DESC:Field of the Invention:
The present application relates to an improved process for the preparation of avacopan and intermediates thereof, which is represented by the following structural formula-I.

Formula-I

Background of the Invention:
Avacopan, a complement 5a receptor (C5aR) antagonist indicated as an adjunctive treatment of adult patients with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]) in combination with standard therapy including glucocorticoids, is approved in USA in 2021and is available in the market with the brand name TAVNEOS® developed by Chemocentryx Inc in the form of capsule oral. The chemical name of avacopan is (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(3-methyl-4-(trifluoro methyl ) phenyl) piperidine-3-carboxamide .
The US patent US8906938B2 first disclosed avacopan free base and pharmaceutically acceptable salts. The US’938 disclosed various processes for preparation of avacopan and intermediates thereof. The final purification of avacopan, its intermediates and analogues was done through flash chromatography using silica gel.
The US9745268B2 reported an alternative process for avacopan and intermediates thereof. The said process involves various chiral reagents to get the chiral pure isomer of avacopan and intermediates thereof.
The US2019144389A1 reported various deuterated analogues for avacopan and intermediates thereof.
The US11603356B2 reported the amorphous form of avacopan and its processes thereof.
The patent US11026935B2 reported crystalline form of avacopan and processes thereof.
As, there are various processes reported for avacopan free base and salts thereof using different solvents, reagents.
The existing methods have certain limitations and deficiencies in the prior arts. Therefore, there is a demand for an enhanced procedure to produce avacopan. This new process should involve uncomplicated experimental steps suitable for large-scale manufacturing. Additionally, it should eliminate the need for column chromatography purification while ensuring the generation of highly pure avacopan. The current invention addresses these concerns by offering improved techniques for avacopan synthesis, its intermediary components, and related salts. These processes are characterized by their efficiency, feasibility for industrial application, and cost-effectiveness.
Brief Description:
The first aspect of the present invention is to provide a process for the preparation of compound of formula-I.
The second aspect of the present invention is to provide a purification process for compound of formula-I.
The third aspect of the present invention is to provide a process for the preparation of crystalline from of compound of formula-I.

Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(3-methyl-4-(trifluoro methyl ) phenyl) piperidine-3-carbo- xamide compound of formula-I obtained as per example -19.
Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine (DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term “reducing” agent used in the present invention refers suitable reducing reagents are selected from Lithium aluminum hydride, sodium borohydride, BF3 etherate solution, Pd/C, Ray-nickel; The term “suitable chiral reagents” refers to L-tartaric acid, D-tartaric acid, camphorsulphonic acid, di-para-toluoyl-L-tartaric acid ,di-para-toluoyl -D-tartaric acid, Phenylalanine, D-(-)-a-Phenylglycine, L-(+)-a-Phenylglycine, D(-) -Phenyl glycinamide, S-(+)mandelicacid, R-(-)mandelicacid, L-(+)tartaric acid, D-(-) tartaric acid, L-malicacid, D-malic acid, D-(+)-maleicacid, (-)- naproxen, (+)-naproxen, (1R)-(-) camphor sulfonic acid, (1S)-(+)- camphor sulfonic acid, (1R)-(+)-bromocamphor-10-sulfonic acid, (1S)-(-)-bromo camphor-10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L-tartaricacid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -tartaric acid monohydrate, (+)-dipara-tolyl-D-tartaric acid, (-)-dipara tolyl-L-tartaric acid, L(-)-pyro glutamic acid, L(+)- pyroglutamic acid, (-)-lacticacid, L-lysine, D-lysine , (2R,3R)-2,3-bis(phenyl sulfonyloxy) succinic acid, (2S,3S)-2,3-bis(phenylsulfonyloxy)succinic acid, benzenesul fonyl derivatives of tratartic acid and mixtures thereof;
The term “suitable acid” agent used in the present invention refers to formic acid, acetic acid, citric acid, D-tartaric acid, L-tartaric acid, di-p-Toluoyl-L-tartaric acid, di-p-Toluoyl-D-tartaric acid, bitartaric acid, benzoic acid, lactic acid, malic acid, fumaric acid, succinic acid, gluconic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid and the like and the inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, trifluoroacetic acid or mixtures thereof
The first aspect of the present invention provides a process for the preparation of compound of formula-I.

Formula-I
Comprising of:
a) Reacting compound of formula-1 with compound of formula-2

Formula-1 Formula-2
in presence of suitable reagents, solvent to provide compound of formula-3,

Formula-3 Formula-5
b) reacting the compound obtained in step-a) with suitable reagent, solvent to provide compound of formula -5 or salts thereof,
c) reacting the compound of formula-5 with the compound-6 (2-fluoro-6-methylbenzoyl chloride) using the suitable reagents, solvents to provide compound of formula-7 or salt thereof,

Formula-7 Formula-8
d)deprotecting the compound of formula-7 with suitable reagent, solvent to provide compound of formula-8 or salts thereof,
e) reacting the compound of formula-8 with compound of formula-9 (cyclopentanone) in presence of suitable reagents, solvents to provide pure compound of formula-10,

Formula-10
f) hydrolyzing the compound of formula-10 with suitable reagents to get the compound of formula-11, optionally purifying using suitable acid, base solvent,

Formula-11
g) reacting the compound of formula-11 with compound of formula-12(4-methyl-3-(trifluoro methyl)aniline) using suitable reagents, solvents to provide the pure compound of formula-I,
h) optionally reacting the compound of formula-10 with compound of formula-12 in presence of suitable solvents, reagents to provide compound of formula-I,
i)optionally purifying the compound of formula-I obtained as step-f) or g) or h) using suitable reagents, solvents to provide pure compound of formula-I.
Wherein in step-a) the suitable reagents are selected from metal catalyst such as palladium, palladium acetate/ triphenyl phosphine, palladium tetrakis, bis (triphenyl phosphine) palladium (II)dichloride, Pd2(dba)3, inorganic base preferable metal carbonates, alkali metal carbonate, alkali metal hydrogen carbonates.
wherein in step-b) the suitable hydrogenation reagents are selected from Raney-Nickel under hydrogen pressure, palladium on carbon under hydrogen pressure, platinum(II) oxide, and hydrogenation sourcing reagents are hydrogen gas, ammonium formate, sodium dithionite, iron-acetic acid, zinc- acetic acid ; the suitable chiral resoluting agent are selected from L-tartaric acid, D-tartaric acid, camphorsulphonic acid, di-para-toluoyl-L-tartaric acid ,di-para-toluoyl -D-tartaric acid, Phenylalanine, D-(-)-a-Phenylglycine, L-(+)-a-Phenyl glycine, D(-) -Phenyl glycinamide, S-(+)mandelicacid, R-(-)mandelicacid, L-(+)tartaric acid, D-(-) tartaric acid, L-malicacid, D-malic acid, D-(+)-maleicacid, (-)- naproxen, (+)-naproxen, (1R)-(-) camphor sulfonic acid, (1S)-(+)- camphor sulfonic acid, (1R)-(+)-bromocamphor-10-sulfonic acid, (1S)-(-)-bromo camphor-10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L-tartaricacid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -tartaric acid monohydrate, (+)-dipara-tolyl-D-tartaric acid, (-)-dipara tolyl-L-tartaric acid, L(-)-pyro glutamic acid, L(+)- pyroglutamic acid, (-)-lacticacid, L-lysine, D-lysine , (2R,3R)-2,3-bis(phenyl sulfonyloxy)succinic acid, (2S,3S)-2,3-bis(phenylsulfonyloxy)succinic acid, benzenesulfonyl derivatives of tratartic acid and mixtures thereof;
wherein in step-c) the suitable reagents are selected from inorganic base, organic base and mixture thereof, wherein in step-d) the suitable reagents are selected from con HCl, dil. HCl, trifluoroaceticacid, sulfuric acid, phosphoric acid, HCl in alcohol, HCl in organic solvent such as dioxane HCl, ethylacetate HCl and mixture thereof. wherein in step-e) the suitable reagents are selected from palladium carbon under hydrogen gas atmosphere, sodium borohydride, sodium cyanoborohydride and sodium triacetoxy borohydride, acetic acid, trifluoroacetic acid and mixture thereof, wherein in step-f) the suitable reagent is selected from sulfuric acid, dil. HCl, Con, HCl, optionally organic base and mixture thereof, wherein in step-g) the suitable reagent is selected from methane sulfonyl chloride, methyl chloroformate, ethyl chloroformate, thionyl chloride, EDC-HCl, HATU, DCC, CDI, organic base and mixture thereof. wherein in step-h) the suitable reagent is selected from trimethyl aluminum, triethyl aluminum and mixture thereof, Wherein in step-a to f) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile solvent, alcohol solvent, acetic acid, formic acid, water or any mixture thereof; suitable temperature is 0-120°C. Wherein in step- k, g, h, i and j) the suitable reagents are selected con HCl, dil. HCl, HCl in alcohol, organic solvent in HCl; suitable salts are selected from HCl, HBr, sulfuric acid, acetic acid, trifluoro acetic acid, tartaric acid and oxalic acid; organic base, inorganic base and mixture thereof.
Wherein in step-a, b, c, d, e, f, g, h, i,) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ketone solvents, nitrile solvents, ester solvents, polar protic solvents, polar aprotic solvents, alcohol solvents, water and any mixture thereof; Wherein the suitable salts are selected from hydrochloric acid, hydro bromic acid, hydroiodic acid, acetic acid, trifluroacetic acid, oxalic acid, tartaric acid, p-toluene sulfonic acid, sulphate, phosphate, mesylate, disulphonate, maleate and nitrate, citric acid, methane sulfonic acid and any mixture thereof; suitable temperature 0 -150°C.
The preferred embodiment of the present invention provides a process for the preparation of compound of formula-I.
Comprising of:
a) Reacting compound of formula-1a with compound of formula-2 in presence

Formula-1a Formula-2
in presence of suitable reagents, solvent to provide compound of formula-3a,
DPTTA
Formula-3a Formula-5a
b) reacting the compound obtained in step-a) with di-toluoyl-L-tartaric acid in presence of platinum oxide, ethanol under hydrogen pressure to provide compound of formula -5a,
c) treating the compound of formula-5a with ammonia in dichloromethane followed by reacting with compound of formual-6 (2-fluoro-6-methylbenzoyl chloride) in presence of HATU, DIPEA in DMF to provide compound of formula-7a,
d)deprotecting the compound of formula-7a with trifluoroacetic acid in dichloromethane, to provide compound of formula-8a,

Formula-7a Formula-8a
e) reacting the compound of formula-8a with compound of formula-9 (cyclopentanone) in presence of palladium carbon under hydrogen gas atmosphere, methanol to provide pure compound of formula-10a,
f) hydrolyzing the compound of formula-10a with HCl to get the compound of formula-11,

Formula-10a Formula-11
g) reacting the compound of formula-11 with compound of formula-12(4-methyl-3-(trifluoro methyl)aniline) using methane sulfonyl chloride, diisopropyl ethylamine in dichloromethane to provide the pure compound of formula-I.
h) stirring the compound of formula-I in methanol to provide pure compound of formula-I as form-I
The present invention provides an alternative process for avacopan the compound of formula-I as mentioned in the schematic representation



The second aspect of the present invention provides a purification process for compound of formula-I.
Comprising of:
a) treating the compound of formula-I with suitable reagent, suitable solvent,
b) optionally heating the compound obtained in step-a) suitable temperature and isolating the compound,
c) treating the compound obtained in step-b) suitable reagent, suitable solvent,
d)isolating the compound of formula-I to get pure compound of formula-I.
The other aspect of the present invention provides a purification process for compound of formula-10.
Comprising of:
a) treating the compound of formula-10 with suitable reagent, suitable solvent,
b) optionally heating the compound obtained in step-a) suitable temperature and isolating the compound,
c) treating the compound obtained in step-b) suitable reagent, suitable solvent,
d)isolating the compound of formula-10 to get pure compound of formula-10.
The other aspect of the present invention provides a purification process for compound of formula-11.
Comprising of:
a) treating the compound of formula-11 with suitable reagent, suitable solvent,
b) optionally heating the compound obtained in step-a) suitable temperature and isolating the compound,
c) treating the compound obtained in step-b) suitable reagent, suitable solvent,
d)isolating the compound of formula-11 to get pure compound of formula-11.
Wherein in the above aspects step-a, c) the suitable reagents are selected con HCl, dil. HCl, methanolic HCl, HCl in organic solvent, suitable salts are selected from HCl, HBr, sulfuric acid, acetic acid, tartaric acid and oxalic acid salt, HCl, HBr, H2SO4, trifluoro acetic acid, benzene sulfonic acid, p-toluenesulfonic acid, napadisylate acid, camphorsulfonic acid, ethanedisulfonic acid, di-paratolyl tartaric acid, oxalic acid, malic acid and suitable bases are selected form inorganic base, organic base and mixture thereof.
Wherein in step-a, b, c, d) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile solvent, alcohol solvent, water or any mixture thereof; suitable temperature is 0-120°C.
The third aspect of the present invention provides a process for crystalline form of compound of formula-I.
Comprising of:
a) stirring the compound of formula-I in a suitable solvent,
b) optionally heating the compound obtained in step-a) at suitable temperature,
c)isolating the compound obtained in step-b) to get the pure crystalline form compound of formula-I.
Wherein in step-a, b, c) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile solvent, alcohol solvent, water or any mixture thereof; suitable temperature is 0-120°C.
The preferred embodiment of the present invention provides a process for crystalline form of compound of formula-I.
Comprising of:
a) stirring the compound of formula-I in methanol at 45-55°C,
b) filtering the pure crystalline form obtained in step-a) to get the pure crystalline form of compound of formula-I.
The other aspect of the present invention provides a process for amorphous form of compound of formula-I.
Comprising of:
a) stirring the compound of formula-I in suitable solvent,
b) evaporating the solution obtained in step-a) to get the pure amorphous form of compound of formula-I.
Wherein in step-a, b) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile solvent, alcohol solvent, water or any mixture thereof; suitable temperature is 0-120°C.
The preferred embodiment of the present invention provides a process for amorphous form of compound of formula-I.
Comprising of:
a) stirring the compound of formula-I in dichloromethane,
b) evaporating the solution obtained in step-a) to get the pure amorphous form of compound of formula-I.
The process for the preparation of avacopan, its salt developed by the present inventors produces highly pure avacopan salt with good yield. All the related substances and residual solvents are controlled well within the limits as suggested by ICH guidelines and most of the related substances are controlled in non-detectable levels.
The compound of formula-I produced by the process of the present invention is
having purity of greater than 99%, preferably greater than 99.5% by HPLC.
The compound of formula-I produced by the process of the present invention is
having particle size distribution of D90 <300 µm, D50 <150 µm. D10 <75 µm.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of compound of formula-3a (ethyl 2-(4-(tert-butoxycarbonyl amino) phenyl) nicotinate
A round bottom flask was charged with water (400 ml), 2-methyl tetrahydro furan (400 ml), under nitrogen bubbling of the reaction for 45 min at 20-30°C. The reaction mass was charged with potassium carbonate (223.37 g) and stirred for 10 min at 20-30°C, followed by subsequent addition of compound of ethyl 2-chloronicotinate (100 g) , compound-2 (127.71 g) and Pd(PPh3)4 (1.245 g), at 20-30°C and stirred for 10 min at 20-30°C. The reaction mixture was heated to 70-80°C and maintained for 18 hr at same temperature. The reaction mass was filtered through hyflow supercel at 20-30°C and washed with ethyl acetate (100 ml). Separated the layers and the aq. layer was extracted with ethyl acetate and the combined organic layer was washed with water, followed by sodium chloride. The organic layer was distilled-off the solvent completely, the obtained compound was stirred in ethyl acetate, filtered the precipitated solid and dried to get the title compound.
Yield: 120.0 g
Example-2: Preparation of compound of formula-5a (2R, 3S)-ethyl 2-(4-(tert-butoxycarbonyl amino) phenyl)piperidine-3-carboxylate- di-p-toluoyl-L- tartaric acid salt).
An auto clave flask was charged with compound-3a (100 g), ethanol (600 ml), di-p-toluoyl-L- tartaric acid (114 g) and stirred for 10 min. Further, the reaction mass is charged with Pd/C (10 g) and stirred under hydrogen atmosphere at 40-50°C for 14 hr. Filtered the reaction mass through hyflow bed and washed with ethanol (200 ml). The reaction mass was distilled-off completely at 50-55°C. The obtained compound was charged with THF and raised the reaction temperature to 60-70°C, charged methyl-tert butyl ether at 60-70°C and stirred for 15 min. Cooled the reaction mixture to 20-30°C, filtered the solid and washed the reaction mass with methyl-tert butyl ether. The obtained compound was taken into another RBF and charged with ethanol at 20-30°C. The reaction mass solvent was distilled-off completely at 50°C, co-distilled with 2-methyl tetrahydrofuran to get the compound. The obtained compound was charged with tetrahydrofuran and raised the temperature to 60-70°C and was charged with methyl-tert butyl ether at 60-70°C and stirred for 15 min. Cooled the reaction mixture to 20-30°C and stirred for 3 hr at same temperature. Filtered the solid, washed with methyl-tert butyl ether and dried the compound to get the title compound.
Yield: 80.0 g
Example-3: Preparation of compound of formula-7a ((2R, 3S)-ethyl 2-(4-(tert-butoxy carbonylamino) phenyl)-1-(2-fluoro-6-methylbenzoyl) piperidine-3-carboxylate)
A round bottom flask was charged with dichloromethane (300 ml), water (300 ml) and compound-5a (100 g) and adjusted the pH of the solution to 11 by using aq. ammonia solution (100 ml). Separated the both layers, the aqueous layer was extracted with dichloromethane and the combined organic layer was distilled-off completely and obtained crude compound.
In another RB flask charged with dimethylformamide (135 ml) and HATU (54.01 g) at 20-30°C and compound-6 (200 ml), diisopropyl ethylamine (58 g) at 20-30°C and stirred for 60 min. To the reaction mixture, the above obtained crude compound in DMF was added and stirred for 2 hr at 20-30°C. The reaction mass was quenched with water, ethyl acetate and separated the layers. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with water and sodium chloride. The organic layer was distilled-off completely under vacuum to obtain crude compound. The crude compound was charged with dichloromethane and heptane and stirred for 45 min at 35-45°C. Cooled the reaction mixture and stirred for 90 min, the resulting solid was filtered and washed with heptane and dried to get the title compound.
Yield: 50 g: HPLC: >98 %; Chiral HPLC >99 %
Example-4: Preparation of compound of formula-8a (2R, 3S)-ethyl 2-(4-aminophenyl)-1-(2-fluoro-6-methylbenzoyl) piperidine-3-carboxylate.
A round bottom flask was charged with compound 7a (100 g), dichloromethane (400 ml), followed by addition of trifluoro acetic acid (211.77 g in dichloromethane) at 20-30°C and stirred for 4 hr at 20-30°C. The reaction mass was quenched with sodium carbonate (300 g in water) and separated the layers. The aqueous layer is extracted with dichloromethane. The combined dichloromethane layer was washed with water, sodium chloride solution. Further, the organic layer was dried and distilled- off completely to obtain the compound.
Yield: 79 g.
Example-5: Preparation of compound of formula-10a (2R, 3S)-ethyl 2-(4-(cyclopentyl amino) phenyl)-1-(2-fluoro-6-methylbenzoyl) piperidine-3-carboxylate
An auto clave was charged with compound-8a (100 g), methanol (500 ml), cyclopentanone (134 g) and Pd/C (10 g) were stirred under hydrogen gas atmosphere at 20-30°C for 8 hr. Filtered the reaction mass through hyflow supercel and washed with methanol, distilled-off the filtrate solution. Further, the crude compound was charged with dichloromethane and water and adjusted the pH of the reaction mass to 10 by using aq. ammonia. The resulting reaction mass was separated, the aqueous layer was extracted with dichloromethane, and the combined organic layer washed with water and sodium chloride solution. The dichloromethane layer was dried and distilled- off completely to obtain the title compound.
Yield: 98 g.
Example-6: Preparation of compound of formula-11 ((2R,3S)-2-(4-(cyclopentyl amino) phenyl)-1-(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylic acid)
A round bottom flask was charged with compound10a (100 g), water (300 ml) at 20-30°C, under nitrogen atmosphere, cooled to 5 to 10°C and charged sulphuric acid (80 ml) slowly and stirred for 10 min. Further, the reaction mass was gradually heated to 85-95°C and stirred for 14 hr at same temperature. Cooled the reaction mass, charged with methyl tert-butyl ether and adjusted the pH of the reaction by using sodium hydroxide solution and separated the layers. The aqueous layer is washed using methyl tert-butyl ether. The aqueous layer is taken into another RBF and adjusted the pH to 4 using hydrochloric acid, charged with dichloromethane and stirred for 15 min and separated the layers. The aqueous layer was extracted with dichloromethane. The combined organic layer was charged with activated carbon and filtered through hyflow supercel and washed with dichloromethane and organic layer was distilled- off completely and dried to obtain the title compound. Yield: 90 g.
Example-7: Preparation of compound of formula-11 ((2R, 3S)-2-(4-(cyclopentyl amino) phenyl)-1-(2-fluoro-6-methylbenzoyl) piperidine-3-carboxylic acid)
A round bottom flask was charged with compound10a (50 g), water (200 ml) at 20-30°C, under nitrogen atmosphere, cooled to 5 to 10°C and charged Conc.HCl (160 ml) slowly and stirred for 10 min. Further, the reaction mass was gradually heated to 85-95°C and stirred for 12 hr at same temperature. Cooled the reaction mass, charged with methyl tert-butyl ether and adjusted the pH of the reaction by using sodium hydroxide solution and separated the layers. The aqueous layer is washed using methyl tert-butyl ether. The aq. layer was taken into another RBF and adjusted the pH to 4 using hydrochloric acid, charged with dichloromethane and stirred for 15 min and separated the layers. The aqueous layer was extracted with dichloromethane. The combined organic layer was charged with activated carbon and filtered through hyflow supercel and washed with dichloromethane and organic layer was distilled- off completely and dried to obtain the title compound. Yield: 32 g.
Example-8: Preparation of compound of formula-I (avacopan).
A round bottom flask was charged with compound-11(100 g), dichloromethane (600 ml), followed by addition of diisopropyl ethylamine (91.34 g) and compound-12 (74.25 g), stirred for 10 min at 20-30°C. Cooled to 0-10°C, charged with methyl sulfonyl chloride (48.57 g) and maintained for 2 hr at 5-10°C. The reaction mixture was quenched with water (300 ml) and separated the two layers. The aqueous layer was extracted with dichloromethane and the combined organic layer was washed with water and sodium chloride solution. The organic layer was distilled-off completely and charged with methanol and stirred for 6 hr at 20-30°C. Filtered the resulting solid and washed with methanol and dried to get the title compound.
Yield: 80 g. HPLC purity: >99.5 %; other isomer <0. 2 %
Example-9: Preparation of compound of formula-I (avacopan).
A round bottom flask was charged with compound-10a (100 g), toluene (1L) and compound-12 (74.25 g) stirred for 10 min at 20-30°C. Cooled to 0-10°C, charged with trimethyl aluminum (167 mL in toluene) and maintained for 4 hr at 80-85°C. The reaction mixture was cooled to 0-5°C, quenched with water, sodium chloride solution and charged dichloro methane and stirred for 15 min. Both the layers were separated, the aqueous layer was extracted with dichloromethane and the combined organic layer was washed with water and sodium chloride solution. The organic layer was distilled-off completely and charged with methanol and stirred for 6 hr at 20-30°C. Filtered the resulting solid and washed with methanol and dried to get the title compound. Yield: 73 g.
Example-10: Preparation of amorphous form of compound of formula-I (avacopan).
A round bottom flask was charged with compound-I (10 g), dichloromethane (100 mL) and stirred at 20-30° C for 1 hr. Distilled-off the reaction mixture, the obtain compound was cooled to 10-15°C, charged with n-heptane and stirred for 30 min. Filtered the precipitated solid and dried to get the title compound. Yield: 9.4 g
Example-11: Preparation of amorphous form of compound of formula-I (avacopan).
A round bottom flask was charged with compound-I (10 g), acetone (80 mL) and stirred at 20-30°C for 1 hr. Distilled-off the reaction mixture, the resulting compound was cooled to 10-15°C, charged with n-heptane and stirred for 20 min. Filtered the precipitated solid and dried to get the title compound. Yield: 9.2 g
Example-12: Preparation of amorphous form of compound of formula-I (avacopan).
A round bottom flask was charged with compound-I (10 g), methanol (300 mL) and stirred at 55-65°C for 1 hr. Distilled-off the reaction mixture, the resulting compound was cooled to 10-15°C, charged with n-heptane and stirred for 30 min. Filtered the precipitated solid and dried to get the title compound. Yield: 9.5 g
Example-13: Preparation of crystalline form of compound of formula-I (avacopan).
A round bottom flask was charged with compound-I (10 g), methanol and stirred at 55-65°C for 2 hr. Cooled the reaction mixture to 10-20°C and stirred for 1 hr. Filtered the precipitated solid and dried to get the title compound. Yield: 9.5 g
Example-14: Preparation of crystalline form of compound of formula-I (avacopan).
A round bottom flask was charged with compound-I (10 g), methanol and stirred at 25-35°C for 4 hr. Filtered the precipitated solid and dried to get the title compound. Yield: 9 g
Example-15: Preparation of crystalline form of compound of formula-I (avacopan).
A round bottom flask was charged with compound-I (10 g), ethyl acetate (100 mL) and stirred at 65-75°C for 3 hr. Cooled the reaction mixture to 10-20°C and stirred for 1 hr. Filtered the precipitated solid and dried to get the title compound. Yield: 9.6 g
Example-16: Preparation of crystalline form of compound of formula-I (avacopan).
A round bottom flask was charged with compound-I (10 g), acetone (100 mL) and stirred at 25-35°C for 4 hr. Filtered the precipitated solid and dried to get the title compound.
Yield: 9 g
Example-17: Preparation of crystalline form of compound of formula-I (avacopan).
A round bottom flask was charged with compound-I (5 g), acetone (50 mL) and stirred at 50-60°C for 2.5 hr. Cooled the reaction mixture to 10-20°C and stirred for 2 hr. Filtered the precipitated solid and dried to get the title compound. Yield: 3.8 g
Example-18: Preparation of crystalline form of compound of formula-I (avacopan).
A round bottom flask was charged with compound-I (10 g), isopropanol (150 mL) and stirred at 55-65°C for 3 hr. Cooled the reaction mixture to 10-20°C and stirred for 2 hr. Filtered the precipitated solid and dried to get the title compound. Yield: 9.28 g
Example-19: Purification of compound of formula-I (avacopan).
A round bottom flask was charged with compound-I (1 g), acetone (10 mL) and stirred for 15 min and charged water (15 mL) at 25-35°C and stirred for 12 hr. Filtered the precipitated solid and dried to get the title compound. The obtained PXRD depicted in figure 1.
Yield: 0.8 g
Example-20: Purification of compound of formula-I (avacopan).
A round bottom flask was charged with compound-I (1 g), acetone (10 mL) and stirred for 15 min at 55-65°C, and charged water (15 mL) at same temperature and stirred for 12 hr. Filtered the precipitated solid and dried to get the title compound. The obtained PXRD similar to the figure-1. Yield: 0.8 g
Example-21: Preparation of compound of formula-I (avacopan).
A round bottom flask was charged with compound-10a (10 g), toluene (100 mL) and compound-12 (8 g) stirred for 10 min at 20-30°C. Cooled to 0-10°C, charged with trimethyl aluminum (18 mL in toluene) and maintained for 3 hr at 75-85°C. The reaction mixture was cooled to 0-5°C, quenched with water, sodium chloride solution and charged dichloro methane and stirred for 15 min. Both the layers were separated, the aqueous layer was extracted with dichloromethane and the combined organic layer was washed with water and sodium chloride solution. The organic layer was distilled-off completely and charged with acetone and water stirred for 12 hr at 25-35°C. Filtered the resulting solid and washed with methanol and dried to get the title compound. The PXRD similar to figure-1. Yield: 73 g.
Example-22: Preparation of compound of formula-5a (2R, 3S)-ethyl 2-(4-(tert-butoxycarbonyl amino) phenyl) piperidine-3-carboxylate- di-p-toluoyl-L- tartaric acid salt).
A round bottom flask was charged with water (400 ml), 2-methyl tetrahydro furan (400 ml), under nitrogen bubbling of the reaction for 45 min at 20-30°C. The reaction mass was charged with potassium carbonate (223.37 g) and stirred for 10 min at 20-30°C, charged compound of formula-1a (ethyl-2-chloronicotinate, 100 g), compound of formula-3 (127.71 g) and Pd (PPh3)4 (1.245 g) at 20-30°C and stirred for 10 min at same temperature. The reaction mixture was heated to 72-78°C and maintained for 18 h at same temperature. The reaction mass was filtered through hyflow bed at 20-30°C and washed with ethyl acetate and separated the layers. The aq. layer was extracted with ethyl acetate and the combined organic layer was washed with water, followed by sodium chloride solution. The organic layer was distilled-off the solvent completely, cooled to 20-30°C stirred in n-heptane (100 mL), at 70-80°C and charged with ethyl acetate (150 mL), maintained for 45 min at 20-30°C. The reaction mixture was gradually cooled to 0-10°C and filtered the precipitated solid and washed with ethyl acetate and n-heptane and dried to get the title compound of formula-3a.
An auto clave flask was charged with compound-3a (150 g), ethanol (780 ml), di-p-toluoyl-L- tartaric acid (166.52 g), platinum oxide (1 g) under hydrogen atmosphere (about ~10 kg) at 45-55°C for 14 h. Filtered the reaction mass and washed with ethanol. The reaction mass was distilled-off completely at 50-55°C, the obtained compound was charged with MTBE (200 mL), ethanol (224 mL) at 45-55°C. Cooled the reaction mixture to 20-30°C, stirred for 4 h at 20-30°C and filtered the obtained solid, washed with a mixture of MTBE, ethanol and dried to get the title compound. Yield: 129.90 g
Example-23: Preparation of compound of formula-7a ((2R, 3S)-ethyl 2-(4-(tert-butoxy carbonylamino) phenyl)-1-(2-fluoro-6-methylbenzoyl) piperidine-3-carboxylate)
A round bottom flask was charged with dichloromethane (400 ml), water (300 ml) and compound-5a (100 g) and adjusted the pH of the solution to 11 by using aq. ammonia solution (~200 ml) and maintained for 15 min at 25-35°C. Separated the both layers, the aqueous layer was extracted with dichloromethane and the combined organic layer was washed with water, sodium chloride solution and distilled-off completely. Cooled the reaction mixture to 25-35°C, charged with DMF under nitrogen atmosphere and stirred for 15 min at same temperature and processed for next step.
In another RB flask charged with dimethylformamide (150 ml) and HATU (59.50 g) at 20-30°C and 2-fluoro-6-methyl benzoic acid (20.97 g), diisopropyl ethylamine (65.08 g) at 20-30°C and stirred for 4 h at 25-35°C. To the reaction mixture, the above obtain crude compound in DMF was added and stirred for 90 min at 20-30°C. The reaction mass was quenched with water, ethyl acetate and separated the layers. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with water and sodium chloride solution. The organic layer was distilled-off completely under vacuum to obtain crude compound. The crude compound was charged with isopropanol, cooled the reaction mixture and stirred for 45 min, the resulting solid was filtered and washed with isopropanol and dried to get the title compound. Yield: 55.0 g
Example-24: Preparation of compound of formula-10a (2R, 3S)-ethyl 2-(4-(cyclopentyl amino) phenyl)-1-(2-fluoro-6-methylbenzoyl) piperidine-3-carboxylate
A round bottom flask was charged with compound 7a (100 g), dichloromethane (800 ml), followed by addition of trifluoro acetic acid (211.77 g in dichloromethane) at 20-30°C and stirred for 6 h at 25-35°C. The reaction mass was quenched with sodium carbonate (300 g in water 700 mL), maintained for 15 min and separated into the layers. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water, sodium bicarbonate solution, followed by addition of activated carbon stirred for 10 min and filtered the solution and washed with dichloromethane. Further, the organic layer was dried and distilled- off completely to obtain the compound of formula-8a.
An auto clave was charged with compound of formula-8a, methanol (650 ml), cyclopentanone (104.16 g) and Pd/C (12 g) were stirred under hydrogen gas atmosphere (~ 6 kg) at 20-30°C for 2 h. Filtered the reaction mass through hyflow and washed with methanol, distilled-off the filtrate solution. Further, the crude compound was charged with dichloromethane (300 mL), water (300 mL) stirred for 1 h. The resulting reaction mass was separated, the aqueous layer was extracted with dichloromethane, and the combined organic layer washed with water and sodium chloride solution. The dichloromethane layer was dried and distilled- off completely, co-distilled with n-heptane. The reaction mixture was stirred in ethyl acetate, n-heptane and stirred for 2 h and filtered the solid and washed with n-heptane and dried to obtain the title compound. Yield: 89.45 g.
Example-25: Preparation of compound of formula-I (avacopan).
A round bottom flask was charged with compound of formaula-10a (100 g), Conc. HCl (500 ml) at 25-35°C, heated the reaction mass to 75-85°C and maintained for 20 h at same temperature. Cooled the reaction mixture to 5-10°C and charged MTBE slowly and stirred for 30 min. Further, cooled the reaction mass to 0-10°C and adjusted the pH of the reaction to 13.5 by using sodium hydroxide solution and separated the layers. The aqueous layer is washed using methyl tert-butyl ether. The aq. layer pH was adjusted to 3.5 using aq. hydrochloric acid. The aq. layer was charged with dichloromethane and stirred for 15 min and separated the layers. The aqueous layer was extracted with dichloromethane, the combined organic layer was dried under sodium sulfate and proceeded to the next stage with the same organic layer.
A round bottom flask was charged with above organic layer, addition of diisopropyl ethylamine (51.4 g) and compound of formula-12 (38.7 g), charged with methyl sulfonyl chloride (25.31 g) and maintained for 40 min at 25-35°C. The reaction mixture was quenched with water and separated the two layers. The organic layer was washed with water, aq. sodium chloride, charged activated carbon and stirred for 20 min at 25-35°C. Filtered the reaction mass through hyflo and washed with dichloromethane, the organic layer was distilled-off completely and charged with methanol (50 mL), acetonitrile (10 mL) and stirred for 6 h at 20-30°C. Filtered the resulting solid and washed with methanol and dried to get the title compound. Yield: 78.74 g.
Particle size distribution of D90 <45 µm, D50 <15 µm. D10 <9 µm.
Example-26: Purification of compound of formula-I (crystalline form of avacopan).
A round bottom flask was charged with compound of formula-I (100 g), dichloromethane (500 mL), stirred for 15 min at 25-35°C. Filtered the reaction mass through hyflo and washed with dichloromethane, and distilled off the solvent completely and co-distilled with methanol. The reaction mass was cooled to 25-35°C, charged with methanol (500 mL), raised the temperature to 45-55°C and maintained for 45 min at same temperature. Cooled the reaction mixture, filtered the obtained solid and washed with methanol and dried to obtain the title compound. Yield: 89.63 g.
Example-27: Preparation of amorphous form of compound of formula-I (avacopan).
A round bottom flask was charged with compound-I (10 g), dichloromethane (300 mL) and stirred at 55-65°C for 1 hr. Distilled-off the reaction mixture, the resulting compound was isolated and dried to the title compound.
Yield: 9.5 g

,CLAIMS:We claim:
1.An improved process for compound of formula-I.

Formula-I
Comprising of:
a)Reacting compound of formula-1 with compound of formula-2

Formula-1 Formula-2
in presence of suitable reagents, solvent to provide compound of formula-3,

Formula-3 Formula-5
b) reacting the compound obtained in step-a) with suitable reagent, solvent to provide compound of formula -5, salts thereof,
c) reacting the compound of formula-5 with the compound-6 (2-fluoro-6-methylbenzoyl chloride) using the suitable reagents, solvents to provide compound of formula-7 or salt thereof,

Formula-7 Formula-8
d)deprotecting the compound of formula-7 with suitable reagent, solvent to provide compound of formula-8 or salts thereof,
e) reacting the compound of formula-8 with compound of formula-9 (cyclopentanone) in presence of suitable reagents, solvents to provide pure compound of formula-10,

Formula-10 Formula-11
f) hydrolyzing the compound of formula-10 with suitable reagents to get the compound of formula-11, optionally purifying using suitable acid, base solvent,
g) reacting the compound of formula-11 with compound of formula-12(4-methyl-3-(trifluoro methyl)aniline) using suitable reagents, solvents to provide the pure compound of formula-I,
h) optionally reacting the compound of formula-10 with compound of formula-12 in presence of suitable solvents, reagents to provide compound of formula-I,
i)optionally purifying the compound of formula-I obtained as step g) or h) using suitable reagents, solvents to provide pure compound of formula-I.
2. A process for preparation of compound of formula -I obtained as per the claim 1, Wherein in step-a) the suitable reagents are selected from metal catalyst such as palladium, palladium acetate/ triphenyl phosphine, palladium tetrakis, bis (triphenyl phosphine) palladium (II) dichloride, Pd2(dba)3, inorganic base preferable metal carbonates, alkali metal carbonate, alkali metal hydrogen carbonates. wherein in step-b) the suitable hydrogenation reagents are selected from raney-Nickel under hydrogen pressure, palladium on carbon under hydrogen pressure, platinum(II) oxide, and hydrogenation sourcing reagents are hydrogen gas, ammonium formate, sodium dithionite, iron-acetic acid, zinc- acetic acid ; the suitable chiral resoluting agent are selected from L-tartaric acid, D-tartaric acid, camphor sulphonic acid, di-para-toluoyl-L-tartaric acid, di-para-toluoyl-D-tartaric acid, Phenylalanine, D-(-)-a-Phenyl glycine, L-(+)-a-Phenyl glycine, D(-) -Phenyl glycinamide, S-(+)mandelicacid, R-(-) mandelic acid, L-(+)tartaric acid, D-(-) tartaric acid, L-malicacid, D-malic acid, D-(+)-maleicacid, (-)- naproxen, (+)-naproxen, (1R)-(-) camphor sulfonic acid, (1S)-(+)- camphor sulfonic acid, (1R)-(+)-bromocamphor-10-sulfonic acid, (1S)-(-)-bromo camphor-10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L-tartaricacid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -tartaric acid monohydrate, (+)-dipara-tolyl-D-tartaric acid, (-)-dipara tolyl-L-tartaric acid, L(-)-pyro glutamic acid, L(+)- pyroglutamic acid, (-)-lacticacid, L-lysine, D-lysine , (2R,3R)-2,3-bis(phenyl sulfonyloxy)succinic acid, (2S,3S)-2,3-bis(phenylsulfonyloxy)succinic acid, benzenesulfonyl derivatives of tratartic acid and mixtures thereof; wherein in step-c) the suitable reagents are selected from inorganic base, organic base and mixture thereof, wherein in step-d) the suitable reagents are selected from con HCl, dil. HCl, trifluoroaceticacid, sulfuric acid, phosphoric acid, HCl in alcohol, HCl in organic solvent such as dioxane HCl, ethyl acetate HCl and mixture thereof. wherein in step-e) the suitable reagents are selected from palladium carbon under hydrogen gas, sodium borohydride, sodium cyanoborohydride and sodium triacetoxy borohydride, acetic acid, trifluoroacetic acid; wherein in step-f) the suitable reagent is selected from sulfuric acid, dil. HCl, Con, HCl, optionally organic base and mixture thereof ; wherein in step-g) the suitable reagent is selected from methane sulfonyl chloride, methyl chloroformate, ethyl chloroformate, thionyl chloride, EDC-HCl, HATU, DCC, CDI, organic base and mixture thereof. wherein in step-h) the suitable reagent is selected from trimethyl aluminum, triethyl aluminum and mixture thereof.
Wherein in step- k, g, h, i and j) the suitable reagents are selected con HCl, dil. HCl, HCl in alcohol, organic solvent in HCl; suitable salts are selected from HCl, HBr, sulfuric acid, acetic acid, trifluoro acetic acid, tartaric acid and oxalic acid; organic base, inorganic base.
Wherein in step-a, b, c, d, e, f, g, h, i,) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ketone solvents, nitrile solvents, ester solvents, polar protic solvents, polar aprotic solvents, alcohol solvents, water and any mixture thereof; Wherein the suitable salts are selected from hydrochloric acid, hydro bromic acid, hydroiodic acid, acetic acid, trifluroacetic acid, oxalic acid, tartaric acid, p-toluene sulfonic acid, sulphate, phosphate, mesylate, disulphonate, maleate and nitrate, citric acid, methane sulfonic acid and any mixture thereof; suitable temperature 0 -150°C.
3. An improved process for the preparation of compound of formula-I.
Comprising of:
a) Reacting compound of formula-1a with compound of formula-2 in presence

Formula-1a Formula-2
in presence of palladium catalyst, potassium carbonate, in water, 2-methyl THF to provide compound of formula-3a,
DPTTA
Formula-3a Formula-5a
b) reacting the compound obtained in step-a) with di-p-toluoyl-L-tartaric acid in presence of platinum oxide, ethanol under hydrogen pressure to provide compound of formula -5a,
c) basifying the compound of formula-5a with ammonia in dichloromethane, further, reacting with the compound of formula-6 (2-fluoro-6-methylbenzoyl chloride) in presence of HATU, DIPEA in DMF to provide compound of formula-7a,

Formula-7a Formula-8a
d)deprotecting the compound of formula-7a with trifluoroacetic acid in dichloromethane, to provide compound of formula-8a,
e) reacting the compound of formula-8a with compound of formula-9 (cyclopentanone) in presence of palladium carbon in methanol under hydrogen atmosphere to provide pure compound of formula-10a,

Formula-10a Formula-11
f) hydrolyzing the compound of formula-10a with HCl to get the compound of formula-11,
g) reacting the compound of formula-11 with compound of formula-12(4-methyl-3-(trifluoro methyl)aniline) in presence of methane sulfonyl chloride, diisopropyl ethylamine in dichloromethane to provide the pure compound of formula-I,
h) stirring the compound of formula-I in dichloromethane, methanol to provide pure compound of formula-I as form-I.
4. A process for amorphous form of compound of formula-I.
Comprising of:
a) stirring the compound of formula-I in dichloromethane,
b) evaporating the solution obtained in step-a) to get the pure amorphous form of compound of formula-I.
5.A process for crystalline form of compound of formula-I.
Comprising of:
a) stirring the compound of formula-I in methanol at 45-55°C,
b) filtering the pure crystalline form obtained in step-a) to get the pure crystalline form of compound of formula-I.
6. A process for crystalline form of compound of formula-I.
Comprising of:
a) stirring the compound of formula-I in a suitable solvent,
b) optionally heating the compound obtained in step-a) at suitable temperature,
c)isolating the pure crystalline form of compound of formula-I.
Wherein in step-a, b, c) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile solvent, alcohol solvent, water or any mixture thereof; suitable temperature is 0-120°C.
7. Avacopan according to the preceding claims is having particle size distribution of D90 <300 µm, D50 <150 µm. D10 <75 µm.
8. Avacopan according to the preceding claims has purity of at least about 95%; preferably of at least about 97%; more preferably of at least about 98%; most preferably of at least about 99% as measured by HPLC.

Dated this day 25th Sep-2024.

Authorized Signatory
(Chakilam Nagaraju)
Maithri Drugs Private Limited