WO2024134683A1

WO2024134683A1 - Novel process for the preparation of intermediate compounds used in the treatment of migraine

Info

Publication number: WO2024134683A1
Application number: PCT/IN2023/051208
Authority: WO
Inventors: Thirumalai Rajan Srinivasan; Eswaraiah Sajja; Rajeshwar Reddy Sagyam; Parameshwarappa Gangajji; Praveen Velishala; Narayana Eppa
Original assignee: Msn Laboratories Private Limited, R&D Center
Priority date: 2022-12-21
Filing date: 2023-12-21
Publication date: 2024-06-27

Abstract

The present application relates to a process for the preparation of (S)-2'-oxo-1',2',5,7- tetrahydrospiro [cyclopenta[b] pyridine-6,3'-pyrrolo [2,3-b] pyridine]-3-carboxylic acid of formula-1, which is a key intermediate compounds for the preparation of Ubrogepant and Atogepant used in migraine treatment. The present invention also provides a novel intermediate compounds and their process for the preparation.

Description

Novel process for the preparation of intermediate compounds used in the treatment of migraine

Related Application:

This application claims the benefit of priority to our Indian patent application number 202241074246 filed on Dec 21, 2022 and 202341063807 filed on Sep 22, 2023 the disclosures of all that are incorporated by reference in their entirety.

Field of the invention:

The present application relates to a process for the preparation of (S)-2'-oxo- T,2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-py^rrolo[2,3-b] pyridine]-3- carboxylic acid of formula- 1 which is a key intermediate of Ubrogepant and Atogepant. The present invention also provides the novel intermediates compounds and their process for the preparation thereof.

Formula- 1.

Background of the invention:

(S)-2'-oxo-l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3- b]pyridine] -3 -carboxylic acid of formula- 1 is a key intermediate for the Atogepant and Ubrogepant and it is represented by the following structural formula.

Formula- 1.

Atogepant is a calcitonin gene -related peptide receptor antagonist indicated for the preventive treatment of episodic migraine in adults under the brand name of Qulipta. Atogepant is represented by the following structural formula as follows:

Atogepant.

Ubrogepant is a calcitonin gene -related peptide receptor antagonist indicated for the acute treatment of migraine with or without aura in adults under the brand name of Ubrelvy. Ubrogepant is represented by the following structural formula as follows:

Ubrogepant.

Ubrogepant and Atogepant described in W02012064911. This patent also describes the process for the preparation of Ubrogepant and Atogepant.

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 (S)-2'-oxo-l',2',5,7-tetrahydrospiro [cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid compound of formula- 1 which is a key intermediate for the Atogepant and Ubrogepant. Summary of the invention:

First embodiment of present invention relates to the process for the preparation of (S)-l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b] pyridine] -3 -carboxylic acid of formula- 1.

Second embodiment of present invention relates to novel intermediates compounds selected from the compound of formulae 8, 9, 10, 11 and 12.

Third embodiment of present invention provides a process for the preparation of (S)-l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b] pyridine]-3- carboxylic acid of formula- 1.

Fourth embodiment of the present invention relates to process for the purification of pure (S)-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2',5,7- tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid of formula- 12.

Fifth embodiment of present invention relates to (S)-l-phenylethanamine (S)- 2'-oxo-r-((2-(trimethylsilyl)ethoxy)methyl)-l',2',5,7-tetrahydrospiro[cyclopenta[b] pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylate of formula- 14.

Brief Description of the Drawings:

Figure-1: Illustrates the PXRD pattern of compound of formula- 1 obtained according to example- 13 and 15.

Figure-2: Illustrates the PXRD pattern of compound of formula- 14 obtained according to example- 12.

Figure-3: Illustrates the PXRD pattern of (3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-l- (2,2,2-trifluoroethyl)piperidin-3-aminium 4-methylbenzoate obtained according to example- 17.

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, dimethyl sulfoxide, N- methylpyrrolidone 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, isopropanol, 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.

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.

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.

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; “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, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), nmethyl pyridine (NMP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0] non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole; “alkalimetal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide and the like; “alkali metal amides” such as sodium amide, potassium amide, lithium amide, lithiumdiisopropyl amide (LDA), sodium bis(trimethylsilyl) amide (NaHMDS), potassiumbis(trimethylsilyl)amide, lithium bis(trimethysilyl) amide (LiHMDS) and the like; or mixtures thereof.

As used herein the term “acid” in the present invention refers to inorganic acid and organic acid; inorganic acid is selected from such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfuric acid; organic acids such as acetic acid, maleic acid, malic acid, oxalic acid, succinic acid, fumaric acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid.

As used herein the term “catalyst” used in the present invention is selected from but not limited to metal catalysts Platinum, Palladium, Rhodium, Ruthenium, and Nickel.

First embodiment of the present invention provides a process for the preparation of (S)-l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b] pyridine] -3 -carboxylic acid of formula- 1

Formula- 1 comprising one or more of the following steps: a) reacting 5-chloro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)picolinaldehyde formula-6 with l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin- 2(3H)-one of formula-7 in presence of a base in a solvent to provide (E)-3-((5- chloro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-2-yl)methylene)-l-((2- (trimethylsilyl)ethoxy)methyl)- lH-pyrrolo[2,3-b]pyridin-2(3H)-one of formula-8, b) reducing the compound of formula-8 with a reducing agent in solvent and followed by deprotection using an acid in a solvent to provide 3-((5-chloro-3- (hydroxymethyl)pyridin-2-yl)methyl)-l-((2-(trimethylsilyl)ethoxy) methyl)- 1H- pyrrolo[2,3-b]pyridin-2(3H)-one of formula-9, c) chlorinating the compound of formula-9 using a chlorinating reagent optionally in a solvent to provide 3-((5-chloro-3-(chloromethyl)pyridin-2-yl)methyl)-l-((2- (trimethylsilyl)ethoxy)methyl)- lH-pyrrolo[2,3-b]pyridin-2(3H)-one of formula- 10, d) cyclization the compound of formula- 10 using a phase transfer catalyst, a base in solvent to provide (S)-3-chloro-l'-((2-(trimethylsilyl)ethoxy)methyl)-5,7-dihydro spiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-2'(l'H)-one of formula-11, e) converting the compound of formula-11 into provide (S)-2'-oxo-l'-((2- (trimethylsilyl)ethoxy)methyl)-l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine- 6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid of formula-12, f) deprotecting the compound of formula- 12 in presence of an acid in a solvent to provide (S)-2'-oxo-r,2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo [2,3-b]pyridine]-3-carboxylic acid of formula- 1.

Base used in step-a) is selected from methyl amine, ethyl amine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine, N-methyl pyridine, 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; reducing agent in step-b) is selected from lithium borohydride, sodium borohydride, potassium borohydride, mixture of sodium borohydride and acetic acid, mixture of sodium borohydride and trifluoroacetic acid, mixture of sodium borohydride and iodine, mixture of sodium borohydride and trimethylchlorosilane, mixture of sodium borohydride and magnesium chloride, mixture of sodium borohydride and calcium chloride, mixture of sodium borohydride and one of transition metal chlorides, boranes, Vitride {=Sodium-bis(2-methoxyethoxy)aluminumhydride} and like; chlorinating agent in step-c) selected from but not limited to N-chlorosuccinimide (NCS), Ch, sulfuryl chloride, thionyl chloride, oxalyl chloride, PCI5, PCI3, POCI3, cyanuric chloride, trichloroisocyanuric acid or combination thereof; phase transfer catalyst in step-d) is selected from mono or bis-quaternary cinchona alkaloid salt, preferably selected from (lS,2R,4S,5R)-l-(2-Bromo-5-methoxybenzyl)-2-((S)-(l-(2- bromo-5 -methoxy benzyl)-6-methoxyquinolin- 1 -ium-4-yl)(hy drox y)methyl)-5 -vinyl quinuclidin-l-ium bromide and (lS,2S,4S,5R)-l-(2-Cyanobenzyl)-2-((R)- hydroxy(quinolin-4-yl) methyl)-5-vinylquinuclidin-l-ium bromide (19) and (lS,2S,4S,5R)-l-(2-cyano benzyl)-2-((R)-hydroxy(l-(4-(trifluoromethyl)benzyl) quinolin- l-ium-4-yl)methyl)-5-vinylquinuclidin-l-ium bromide; conversion in step-e) is carried out in presence of a palladium catalyst, carbon monoxide, a base and a ligand; wherein ligand is selected from l,3-bis(dicyclohexylphosphino)ethane (DCPE) and l,3-bis(dicyclohexyl phosphino)-propane (DCPP); base is selected from inorganic base as defined above; acid in step-f) 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, oxalic acid, succinic acid, fumaric acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid.

The process for the preparation of compound of formula- 1 of present application is schematically represented as below:

Second embodiment of present invention provides the novel intermediates compounds selected from the below compounds of formulae:

In an aspect of the second embodiment, novel intermediate compounds of formula-8, formula-9, formula- 10, formula- 11 and formula- 12 are used in the preparation of compound of formula- 1.

Third embodiment of the present invention provides a process for the preparation of (S)-T,2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b] pyridine] -3 -carboxylic acid of formula- 1

Formula- 1 comprising the following steps: a) reacting (S)-2'-oxo-r-((2-(trimethylsilyl)ethoxy)methyl)-l',2',5,7-tetrahydrospiro [cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid of formula- 12 with (S)-phenyl ethylamine of formula-13 in a solvent to provide (S)-l- phenylethanamine (S)-2'-oxo-r-((2-(trimethylsilyl)ethoxy)methyl)-l',2',5,7- tetrahydrospiro[cyclopenta[b]pyridine-6,3'-py^rrolo[2,3-b]pyridine]-3-carboxylate of formula- 14, b) treating the compound of formula- 14 with an acid in a solvent to provide (S)- r,2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b] pyridine]-3- carboxylic acid of formula- 1.

Solvent in step-a) and b) is selected from alcohol solvents, ether solvent, ketone solvents, nitrile solvent, ester solvents, water and/or mixtures thereof; acid in step-b) is selected from inorganic acid and organic acid; inorganic acid is selected from such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid or mixtures thereof.

Fourth embodiment of the present invention provides a process for the purification of (S)-2'-oxo-r-((2-(trimethylsilyl)ethoxy)methyl)-l',2',5,7-tetrahydro spiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid of formula- 12 comprising the following steps: a) reacting the (S)-2'-oxo-r-((2-(trimethylsilyl)ethoxy)methyl)-l',2',5,7-tetrahydro spiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid of formula- 12 with (S)-phenyl ethylamine of formula- 13 in a solvent to provide (S)- 1-phenylethanamine (S)-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-l',2',5,7-tetra hydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylate of formula- 14, b) treating the compound of formula- 14 with base in a solvent to get pure (S)-2'-oxo- r-((2-(trimethylsilyl)ethoxy)methyl)-l',2',5,7-tetrahydrospiro[cyclopenta[b] pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid.

Solvent in step-a) and b) is selected from alcohol solvents, ether solvent, ketone solvents, nitrile solvent, ester solvents, water and/or mixtures thereof; base in step-a) is selected from 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.

First aspect of the fourth embodiment of the present invention, wherein alkali salt of compound of formula- 12 obtained in step-b) further treated with an acid to get compound of formula- 12.

Second aspect of the fourth embodiment of the present invention, the pure compound of formula- 12 is further converted to compound of formula- 1 according to process described in present invention.

Third and fourth embodiments of the present inventions are schematically represented as below:

Fifth embodiment of the present invention provides a (S)-l-phenylethanamine (S)-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-r,2',5,7-tetra hydrospiro [cyclopenta [b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylate of formula- 14.

First aspect of the fifth embodiment provides, (S)-l-phenylethanamine (S)-2'- oxo-r-((2-(trimethylsilyl)ethoxy)methyl)-r,2',5,7-tetrahydrospiro[cyclopenta [b] pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylate of formula-14 as a solid.

Second aspect of the fifth embodiment provides (S)-l-phenylethanamine (S)- 2'-oxo-r-((2-(trimethylsilyl)ethoxy)methyl)-l',2',5,7-tetrahydrospiro [cyclopentafb] pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylate of formula-14 as crystalline solid.

Third aspect of the fifth embodiment provides, the use of (S)-l- phenylethanamine (S)-2'-oxo-r-((2-(trimethylsilyl)ethoxy)methyl)-r,2',5,7-tetra hydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylate formula- 14 obtained according to the present invention in the preparation of (S)- l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b] pyridine]-3- carboxylic acid of formula- 1.

Fourth aspect of the fifth embodiment provides, conversion of (S)-l- phenylethanamine (S)-2'-oxo-r-((2-(trimethylsilyl)ethoxy)methyl)-r,2',5,7-tetra hydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylate formula- 14 to (S)-l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b] pyridine] -3 -carboxylic acid of formula- 1 is carried out by process described in the present application.

As used herein the term “pure” refers to the compound of formula- 12 and the compound of formula- 1 contains chiral purity greater than about 99.50% by chiral high performance liquid chromatography (HPLC) or greater than about 99.70% by chiral HPLC or greater than about 99.80% by chiral HPLC or greater than about 99.90% by chiral HPLC.

As used herein the term “pure” refers to the compound of formula- 12 and the compound of formula- 1 contains purity greater than about 98% by high performance liquid chromatography (HPLC) or greater than about 99% by HPLC or greater than about 99.5% by HPLC.

High Performance Liquid Chromatography (HPLC) and chiral High Performance Liquid Chromatography (HPLC) analysis of intermediate compounds and compound of formula- 1 is carried out by methods known in art.

In an embodiment of the present invention, the compound of formula- 1 obtained according to the present invention is further converted to Ubrogepant or Atogepant by the process described in present application, WO2012064911, or WO2013138418.

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 (2-bromo-5-chloropyridin-3-yl)methanol [formula-4]

Isopropylmagnesium chloride lithium chloride solution (368 ml) slowly added to the solution of 2,3-dibromo-5-chloropyridine (100 g) in tetrahydrofuran (400 ml) at -55 to -65 °C and stirred at the same temperature. Dimethylformamide (94 g) was added to the reaction mixture at -55 to -65°C, raised the temperature to 25-30°C and stirred at the same temperature. The reaction mixture was slowly added into pre-cooled aqueous hydrochloric acid solution at 5-10°C and then methyl tertiary butyl ether added. Raised the reaction mixture temperature to 25-30°C, separated the both organic and aqueous layers and the aqueous layer was extracted with methyl tertiary butyl ether. Combined the organic layers and washed with water, then followed by aqueous sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure. Methanol (500 ml) was added to the obtained compound at 25-30°C. Cooled the mixture to 0-5°C and sodium borohydride (4.2 g) was slowly added and stirred at the same temperature. Water added to the reaction mixture at 0- 5 °C and stirred at the same temperature. The solvent was removed under reduced pressure. Methyl tertiary butlyl ether and water were added to the obtained compound at 25-30°C and separated the both the organic and aqueous layers. Organic layer was washed with aqueous sodium chloride. Distilled off the solvent under reduced pressure. Toluene (150 ml) added to obtained compound, heated to 45-50°C and stirred at the same temperature. Cooled the mixture to 0-5°C and stirred at the same temperature. Filtered the solid, washed with toluene and dried to get the title compound. Yield: 55 g.

Example-2: Preparation of (E)-3-((5-chloro-3-(((tetrahydro-2H-pyran-2-yl)oxy) methyl) pyridin-2-yl)methylene)- 1 - ((2- (trimethylsilyl)ethoxy)methyl) - IH-pyrrolo [2,3-b]pyridin-2(3H)-one [Formula-8]

3,4-dihydro-2H-pyran (45.37 g) slowly added to the mixture of (2-Bromo-5- chloropyridin-3-yl)methanol (100 g) and toluene (400 ml) at 25-30°C. Cooled the reaction mixture to 0-5°C, sulfuric acid (2.64 g) in 100 ml of toluene added and stirred the reaction mixture at 0-5°C. Raised the reaction mixture temperature to 25- 30°C and stirred at the same temperature. Water added to the reaction mixture at 25- 30°C and separated the both organic and aqueous layers. Aqueous layer extracted with toluene. Combined the organic layers, washed with aqueous sodium bicarbonate solution followed by with aqueous sodium chloride solution. Cooled the organic layer to -5 to 0°C temperature, isopropylmagnesium chloride lithium chloride solution (795 ml) was slowly added and stirred at the same temperature. Dimethylformamide (131 g) added to the above reaction mixture at -5 to 0°C and stirred at the same temperature. The reaction mixture was quenched by addition of aqueous citric acid solution at -5 to 0°C and raised the temperature to 25-30°C. Separated the both organic and aqueous layers and aqueous layer was extracted with toluene. Combined the organic layers, washed with aqueous sodium chloride solution and distilled off the solvent completely from the organic layer under reduced pressure. Isopropanol (500 ml) added to the obtained compound and cooled to 0-5°C. 1,8-Diazabicyclo [5.4.0]undec-7-ene (6.84 g) and l-((2-(trimethylsilyl)ethoxy)-methyl)-lH-pyrrolo [2,3-b]pyridin-2(3H)-one (83.28 g) were slowly added to the above mixture at -5 to 0°C and stirred at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred at this temperature. Isopropanol (300 ml) added to the reaction mixture at 25-30°C and stirred at the same temperature. Filtered the solid, washed with isopropanol and dried to get the title compound.

Yield: 130 g.

Example-3: Preparation of 3-((5-chloro-3-(chloromethyl)pyridin-2-yl)methyl)-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-2(3H)-one [Formula- 10]

Sodium borohydride (8.9 g) slowly added in lot-wise to the pre-cooled mixture of (E)-3-((5-chloro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-2-yl)methylene)- l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-2(3H)-one (100 g) and methanol (500 ml) at 0-5°C and stirred at the same temperature. IPA-Hydrochloric acid solution (150 ml) was slowly added to the reaction mixture at 0-5°C and stirred at the same temperature. The mixture was concentrated under reduced pressure. Cooled the obtained residue to 0-5 °C, water and methyl tertiary butyl ether were added. Raised the reaction mixture temperature to 25-30°C, separated the both organic and aqueous layers. Aqueous layer extracted with methyl tertiary butyl ether. Combined the organic layers, washed with water and followed by with aqueous sodium chloride solution. Distilled off the solvent from the organic layer and codistilled with dichloromethane to get 3-((5-chloro-3-(hydroxymethyl)pyridin-2- yl)methyl)- 1 -((2-(trimethylsilyl)ethoxy) methyl)- lH-pyrrolo[2,3-b]pyridin-2(3H)-one [Formula-9] obtained as residue. To this residue dimethyl formamide (1 ml) and dichloromethane (500 ml) added and cooled to 0-5 °C temperature. To this mixture thionyl chloride (35.55 g) was slowly added at 0-5°C and stirred at the same temperature. Water added to the reaction mixture at 0-5 °C and separated the both organic and aqueous layers. Aqueous layer extracted with dichloromethane. Combined the organic layers, washed with water, with aqueous sodium bicarbonate solution and followed by with aqueous sodium chloride solution. Distilled off the solvent from the organic layer to get the title compound.

Yield: 76 g.

Example-4: Preparation of (S)-3-chloro-l'-((2-(trimethylsilyl)ethoxy)methyl)-5,7- dihydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-2'(l'H)-one [Formula-11]

A mixture of quinidine (2.44 g), 2-bromo-5-methoxy benzylbromide (5.36 g), dimethylformamide (8.57 ml) and isopropanol (1.25 ml) heated to 80-85°C and stirred at the same temperature to get (lS,2R,4S,5R)-l-(2-bromo-5-methoxybenzyl)- 2-((S)-( 1 -(2-bromo-5-methoxybenzyl) -6-methoxyquinolin- 1 -ium-4-yl)(hydroxy) methyl)-5-vinylquinuclidin-l-ium bromide salt. The above slat mixture was added to pre-cooled mixture of 3 -((5 -chloro-3 -(chloromethyl) pyridin-2-yl)methyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-2(3H)-one (100 g) and toluene (3000 ml) at -20 to -10°C and stirred at the same temperature. Aqueous potassium hydroxide solution (38.39 g of potassium hydroxide in 500 ml of water) was slowly added to the reaction mixture at -20 to -10°C and stirred at the same temperature. Raised the reaction mixture temperature to 25-30°C, water added. Separated the both organic and aqueous layers and aqueous layer was extracted with toluene. Combined the organic layers, washed with aqueous sodium chloride solution. Distilled off the solvent from the organic layer to get the title compound.

Yield: 73 g.

Example-5: Preparation of (S)-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)- l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3- carboxylic acid [Formula-12] Dimethylformamide (500 ml), potassium carbonate (80.85 g), water (8.75 g), (S)-3- chloro- 1 '-((2-(trimethylsilyl)ethoxy)methyl)-5,7-dihydro spiro[cyclopenta[b]pyridine- 6,3'-pyrrolo[2,3-b]pyridin]-2'(l'H)-one (100 g) are added into autoclave and applied the carbon monoxide gas in autoclave, heated to 125-135°C and stirred at the same temperature. Cooled the reaction mixture to 25-30°C and distilled off the solvent completely from the organic layer. Cooled the obtained compound and water and ethyl acetate were added to it and stirred at the same temperature. Separated both organic and aqueous layer and aqueous layer was extracted with ethyl acetate. Acidified the organic layer using aqueous hydrochloric acid solution. Filtered the solid, washed with water and dried to get the title compound.

Yield: 62 g.

Example-6: Preparation of compound of (S)-2'-oxo-l',2',5,7-tetrahydrospiro [cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid formula-1

(S)-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-r,2',5,7-tetrahydrospiro[cyclopenta [b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (100 g) was added to the mixture of water (500 ml) and concentrated sulfuric acid (52.38 g) at 25-30°C, heated the reaction mixture to 95-100°C and stirred at the same temperature. Cooled the reaction mixture to 25-30°C and ethyl acetate added. Filtered the reaction mixture through hy-flow bed and washed with ethyl acetate. Separated the both organic and aqueous layers and aqueous layer washed with ethyl acetate. Basified the aqueous layer using aqueous ammonia at 25-30°C, ethyl acetate added and stirred at the same temperature. Separated the both organic and aqueous layers and aqueous layer is washed with ethyl acetate. Acidified the aqueous layer using aqueous hydrochloric acid solution. Ethyl acetate (500 ml) added to the above mixture and stirred at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get the title compound.

Yield: 50 g

Example-7: Preparation of l-((2-(trimethylsilyl)ethoxy)-methyl)-lH-pyrrolo[2,3- b]pyridin-2(3H)-one N, N-Diisopropylethylamine (273 g) and 2-(trimethylsilyl)ethoxymethyl chloride (211 g) were added to pre-cooled mixture at lH-pyrrolo[2,3-b]pyridine (100 g) and ethyl acetate (500 ml) at 0-5°C, heated to 25-30°C and stirred at the same temperature. Water added to the reaction mixture at 25-30°C and separated the both organic and aqueous layers. Aqueous layer was an extracted with ethyl acetate and organic layer washed with water and followed by aqueous sodium chloride solution. Distilled off the solvent from the organic layer. Ethyl acetate (1400 ml) added to the above-obtained compound at 25-30°C and cooled to 0-5°C. Pyridine-hydrobromic acid (810 g) slowly added to the reaction mixture at 0-5°C and stirred at the same temperature. Aqueous sodium bicarbonate solution added to the reaction mixture at 0- 5 °C and separated the both organic and aqueous layers. Organic layer washed with aqueous sodium bicarbonate solution and followed by with aqueous sodium chloride solution. Cooled the organic layer to 0-5°C, ammonium chloride (271 g) in water (800 ml) added, then further zinc dust (330 g ) slowly added to it and stirred at the same temperature. Filtered the reaction mixture through the hy-flow bed and washed with ethyl acetate. Separated the both organic and aqueous layers, then organic layer was washed with water and followed by with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer and co-distilled with n- heptane. Slurried the obtained compound in n-heptane, filtered the solid, washed with n-heptane and dried to the get the title compound.

Yield: 104 g.

Example-8: Preparation of isopropyl 2-((tert-butoxycarbonyl)amino)-5-oxo-4- phenylhexanoate

Methane sulfonyl chloride (80.8 ml) was slowly added to the pre-cooled mixture of isopropyl 2-((tert-butoxycarbonyl)amio)-3-hydroxypropanoate (200 g) and dimethylformamide (800 ml) at 0-5 °C and followed by triethylamine (284 ml) 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. Combined the organic layers, washed with aqueous citric acid solution and followed by with water. Distilled off the solvent from organic layer and to the obtained compound dimethylsulfoxide added. The obtained mixture was slowly added to the mixture of dimethylsulfoxide (760 ml), cesium carbonate (123.84 g) and phenyl acetone (105.16 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. To the obtained filtrate aqueous sodium chloride solution added and separated both organic and aqueous layers. Organic layer washed with aqueous sodium chloride solution. Distilled off solvent completely from the organic layer. n-Heptane added to the obtained compound, cooled to 5-10°C and stirred at the same temperature. Filtered the solid and dried to get the title compound.

Yield: 146 g

Example-9: Preparation of tert-Butyl ((5S,6R)-6-methyl-2-oxo-5-phenyl piperidin-3-yl)carbamate

Aqueous HC1 solution added to the mixture of isopropyl amine (43 ml) added to the mixture of water (350 ml) and disodium tetraboratedecahydrate (9.6 g) at 15-20°C. Pyrdioxial phosphate (1 g), enzyme (250 g) and isopropyl 2-((tert- butoxycarbonyl)amino)-5-oxo-4-phenylhexanoate (50 g) in dimethyl sulfoxide (350 ml) were added to the above mixture at 15-20°C, heated to 55-60°C and stirred at the same temperature. Isopropylamine (170 ml) 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 and neutralized using concentrated hydrochloric acid. Isopropanol and hi-flow added to the reaction mixture, filtered and washed with methyl tertiary butyl ether. Distilled off the solvent from the filtrate. To the obtained compound methyl tertiary butyl ether and aqueous sodium chloride solution were added and separated the both organic and aqueous layers. Distilled off the solvent completely from organic layer and obtained crude slurried in n-heptane to get the title compound.

Yield: 22 g. Example-10: Preparation of (3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-l-(2,2,2- trifluoroethyl)piperidin-3-aminium 4-methylbenzoate

N, N’ -Dimethylpropyleneurea (33.1 g) was slowly added to the mixture tert-Butyl ((5S,6R)-6-methyl-2-oxo-5-phenylpiperidin-3-yl)carbamate (50 g) and tetrahydrofuran (400 ml) at -20° to -10°C and stirred. Lithium tert-amoxide (21 ml) slowly added to above reaction mixture at -20° to -10°C and stirred at the same temperature. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (23.6 ml) was slowly added to the reaction mixture at -20° to -10°C and stirred at the same temperature. Another lot of lithium tert-amoxide solution (21 ml) was added to the above reaction mixture and followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (23.6 ml) at -10 to -20°C temperature and stirred at the same temperature. Lithium tert-amoxide solution (63 ml) slowly added to the reaction mixture in three lots at -20 to -10°C and followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (23.6 ml) was added and stirred at the same temperature. Aqueous hydrochloric acid solution added to the reaction mixture and followed by methyl t-butyl ether was added. Raised the temperature of the reaction mixture to 25-30°C and stirred. Separated the both organic and aqueous layers and aqueous layer is extracted with methyl t-butyl ether. Combined the organic layers and distilled off the solvent from the organic layer under reduced pressure. Methyl ter-butyl ether (200 ml) was added to the obtained residue and cooled to 10-20°C. Aqueous hydrochloric acid solution (144 ml HC1 in 256 ml of water) was to the above mixture, heated to 50-55°C and stirred at the same temperature. n-Heptane was added and stirred at the same temperature. Separated the both organic and aqueous layers and aqueous layer washed with n-heptane. Cooled the aqueous layer to 10- 15 °C, methyl tertiary butyl ether added to it and added aqueous sodium carbonate solution. Separated the both organic and aqueous layers and aqueous layer is extracted with methyl tertiary butyl ether. Combined the organic layers, washed with aqueous sodium chloride solution and distilled off the solvent from the organic layer under reduced pressure. Obtained residue was dissolved in 440 ml of methyl tertiary butyl ether at below 40°C. A mixture of p-Toluic acid (19.4 g), 3,5-dichlorosalicylaldehyde (0.27 g) in methyl tertiary butyl ether (40 ml) was heated to 50-55°C and to this reaction mixture above obtained solution added and stirred at the same temperature. Cooled the reaction mixture to -5 °C to 0°C and stirred at the same temperature. Filtered the solid, washed with methyl tertiary butyl ether and dried to get the title compound.

Yield: 32 g.

Example-11: Preparation of Ubrogepant

Aqueous hydrochloric acid solution (1200 ml) was added to the mixture of (3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-3-aminium 4- methylbenzoate (200.0 g) and methyl tertiary butyl ether (2000 ml) at 25- 30°C and stirred at the same temperature. Separated the both organic and aqueous layers and the organic layer was extracted with aqueous hydrochloric acid solution. Aqueous layer was washed with methyl tertiary butyl ether. Neutralized aqueous layer with aqueous sodium bicarbonate solution and methyl tertiary butyl ether added to it. Separated both the organic and aqueous layers and organic layer was washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. The above obtained compound was dissolved in acetonitrile (1200 ml) and added to water (1200 ml) at 25-30°C. To this mixture (6S)- 2'-oxo-T,2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3- carboxylic acid (133 g) added and stirred. Aqueous solution of sodium hydroxide solution added to the reaction mixture and stirred. Hydroxybenzotriazole hydrate (6.2 g) and l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (101 g) were added to the above reaction mixture at 25-30 °C and stirred at the same temperature. Ethanol (800 ml) added to the reaction mixture at 25-30°C, this reaction mixture was added to the water (2000 ml) at 25-30°C and stirred. Filtered the solid, washed with water and dried to get the title compound. Dissolved the obtained compound in ethyl acetate at 45-55°C and carbon treatment given at the same temperature. The obtained filterate was added to n-heptane at 25-30°C and stirred at the same temperature. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 190.0 g.

Example-12: Preparation of (S)-l-phenylethanamine (S)-2'-oxo-l'-((2-(trimethyl silyl)ethoxy)methyl)-l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo [2,3-b]pyridine]-3-carboxylate of formula-14

A mixture of (S)-2'-oxo-r-((2-(trimethylsilyl)ethoxy)methyl)-r,2',5,7-tetrahydrospiro [cyclopenta [b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (50 g), (S)- phenyl ethylamine (14.72 g), acetonitrile (150 ml) and water (7.5 ml) was stirred at 25-30°C. The compound of formula- 14 (50 mg) was seeded to the reaction mixture at 25-30°C and stirred at the same temperature. Cooled the reaction mixture to 20- 25°C and stirred at the same temperature. Filtered the solid, washed with acetonitrile. The obtained compound was added to ethyl acetate (150 ml) at 25-30°C and stirred. Methanol (3 ml) was added to above mixture, heated the obtained mixture to 70-75°C and stirred at the same temperature. Cooled the mixture to 15-25°C and stirred at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get the title compound.

Yield: 29 g; Purity by Chiral HPLC: 100% and other isomer impurity: Not detected. PXRD pattern of the obtained compound is depicted in Figure-2.

Example-13: Preparation of (S)-l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine- 6,3'-pyrrolo[2,3-b] pyridine]-3-carboxylic acid of formula-1

Hydrochloric acid (290 ml) is added to the mixture of (S)-l-phenylethanamine (S)-2'- oxo-r-((2-(trimethylsilyl)ethoxy)methyl)-r,2',5,7-tetrahydrospiro[cyclopenta[b] pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylate of formula-14 (58 g) and water (116 ml) at 25-30°C. Heated the reaction mixture to 60-65°C and stirred at the same temperature. Further heated the reaction mixture to 95-105°C and stirred at the same temperature. Cooling the reaction mixture to 60-65 °C and distilled off the solvent completely from the reaction mixture. Water is added the obtained residue and followed by ethyl acetate and carbon (5.8 g) were added to the mixture at 25-30°C and stirred at the same temperature. Filtered the mixture through hyflow bed and washed bed with water. Separated the both organic and aqueous layers from the filtrate and aqueous layer is washed with ethyl acetate. Basified the aqueous layer using aqueous ammonia solution and washed the mixture with ethyl acetate. Acidified an aqueous layer with aqueous hydrochloric acid solution and stirred at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.

Yield: 28 g; Purity by chiral HPLC: 100%; Other isomer impurity: not detected; Purity by HPLC: 99.66%; PXRD pattern of the obtained compound is depicted in Figure- 1.

Example-14: Preparation of pure (S)-2'-oxo-l'-((2-(trimethylsilyl)ethoxy) methyl)-l',2',5,7-tetrahydrospiro[cyclopenta [b]pyridine-6,3'-pyrrolo[2,3-b] pyridine]-3-carboxylic acid of formula-12

Treating the solution of (S)-l-phenylethanamine (S)-2'-oxo-l'-((2-(trimethylsilyl) ethoxy)methyl)-l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b] pyridine] -3 -carboxylate of formula- 14 (63 g) in water (252 ml) with aqueous potassium carbonate solution at and stirred at the same temperature. Ethyl acetate added to mixture and separated the both organic and aqueous layers. Aqueous hydrochloric acid solution is added to the above obtained aqueous layer and stirred. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 41 g; Purity by Chiral HPLC: 100%, Other isomer impurity: Not detected; Purity by HPLC: 99.42%

Example-15: Preparation of (S)-l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine- 6,3'-pyrrolo[2,3-b] pyridine]-3-carboxylic acid of formula-1

Hydrochloric acid (200 ml) is added to the solution of S)-2'-oxo-l'-((2- (trimethylsilyl)ethoxy)methyl)-r,2',5,7-tetrahydrospiro [cyclopenta [b]pyridine-6,3'- pyrrolo[2,3-b]pyridine]-3-carboxylic acid of formula-12 (40 g) in water (80 ml) at 25- 35°C, heated the obtained mixture to 55-65°C and stirred at the same temperature. Lurther heated the reaction mixture 95-105°C and stirred at the same temperature. Distilled off the solvent completely from the reaction mixture to get residue. Water (200 ml), ethyl acetate (200 ml) and carbon (4 g) were added to the obtained residue at 25-35°C and stirred at the same temperature. Filtered the mixture through hy-flow bed and washed the bed with water. Separated the both organic and aqueous layers and aqueous layer is washed with ethyl acetate. Basified the aqueous layer using aqueous ammonia solution and washed with ethyl acetate. Aqueous hydrochloric acid solution is added to the above obtained aqueous layer and stirred at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.

Yield: 24 g; Purity by Chiral HPLC: 100%, Other isomer impurity: Not detected; Purity by HPLC: 99.58%; PXRD pattern of the obtained compound is depicted in Figure- 1.

Example-16: Preparation of tert-Butyl ((5S,6R)-6-methyl-2-oxo-5-phenyl piperidin-3-yl)carbamate

Pyridoxal phosphate hydrate (1 g), enzyme mass (325 g) and solution of isopropyl 2- ((tert-butoxycarbonyl)amino)-5-oxo-4-phenylhexanoate (50 g) in dimethyl sulfoxide (350 ml) are added to the pre-cooled solution of disodium tetraboratedecahydrate (9.4 g) in water (350 ml) at 10-20°C. Heated the reaction mixture to 50-60°C and stirred at the same temperature. 8M Isopropylamine solution (55.5 ml in 26.2 ml of water ) is added in lot wise to the above reaction mixture at 50-60°C and stirred at the same temperature. Enzyme mass (175 g) in water (75 ml) is added to the above reaction mixture at 50-60°C and stirred at the same temperature. 8M Isopropylamine solution (11.7 ml in 5.5 ml of water ) is added in lot wise to the above reaction mixture at 50- 60°C and stirred at the same temperature. Enzyme mass (73 g) is added to the above reaction mixture at 50-60°C and stirred at the same temperature. 8M Isopropylamine solution (5.8 ml in 2.7 ml of water) is added to the above reaction mixture at 50-60°C and stirred at the same temperature. Cooled the reaction mixture to 20-30°C, isopropanol and dichloromethane are added to the reaction mixture and stirred at the same temperature. Decaned the clear layer from the mixture. Water, dichloromethane added to the above obtained layer, followed by isopropanol added and stirred. The organic layer is separated from the mixture and washed with water, followed by with aqueous sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure. To the obtained compound methyl tertiary butyl ether and followed by water were added and separated the both organic and aqueous layers. Distilled off the solvent completely from organic layer and co-distilled with n- heptane. The obtained compound slurried in n-heptane, filtered and dried to get the title compound.

Yield: 21 g.

Example-17: Preparation of (3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-l-(2,2,2- trifluoroethyl)piperidin-3-aminium 4-methylbenzoate

N, N’ -Dimethylpropyleneurea (31.2 g) was slowly added to the mixture tert-Butyl ((5S,6R)-6-methyl-2-oxo-5-phenylpiperidin-3-yl)carbamate (50 g) and tetrahydrofuran (400 ml) at -20° to -10°C and stirred. Lithium tert-amoxide (21 ml) slowly added to above reaction mixture at -20° to -10°C and stirred at the same temperature. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (23.6 ml) was slowly added to the reaction mixture at -20° to -10°C and stirred at the same temperature. Another lot of lithium tert-amoxide solution (21 ml) was added to the above reaction mixture and followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (23.6 ml) at -10 to -20°C temperature and stirred at the same temperature. Lithium tert-amoxide solution (63 ml) slowly added to the reaction mixture in three lots at -20 to -10°C and followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (23.6 ml) was added and stirred at the same temperature. Aqueous hydrochloric acid solution added to the reaction mixture and followed by methyl t-butyl ether was added. Raised the temperature of the reaction mixture to 25-30°C and stirred. Separated the both organic and aqueous layers and aqueous layer is extracted with methyl t-butyl ether. Combined the organic layers and distilled off the solvent from the organic layer under reduced pressure. Methyl ter-butyl ether (200 ml) was added to the obtained residue and cooled to 10-20°C. Aqueous hydrochloric acid solution (144 ml HC1 in 256 ml of water) was to the above mixture, heated to 45-55°C and stirred at the same temperature. Cooled the reaction mixture to 35-45°C, n-Heptane was added and stirred at the same temperature. Separated the both organic and aqueous layers and aqueous layer washed with n-heptane. Cooled the aqueous layer to 5-15°C, methyl tertiary butyl ether added to it and basified by using aqueous sodium hydroxide solution. Raised the reaction mixture temperature to 25-30°C and stirred at the same temperature. Separated the both organic and aqueous layers and aqueous layer is extracted with methyl tertiary butyl ether. Combined the organic layers, washed with aqueous sodium chloride solution and distilled off the solvent from the organic layer under reduced pressure. Obtained residue was dissolved in 440 ml of methyl tertiary butyl ether at below 40°C. A mixture of p-Toluic acid (19.4 g), 3,5- dichlorosalicylaldehyde (0.27 g) in methyl tertiary butyl ether (40 ml) was heated to 45-55 °C and to this reaction mixture above obtained solution added and stirred at the same temperature. Cooled the reaction mixture to -10°C to 0°C and stirred at the same temperature. Filtered the solid, washed with methyl tertiary butyl ether and dried to get the title compound.

Yield: 30 g; PXRD pattern of the obtained compound is depicted in Figure-3.

Example-18: Preparation of Ubrogepant

Aqueous hydrochloric acid solution (452.4 ml) was added to the mixture of (3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-l-(2,2,2-trifluoroethyl)piperidin-3-aminium 4- methylbenzoate (65 g) and methyl tertiary butyl ether (650 ml) at 25- 30°C and stirred at the same temperature. Separated the both organic and aqueous layers and the organic layer was extracted with aqueous hydrochloric acid solution. Aqueous layer washed with methyl tertiary butyl ether. Neutralized aqueous layer with aqueous sodium bicarbonate solution and methyl tertiary butyl ether added to it. Separated both the organic and aqueous layers and organic layer was washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. The above obtained compound was dissolved in acetonitrile (390 ml) and added to water (390 ml) at 25-30°C. To this mixture (6S)-2'-oxo- r,2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3- carboxylic acid (133 g) added and stirred. Aqueous solution of sodium hydroxide solution added to the reaction mixture and stirred. Hydroxybenzotriazole hydrate (2.07 g) and l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (35.39 g) were added to the above reaction mixture at 25-30°C and stirred at the same temperature. Ethanol (800 ml) added to the reaction mixture at 25-30°C, heated to 35- 45°C, carbon (6.5 g) added to it and stirred and filtered. Water added to the obtained filtrate at 25-30°C and stirred at the same temperature. Cooled the reaction mixture to 5-15°C and stirred at the same temperature. Filtered the solid and washed with water. Water (130 ml), acetonitrile (260 ml) and ethanol (130 ml) were added to the obtained compound at 25-30°C and stirred at the same temperature. The above obtained mixture is added to the water (650 ml) at 25-30°C and stirred at the same temperature. Filtered the solid, washed with water and dried to get the title compound.

Yield: 60 g; Purity by HPEC: 99.77%.

Claims

Claims:

1. A process for the preparation of (S)-l',2',5,7-tetrahydrospiro[cyclopenta[b] pyridine-6,3'- pyrrolo[2,3-b] pyridine]-3-carboxylic acid of compound 1

Formula- 1 comprising one or more the following steps: a) reacting 5-chloro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)picolinaldehyde formula-6 with l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-2(3H)-one of formula-

7 in presence of base in a solvent to provide (E)-3-((5-chloro-3-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)pyridin-2-yl)methylene)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[2,3-b]pyridin-2(3H)-one of formula-8,

b) reducing the compound of formula-8 with a reducing agent in solvent and followed by deprotection using an acid in a solvent to provide 3-((5-chloro-3-(hydroxymethyl)pyridin- 2-yl)methyl)-l-((2-(trimethylsilyl)ethoxy) methyl)- lH-pyrrolo[2,3-b]pyridin-2(3H)-one of formula-9,

Formula 8 Formula 9 c) chlorinating the compound of formula-9 using a chlorinating reagent optionally in a solvent to provide 3-((5-chloro-3-(chloromethyl)pyridin-2-yl)methyl)-l-((2-(trimethyl silyl)ethoxy)methyl)- lH-pyrrolo[2,3-b]pyridin-2(3H)-one of formula- 10,

d) cyclization the compound of formula- 10 using phase transfer catalyst, base in solvent to provide (S)-3-chloro- l'-((2-(trimethylsilyl)ethoxy)methyl)-5,7-dihydro spiro [cyclopenta

[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-2'(rH)-one of formula-11,

e) converting the compound of formula-11 into (S)-2'-oxo-l'-((2-(trimethylsilyl) ethoxy)methyl)-r,2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3- b]pyridine]-3-carboxylic acid of formula-12,

f) deprotecting the compound of formula- 12 in presence of an acid in a solvent to provide (S)-2'-oxo-r,2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo [2,3-b]pyridine]-3- carboxylic acid of formula- 1

2. The process according to claim 1, wherein the base used in step-a) is selected from methyl amine, ethyl amine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert.butyl amine, pyridine, 4-dimethyl aminopyridine (DMAP), N-methyl morpholine, N-methyl pyridine, 1,8-diaza bicyclo[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) and imidazole.

3. The process according to claim 1, wherein the reducing agent in step-b) is selected from lithium borohydride, sodium borohydride, potassium borohydride, mixture of sodium borohydride and acetic acid, mixture of sodium borohydride and trifluoroacetic acid, mixture of sodium borohydride and iodine, mixture of sodium borohydride and trimethylchlorosilane, mixture of sodium borohydride and magnesium chloride, mixture of sodium borohydride and calcium chloride, mixture of sodium borohydride and one of transition metal chlorides, boranes, Vitride {=Sodium-bis(2- methoxyethoxy) aluminumhydride } .

4. The process according to claim 1, wherein the chlorinating agent in step-c) selected from but not limited to N-chlorosuccinimide (NCS), Ch, sulfuryl chloride, thionyl chloride, oxalyl chloride, PCI5, PCI3, POCI3, cyanuric chloride, trichloroisocyanuric acid or combination thereof.

5. The process according to claim 1, wherein the phase transfer catalyst in step-d) is selected from mono or bis-quaternary cinchona alkaloid salt, preferably selected from (1S,2R,4S, 5R)-l-(2-Bromo-5-methoxybenzyl)-2-((S)-(l-(2-bromo-5-methoxy benzyl) -6-methoxy quinolin-l-ium-4-yl)(hydroxy)methyl)-5-vinyl quinuclidin-l-ium bromide and (1S,2S,4S, 5R)-l-(2-Cyanobenzyl)-2-((R)-hydroxy(quinolin-4-yl) methyl)-5-vinylquinuclidin-l-ium bromide (19) and (lS,2S,4S,5R)-l-(2-cyano benzyl)-2-((R)-hydroxy(l-(4-(trifluoro methyl)benzyl) quinolin- l-ium-4-yl)methyl)-5-vinylquinuclidin- 1-ium bromide.

6. The process according to claim 1, wherein the conversion in step-e) is carried out in presence of a palladium catalyst, carbon monoxide, a base and a ligand; wherein ligand is selected from l,3-bis(dicyclohexylphosphino)ethane (DCPE) and l,3-bis(dicyclohexyl phosphino)-propane (DCPP); base is selected from inorganic base.

7. The process according to claim 1, wherein the acid in step-f) 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, oxalic acid, succinic acid, fumaric acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid.

8. The process according to claim 1, wherein the compound of formula- 1 is further converted into Ubrogepant or Atogepant.

9. A compound selected from the following group consisting of:

Formula 12

10. A process for the purification of (S)-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)- l',2',5,7-tetrahydro spiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3- carboxylic acid of formula- 12

comprising the following steps: a) reacting the (S)-2'-oxo-r-((2-(trimethylsilyl)ethoxy)methyl)-r,2',5,7-tetrahydro spiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid of formula-12 with (S)-phenyl ethylamine of formula-13

Formula- 13 in a solvent to provide (S)-l -phenyl ethanamine (S)-2'-oxo-l'-((2-(trimethyl silyl) ethoxy)methyl)-l',2',5,7-tetra hydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3- b]pyridine]-3-carboxylate of formula- 14,

b) treating the compound of formula- 14 with base in a solvent to get pure (S)-2'-oxo- r-((2-(trimethylsilyl)ethoxy)methyl)-r,2',5,7-tetrahydrospiro[cyclopenta[b] pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid of formula-12.

11. The process according to claim 10, wherein base in step-b) is selected from 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.

12. The process according to claim 10, wherein alkali salt of compound of formula-12 obtained in step-b) further treated with an acid to get compound of formula- 12.

13. The process according to claim 10, wherein the pure compound of formula-12 is converted to compound of formula- 1.

14. A process for the preparation of (S)-l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine- 6,3'-pyrrolo[2,3-b] pyridine] -3 -carboxylic acid of formula- 1

Formula- 1 comprising the following steps: a) reacting (S)-2'-oxo-r-((2-(trimethylsilyl)ethoxy)methyl)-r,2',5,7-tetrahydrospiro

[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylic acid of formula-

with (S)-phenyl ethylamine of formula- 13

Formula- 13 in a solvent to provide (S)-l -phenyl ethanamine (S)-2'-oxo-l'-((2-(trimethyl silyl) ethoxy)methyl)-r,2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b] pyridine]-3-carboxylate of formula- 14,

Formula- 14 b) treating the compound of formula- 14 with an acid in solvent to provide (S)- l',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b] pyridine]-3- carboxylic acid of formula- 1.

15. The process according to claim 14, wherein acid in step-b) is selected from inorganic acid and organic acid; inorganic acid is selected from such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid or mixtures thereof.

16. (S)-l -phenyl ethanamine (S)-2'-oxo-l'-((2-(trimethylsilyl)ethoxy)methyl)-r,2',5,7- tetra hydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylate of formula- 14

Formula- 14.

17. (S)-l -phenyl ethanamine (S)-2'-oxo-r-((2-(trimethylsilyl)ethoxy)methyl)-r,2',5,7- tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxylate formula-14 used in the preparation of (S)-l',2',5,7-tetrahydrospiro

[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b] pyridine]-3-carboxylic acid of formula- 1.