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

Formula-I

Background of the Invention:
Mitapivat, is a pyruvate kinase activator, as a sulfate salt is approved in USA for the treatment of hemolytic anemia and is available in the market with the brand name PYRUKYND® developed by Agio pharmaceutical in the form of tablet. The chemical name of mitapivat sulfate is 8-quinolinesulfonamide, N-[4-[[4(cyclopropylmethyl)-1-piperazinyl] carbonyl]phenyl]-, sulfate, hydrate (2:1:3).
The US patent US8785450B2 first disclosed mitapivat free base and pharmaceutically acceptable salts. The US’450 disclosed various processes for preparation of mitapivat. The said patent reported purification of mitapivat by using column chromatography in a mixture of methanol and dichloromethane.
The US11254652B2 reported mitapivat sulfate, hemi sulfate hydrate and their polymorphs. Additionally, the said patent reported alternative process for preparation of mitapivat sulfate salt and its polymorphs and processes thereof.
The PCT application publication WO2020237047A1 reported various salts of mitapivat and polymorphs thereof.
There are various processes reported for mitapivat free base and salts thereof using different solvents, reagents.
Based on drawbacks the prior art processes, there is a need for providing an improved process for the preparation of mitapivat sulfate, which involves simple experimental procedures, well suited to industrial production, which avoids the use of column chromatography purification, and which affords high pure mitapivat sulfate.
The present invention provides various processes for preparation of mitapivat, intermediates thereof and sulfate salts, which is efficient, industrially viable and cost effective.
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 process for the preparation of compound of formula-8.
The third aspect of the present invention is to provide a process for the preparation of compound of formula-6.

Brief description of the drawings:

Figure 1: Illustrates the PXRD pattern of crystalline Form of compound of formula-8 (N-(4-(4-(cyclopropyl methyl) piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide).

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 aluminium hydride, sodium borohydride, BF3 etherate solution, Pd/C, Ray-nickel;
The first aspect of the present invention provides a process for the preparation of compound of formula-I.

Comprising of:
a) Reacting compound of formula-1 with compound of formula-2 in presence of suitable reagents, solvent to provide compound of formula-3,

Formula-1 Formula-2
b) reducing the compound obtained in step-a) with suitable reagent, solvent to provide compound of formula -4,

Formula-3 Formula-4

c) coupling of the compound of formula-5 with compound of formula-4 in presence of suitable reagent, solvent to provide compound of formula-6,

Formula-6
d) deprotecing the compound of formula-6 using the suitable reagents, solvents to provide compound of formula-7 or salt thereof, salts such as HCl, HBr, acetic acid, trifluoroacetic acid, sulfate salt,

Formula-7
e)reacting the compound of formula-7 with suitable reagent, solvent to provide compound of formula-8,

Formula-8
f)optionally purifying the compound of formula-8 with suitable reagents, solvents to provide pure compound of formula-8,
g)treating the compound of formula-8 with suitable reagents to get the compound of formula-I as hydrate.
h)optionally purifying the compound of formula-I using suitable reagents, solvents to provide the pure compound of formula-I.
Wherein in step-a) suitable reagents are selected from EDC.HCl, HOBt, PyBOP, thionyl chloride, oxalylchloride, CDI, organic base, inorganic base and mixture thereof;
wherein in step-b) the suitable reagents are selected from Raney-Nickel under hydrogen pressure, palladium carbon hydrogen pressure, ammonium formate, sodium dithionite, iron-acetic acid, zinc, acetic acid and mixture thereof
wherein in step-c) the suitable reagents are selected from organic base or inorganic base and mixture thereof.
wherein in step-d) the suitable reagents are selected con HCl, dil. HCl, methanolic HCl, orange solvent in HCl,; suitable salts are selected from HCl, HBr, sulfuric acid, acetic acid, tri fluoro acetic acid, tartaric acid and oxalic acid salt and mixture thereof.
wherein in step-e) the suitable reagents are selected cyclopropanecarbaldehyde, (bromo methyl) cyclopropane, (chloromethyl)cyclopropane, (iodomethyl) cyclopropane, organic base, inorganic base, sodium borohydride, sodium cyanoborohydride and sodium triacetoxy borohydride , acetic acid, trifluoroacetic acid and mixture thereof;
wherein in step-g) the suitable reagent is sulfuric acid and mixture thereof;,
wherein in step-f, h) the suitable reagents HCl, HBr, H2SO4, acetic acid, trifluoro acetic acid,
inorganic base, organic base and mixture thereof;
Preferred water content range for compound of formula-I : 4.1w/w % to 6.1w/w %;
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, water or any mixture thereof;
The embodiment of the present invention provides a process for the preparation of compound of formula-I.

Comprising of:
a)Reacting compound of formula-1 with thionyl chloride in presence of DMF in toluene to provide 4-nitrobenzoyl chloride, is further reacting with compound of formula-2 in presence of triethyl amine in toluene to provide compound of formula-3,

Formula-1 Formula-2
b)reducing the compound obtained in step-a) with iron powder, ammonium chloride in toluene, water to provide compound of formula -4,

Formula-3 Formula-4
c)coupling of the compound of formula-5 with compound of formula-4 in presence of 4-methyl morpholine in acetonitrile to provide compound of formula-6,

Formula-6
d) deprotecing the compound of formula-6 using HCl in dichloromethane to provide compound of formula-7 ,

Formula-7

e)reacting the compound of formula-7 with cyclopropanecarbaldehyde in presence sodium triacetoxy borohydride, acetic acid in dichloromethane to provide compound of formula-8,

Formula-8
f) purifying the compound of formula-8 in toluene, ethanol to provide compound of formula-8,
g)treating the compound of formula-8 with toluene, ethanol, water, sulfuric acid to get the compound of formula-I as hydrate (water content 5.5 w/w %).
The present invention provides a process for the preparation of Mitapivat sulfate described in schematic representation in scheme-I

The second aspect of the present invention provides a process for the preparation of compound of formula-8

Formula-8
Comprising of:
a)Reacting compound of formula-1 with compound of formula-9 or salt thereof in presence of suitable reagents, solvent to provide compound of formula-10

Formula-1 Formula-9
b) reducing the compound obtained in step-a) with suitable reagent, solvent to provide compound of formula -11,

Formula-10 Formula-11
c) coupling of the compound of formula-5 with compound of formula-11 in presence of suitable reagent, solvent to provide compound of formula-8,

Formula-8
d)optionally purifying the compound of formula-8 with suitable reagents, solvents to provide pure compound of formula-8,
e)treating the compound of formula-8 with suitable reagents to get the compound of formula-I.
f)optionally purifying the compound of formula-I using suitable reagents, solvents to provide the pure compound of formula-I.
Wherein in step-a) suitable reagents are selected from EDC.HCl, HOBt, PyBOP, thionyl chloride, oxalylchloride, CDI, organic base, inorganic base, any mixture thereof;
wherein in step-b) the suitable reagents are selected from Raney-Nickel under hydrogen pressure, palladium carbon hydrogen pressure, ammonium format, sodium dithionite, iron-acetic acid, zinc acetic acid, any mixture thereof;
wherein in step-c) the suitable reagents are selected from organic base, inorganic base, any mixture thereof;
wherein in step-d) the suitable reagents are selected con HCl, dil. HCl, methanolic HCl, orange solvent in HCl,; suitable salts are selected from HCl, HBr, sulfuric acid, acetic acid, tri fluoro acetic acid, tartaric acid and oxalic acid salt, any 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, water or any mixture thereof;
The present invention provides alternative process for Mitapivat sulfate the compound of formula-I as mentioned in the schematic representation-II

The third aspect of the present invention provides a process for the preparation of compound of formula-6.

Formula-6.
Comprising of:
a)Reacting compound of formula-5 with compound of formula-12 (R: alkyl) in presence of suitable reagents, solvent to provide compound of formula-13,

Formula-5 Formula-12
b) hydrolyzing the compound obtained in step-a) with suitable reagent, solvent to provide compound of formula -14,

Formula-13 Formula-14
c) coupling of the compound of formula-15 or salts thereof with compound of formula-14 in presence of suitable reagent, solvent to provide compound of formula-6,

Formula-15 Formula-6 Formula-7

d)deprotecting the compound of formula-6 using the suitable reagents, solvents to provide compound of formula-7 or salt thereof, salts such as HCl, HBr, acetic acid, trifluoroacetic acid and sulfate salt,
e)reacting the compound of formula-7 with suitable reagent, solvent to provide compound of formula-8,

Formula-8
f)optionally purifying the compound of formula-8 with suitable reagents, solvents to provide pure compound of formula-8,
g)treating the compound of formula-8 with suitable reagents to get the compound of formula-I.
h)optionally purifying the compound of formula-I using suitable reagents, solvents to provide the pure compound of formula-I.
Wherein in step-a) suitable reagents are selected from EDC.HCl, HOBt, PyBOP, thionyl chloride, oxalylchloride, CDI, organic base, inorganic base, any mixture thereof;
wherein in step-b) the suitable reagents are selected from Raney-Nickel under hydrogen pressure, palladium carbon hydrogen pressure, ammonium format, sodium dithionite, iron-acetic acid, zinc acetic acid, any mixture thereof
wherein in step-c) the suitable reagents are selected organic base, inorganic base, any mixture thereof
wherein in step-d) 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, tri fluoro acetic acid, tartaric acid and oxalic acid salt, any mixture thereof
wherein in step-e) the suitable reagents are selected 2-cyclopropylacetaldehyde, (bromo methyl) cyclopropane, (chloromethyl)cyclopropane, (iodomethyl) cyclopropane, organic base, inorganic base, sodium borohydride, sodium cyanoborohydride and sodium triacetoxy borohydride , acetic acid, trifluoroacetic acid, any mixture thereof
wherein in step-g) the suitable reagents is sulfuric acid, any mixture thereof
wherein in step-f, h) the suitable reagents HCl, HBr, H2SO4, acetic acid, trifluoro acetic acid,
inorganic base, organic base, any 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, water or any mixture thereof;

The present invention is an improved process for the process of mitapivat sulfate can be represented schematically as follows in scheme-III:

The process for the preparation of mitapivat, its sulfate salt developed by the present
inventors produces highly pure mitapivat sulfate 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 99.5%, preferably greater than 99.7%, more preferably greater
than 99.9% by HPLC
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 tert-butyl 4-(cyclopropylmethyl) piperazine-1-carboxylate
A round bottom flask was charged with N-Boc piperazine (100 g) acetonitrile (500 ml) triethyl amine (81.34 g) at 25-30°C and slowly heated to 60°C, charged cyclopropyl methyl bromide (86.90 g) in drop wise manner and stirred at reflux temperature for 6 hr. The reaction mixture was cooled to 25°C, quenched with water and stirred for 30 min. The precipitated solid was filtered and dried to get the title compound.
Yield: 116.0 g
Example-2: Preparation of 1-(cyclopropylmethyl)piperazine hydrochloride.
A round bottom flask was charged with tert-butyl 4-(cyclopropylmethyl)piperazine-1-carboxylate (100 g), ethyl acetate (500 ml) and Con. hydrochloric acid (300 ml) at 25-30 ° C and stirred for 6 hr. The reaction mixture was charged with water (500 ml) and separated the aq. layer. The aq. layer pH was adjusted to 9.5 with saturated potassium carbonate solution and extracted into dichloromethane. The organic layer was distilled off completely and the residue stirred in methyl tert-butyl ether for 1 hr and filtered the solid to get the title compound.
Yield: 62.0 g
Example-3: Preparation of compound of formula-10.
A round bottom flask was charged with 4- nitro benzoic acid (100 g) and toluene (500 ml) and DMF (10 ml) at 25-30 ° C and stirred for 15 min. Thionyl chloride (128.17 g) was charged slowly to the reaction at 25-30 ° C, and gradually heated to reflux and stirred for 3 hr. The reaction mixture was distilled off completely under vacuum to get the residue compound.
The obtained compound was dissolved in toluene (500 ml) charged to a solution of 1-(cyclo propylmethyl) piperazine hydrochloride (95.15 g), toluene (500 ml) and triethyl amine (132.90 g ) at 25-30 ° C and stirred for 3 hr at 15-20°C. The reaction mixture was charged with water and extracted with ethyl acetate and separated organic layer. The organic layer was distilled off completely and purified in n-heptane to obtained pure title compound.
Yield: 154.0 g
Example-4: Preparation of compound of formula-8.
A round bottom flask was charged with compound-10 (100 g), toluene (800 ml) and water (200 ml), ammonium chloride (5.5 g) at 25-30 ° C and stirred for 13 min. Charged iron powder (115.70 g) in portion wise to the reaction mixture at 25-30°C, and heat to reflux continued stirring for 6 hr. Cooled the reaction mixture to 60° C, filtered the reaction mass through hy-flow bed and evaporated the solvent under vacuum to get a solid compound. The obtained compound was isolated from water.
The obtained compound was charged with acetonitrile (500 ml) and pyridine (54.6 g) at 25-30° C, slowly charged a solution of compound -5 (236.0 g) in acetonitrile and stirred for 30 min. The resulting mixture was slowly heated to reflux and stirred for 6 hr. Cooled the reaction mixture to 20-25°C, charged with water and stirred for 30 min, filtered the solid and dried to get the title compound.
Yield: 124.0 g
Example-5: Preparation of compound of formula-I.
A round bottom flask was charged with compound-8(111.0 g,), and a pre-mixed process solvent of ethanol (638.6 g), toluene (266.1 g) and water (159.6 g). The suspension was stirred and heated to 60°C to dissolve the solids, and then the resulting solution was cooled to 50°C. To the solution was added an aqueous solution of H2SO4, suspension was cooled and stirred for 8 h. The solids were filtered washed with water and to give the title product as hydrated; water content: 5.45 w/w%
Yield: 135 g
Example-6: Preparation of compound of formula-3.
A round bottom flask was charged with 4- nitro benzoic acid (100 g) and toluene (500 ml) and DMF (10 ml) at 25-30 ° C and stirred for 15 min. Thionyl chloride (128.17 g) was charged slowly to the reaction at 25-30 ° C, and gradually heated to reflux and stirred for 3 hr. The reaction mixture was distilled out completely under vacuum to get the residue compound.
The obtained compound was dissolved in toluene (5.0 vol) charged to a solution of compound-2 (100 g ), toluene (1L ) and triethylamine (133.48 g ) at 25-30 ° C and stirred for 3 hr at 15-20 ° C. The reaction mixture was charged with water (500 ml) and extracted with ethyl acetate and separated organic layer. The organic layer was distilled off completely, purified from n-heptane (500 ml) and dried to get the title compound.
Yield: 190.0 g
Example-7: Preparation of compound of formula-4.
A round bottom flask was charged with compound-3 (100 g), toluene (800 ml) and water (200 ml), ammonium chloride (4.785 g) at 25-30 ° C and stirred for 13 min. Charged Iron powder (99.80 g) in small portions to the reaction mixture at 25-30°C, and heated to reflux and stirred for 6 hr. Cooled the reaction mixture to 60°C, filtered the reaction mass through hy-flow bed and evaporated the solvent under vacuum to get the solid compound. Further the title compound was stirred in water for 30 min, filtered the obtained solid as title compound.
Yield: 83.77 g
Example-8: Preparation of compound of formula-7 as HCl salt.
A round bottom flask was charged with chlorosulfonic acid (2 kg), quinolone (200 g) at 0-5°C and stirred at 140-150° C for 6 hr. Cooled the reaction mixture to 0-5 °C, charged with cold water and stirred for 30 min. filtered the precipitated solid and the wet compound was directly used without drying.
In another RBF, charged compound -4(100 g), acetonitrile (500 ml), pyridine (51.80 g) at 25-30°C and slowly heated to 50-60° C, followed by addition of a solution of compound-5 in acetonitrile (500 ml) and gradually heated to reflux and stirred for 6 hr. Cooled the reaction mixture to 25-35° C, charged with water and stirred for 30 min. The obtained solid was filtered to get the title compound -6.
The obtained compound-6 (162.50 g), ethyl acetate (500 ml) was taken into another RBF charged with Con. hydrochloric acid (300 ml) at 25-30°C and stirred for 6 hr. The reaction mixture was distilled off completely and dried to get the title compound.
Yield: 120.50 g
Example-9: Preparation of compound of formula-8.
A round bottom flask was charged with compound-7 (100 g), acetonitrile (500 ml) triethylamine (34.99 g) at 25-30 °C, added cyclopropyl methyl bromide (37.42 g) drop wise and stirred at reflux for 6 hr. The reaction mixture was cooled to 25° C, charged with water and stirred for 30 min. The precipitated solid was filtered and dried to get the title compound.
Yield: 93.66 g
Example-10: Preparation of compound of formula-13a.
A round bottom flask was charged with methyl-4-aminobenzoate (50 g) and acetonitrile (250 ml), pyridine (52.32 g) at 25-30 ° C and slowly heated to 50-60° C, followed by addition of a solution of compound-5 (236.0 g) in acetonitrile (250 ml) and gradually heated to reflux and stirred for 6 hr. Cooled the reaction mixture to 25-35° C, charged with water and stirred for 30 min. The obtained solid was filtered to get the title compound
Yield: 101.92 g
Example-11: Preparation of compound of formula-14.
A round bottom flask was charged with compound-13a (100 g), water (500 ml) and NaOH solution (17.52 g) and stirred at 75°C for 3 hr. Cooled the reaction mixture to15- 20°C, charged with THF (150 ml), hydrochloric acid (81 ml) over 1 hour to make the reaction mixture pH of 3.0. The precipitated solid was filtered and washed with water and dried to get the title compound.
Yield: 83.43 g
Example-12: Preparation of compound of formula-6.
A round bottom flask was charged with compound-14(1.0 mole eq), dimethyl acetamide (500.0 mL), CDI (1.2 mole eq) in portions at 25 °C and the mixture was stirred at 25 °C for 2 h. To the resulted suspension N-Boc piperazine (1.1 mole eq) was added in one portion at 25 °C and the mixture was stirred at 25 °C for 4 h. The reaction mixture quenched with water and stirred for 2 hr. The precipitated solid was filtered at 25-35°C, washed with water and dried to afford the title compound.
Example-13: Preparation of compound of formula-3 (tert-butyl 4-(4-nitrobenzoyl) piperazine-1-carboxylate).
A round bottom flask was charged with 4- nitro benzoic acid (206 g) and toluene (1000 ml) and DMF (8 ml) at 25-30 ° C and stirred for 15 min. Thionyl chloride (312.9 g) was charged slowly to the reaction at 25-30 ° C, and gradually heated to 85-95°C and stirred for 3 hr. Cooled the reaction mixture, distilled-off completely under vacuum to get the residue compound.
The obtained crude compound was dissolved in toluene (1 L) charged to a pre stirred solution of compound-2 (200 g ), toluene (2L ) and triethylamine (380 g ) at -5 to 5 ° C and stirred for 3 hr at same temperature. The reaction mixture was charged with water (1000 ml), ethyl acetate (1000 mL) and separated organic layer. The aqueous layer was extracted with ethyl acetate and separated the both layers. The combined organic layer was washed with sodium bicarbonate solution, water and brine solution, further distilled-off the organic solvent completely to get the crude compound. The obtained compound was charged with n-heptane, ethyl acetate and stirred at 70-80°C for 1 hr. Cooled the reaction mixture to 20-30°C and stirred for 2 hr. Filtered the obtain solid compound and washed with n-heptane and dried to get the title compound.
Yield: 320 g
Example-14: Preparation of compound of formula-4 (tert-butyl 4-(4-aminobenzoyl) piperazine-1-carboxylate).
A round bottom flask was charged with compound-3 (100 g), toluene (800 ml), water (200 ml), ammonium chloride (4.785 g) and Iron powder (99.80 g) at 25-30 ° C and heated to 90-100°C and stirred for 6 hr at same temperature. Cooled the reaction mixture to 60°C, filtered the reaction mass through hy-flow bed and washed with toluene. The filtrate solution was cooled to 20-30°C, and charged with water and stirred for 3 h at 20-30°C. Filtered the obtained solid and washed with water and dried to get the title compound.
Yield: 74.5 g
Example-15: Preparation of compound of formula-7(N-(4-(piperazine-1-carbonyl) phenyl) quinoline-8-sulfonamide).
A round bottom flask was charged with chlorosulfonic acid (750 g) and cooled to 0-5°C, charged with quinolone (150 g) and stirred at 110-120° C for 50 hr. Cooled the reaction mixture to -5 to 5 °C and charged the above reaction mixture to cold water (3.5 L) and stirred for 1 hr. Filtered the precipitated solid and washed with water and dried to get the compound of formula -5.
In another RBF, charged compound -4(100 g), acetonitrile (200 ml), 4-methyl morpholine (72.8 g) at 25-30°C and slowly heated to 55-65° C, followed by addition of a solution of compound-5 in acetonitrile (200 ml) and gradually heated to 75-85°C and stirred for 4 hr. Cooled the reaction mixture to 25-35° C, charged with water (1200 ml) and stirred for 30 min. The obtained solid was filtered and washed with water to get the compound of formula-6.
The obtained compound-6 (162.50 g), dichloromethane (300 ml) was taken into another RBF and charged with Con. hydrochloric acid (150 ml) at 25-30°C and stirred for 1 hr. The reaction mixture was charged with water (800 mL) and stirred for 30 min and both the layers were separated. The aqueous layer was washed with dichloromethane and the aqueous layer was charged with activated carbon and stirred for 10 min. Filtered the aqueous layers and adjusted the pH to ~ 9.5 with potassium carbonate solution and stirred for 1 hr at 20-30°C. Filtered the obtained solid and washed with water and dried to get the title compound.
Purity by HPLC: 99.33 %
Yield: 101 g
Example-16: Preparation of compound of formula-8 (N-(4-(4-(cyclopropyl methyl) piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide).
A round bottom flask was charged with compound-7 (100 g), dichloromethane (3000 ml) and acetic acid (10 g) at 25-30 °C were stirred for 15 min. Cooled the reaction mixture to -5 to 5°C, charged cyclopropane carbaldehyde (21.18 g) and sodium triacetoxy borohydride (112.26 g) and stirred at same temperature for 4 hr. The reaction mixture was charged with water and adjusted pH to ~8 with sodium carbonate solution and stirred for 30 min at 20-30°C and separated the layers. The aqueous layer was extracted with dichloromethane, the combined organic layer was washed with sodium chloride, water and distilled-off completely. The obtained compound was co-distilled with toluene and the resulting compound was stirred in a mixture of toluene, ethanol at 65-75°C for 1 hr. Cooled the solution and the precipitated solid was filtered and washed with dichloromethane and dried to get the title compound. The obtained compound PXRD is depicted in figure-1
Yield: 75.5 g
Example-17: Preparation of compound of formula-1 (crystalline form-A)
A round bottom flask was charged N-(4-(4-(cyclopropylmethyl)piperazine-l-carbonyl) phenyl)quinoline-8-sulfonamide (100 g) , ethanol (280 ml), toluene (720 ml) and water (145 ml) were heated to 65-75°C and stirred for 1 hr. Charged sulfuric acid solution (11.31 g in 46 ml of water) to the reaction mixture at 35-45°C and stirring for 4 hr. Filtered the solid compound and washed with a mixture of ethanol, toluene and dried to give the wet compound. The wet compound was charged with toluene, ethanol and water and heated to 35-45°C for 1 hr, filtered the obtained solid and washed with toluene, ethanol and dried to get the title compound. Water content: 5.5 w/w %
Particle size D(90) :39 µm, D(50) :9.89 µm, D(10) :3.45 µm,
Yield: 200 g;
,CLAIMS:We claim:
1.An improved process for the preparation of compound of formula-I.

Comprising of:
a)Reacting compound of formula-1 with compound of formula-2 in presence of suitable reagents, solvent to provide compound of formula-3,

Formula-1 Formula-2
b)reducing the compound obtained in step-a) with suitable reagent, solvent to provide compound of formula -4,

Formula-3 Formula-4
c)coupling of the compound of formula-5 with compound of formula-4 in presence of suitable reagent, solvent to provide compound of formula-6,

Formula-6
d) deprotecing the compound of formula-6 using the suitable reagents, solvents to provide compound of formula-7 or salt thereof, salts such as HCl, HBr, acetic acid, trifluoroacetic acid, sulfate salt

Formula-7
e)reacting the compound of formula-7 with suitable reagent, solvent to provide compound of formula-8,

Formula-8
f)optionally purifying the compound of formula-8 with suitable reagents, solvents to provide pure compound of formula-8,
g)treating the compound of formula-8 with suitable reagents to get the compound of formula-I.
h)optionally purifying the compound of formula-I using suitable reagents, solvents to provide the pure compound of formula-I.
2. A process for compound of formula-I according to any proceeding claims wherein in step-a) suitable reagents are selected from EDC.HCl, HOBt, PyBOP, thionyl chloride, oxalylchloride, CDI, organic base, inorganic base and mixture thereof; wherein in step-b) the suitable reagents are selected from Raney-Nickel under hydrogen pressure, palladium carbon hydrogen pressure, ammonium formate, sodium dithionite, iron-acetic acid, zinc, acetic acid and mixture thereof;
wherein in step-c) the suitable reagents are selected from organic base or inorganic base and mixture thereof; wherein in step-d) the suitable reagents are selected con HCl, dil. HCl, methanolic HCl, orange solvent in HCl,; suitable salts are selected from HCl, HBr, sulfuric acid, acetic acid, tri fluoro acetic acid, tartaric acid and oxalic acid salt and mixture thereof;
wherein in step-e) the suitable reagents are selected cyclopropanecarbaldehyde, (bromo methyl) cyclopropane, (chloromethyl)cyclopropane, (iodomethyl) cyclopropane, organic base, inorganic base, sodium borohydride, sodium cyanoborohydride and sodium triacetoxy borohydride , acetic acid, trifluoroacetic acid, and mixture thereof; wherein in step-g) the suitable reagent is sulfuric acid, and mixture thereof; wherein in step-f, h) the suitable reagents HCl, HBr, H2SO4, acetic acid, trifluoro acetic acid, inorganic base, organic base, and mixture thereof;
3. A process for compound of formula-I according to any proceeding claims 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, water or any mixture thereof;
4. An improved process for the preparation of compound of formula-I.

Comprising of:
a)Reacting compound of formula-1 with thionyl chloride in presence of DMF in toluene to provide 4-nitrobenzoyl chloride, is further reacting with compound of formula-2 in presence of triethyl amine in toluene to provide compound of formula-3,

Formula-1 Formula-2
b)reducing the compound obtained in step-a) with iron powder, ammonium chloride in toluene, water to provide compound of formula -4,

Formula-3 Formula-4
c)coupling of the compound of formula-5 with compound of formula-4 in presence of 4-methyl morpholine in acetonitrile to provide compound of formula-6,

Formula-6
d) deprotecing the compound of formula-6 using HCl in dichloromethane to provide compound of formula-7 ,

Formula-7
e)reacting the compound of formula-7 with cyclopropanecarbaldehyde in presence sodium triacetoxy borohydride, acetic acid in dichloromethane to provide compound of formula-8,

Formula-8
f) purifying the compound of formula-8 in toluene, ethanol to provide compound of formula-8,
g)treating the compound of formula-8 with toluene, ethanol, water, sulfuric acid to get the compound of formula-I (water content: 5.5 w/w %).
5. A process for preparation of compound of formula-8
Comprising of
a)coupling of the compound of formula-5 with compound of formula-4 in presence of 4-methyl morpholine in acetonitrile to provide compound of formula-6,

Formula-6
b) deprotecing the compound of formula-6 using HCl in dichloromethane to provide compound of formula-7 ,

Formula-7
c)reacting the compound of formula-7 with cyclopropanecarbaldehyde in presence sodium triacetoxy borohydride, acetic acid in dichloromethane to provide compound of formula-8,

Formula-8
d) purifying the compound of formula-8 in toluene, ethanol to provide compound of formula-8,
6. mitapivat sulfate hydrate according to the preceding claims is having particle size distribution of D90 <50 pm.
7. mitapivat sulfate hydrate obtained according to the preceding claims is having 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 99.9% as measured by HPLC; the acid impurity is less than 0.15% as measured by HPLC.

Dated this day Mar-2024.