Field of the invention:

The present invention relates to an improved process for the preparation of (N4- (4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-methylphenyl)-N 6-(4,4-dimethyl-4,5- dihydrooxazol-2-yl)quinazoline-4,6-diamine compound of formula- 1 exists as hemi ethanolate solvate which is represented by the following structural formula. Hereafter Tucatinib hemi ethanolate is referred as Tucatinib.

Formula- 1

Background of the Invention:

Tucatinib is chemically known as (N4-(4-([l,2,4]triazolo[l,5-a]pyridin-7- yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2- yl)quinazoline-4,6- diamine hemi ethanolate. Tucatinib was developed by Array BioPharma and approved by USFDA as Tukysa tablets which is indicated for the treatment of metastatic HER2- positive breast cancer.

There are several processes available in the art for the preparation of Tucatinib. The disadvantage associated with the prior art process is usage of chromatographic techniques for the purification of Tucatinib which is commercially not viable. There exists a need to have simple, easy to handle and cost-effective process for the preparation of Tucatinib with high chemical purity and yields which is amenable for commercial scale process.

Thus, the present inventors have developed an improved process for the preparation of Tucatinib that avoids the usage of column chromatography techniques which are commercially not viable. The present invention provides an efficient, economically viable, easily scalable process for the preparation of Tucatinib.

Brief description of the Invention:

The first aspect of the present invention is to provide an improved process for the preparation of Tucatinib compound of formula- 1.

The second aspect of the present invention is to provide a novel crystalline form of Tucatinib Triflate of formula- 1 a hereinafter designated as “Form-N” and its process for the preparation.

The third aspect of the present invention is to provide process for making Tucatinib hemi ethanolate (1) from Tucatinib triflate salt of formula- la.

Brief description of the Drawings:

FIG.1 : Illustrates the characteristic PXRD pattern of crystalline form-N of Triflate salt of Tucatinib compound of formula- 1 a.

FIG.2: Illustrates the DSC thermogram of crystalline form-N of Triflate salt of Tucatinib compound of formula- la.

FIG.3: Illustrates the characteristic PXRD pattern of crystalline form of Tucatinib obtained according to Example-6.

Detailed description of the Invention:

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" selected from aliphatic hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether and aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethoxy ethane, tetrahydrofuran, 1,4- dioxane, monoxime, dioxime and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, N- methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane/methylene chloride, dichloroethane, chloroform, carbon tetrachloride 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 and the like; "polar solvents" such as water or mixtures thereof.

As used herein the present invention, the term "anti-solvent" refers to a solvent which is used to precipitate the solid from a solution.

As used herein the present invention the term “suitable acid” refers to organic acids or inorganic acids. The “inorganic acid” is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and “organic acid” is selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, malonic acid, maleic acid, fumaric acid, malic acid, succinic acid, citric acid, aspartic acid, tartaric acid, mandelic acid, benzoic acid, salicylic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like or mixtures thereof.

As used herein the present invention the term “suitable 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; Ammonia; and organic bases like dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4- dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.

The first aspect of the present invention is to provide an improved process for the preparation of Tucatinib compound of formula- 1, comprising of: a) Reacting N4-[3-methyl-4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)phenyl ] quinazoline-4,6-diamine compound of formula-6 with 4, 4-dimethyl-2- methylsulfanyl-4, 5 -dihydrooxazole trifluoromethanesulfonate compound of formula-7 in a suitable solvent followed by isolating the compound using addition of suitable anti-solvent to provide Tucatinib Triflate of formula- la, b) optionally, purifying the obtained compound with a suitable solvent mixture to provide pure Triflate salt of Tucatinib of formula- la, c) treating the Tucatinib triflate of formula- la with a suitable base in a suitable solvent followed by treatment of Tucatinib in ethanol to provide Tucatinib of formula- 1.

Wherein,

In step-a), b) & c) the suitable solvent & anti-solvent used is selected from benzene, toluene, xylene, pyridine, methyl tert-butyl ether, 1 ,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) dichloromethane/methylene chloride, dichloroethane, chloroform, acetone, methyl ethyl ketone, methyl isobutyl ketone acetonitrile, methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, t-butanol, water or mixtures thereof.

In step-c) the suitable base used is selected from diethylamine, diisopropylamine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4- dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide or any other suitable base.

The preferred embodiment of the present invention provides an improved process for the preparation of Tucatinib of formula- 1, comprising of: a) Reacting N4-[3-methyl-4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)phenyl ] quinazoline-4,6-diamine compound of formula-6 with 4, 4-dimethyl-2- methylsulfanyl-4, 5 -dihydrooxazole trifluoromethanesulfonate compound of formula-7 in pyridine followed by isolating the crude compound using n-butanol to provide Tucatinib Triflate of formula- la, b) purifying the obtained compound of formula- la in a solvent mixture comprising dimethylformamide and n-butanol to provide pure Tucatinib Triflate of formula- la, c) treating the compound of formula- la with triethylamine in methanol followed by further treatment with ethanol to provide Tucatinib of formula- 1.

The second aspect of the present invention is to provide a novel crystalline form-N of Tucatinib Triflate of formula- la, which is characterized by: i) Its powder X-ray diffractogram having peaks at about 5.3, 7.2, 10.6, 11.9, 16.0, 19.4, 21.4 and 22.7± 0.2 degrees 2-theta. ii) Its powdered X-ray diffraction pattern as shown in figure- 1. iii) Its DSC thermogram as shown in figure-2.

Further, the present invention also provides a process for the preparation of crystalline Form-N of Tucatinib Triflate of formula-la, comprising steps of: a) Reacting compound of formula-6 with compound of formula-7 in a suitable solvent and adding a suitable anti-solvent for the isolation of compound of formula- 1 a, b) dissolving the compound obtained in step-(a) in a suitable solvent, c) precipitating the compound of formula- 1 a using a suitable anti-solvent, d) filtering, washing and drying the compound to get the crystalline form-N of Tucatinib Triflate of formula- la.

Wherein,

In step-a), b) & c) the suitable solvent & anti-solvent used is selected from benzene, toluene, xylene, pyridine, methyl tert-butyl ether, 1 ,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) dichloromethane/methylene chloride, dichloroethane, chloroform, acetone, methyl ethyl ketone, methyl isobutyl ketone acetonitrile, methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, t-butanol, water or mixtures thereof.

The preferred embodiment of the present invention provides a process for the preparation of crystalline Form-N of Tucatinib Triflate of formula- la, comprising steps of: a) Reacting compound of formula-6 with compound of formula-7 in pyridine followed by isolating the crude compound of formula- la using n-butanol to provide Tucatinib Triflate of formula- la, b) dissolving the compound obtained in step-(a) in N,N-dimethylformamide, c) precipitating the compound of formula- la using n-butanol, d) filtering, washing and drying the compound to get the crystalline form-N of Tucatinib Triflate of formula- 1 a. The 2-Amino-5-nitro-benzonitrile compound of formula-2 can be prepared from the processes known in the art. The preparation of 3-methyl-4- ([l,2,4]triazolo[l,5-a]pyridine-7-yloxy)aniline compound of formula-4 and 4, 4- dimethyl-2-methylsulfanyl-4, 5 -dihydrooxazole trifluoromethanesulfonate compound of formula-7 are prepared from the present invention or processes known in the art.

Advantages of the present invention:

1. The present invention involves the usage of pyridine as a solvent which efficiently transforms the compound of formula-6 to compound of formula- la with improved yield and quality.

2. The present invention involves the transformation of compound of formula-6 to compound of formula- la at ambient temperatures which are suitable for commercial scale process.

3. The present invention successfully avoids chromatographic techniques which are commercially not viable.

4. The present invention involves the isolation Tucatinib as its triflate salt which enhances the purity of the desired compound i.e., Tucatinib by the removal of undesired impurities.

5. The present invention involves the usage of low cost reagents & solvents which reduce the cost of production and also best suitable for commercial scale process.

PXRD method of analysis:

PXRD analysis of the crystalline forms of Tucatinib & its salt were carried out using Panlytical Expert Pro DY3248 X-ray powder diffractometer using Cu-Ka radiation of 10 wavelength 1.5406 A° and at continuous scan speed of 0.037min.

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

Scheme-I:

Scheme-II:

The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples provide as illustration only and hence should not 5 be construed as limitation of the scope of the invention.

Examples:

Exampe-1: Process for the purification of 2-Amino-5-nitro-benzonitrile 0 (Formula-2)

2-Amino-5-nitro-benzonitrile (100.0 g) compound of formula-2 and ethyl acetate (4.0 Lt) were charged at 25-30°C and heated to 75-80°C for dissolution. The resulting solution was treated with activated carbon (0.1 W) at 65-70°C for 30-45 min. Subsequently the reaction mass was filtered over Hyflo and the filtrate was distilled at 5 below 50 °C leaving 10 V of solvent inside the flask. The resulting precipitate was stirred for 2-2.5 hrs at 25-30°C. The precipitated-out product was filtered and dried to afford compound of formula-2 (76.1 g, 76.1%). HPLC Purity: 99.97%.

Exampe-2: Process for the preparation of N’-(2-cyano-4-nitro-phenyl)-N,N- dimethylformamidine (Formula-3) 2-Amino-5-nitro-benzonitrile compound of formula-2 (65 g) and methanol (195 mL) were charged into RB Flask and stirred for 5 min at 25-30 °C. The resulting solution was charged with N,N-dimethylformamide dimethylacetal (DMF-DMA) (71.21 g, 1.5 eq.) into the reaction mass and the temperature of the reaction mass was raised to 50-55 °C and stirred for 3-4 hrs at the same temperature. After completion of reaction, reaction mass was cooled to 0-5 °C and stirred for 2 hrs at the same temperature. The resultant precipitate was filtered and washed with methanol and dried to get the title compound (Yield: 82.4 g, 94.77%). HPLC Purity: 99.7%.

Exampe-3: Process for the preparation of N-[3-methyl-4-([l,2,4]triazolo[l,5- a]pyridin-7-yloxy)phenyl]-6-nitro-quinazolin-4-amine (Formula-5)

3 -methyl-4-( [ 1 ,2,4] triazolo [ 1 ,5 -a]pyridine-7 -yloxy)aniline compound of formula-4 (45.0 g, 1.0 eq.), N’-(2-cyano-4-nitro-phenyl)-N,N-dimethylformamidine compound of formula-3 (42.91 g, 1.05 eq.) and acetic acid (270 mL) were charged into RB Flask and stirred for 5 min at 25-30°C. Raised the temperature of reaction mixture to 80-85°C and stirred for 4-5 hrs at the same temperature. After completion of reaction, charged DM water (225 mL) to the reaction mass at 80-85 °C and the resulting reaction mass was cooled to 50-55°C. Subsequently the reaction mass was precipitated by adding methanol (900 mL) at 50-55°C. The resulting precipitate was cooled to 25-30°C and the precipitate was stirred for 2-2.5 hrs at 25-30°C. Thereafter, the resulting precipitate of compound of formula-5 was filtered and washed with methanol and dried to afford the title compound (75.37 g, 97.35% yield). HPLC Purity: 99.6%.

Exampe-4: Process for the preparation of N4-[3-methyl-4-([l,2,4]triazolo[l,5- a]pyridin-7-yloxy)phenyl]quinazoline-4,6-diamine (F ormula-6)

The compound of formula-5 (65.0 g), methylene chloride (975 mL) and methanol (975 mL) were charged into the hydrogenator and stirred for 5-10 min at 25- 30°C. The resulting reaction mass was charged with 10% Pd/C (0.075 % w/w) at 25- 30°C and temperature of the reaction mass was raised to 35-40 °C. The resulting reaction mass was stirred at the same temperature for 8-9 hrs. After completion of reaction, the resulting reaction mass was cooled to 25-30°C and filtered through hyflo bed, washed with methylene chloride and methanol mixture. The filtrate thus obtained was distilled at below 50 °C. Thereafter the resulting precipitate was co-distilled with methanol twice (5 V). Subsequently the resulting precipitate was cooled to 25-30°C and the precipitate was stirred for 2-2.5 hrs at the same temperature. The resulting mass of compound of formula-6 was filtered, washed with methanol and dried to afford the title compound (55.54 g, 92.13% yield). HPLC Purity: 99.81%.

Exampe-5: N6-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-N4-[3-methyl-4-([l, 2,4] triazolo[l,5-a]pyridin-7-yloxy)phenyl]-4,6-quinazolinediamin e, 144- trifluoromethanesulfonic acid (1:1) Formula-la

The compound of formula-6 (90.0 g) and pyridine (360 mL) were charged into a flask and stirred for 10 min at 25-30°C. The resulting reaction mass was charged with 4, 4-dimethyl-2-methylsulfanyl-4, 5 -dihydrooxazole trifluoromethanesulfonate compound of formula-7 (103.94 g, 1.5 eq.) and the reaction mass was maintained for 48 hrs at 25-30°C. After completion of reaction, the reaction mass was charged with n-butanol (2.25 Lt) and temperature of the reaction mass was cooled to 0-5°C. The resulting slurry was maintained for 3.5-4 hrs at the same temperature. The precipitated- out product was filtered and washed with n-butanol, dried to get the crude compound (118.4 g).

Crude compound thus obtained was charged into a flask and dissolved in DMF (350 mL). The resulting solution was charged with n-butanol (4.68 Lt) at 25-30°C and the precipitate was maintained for 5-6 hrs at the same temperature. Subsequently, the precipitate was cooled to 0-5 °C and stirred for 2.5-3 hrs at the same temperature. The precipitated-out product was filtered, washed with pre-cooled n-butanol and dried to get the title compound as purified product (103.2 g). HPLC Purity: 99.92%.

The PXRD of Triflate salt of Tucatinib compound of formula- la is illustrated in figure- 1 and DSC thermogram is illustrated in figure-2. Exampe-6: N6-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-N4-[3-methyl-4-([l, 2,4] triazolo[l,5-a]pyridin-7-yloxy)phenyl]-4,6-quinazolinediamin e (Formula-1)

The above obtained compound of formula- la (102.0 g) was charged into mixture of triethylamine (112 g) and methanol (2.04 Lt) at 25-30°C. The resulting slurry was maintained for 4.5-5 hrs at 25-30°C. Subsequently the precipitate was cooled to 5-10°C and stirred at the same temperature for about 2-2.5 hrs. The obtained product was filtered and washed with methanol, dried the wet sample under vacuum to afford 72.95 g of title compound.

The PXRD of Tucatinib compound of formula- 1 is illustrated in figure-3.

Exampe-7: N6-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-N4-[3-methyl-4-([l, 2,4] triazolo[l,5-a]pyridin-7-yloxy)phenyl]-4,6-quinazolinediamin e hemi ethanol (1.0:0.5)

Ethanol (350 mL) was charged to 70.0 g of N ⁶ -(4,5-dihydro-4,4-dimethyl-2- oxazolyl)-N ⁴ -[3-methyl-4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)ph enyl]-4,6- quinazolinediamine compound of formula- 1 at 25-30°C. The resulting slurry mass was heated to 70-75°C and maintained at the same temperature for 2-4 hrs. After completion of maintenance, the reaction mass was cooled to 25-30°C and stirred the precipitate for 2-2.5 hrs at 25-30 °C. The obtained product was filtered, washed with ethanol and dried the wet sample under vacuum to afford Tucatinib hemiethanolate 65.42 g (55.34% yield). HPLC Purity: 99.93%.

Exampe-8: 4,5-diliydro-4,4-dinietliyl-2-(niethylthio)oxazole,l,l,l-tri fliioro methanesulfonic acid (1:1) (Formula-7)

Step-(a): Preparation of 4,4-dimethyl-2-oxazolidinethione

2-Amino-2-methyl- 1 -propanol (80.0 g) and methylene chloride (400 mL) are charged into a flask at 25-30°C under nitrogen atmosphere and stirred for 5-10 min at the same temperature. Subsequently, reaction mass was cooled to 20-25 °C and a solution of 1,1’ -Thiocarbonyldiimidazole (208 g, 1.3 eq.) in methylene chloride (1.6 Lt) was charged to the reaction mass for 90-120 min at 20-25 °C under nitrogen atmosphere. After the addition of reagent, reaction mass was warmed to 25-30 °C and stirred at the same temperature for 5-6 hrs at the same temperature. After completion of reaction, DM water (0.8 Lt) was charged into the reaction mass and the resulting biphasic mass was stirred for 15-20 min. Subsequently, organic and aqueous layers were separated and the separated aqueous layer was extracted with methylene chloride (400 mL). Combined organic layers were washed with DM water (800 mL) and separated. The organic layer was transferred into a flask and distilled at below 35 °C under vacuum leaving approximately 3 V of solvent inside the flask undistilled. Subsequently, MTBE (240 mL) was charged into the flask and the resulting mass was cooled to 0-5 °C and stirred for 2 hrs. Precipitated-out compound was filtered, washed with chilled MTBE and dried under vacuum to afford 70.51 g of title compound (59.88% yield).

Step-(b): 4,5-diliydro-4,4-dimetliyl-2-(methylthio)oxazole,l,l,l-trifh ioro methane sulfonic acid (1:1)

4,4-dimethyl-2-oxazolidinethione (50.0 g) and methylene chloride (250 mL) was charged into a flask and stirred for 5-10 min at 25-30°C. Subsequently, reaction mass cooled to 20-25 °C and methyl trifluoromethanesulfonate (81.27 g, 1.3 eq.) was charged to the reaction mass at the same temperature. After the addition of reagent, reaction mass was warmed to 25-30°C and stirred at the same temperature for 5-6 hrs at the same temperature. After completion of reaction, MTBE (1.0 Lt) was charged into the reaction mass and cooled the reaction mass to 0-5°C. The heterogeneous mass thus obtained was stirred at the same temperature for 2-2.5 hrs and filtered, washed with chilled MTBE (100 mL). Wet compound of formula-7 thus obtained was dried under vacuum to afford 107.0 g of title compound of formula-7 (95.08% yield). HPLC Purity: 99.25%.

Compound of formula-7 (20.0 g) prepared by following the above process was repurified in MDC and MTBE to obtain 18.75 g of pure compound of formula-7 with enhanced purity, HPLC Purity: 99.64% (93.75% yield for purification). Exampe-9: Process for the preparation of 3-methyl-4-([l,2,4]triazolo[l,5-a] pyridine-7 -yloxy)aniline (F ormula-4)

Step-(a): 4-(2-Methyl-4-nitrophenoxy)-2-Pyridinamine (Formula-10):

2-Methyl-4-nitrophenol (300 g) compound of formula-8 was treated with 4- Chloropyridine-2-amine (327.4 g, 1.3 m.eq.) compound of formula-9 in the presence of DIPEA (379.8 g, 1.5 m.eq.) in NMP (1.5 Lt) at 170-175 °C under 4Kg/cm ^-2 nitrogen pressure for about 23-25 hrs. After completion of reaction, the reaction mass was cooled and reaction mass containing compound of formula- 10 was used directly in the next stage without any further isolation at step-(a) stage.

Step-(b): N,N-dimethyl-N'-[4-(2-methyl-4-nitro phenoxy)-2-pyridyl]formamidine (Formula-11):

The compound of formula- 10 reaction mass was treated with DMF-DMA (560 g, 2.4 m. eq.) in isopropyl alcohol (720 mL) at 80-85 °C for about 3-4 hrs. After completion of reaction, the reaction mass was cooled and the reaction mass containing compound of formula- 11 was used directly in the next stage without further isolation at step-(b) stage.

Step-(c): N-hydroxy-N'-[4-(2-methyl-4-nitro-phenoxy)-2-pyridyl]formami dine (Formula-12):

The compound of formula- 11 reaction mass was treated with hydroxylamine.HCl (163 g, 1.2 m. eq.) at 40-45 °C for about 2-3 hrs. After completion of reaction, the reaction mass was cooled to room temperature, quenched by addition of DM water and the resulting product was filtered and washed with methanol. The wet product (345 g) thus obtained was dried under vacuum and further purified from DMF- Methanol by precipitation method to afford the compound of formula- 12 as solid (276.0 g, 48.8%) which was used in the next stage without further analysis. Step-(d): 7-(2-Methyl-4-nitrophenoxy)-[l, 2, 4] triazolo[l,5-a] pyridine (Formula-13):

The compound of formula- 12 (125.0 g) was treated with trifluoroacetic anhydride (136.6 g, 1.5 m. eq.) in methylene chloride (6.0 Lt) at 32-36 °C for about 4- 5 hrs. After completion of reaction, the reaction mass was cooled and treated with aq. Sodium carbonate and the methylene chloride was distilled off under vacuum at about 45 °C. After distillation, the reaction mass was cooled to 25-30 °C and maintained for

2-3 hrs at the same temperature and filtered. The wet product thus obtained was purified from methanol at 65-70 °C and filtered at 25-30 °C. The wet product was dried at 45- 50 °C to afford compound of formula-13 (75.00 g, 64.5%) as crystalline solid which was characterized and used for Formula-4 formation. HPLC Purity: 99.26%.

Step-(e): 3-Methyl-4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)aniline (Formula-4):

The compound of formula- 13 (70.0 g) was hydrogenated in the presence of -10% Pd/C (3.5 g) and hydrogen pressure in methanol (1050 mL) at 45-50 °C for about 8-9 hrs. After completion of reaction, the catalyst was filtered, and methanol was partially distilled under vacuum at below 50 °C. After distillation, the reaction mass was cooled to room temperature and treated with aq. Ammonia solution (750 mL) for

3-4 hrs at 25-30 °C. The resulting precipitated out product was filtered and dried under vacuum to afford compound of formula-4 as crystalline solid (53.6 g, 86.1%). HPLC Purity: 99.38%.

Compound of formula-4 (50.0 g) prepared by following the above process was repurified in methanol and aqueous ammonia to obtain 47.0 g of pure compound of formula-4 with enhanced purity, HPLC Purity: 99.47% (94.00% yield for purification).