic and aqueous layers. Organic layer washed with water and distilled the solvent completely from the organic layer. Co-distilled the obtained compound with n- heptane. The obtained compound slurried in n-heptane (600 ml), filtered and dried to get the title compound.

Yield: 129 g.

Example-3: Preparation of tert-butyl ((5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoro ethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)carbamate of formula-8

Lithium tert-butoxide (492 ml) added to the pre-cooled solution of tert-butyl ((5S,6R)-6-methyl-2-oxo-5-(2,3,6-trifluorophenyl) piperidin-3-yl)carbamate of formula-6 (120 g) in tetrahydrofuran (840 ml) at 0° to 5°C and stirred at the same temperature. 2,2,2-trifluoroethyl trifluoromethanesulfonate of formula-7 (155.44 g) was added to the above reaction mixture at 0° to 5 °C and stirred at the same temperature. N, N’ -Dimethylpropyleneurea (101.73 g) in tetrahydrofuran (96 ml) was added to the reaction mixture at 0° to 5 °C and stirred at the same temperature. Another lot of lithium tert-butoxide solution (174 ml) was added to the above reaction mixture at 0-5 °C and stirred at the same temperature. Aqueous hydrochloric acid solution added to the reaction mixture at 0-5 °C temperature and raised the temperature to 25-30°C. n-Heptane added to the above mixture at 25-30°C, separated the both organic and aqueous layers and aqueous layer is extracted with ethyl acetate. Combined the organic layers, washed with aqueous citric acid solution and followed by with aqueous sodium bicarbonate solution. Distilled off the solvent completely from organic layer. The obtained compound purified by silica gel column chromatography by eluted with cyclohexane followed by with the mixture of ethyl acetate and cyclohexane to get the title compound.

Yield: 79 g.

Example-4: Preparation of ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5- (2,3,6-trifluorophenyl)piperidin-3-aminium (S)-2-acetamido-3-phenylpropanoate of formula-10 Para-toluenesulfonic acid (19.43 g) was added to the solution of tert -butyl ((5S,6R)- 6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3- yl)carbamate of formula-8 (30 g) in isopropyl acetate (429 ml) at 25-30°C, heated to 55-60°C and stirred at the same temperature. Cooled the reaction mixture to 20-25°C and basified using aqueous potassium carbonate solution temperature. Separated the both organic and aqueous layers and aqueous layer extracted with isopropyl acetate. Combined the organic layers, heated to 55-60°C, N-acetyl L-phenyl alanine (1.12 g) added and stirred at the same temperature. Cooled the reaction mixture to 15 -25 °C, another lot of N-acetyl L-phenyl alanine (14.11 g) and followed by 2 -hydroxy-5 -nitro benzaldehyde (14.11 g) were added. Stirred the reaction mixture at 15 -25 °C. Cooled the reaction mixture to 0-5 °C and stirred at the same temperature. Filtered the solid, washed with isopropyl acetate and dried to get the title compound.

Yield: 16 g.

Example-5: Preparation of Atogepant of formula-1

Aqueous ammonia (76 ml) added to the pre-cooled mixture of ((3S,5S,6R)-6-methyl- 2-oxo-l-(2,2,2-trifhroroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-aminium (S)-2- acetamido-3-phenylpropanoate of formula- 10 (38 g), ethyl acetate (380 ml) and water (380 ml) at 0- 5°C and stirred. Raised reaction mixture temperature to 25-30°C, separated the both organic and aqueous layers and the aqueous layer was extracted with ethyl acetate. Combined the organic layers, washed with water and followed by aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer. The obtained free base dissolved in acetonitrile (152 ml) and added to the mixture of (6S)-2'-oxo-l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'- pyrrolo[2,3-b] pyridine] -3 -carboxylic acid of formula-11 (17.57 g), 10N aqueous sodium hydroxide solution (6.84 ml), water (152 ml) and acetonitrile (304 ml) at 25- 30°C. Hydroxybenzotriazole hydrate (11.44 g) and l-(3-dimethylaminopropyl)-3- ethyl carbodiimide hydrochloride (19.96 g) were added to the above reaction mixture at 25-30 °C and stirred at the same temperature. Isopropyl acetate added to the reaction mixture at 25-30°C and separated the both organic and aqueous layers. Aqueous layer was extracted with isopropyl acetate. Combined the organic layer, washed with aqueous sodium bicarbonate solution, followed by with aqueous citric acid solution and further with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer to get the crude Atogepant. The mixture of obtained crude compound and methanol (152 ml) added to the mixture of water (380 ml) and methanol (38 ml) at 25-30°C. Water (380 ml) added to the above mixture at 25-30°C and stirred at the same temperature. Filtered the solid, washed with mixture of water and methanol. The mixture of obtained compound and methanol (152 ml) added to the mixture of water (380 ml) and methanol (38 ml) at 25-30°C. Water (380 ml) added to the reaction mixture at 25-30°C and stirred at the same temperature. Filtered the solid, washed with mixture of water and methanol and dried to get the title compound. Yield: 34 g; Purity by HPLC: 98.53%.

Example-6: Preparation crystalline form-M of Atogepant

Dissolving Atogepant (26.5 g) in the mixture of isopropanol (53 ml) and acetonitrile (265 ml) at 25-30°C and stirred at the same temperature for 2 hours at the same temperature. Cooled the reaction mixture to 10-15°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with mixture of isopropanol and acetonitrile and dried. This process repeated one more time to get the title compound. Yield: 19.5 g; Purity by HPLC: 99.67%; Obtained compound PXRD pattern is depicted in figure- 1.

Example-7: Preparation of Atogepant monohydrate

Isopropyl acetate (10 ml) added to the mixture of Atogepant (1 g) and isopropanol (2 ml) at 25-30°C, heated the mixture to 55-60°C and stirred at the same temperature. Filtered the reaction mixture through the hy-flow bed and hy-flow bed washed with isopropyl acetate. Filtrate was cooled to 25-30°C and stirred at the same temperature. Filtered the solid, washed with mixture of isopropanol and isopropyl acetate and dried to get the title compound.

Yield: 0.45 g; Purity by HPLC: 99.61%.

Example-8: Preparation of Atogepant monohydrate Solution of crystalline form-M of Atogepant (19 g) in methanol (285 ml) is subjected to particle free filtration and distilled off the solvent from the obtained filtrate. The obtained residue taken in methanol (76 ml), added to the mixture of water (190 ml) and methanol (19 ml) at 25-30°C and stirred at the same temperature. Water (190 ml) added to the above mixture at 25-30°C and stirred at the same temperature. Filtered the solid, washed with mixture of water and methanol and dried to get the title compound.

Yield: 18 g; Purity by HPLC: 99.85%.

Example-9: Preparation of ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5- (2,3,6-trifluorophenyl)piperidin-3-aminium (S)-2-acetamido-3-phenylpropanoate of formula-10

Lithium tert-butoxide (126 ml) was slowly added to the pre-cooled solution of tertbutyl ((5S,6R)-6-methyl-2-oxo-5-(2,3,6-trifluorophenyl) piperidin-3-yl)carbamate of formula-6 (100 g) in tetrahydrofuran (700 ml) at 15° to 25°C and stirred at the same temperature. To this reaction mixture, dimethyl formamide (70 ml) added at 15-25°C and stirred at the same temperature. 2,2,2-trifluoroethyl trifluoromethanesulfonate of formula-7 (103.6 g) was added to the above reaction mixture at 15° to 25 °C and stirred at the same temperature. Another lot of lithium tert-butoxide solution (36 ml) was added to the above reaction mixture at 15 -25 °C and stirred at the same temperature. Cooled the reaction mixture to -5° to 5 °C, aqueous hydrochloric acid solution added to the reaction mixture at -5 to 5°C. Further, n-heptane added to the above mixture and raised the temperature to 5- 15 °C. Separated the both organic and aqueous layers and aqueous layer is extracted with n-heptane. Combined the organic layers, washed with aqueous citric acid solution and followed by with aqueous sodium bicarbonate solution. Distilled off the solvent completely from organic layer and co-distilled with isopropyl acetate to get tert-butyl ((5S,6R)-6-methyl-2-oxo-l- (2,2,2-trifhroroethyl)-5-(2,3,6-trifluorophenyl) piperidin-3-yl)carbamate of formula-8. Dissolved the obtained compound in isopropyl acetate (600 ml) at 25-30°C. Paratoluenesulfonic acid (63.7 g) was added to the above solution, heated the reaction mixture to 50-60°C and stirred at the same temperature. Cooled the reaction mixture to -5 to 5 °C and added aqueous potassium carbonate solution to the reaction mixture. Raised the reaction mixture temperature to 25-30°C, separated the both organic and aqueous layers and the aqueous layer extracted with isopropyl acetate. Combined the organic layers. N-acetyl L-phenyl alanine (57.83 g) and 2-hydroxy-5 -nitro benzaldehyde (2.33 g) were added to the above obtained organic layer at 25-30°C and stirred at the same temperature. Cooled the reaction mixture to -5 to 5°C and stirred at the same temperature. Filtered the solid and washed with isopropyl acetate.

Purity: 98.98% by HPLC.

Example-10: Purification of ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)- 5-(2,3,6-trifluorophenyl)piperidin-3-aminium (S)-2-acetamido-3-phenyl propanoate of formula-10

Methanol (300 ml) added to ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5- (2,3,6-trifluorophenyl)piperidin-3-aminium (S)-2-acetamido-3-phenylpropanoate of formula-10 at 25-30°C, heated the mixture to 45-55°C. Isopropanol (1200 ml) added to it at 45-55°C and stirred at the same temperature. Cooled the mixture to 25-30°C and stirred at the same temperature. Filtered the solid, washed with mixture of isopropanol and methanol. The above process repeated one more time to get the title compound.

Yield: 57 g, Purity: 99.90% by HPLC.

Example-11: Preparation of Atogepant

Aqueous tri potassium phosphate monohydrate solution (82.5 g in 1650 ml of water) added to the mixture of ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-aminium (S)-2-acetamido-3-phenylpropanoate of formula-10 (100 g) and methyl tertiary butyl ether (1000 ml) at 25-30°C and stirred at the same temperature. Separated the both organic and aqueous layers. Organic layer washed with aqueous tri potassium phosphate monohydrate solution, followed by with water and further with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer. The obtained free base dissolved in acetonitrile (400 ml) and added the solution to the mixture of (6S)-2'-oxo-l',2',5,7- tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b] pyridine] -3-carboxylic acid of formula- 11 (47.5 g), ION aqueous sodium hydroxide solution (18 ml), water (400 ml) and acetonitrile (800 ml) at 25-30°C. Hydroxybenzotriazole hydrate (30.84 g) and l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (52.5 g) were added to the above reaction mixture at 25-30°C and stirred at the same temperature. Methyl tertiary butyl ether added to the reaction mixture at 25-30°C and separated the both organic and aqueous layers. Aqueous layer was extracted with methyl tertiary butyl ether. Combined the organic layers Washed the organic layer with aqueous sodium bicarbonate solution, followed by with aqueous citric acid solution and followed by with aqueous sodium chloride solution and further with aqueous sodium bicarbonate solution. Distilled off the solvent completely from the organic layer and co-distilled with methanol to get Atogepant. Methanol (500 ml) added to the obtained compound at 25-30°C. Water (2000 ml) added to the obtained mixture at 25-30°C and stirred at the same temperature. Filtered the solid, washed with mixture of water and methanol to get the Atogepant.

Purity by HPLC: 99.11%, diastereomer impurity: 0.26%, acid impurity: 0.01%, amine impurity: 0.01% and acetyl impurity: 0.15%.

Example-12: Purification of Atogepant

Atogepant obtained in example- 11 added to the mixture of isopropyl alcohol (25 ml) and acetonitrile (1000 ml) at 25-30°C and stirred at the same temperature. Cooled the mixture to 5- 15 °C and stirred at the same temperature. Filtered the solid, washed with acetonitrile and dried get the pure Atogepant.

Purity by HPLC: 99.82%, diastereomer impurity: 0.05%, acid impurity: Not detected, amine impurity: Not detected and acetyl impurity: 0.01% [724]

Exapmle-13: Preparation Atogepant monohydrate

Dissolved Atogepant obtained in example- 12 in methanol (1500 ml) and filtered for particle free and washed with methanol. Distilled off the solvent completely from the filtrate. Methanol (500 ml) added to the obtained compound at 25-30°C and stirred. Water (2000 ml) was slowly added to the above mixture at 25-30°C and stirred at the same temperature. Filtered the solid, washed with mixture of methanol and water and dried to get the pure title compound.

Yield: 70.0 g; Purity by HPLC: 99.83%, diastereomer impurity: 0.05%, acid impurity: Not detected, amine impurity: Not detected and acetyl impurity: 0.01%.

Example-13: Process for the preparation of ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2- trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-aminium (S)-2-acetamido-3- phenylpropanoate formula-10

Lithium tert-amoxide (270 ml) added to the pre-cooled solution of tert-butyl ((5S,6R)-6-methyl-2-oxo-5-(2,3,6-trifluorophenyl) piperidin-3-yl)carbamate of formula-6 (300 g) in tetrahydrofuran (2100 ml) at 15° to 25°C and stirred at the same temperature. Dimethylformamide (210 ml) added to the reaction mixture at 15 -25 °C and stirred at the same temperature. 2,2,2-Trifluoroethyl trifluoromethanesulfonate of formula-7 (310.9 g) slowly added to the reaction mixture at 15° to 25°C and stirred at the same temperature. Lithium tert-amoxide (108. ml) added to the reaction mixture at 15-25°C and stirred at the same temperature. Cooled the reaction mixture to 0-5°C, aqueous hydrochloric acid solution added to the reaction mixture and followed by n- heptane added. Separated the both organic and aqueous layers and aqueous layer is extracted with n-heptane. Combined the organic layers, washed with aqueous citric acid solution and followed by with aqueous sodium bicarbonate solution. Distilled off the solvent completely from organic layer and co-distilled with isopropyl acetate to get the tert-butyl ((5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-yl)carbamate of formula-8. The obtained compound is dissolved in in isopropyl acetate (1800 ml) and added para-toluenesulfonic acid (191.09 g) at 25-30°C. Heated the reaction mixture to 55-65°C and stirred at the same temperature. Cooled the reaction mixture to 0-5 °C and basified with aqueous potassium carbonate solution at the same temperature. Raised the mixture temperature to 25-30°C, separated the both organic and aqueous layers and the aqueous layer extracted with isopropyl acetate. Combined the organic layers. N- acetyl L-phenyl alanine (173.48 g) and 2-hydroxy-5-nitro benzaldehyde (6.99 g) were added to the organic layer at 25-30°C and stirred at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred at the same temperature. Filtered the solid, washed with isopropyl acetate to get the title compound.

Purity by HPLC: 99.21% and other isomer impurity: 0.60%.

Example-14: Purification of ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)- 5-(2,3,6-trifluorophenyl)piperidin-3-aminium (S)-2-acetamido-3-phenyl propanoate formula-10

A mixture of methanol (9000 ml) and ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2- trifluoroethyl)-5-(2,3,6-trifhiorophenyl)piperidin-3-aminium (S)-2-acetamido-3- phenylpropanoate obtained in example-13 heated to 45-55°C, isopropanol (3600 ml) added to it and stirred at the same temperature. Cooled the mixture to 25-30°C and stirred at the same temperature. Filtered the solid, washed with mixture of methanol and isopropanol. Repeated the same process for another time and dried to get the title compound.

Yield: 158.0 g; Purity by HPLC: 99.83% and other isomer impurity: 0.12%.

Example-15: Preparation of Atogepant of formula-1

A solution of potassium phosphate tribasic (206.25 g) in water (4125 ml) added to the mixture of ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluoro phenyl)piperidin-3-aminium (S)-2-acetamido-3-phenylpropanoate of formula- 10 (250 g) and methyl tertiary butyl ether (2500 ml) at 25-30°C and stirred at the same temperature. Separated the both organic and aqueous layer. Organic layer washed with aqueous potassium phosphate tribasic solution, with water and followed by with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer. The obtained free base dissolved in acetonitrile (1000 ml) and added to the mixture of (6S)-2'-oxo-l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'- pyrrolo[2,3-b] pyridine] -3 -carboxylic acid of formula-11 (115.57 g), aqueous sodium hydroxide solution (18 g of sodium hydroxide in 45 ml), water (1000 ml) and acetonitrile (2000 ml) at 25-30°C. Hydroxybenzotriazole hydrate (75.025 g) and l-(3- dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (131.25 g) were added to the above reaction mixture at 25-30 °C and stirred at the same temperature. Isopropyl acetate added to the reaction mixture at 25-30°C and separated the both organic and aqueous layers. Aqueous layer was extracted with isopropyl acetate. Combined the organic layers, washed with aqueous sodium bicarbonate solution, followed by with aqueous citric acid solution and further with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer and further co-distilled with methanol. The obtained compound is dissolved in methanol and added to the mixture of water (2500 ml) and methanol (250 ml) at 25-30°C. Water (2500 ml) added to the above mixture at 25-30°C and stirred at the same temperature. Filtered the precipitated solid, washed with mixture of water and methanol. The obtained compound is dissolved in methanol, filtered and distilled off the solvent completely from the filtrate. The obtained compound is dissolved in methanol and added to the mixture of water (2500 ml) and methanol (250 ml) at 25-30°C. Water (2500 ml) added to the mixture at 25-30°C and stirred at the same temperature. Filtered the precipitated solid, washed with mixture of water and methanol and dried to get the title compound. Yield: 220 g.

Example-16: Preparation of Amorphous Atogepant

A solution of potassium phosphate tribasic (8.25 g) in water (165 ml) added to the mixture of ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluoro phenyl)piperidin-3-aminium (S)-2-acetamido-3-phenylpropanoate of formula-6 (10 g) and methyl tertiary butyl ether (100 ml) at 25-30°C and stirred at the same temperature. Separated the both organic and aqueous layer. Organic layer washed with aqueous potassium phosphate tribasic solution, with water and followed by with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer. The obtained free base dissolved in acetonitrile (40 ml) and added to the mixture of (6S)-2'-oxo-l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'- pyrrolo[2,3-b] pyridine] -3-carboxylic acid of formula-7 (4.62 g), aqueous sodium hydroxide solution (0.72 g of sodium hydroxide in 1.8 ml), water (40 ml) and acetonitrile (80 ml) at 25-30°C. Hydroxybenzotriazole hydrate (3.01 g) and l-(3- dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (5.25 g) were added to the above reaction mixture at 25-30 °C and stirred at the same temperature. Isopropyl acetate added to the reaction mixture at 25-30°C and separated the both organic and aqueous layers. Aqueous layer was extracted with isopropyl acetate. Combined the organic layers, washed with aqueous sodium bicarbonate solution, followed by with aqueous citric acid solution and further with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer and further co-distilled with ethanol. The obtained compound added to ethanol (30 ml) at 25-30°C, heated to 45-55 °C. Filtered the mixture and obtained is added to the pre-cooled water (180 ml) at 0-5 °C and stirred at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 7.0 g; PXRD pattern of the amorphous form of Atogepant is depicted in figure- 1.

Example-17: Preparation of amorphous form of Atogepant

A mixture of Atogepant (5 g) and ethanol (100 ml) heated to 50-55°C and stirred at the same temperature. This mixture is added to pre-cooled water (20 ml) at 0-5°C and stirred at the same temperature. Filtered the precipitated solid, wash with mixture of ethanol and water and dried to get the title compound.

Yield: 3.69 g; PXRD pattern of the amorphous form of Atogepant is depicted in figure-2.

Example-18: Preparation of amorphous form of Atogepant

Atogepant (20 g) was dissolved in methanol (300 ml) and stirred at 25-30°C. Reaction mixture spray dried under following conditions:

Inlet temperature: 70°C; Outlet temperature: 60°C; Feed rate: 8 ml/min; Aspirator flow rate: 80%

Yield: 12 g; The PXRD pattern of the obtained compound was similar to the PXRD pattern illustrated in figure-2.

Claims

1. Pure Atogepant of formula- 1 having less than about 0.15% of diasteromer impurity measured by HPLC {High-performance liquid chromatography}

Formula- 1 Diastereomer impurity.

2. The pure Atogepant claimed according to claim 1, which is having a purity of greater than about 99.7% by HPLC.

3. The pure Atogepant claimed according to claim 1, which is having a purity of less than about 0.1% of diasteromer impurity by HPLC.

4. The pure Atogepant claimed according to claim 1, which is crystalline or amorphous Atogepant.

5. A process for the preparation of pure Atogepant comprising: a) contacting Atogepant with isopropanol and acetonitrile, b) isolating a pure Atogepant.

6. The process claimed according to claim 5, isolating pure Atogepant in step-b) by cooling the mixture to lower temperatures followed by filtration of the mixture.

7. A crystalline form-M of Atogepant which is characterized by its PXRD (Powder X- Ray Diffraction) pattern having peaks at about 5.3, 7.9, 9.8, 12.8 and 17.3 ± 0.2° 29.

8. A process for the preparation of crystalline form-M of Atogepant according to claim 7 comprising: a) contacting Atogepant in a solvent or a mixture of solvents and b) isolating crystalline form-M of Atogepant of formula- 1.

9. The process according to claim 8, wherein isolating crystalline form-M of Atogepant in step-b) is by solvent removal by filtration, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture.

10. A process for the purification of ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)- 5-(2,3,6-trifluoro phenyl)piperidin-3-aminium (S)-2-acetamido-3-phenylpropanoate of formula- 10 having purity greater than about 99% by HPLC

Formula- 10 comprising: a) contacting ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluoro phenyl)piperidin-3-aminium (S)-2-acetamido-3-phenylpropanoate of formula- 10 with methanol, b) combining the mixture obtained in step-a) with isopropanol, c) isolating pure ((3S,5S,6R)-6-methyl-2-oxo-l-(2,2,2-trifluoroethyl)-5-(2,3,6- trifluorophenyl)piperidin-3-aminium (S)-2-acetamido-3-phenylpropanoate of formula- 10.

11. The process according to claim 10, wherein the pure compound of formula- 10 is further converted to Atogepant of formula- 1.

12. A process for the preparation compound of formula- 8

Formula- 8 comprising reacting a compound of formula-6 with a compound of formula-7

Formula-6 Formula-7 in presence of a base selected is from lithium tert-butoxide, lithium tert-pentoxide or lithium tert-amoxide in the presence of dimethylformamide in a solvent.

13. A process for the preparation of amorphous form of Atogepant of formula- 1

Formula- 1 comprising: a) contacting Atogepant of formula- 1 with a solvent, b) isolating amorphous form of Atogepant.

14. The process according to claim 13, wherein ‘contacting Atogepant of formula-1 with a solvent’ means bringing the Atogepant and the solvent into contact with each other, or obtaining Atogepant from the synthetic process in which it is prepared; this is done by mixing the Atogepant and solvent together or dissolving the Atogepant in the solvent; the solvent in step-a) is selected from ester solvent, alcohol solvent, ketone solvent, polar- aprotic solvents.

15. The process according to claim 13, wherein isolating amorphous form of Atogepant in step-b) by spray drying.

16. The process according to claim 13, wherein isolating amorphous form of Atogepant in step-b) by combining with an anti- solvent wherein anti- solvent is a selected from ether solvents, hydrocarbon solvents water or mixture thereof.

17. A process for the preparation of Atogepant monohydrate comprising: a) dissolving Atogepant in a solvent or a mixture of solvents, b) isolating Atogepant monohydrate.

18. The process according to claim 17, wherein, dissolving Atogepant in step-a) can be done at a temperature ranging from about 25 °C to reflux temperature of the solvent used; the solvent in step-a) is selected from alcohol solvents, ether solvent, ketone solvents, ester solvents, water and/or mixtures thereof; isolating Atogepant monohydrate in step-b) is by cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, crystallization or by combining with an anti- solvent.

19. The process according to claim 17, wherein the process is carried out optionally in presence of moisture or in water.

20. A pharmaceutical composition comprising pure Atogepant of claim 1, and a pharmaceutically acceptable carrier for use in the treatment of migraine.