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

Formula-I
Background of the Invention:
Vericiguat, with the chemical name of vericiguat is methyl {4,6-diamino-2-[5-fluoro-1-(2-fluoro benzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl] pyrimidin-5-yl} carbamate, is a soluble guanylate cyclase (sGC) stimulator. It is indicated to reduce the risk of cardiovascular death and hospitalization due to heart failure (HF) following a hospitalization for heart failure or need for outpatient IV diuretics, in adults with symptomatic chronic HF. Vericiguat is approved in USA and is available in the market with the brand name VERQUVO ®. It has been developed by Merck Sharp and Dhome Corp in the form of tablet oral.
The patent US8420656B2 (referred to as US’686) initially reported vericiguat and pharmaceutically acceptable salts. The US’686 disclosed a process for preparation of vericiguat free base and its intermediates thereof. The patent also reported various salts like vericiguat hydrochloride, sulphate, phosphate, mesylate, disulphonate, maleate and nitrate.
The patent US9096592B2 described a comprehensive process for the preparation of vericiguat and various intermediate compounds. The said patent also reported isolation of intermediates, as salts and hydrates.
The PCT publication WO2020126983A1 reported various purification processes for vericiguat.

There are various processes reported for vericiguat free base and salts and intermediate’s thereof using different solvents, reagents. Based on the certain limitations and drawbacks of the prior art methods there is a need for providing an improved process for the preparation of vericiguat, which involves straightforward experimental procedures suitable for industrial-scale production, while circumventing the necessity for purification by column chromatography and with the aim to get highly pure vericiguat.
The present invention introduces an improved process for preparation of vericiguat free base and salts thereof. This improved process ensures free from nitroso impurities, which is efficient, aligned with industrial feasibility and cost effective.
Brief Description:
The first aspect of the present invention is to provide a process for the preparation of vericiguat compound of formula-I
The second aspect of the present invention is to provide a purification process for vericiguat compound of formula-I
Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of methyl {4,6-diamino-2-[5-fluoro-1-(2-fluoro benzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl] pyrimidin-5-yl} carbamate oxalic acid obtained as per example -18.
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), dimethylsulfoxide (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 “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 used, to provide an acid addition salt, may include an 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 an improved process for the preparation of vericiguat compound of formula-I,
Comprising of:
a) Reacting 2, 6-dichloro-5-fluoronicotinonitrile in presence of suitable reagent, solvent to provide compound of formula-1,

Formula-1
b) reacting of compound of formula-1 in presence of suitable reagent, solvent to provide compound of formula-2,
c)reacting the compound obtained in step-b) with suitable reagent, solvent to provide compound of formula-3,

Formula-2 Formula-3
d) optionally reacting the compound 2,6-dichloro-5-fluoronicotinonitrile with suitable reagent, solvent to provide compound of formula-3,
e) reacting the compound obtained in step-c) or d) with suitable reagent, solvent to provide compound of formula-4,

Formula-4 Formula-5
f) reacting the compound obtained in step-e) with suitable reagent, solvent to provide compound of formula-5 (X : Cl/ Br/ I),
g) reacting the compound obtained in step-f) with suitable reagent, solvent to provide compound of formula-6 (X : Cl/ Br/ I),

Formula-6 Formula-7
h) reacting the compound obtained in step-g) with suitable reagent, solvent to provide compound of formula-7
i) reacting the compound obtained in step-h) with suitable reagent, solvent to provide compound of formula-8 or salts thereof

Formula-8
j) reacting the compound obtained in step-i) with suitable reagent, solvent to provide compound of formula-9 or salts thereof,
k)reacting the compound obtained in step-j) with suitable reagent, solvent to provide compound of formula-10 or salts thereof,

Formula-9 Formula-10
l)reacting the compound obtained in step-k) with suitable reagent, solvent to provide compound of formula-I or salts thereof,
m) optionally purifying the compound obtained in the above steps with suitable acid, base in suitable solvent to provide the pure compound of formula-I,
Wherein in step-a, b, c, d, e, f, g, h, i, j, k, l, m) 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.
wherein in step-a) the suitable reagents are selected from sulfuric acid, wherein in step-b), d) the suitable reagents are selected from zinc, iron, acetic acid, ammonium chloride, hydrochloride and any mixture thereof, wherein in step-c) the suitable reagents are selected from phosphorous oxychloride, trifluoro acetic anhydride, organic base and any mixture thereof, wherein in step-e) the suitable reagents are selected from hydrazine hydrate, aqueous hydrazine hydrate, wherein in step-f) the suitable reagents are selected from boron trifluoride etherate, isoamyl nitrite, tert-butyl nitrite, NaI, NaBr, NaCl, CuI, CuBr, CuCl, sulfuric acid, hydrochloric acid, sodium nitrite, trifluoro methane sulphonic acid and nitric acid or mixture thereof, wherein in step-g) the suitable reagents are selected from 2-fluorobenzyl chloride, 2-fluorobenzyl bromide, 2-fluoro benzyl iodide, 2-fluoro benzyl tosylate, 2-fluoro benzyl mesylate / 2-fluoro benzyl sulfonate, organic base, inorganic base and any mixture thereof.
wherein in step-h) the suitable reagents are selected from CuCN, NaCN, KCN, Zn(CN)2, K4Fe(CN)6, ligands are selected from tBuXPhos Pd(dba)3, palladium catalyst, Pa(OAc)2 , palladium tetrakis, Pa(OH)2, tBuXPhos, Xphos, Xhanth phos, triphenyl phosphine, BINAP; ammonium chloride, acetic acid, HCl, HBr, trifluoroacetic acid, organic bases such as sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium t-butoxide, triethylamine and any mixture thereof; wherein in step-i) the suitable reagents are selected from aniline, malononitrile, sodium nitrite, Con. HCl, sodium acetate, potassium acetate, organic base, inorganic base and any mixture thereof; wherein in step-j) the suitable reagents are selected from Pd/C, hydrogen gas, Raney nickel, ammonium chloride, acetic acid, zinc, iron, ammonium acetate, ammonium formate and any mixture thereof; wherein in step-k) the suitable reagents are selected from organic base, inorganic base, methylchloro formate and any mixture thereof.
The preferred embodiment of aspect of the present invention provides an improved process for the preparation of vericiguat compound of formula- I,
Comprising of:
a) Reacting 2, 6-dichloro-5-fluoronicotinonitrile in presence of Con. sulfuric acid to provide compound of formula-1,

Formula-1
b) reacting of compound of formula-1 with zinc, ammonium chloride in methanol to provide compound of formula-2,

Formula-2 Formula-3
c)reacting the compound obtained in step-b) with phosphorous chloride, triethylamine in dichloromethane to provide compound of formula-3,
e) reacting the compound obtained in step-c) hydrazine hydrate to provide compound of formula-4,
f) reacting the compound obtained in step-e) with sodium nitrite, sulfuric acid, sodium iodide, copper iodide in water to provide compound of formula-5a,

Formula-4 Formula-5a
g) reacting the compound obtained in step-f) with 2-fluorobenzyl chloride in presence of potassium carbonate in DMF to provide compound of formula-6a,

Formula-6a Formula-7
h) reacting the compound obtained in step-g) with copper cyanide in DMF to provide compound of formula-7,
i) reacting the compound obtained in step-h) with sodium methoxide, ammonium chloride in methanol, acetic acid to provide compound of formula-8a,

Formula-8a
j) reacting the compound obtained in step-i) with 2-(phenyldiazenyl) malononitrile in presence of potassium carbonate in toluene to provide compound of formula-9,
k) reacting the compound obtained in step-j) with palladium carbon under hydrogen gas atmosphere in DMF to provide compound of formula-10,
l)reacting to the compound obtained in step-k) with methyl chloroformate in presence of sodium carbonate in water, tetrahydrofuran to provide compound of formula-I .
m) treating the compound obtained in step-i) in DMSO with oxalic acid in acetone or ethyl acetate to provide vericiguat oxalate salt,
n) basifying the compound obtained in step-m) with ammonia or sodium bicarbonate in water and DMSO to provide pure compound-I.
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 preferred embodiment of the present invention provides a purification process for compound of formula-I (crystalline form I)
Comprising of: a) dissolving the compound of formula-I in a solvent,
b) adding the compound obtained in step-a) to suitable acid in a suitable solvent,
c) isolating the compound obtained in step-b) as acid salt,
d) treating the compound obtained in step-c) with suitable base to get pure compound of formula-I.
The preferred embodiment of the present invention provides a purification process for compound of formula-I (crystalline form I)
Comprising of: a) dissolving the compound of formula-I in DMSO
b) adding the compound obtained in step-a) to oxalic acid in acetone or ethyl acetate,
c) isolating the compound obtained in step-b) as vericiguat oxalic acid salt,
d) treating the compound obtained in step-c) with ammonia or sodium carbonate in water 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-I.
Wherein in the above aspects step-a, c) the suitable acids are selected from Con . HCl, dil. HCl, methanolic HCl, HCl in organic solvent, HBr, sulfuric acid, acetic acid, trifluoro acetic acid, tartaric acid, oxalic acid, benzene sulfonic acid, p-toluene sulfonic acid, napadisylate acid, camphor sulfonic acid, methanesulfonic acid, di-paratolyl tartaric acid, malic acid and suitable bases are selected form inorganic base, organic base. 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 0-150°C.
The process for the preparation of vericiguat developed by the present inventors produces highly pure vericiguat and vericiguat salt without nitroso amine compounds 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 %, more preferably greater than 99.5% by HPLC .
Moreover, the vericiguat and its polymorphs produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product. Vericiguat according to the present invention is having particle size distribution of D90 <300 µm, D50 <150 µm. D10 <75 µm.
Powder X-ray Diffraction (PXRD) analysis of vericiguat was conducted employing a BRUKER D8 ADVANCED/AXS X-Ray diffractometer, utilizing Cu Ka radiation with a wavelength of 1.5406 Å and maintaining a continuous scan speed of 0.03°/min. Furthermore, Infrared (IR) spectra were recorded using a Perkin-Elmer FTIR spectrometer.
The schematic representation of the current invention's process is as follows scheme-I

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 the compound of formula-1 (2,6-dichloro-5-fluoro nicotinamide).
A round bottom flask was charged with 2,6-dichloro-5-fluoronicotinonitrile (50 g), conc. sulphuric acid (250 mL) and gradually heated the reaction mass to 55-65°C and maintained the reaction for 2 hr at same temperature. Further, cooled the reaction mass and charged to water slowly at 5-15°C and stirred for 20 min at 20-30°C. Filtered the compound obtain and washed with water and sodium bicarbonate solution and dried to get the title compound.
Yield: 49.87 g
Example-2: Preparation of the compound of formula-2 (2-chloro-5-fluoronicotinamide).
A round bottom flask was charged with compound of formula-1 (50 g), zinc dust (34.4 g) and ammonium chloride (28 g in water 100 mL), methanol (150 mL) heated to 60-70°C and maintained the reaction mass for 6 hr at same temperature. Subsequently, cooled the reaction mass to 25-35°C and filtered the solid waste and distilled the resulting filtrate solution. The obtained residue compound was charged with water and stirred for 10 min, the precipitated solid was filtered and washed with water to get the title compound. Yield: 24 g.
Example-3: Preparation of the compound of formula-3 (2-chloro-5-fluoro nicotinonitrile).
A round bottom flask was charged with compound-1 (500 g), methanol (2500 mL), zinc dust (385.11 g) and acetic acid (345.56 g) were heated the reaction mass to 60-70°C, maintained for 6 hr at same temperature. Further, cooled the reaction mass to 25-35°C and filtered the solid waste and distilled-off the resulting filtrate solution to get the compound as residue. The residue compound was charged with ethyl acetate and stirred for 15 min at 25-35°C. The reaction solution was charged with water and stirred for 20 min and separated the layers. The aqueous layer was extracted with ethyl acetate and the combined organic layer was distilled-off the solvent completely to get the compound as residue.
The above residue compound was charged with dichloromethane (250 ml) and stirred for 15 min at 25-35°C, charged with triethylamine (423.1 g) and stirred for 10 min. Further, cooled the reaction mass to 0-5°C and charged POCl3 (320.43 g) slowly and maintained the reaction mass for 4 hr at 5-15°C. The reaction mixture was quenched with sodium bicarbonate solution and stirred the reaction for 10-15 min. Separated both layers, the aqueous layer was extracted with methylene chloride. The combined organic layer was washed with sodium bicarbonate solution and water subsequently. The organic layer was distilled-off completely under vacuum to get compound-3 as residue. Yield:350 g
Example-4: Preparation of the compound of formula-4 (5-fluoro-1H-pyrazolo [3,4-b] pyridin-3-amine).
A round bottom flask was charged with the above of compound-3, water (200 mL) and hydrazine hydrate (900 mL) at 25-35°C and heated to 60-70°C and stirred for 4 hr. Cooled the reaction mass to 25-35°C, charged with water (600 mL) and maintained the reaction mass at 10-15°C for 2 hr. Filtered the resulting solid and washed with water and dried to get the title compound. Yield: 135 g.
Example-5: Preparation of the compound of formula-5a (5-fluoro-3-iodo-1H-pyrazolo [3, 4-b]pyridine)
A round bottom flask was charged with compound-4 (100 g), tetrahydrofuran (l L) at 25-35°C and cooled the solution to 0-10°C and charged boron trifluoro diethyl etherate solution (89.39 g), isopentyl nitrite (100.4 g) and stirred the reaction mass for 2 hr at same temperature. Charged the reaction mixture with methyl tertiary butyl ether (1.5 L) and stirred for 1 hr and filtered the reaction mass, washed with methyl tertiary butyl ether to get the wet compound. In another RB flask charged acetone (1500 ml), sodium iodide (127.75 g) and the above wet compound at 0-10°C and stirred for 3 hr at 25-35°C. The reaction mixture was quenched with water and distilled off the solvent, the resulting solution was stirred for 2 hr. The obtained solid was filtered and washed with water and dried to get the title compound.
Yield: 100 g.
Example-6: Preparation of the compound of formula-5a (5-fluoro-3-iodo-1H-pyrazolo [3,4-b]pyridine)
A round bottom flask was charged with water (375 mL) and charged sulfuric acid (135 g) at 0-5°C and followed by compound-4(100 gr). Further, charged with a solution of sodium nitrite (14.97 g) the resulting diazotization mixture was stirred for 3 hr, at 0 to 5°C and 2 hr at 25-35°C. In another RBF charged with water (25 mL), sodium iodide (29.55), copper iodide (3.13 g) and stirred for 30 min at 25-35°C. To this solution, the above diazotization mixture was added slowly and stirred for 2 hr at 25-35°C. The reaction mixture pH was adjusted to 7.5 with ammonia solution, charged with ethyl acetate and sodium metabisulphate. Filtered the reaction mixture over hyflo and washed with ethyl acetate. The filtrate solution was separated, the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried and distilled-off completely.
The obtained compound was charged with water and stirred for 20 min, the resulting solid was filtered. The obtained wet compound was stirred in a mixture of water and sulfuric acid stirred for 1 hr and charged with water. Filtered the resulting solid and washed with water. The wet compound was charged with water, ammonia solution and stirred for 1 hr. Filtered the solid, the solid compound was charged with toluene and stirred for 1 hr at 60-70°C. The obtained solid was filtered and washed with water and dried to get the title compound.
Yield: 86 g.
Example-7: Preparation of the compound of formula-6a (5-fluoro-1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine)
A round bottom flask was charged with compound-5a (135 g), dimethyl formamide (1350 mL), potassium carbonate (106.25 g) and 2-fluoro benzyl chloride (89.03 g) at 25-35°C and maintained the reaction mass for 5 hr. The reaction mixture was quenched with water and stirred for 1 hr, filtered the reaction mass and washed with water and sodium bicarbonate solution and dried the compound to get the title compound. Yield: 102 g.
Example-8: Preparation of the compound of formula-6a (5-fluoro-1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine)
A round bottom flask was charged with compound-5a (70 g), dimethyl formamide (600 mL), potassium carbonate (49.5 g) and 2-fluoro benzyl bromide (116.41 g) at 25-35°C and maintained the reaction mass for 5 hr. The reaction mixture was quenched with water and stirred for 1 hr, filtered the reaction mass and washed with water and sodium bicarbonate solution and dried the compound to get the title compound. Yield: 62 g.
Example-9: Preparation of the compound of formula-7(5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridine-3-carbonitrile).
A round bottom flask was charged with compound-6 (100 g), dimethylformamide (500 mL), and copper cyanide (26.55 g) at 25-35°C, heated the reaction mass to 120-130°C and stirred for 8 hr at same temperature. Cooled the reaction mixture to 25-35°C, charged with water (1500 mL) and aqueous ammonia (500 mL) and ethyl acetate and stirred for 20 min. Filtered the reaction mass and washed with ethyl acetate and separated the layers. The aqueous layer was extracted with ethyl acetate and the combined organic layers were distilled-off completely to get the title compound. Yield: 75 g
Example-10: Preparation of the compound of formula-7(5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile).
A round bottom flask was charged with compound-6 (100 g), potassium ferrocyanide (50 g), t-BuXPhos Pd G3 (8 g), t-BuXPhos (4 g), dioxane (1000 mL) and water (1000 mL) followed by potassium acetate (4 g) at 25-35°C under a nitrogen atmosphere. The mixture was stirred at reflux temperature for 20-24 h and then distilled the reaction mass. The obtained residue was partitioned between ethyl acetate and brine solution. The organic layer was concentrated to give the crude product, was further stirred in methyl tert-butyl ether for 1 hr. The obtained solid was filtered and dried to get title compound. Yield: 75 g
Example-11: Preparation of the compound of formula-8a (5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide acetate).
A round bottom flask was charged with compound-7 (80 g), methanol (400 mL) and sodium methoxide solution (80 mL) at 25-35°C and stirred for 3 hr. The reaction mixture was quenched with ammonium chloride (16 g in water) stirred for 20 min, and charged with acetic acid (64 g) heated the reaction mass to 60-70°C and stirred for 8 hr. The reaction mixture was distilled-off completely, the resulting residue was charged with ethyl acetate and stirred for 30 min at 75-85°C. Cooled the reaction mixture to 25-35°C, the precipitated solid was filtered, the wet compound was charged with water and filtered to get the title compound as acetate salt. Yield: 45 g
Example-12: Preparation of the compound of formula-9 ((E)-2-(5-fluoro-1-(2-fluoro benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine)
A round bottom flask was charged with aniline (10 g), water (80 mL), and HCl (20 mL) were cooled to 0-10°, followed by charged with sodium nitrite (7.4 g in water) solution and stirred for 0.5 hr at same temperature. Subsequently, sodium acetate (11.4 g) solution and malononitrile (7 g in ethanol 24 mL) were added to the reaction mixture and stirred for 1.5 hr at 0-10°C. Filtered the resulting solid and washed with water to get the azo compound. In another round bottom flask was charged with compound of formula-8a (30 g), toluene (300 mL) potassium carbonate (23.8 g) and the above obtained azo compound and stirred for 4 hr at 50-60°. The reaction mixture was quenched with water, and stirred for 30 min. The resulting solid was filtered and washed with water to get the title compound. Yield: 33 g
Example-13: Preparation of the compound of formula-10 (2-(5-fluoro-1-(2-fluoro benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine)
An autoclave was charged with compound-9 (25 g), palladium carbon (2.5 g), and dimethyl formamide (500 mL) were stirred under hydrogen atmosphere for 6 hr at 60-65°C. Filtered the reaction mixture through hyflo bed and washed with methanol and evaporated the solvent to get the crude compound. Further, charged with ethyl acetate and stirred for 1 hr, filtered the reaction mixture and washed with ethyl acetate to get the title compound. Yield: 20 g
Example-14: Preparation of the compound of formula-10 (2-(5-fluoro-1-(2-fluoro benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine)
An autoclave was charged with compound-9 (25 g), Raney nickel (12.5 g), and dimethyl formamide (350 mL) were stirred under hydrogen atmosphere for 8 hr at 60-70°C. Filtered the reaction mixture through hyflo bed and washed with methanol and evaporated the solvent to get the crude compound. Further, charged with ethyl acetate and stirred for 1 hr, filtered the reaction mixture and washed with ethyl acetate to get the title compound. Yield: 21.5 g
Example-15: Preparation of the compound of formula-I
A round bottom flask was charged with compound-10 (25 g), tetrahydrofuran (175 mL) and sodium carbonate (11 g in water) and stirred for 1 hr at 25-35°C. Cooled the reaction mixture for 0-5°C, charged with methyl chloroformate solution (9.97 g in THF) slowly and stirred for 1 hr at same temperature. The reaction mixture was diluted with water and stirred for 1 hr, the precipitated solid was filtered and washed with water and dried to get the title compound.
Yield: 20 g; purity by HPLC >99 %; The obtained PXRD is similar to the in figure-1
Example-16: Preparation of the compound of formula-I
A round bottom flask was charged with compound-10 (25 g), tetrahydrofuran (175 mL) and sodium carbonate (11 g in water) and stirred for 1 hr at 25-35°C. Cooled the reaction mixture for 0-5°C, charged with methyl chloroformate solution (9.97 g in THF) slowly and stirred for 1 hr at same temperature. The reaction mixture was quenched with water and stirred for 1 hr, the precipitated solid was filtered and washed with water. The wet compound was charged with dimethyl sulfoxide (75 mL) and heated to 60-70°C and charged oxalic acid (15.2 g in ethyl acetate 500 mL) stirred reaction mixture for 1 hr. Cooled the reaction mixture to 25-35°C and stirred for 1 hr and filtered the solid compound, washed with ethyl acetate to obtain wet compound. The wet compound was charged with water and adjusted the pH to 9-10 with aq. ammonia solution and stirred for 10 min. The obtained solid was filtered and washed with water. The wet compound was charged with dimethyl sulfoxide and ethyl acetate and heated to 65-75°C, charged with carbon and filtered through hyflow and washed with ethyl acetate. The filtrate solution was charged to preheated mixture of ethanol and ethyl acetate solvents stirred for 2 hr at 60-70°C. Cooled the reaction mixture to 25-35°C, stirred for 1 hr and the resulting solid was filtered and washed with ethyl acetate and dried to get the title compound.
Yield: 18.4 g; purity by HPLC >99 %; The obtained PXRD is similar to the in figure-1.
Example-17: Purification of the compound of formula-I
A round bottom flask was charged with compound-I (25 g), dimethyl sulfoxide (75 mL) and heated to 60-70°C, and stirred for 1 hr at same temperature. Charge activated carbon and stirred for 30 min and filtered through hyflo and washed with ethyl acetate. The filtered solution was heated to 60-70°C and charged with a solution of oxalic acid (15.2 g in 50 ml of ethyl acetate) and stirred for 1 hr at same temperature. Cooled the reaction mixture for 25-35°C and stirred for 1 hr. Filtered the reaction mixture and washed with ethyl acetate, the resulting wet compound was charged with water and adjusted the pH to 9-10 with aq. ammonia solution and stirred for 1 hr. Filtered the solid and washed with water and dried to get the title compound.
Yield: 17.5 g; purity by HPLC >99.5%. The obtained PXRD is depicted in figure-1
Example-18: Preparation of oxalic acid salt of compound of formula-I
A round bottom flask was charged with compound-10 (10 g), tetrahydrofuran (100 mL) and sodium carbonate (5.2 g in water) and stirred for 1 hr at 25-35°C. Cooled the reaction mixture for 0-5°C, charged with methyl chloroformate solution (5 g in THF) slowly and stirred for 30 min at same temperature. The reaction mixture was quenched with water and stirred for 30 min, the precipitated solid was filtered and washed with water. The wet compound was charged with dimethyl sulfoxide (40 mL) and heated to 60-70°C and charged oxalic acid (7.4 g in ethyl acetate 200 mL) stirred reaction mixture for 30 min. Cooled the reaction mixture to 25-35°C and stirred for 1 hr and filtered the solid compound, washed with ethyl acetate and dried to obtain oxalic acid salt of compound of formula-I.
The obtained PXRD is depicted in figure-2
Example-19: Preparation of the compound of formula-1 (2,6-dichloro-5-fluoro nicotinamide).
A round bottom flask was charged with 2,6-dichloro-5-fluoronicotinonitrile (50 g), conc. sulphuric acid (270 g) and gradually heated the reaction mass to 55-65°C and maintained the reaction for 3 hr at same temperature. Further, cooled the reaction mass to 25-35°C, was charged to a precooled water (900 mL) at 5-15°C and stirred at 25-35°C for 20 min. Filtered the compound obtain and washed with water and sodium bicarbonate solution and dried to get the title compound. Yield: 49.87 g.
Example-20: Preparation of the compound of formula-4 (5-fluoro-1H-pyrazolo[3,4-b] pyridine-3-amine).
A round bottom flask was charged with compound-1 (500 g), methanol (2500 ml), zinc dust (344 g) and ammonium chloride (191.2 g) were heated to 60-70°C and maintained the reaction mass for 3 hr at same temperature. Cooled the reaction mass to 25-35°C and filtered the solid waste and washed the unwanted solid with methanol and distilled off the resulting filtrate solution. Cooled the obtain residue compound, charged with ethyl acetate (5000 mL), stirred for 10 min at 25-35°C and charged water (1000 mL) and stirred for 30 min, the precipitated solid was filtered and washed with ethyl acetate (250 mL) and separated both layers. The aqueous layer was charged with ethyl acetate (1000 mL), stirred for 30 min at 25-35°C and separated into layers. The combined organic layer was distilled off completely under vacuum, cooled the reaction mass to 25-35°C, charged methylene chloride (250 mL), stirred for 15 min and distilled off completely. The residue compound was cooled to 25-35°C charged methylene chloride stirred for 30 min at 25-35°C, filtered the precipitate and washed with methylene chloride (250 mL) and dried to obtain the crude wet compound-2. The above obtained wet compound was charged with dichloromethane (3000 ml) and triethylamine (845.57 g) at 25-35°C. Further, cooled the reaction mass to 0-5°C and added slowly POCl3 (365.98 g) and maintained the reaction mass for 3 hr at 5-15°C. The reaction mixture was quenched with aq. sodium bicarbonate solution and stirred for 10-15 min. Separated both layers, the aqueous layer was extracted with methylene chloride. The combined organic layer was washed with sodium bicarbonate solution and water subsequently and distilled-off the organic layer completely under vacuum to get compound-3 as residue.
The above obtained wet compound-3 was charged with hydrazine hydrate (1750 g) at 25-35°C and heated to 50-60°C and maintained the reaction mass for 3 hr at same temperature. Cooled the reaction mass to 25-35°C, charged with water (1500 mL) and maintained the reaction mass at 25-35°C for 2 hr and filtered the resulting solid compound and washed with water and dried to get the title compound. Yield: 164.63 g.
Example-21: Preparation of the compound of formula-5a (5-fluoro-3-iodo-1H-pyrazolo [3,4-b] pyridine).
A round bottom flask was charged with compound-4 (50 g), water (750 mL), sulphuric acid (270 g), cooled the reaction mass to 0-10°C, gradually added sodium nitrite (29.4 g), and stirred for 2 hr at same temperature. Further the reaction mass temperature was raised to 25-35°C and charged to a solution of water (500 mL), sodium iodide (59.1 g), copper iodide (6.26 g) at 25-35°C and maintained for 2 hr at the same temperature. The reaction mass was charged with ethyl acetate (500 mL), aq. sodium metabisulphite and stirred for 20 min at same temperature and filtered the reaction mass through hyflo and washed with ethyl acetate and suck dried. The above unwanted compound was charged into another RB flask and followed by addition of ethyl acetate (500 mL), stirred for 30 min at 25-35°C. Filtered the reaction mass, washed with ethyl acetate (100 mL) and suck dried. The filtrate is collected and charged into another RB flask, stirred for 30 min and separated into two layers. The aqueous layer was charged with ethyl acetate, stirred for 20 min at 25-35°C and separated into two layers. All the organic layers are combined and charged into RB flask at 25-35°C, charged water (150 mL), aq. ammonia (100 mL), stirred for 20 min at 25-35°C and separated into two layers. Distilled off the organic layer completely under vacuum, cooled the reaction mass to 25-35°C, charged with water (150 mL), stirred for 20 min at 25-35°C, filtered the solid and suck dried. To another RB flask, the above compound was charged, followed by addition of aq. sodium metabisulphite at 25-35°C, stirred for 20 min at same temperature and filtered the solid at 25-35°C, washed with water and suck dried. To another RB flask charged the above wet compound, charged aq. sodium hydroxide at 25-35°C, maintained the reaction mass at 25-35°C for 90 min, filtered the solid at 25-35°C and washed with water and dried to obtain the title compound. Yield: 45.0 g.
Example-22: Preparation of the compound of formula-6a (5-fluoro-1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridine)
A round bottom flask was charged with compound-5a (75g), dimethyl formamide (375 mL), potassium carbonate (59.01 g) and 2-fluoro benzyl chloride (49.44 g) at 25-35°C and maintained the reaction mass for 4 hr, Cooled the reaction mass to 15-25°C, quenched with water (750 mL) and stirred the reaction mass at 25-35°C for 1 hr. Filtered the reaction mass and washed with water (150 mL) and dried. The obtained compound was charged to pre-mixed solution of sodium bicarbonate (36 g) and water (450 mL) and heated the reaction mass to 55-65°C, stirred for 1 hr. Filtered the reaction mass and washed with water and suck dried. The obtained solid was charged with methanol, cyclohexane and heated to 55-65°C, maintained the same temperature for 1 hr and filtered the obtained solid and washed with methanol and dried to get the title compound. Yield: 81.39 g.
Example-23: Preparation of the compound of formula-8a (5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide acetate).
A round bottom flask was charged with compound-6a (100 g), dimethylformamide (500 mL), and copper cyanide (36.14 g) at 25-35°C were heated to 120-130°C and maintained for 10 hr at same temperature. Cooled the reaction mixture to 25-35°C, charged with aqueous ammonia (500 mL) and stirred for 10 min. The reaction mixture was added to water (1500 mL) at 0-10°C, stirred for 20 min and charged with ethyl acetate (800 mL) and stirred for 20 min. Filtered the reaction mass and washed with ethyl acetate and separated the layers. The aqueous layer was extracted with ethyl acetate and the combined organic layers were distilled-off completely. The obtained residue was charged with methanol (100 mL) at 25-35°C, stirred for 15 min and distilled off the solvent completely to get the crude compound of formula-7
The above obtained compound was charged with methanol (600 mL) and sodium methoxide solution (80 mL) at 25-35°C and stirred for 10 min and maintained at same temperature for 4h. The reaction mixture was quenched with ammonium chloride (14.4 g) stirred for 15 min, and charged with acetic acid (64.56 g) heated the reaction mass to 60-70°C and maintained for 11 hr. The reaction mixture was distilled-off completely, the resulting residue was charged with ethyl acetate and water stirred for 1hr at 75-85°C. Cooled the reaction mixture to 25-35°C, charged water (500 mL), and stirred for 45 min at 25-35 ° C. The precipitated solid was filtered, the wet compound was charged with water and ethyl acetate and suck dried. The obtained compound was charged with dichloromethane, stirred for 30 min at 40-50°C. Cooled the reaction mass and filtered and washed with dichloromethane and dried to get the title compound. Yield: 44.81 g
Example-24: Preparation of the compound of formula-9 (2-(5-fluoro-1-(2-fluoro benzyl)-1H-pyrazolo [3,4-b]pyridin-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine)
A round bottom flask was charged with aniline (20.11 g), water (165 mL), and HCl (39 mL) were cooled to 0-10°C, followed by charged with sodium nitrite (15.5 g in water) solution and maintained for 15 min at same temperature. Subsequently added sodium acetate (23 g) solution and malononitrile (14.25 g in ethanol 52.5 mL) to the reaction mixture and stirred for 1hr at 0-10°C. Filtered the resulting solid and washed with water (25 mL) to get the azo compound as crude. In another round bottom flask was charged with compound-8a (50 g), toluene (1 L), potassium carbonate (39.7 g) and the above obtained azo compound and heated the reaction mass to 55-65°C and stirred for 4 hr at same temperature. Cooled the reaction mixture, quenched with water, stirred for 1 hr at same temperature. The resulting solid was filtered and washed with water and suck dried. The obtained compound was charged with N-methyl-2-pyrrolidone, heated the reaction mass to 50-60°C, stirred for 1 hr at same temperature. Cooled the reaction mixture, charged with water and stirred for 2 hr and filtered and dried to get the title compound. Yield: 47.3 g
Example-25: Preparation of the compound of formula-10 (2-(5-fluoro-1-(2-fluoro benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine)
An autoclave was charged with compound-9 (100 g), palladium carbon (15 g), and dimethyl formamide (2200 mL) were stirred under hydrogen atmosphere (~10 kg ) for 16 hr at 25-35°C. Cooled the reaction mass , quenched with water, and cooled to 25-35°C and filtered the reaction mixture through hyflo bed and washed with methanol (200 mL) and distilled off completely, The obtained residue was charged with ethyl acetate (300 mL), heated the reaction mass to 70-80°C, and stirred for 1 hr at same temperature. Filtered the obtained compound and further charged the resulting compound with water and heated to 55-65°C stirred for 1 hr. Filtered the obtained solid and washed with water to get the title compound. Yield: 78.4 g
Example-26: Preparation of the compound of formula-I
A round bottom flask was charged with compound-10 (100 g), tetrahydrofuran (1000 mL) and sodium carbonate (43.16 g in water) and stirred for 45 min at 25-35°C. Cooled the reaction mixture for 0-5°C, charged with methyl chloroformate solution (38.78 g in THF) slowly and stirred for 5 hr at same temperature. The reaction mixture was quenched with water and stirred for 1hr, the precipitated solid was filtered and washed with water and methanol. The obtained compound was slurried in methanol and filtered the compound. The isolated compound was charged with DMSO (600 mL) and heated to 70-80° C for 1 hr and charged to methanol (1 L) at 55-65°C and stirred for 2 hr at same temperature. Cooled the reaction mixture to 25-35°C, filtered the compound and washed with methanol. The obtain compound was charged with DMSO (300 mL) and stirred for 15 min at 65-75°C, Cooled the reaction mass was charged with oxalic acid (85.56 g in acetone 700 mL) and stirred for 90 min. Cooled the reaction mixture to 25-35°C and stirred for 1 hr and filtered the obtain solid compound, washed with acetone to obtain the oxalate salt compound. The obtain compound was charged with water (1.5 L) and stirred for 15 min at same temperature and adjusted the pH to 9-10 with aq. ammonia solution (100 mL) and stirred for 1 hr. Filtered the obtain solid and washed with water and dried to get the title compound. Yield: 67.1 g.
PSD: D90 <75 µm, D50 <45 µm. D10 <15 µm
Example-27: Purification of the compound of formula-I (crystalline form I)
A round bottom flask was charged with compound-I (100 g), dimethyl sulfoxide (300 mL) and heated to 70-80°C, and stirred for 45 min at same temperature. Charge activated carbon (15 g) and stirred for 45 min and filtered through hyflo and washed with ethyl acetate (200 mL). The filtered solution was heated to 70-80°C and charged with a solution of oxalic acid (73.91 g in 2000 ml of ethyl acetate) and stirred for 30 min at same temperature. Cooled the reaction mixture to 25-35°C and stirred for 1 hr, filtered the reaction mixture and washed with ethyl acetate. The resulting wet compound was charged with aq. sodium bicarbonate solution (120 g in 2000 mL) and stirred for 5 hr at 25-35°C. Filtered the obtained compound and washed with water. The obtained wet compound was charged with water (3 L) and stirred for 12 hr at 90-100°C and filtered the solid and washed with water and dried to get the title compound. Yield: 89.6 g.
Example-28: Purification of the compound of formula-I (crystalline form I)
A round bottom flask was charged with compound-I (10 g), dimethyl sulfoxide (30 mL) and heated to 70-80°C, and stirred for 45 min at same temperature. Charge activated carbon and stirred for 45 min and filtered through hyflo and washed with ethyl acetate (20 mL). The filtrated solution was heated to 70-80°C and charged with a solution of oxalic acid (7.3 g in 200 ml of ethyl acetate) and stirred for 30 min at same temperature. Cooled the reaction mixture to 25-35°C and stirred for 1 hr, filtered the reaction mixture and washed with ethyl acetate. The resulting wet compound was charged into a suspension of dimethyl sulfoxide, aq. sodium bicarbonate (12 g in 200 mL) and stirred for 5 hr at 25-35°C. Filtered the obtained compound and washed with water. The obtained wet compound was again charged into a solution of aq. sodium bicarbonate and stirred for 5 hr 25-35°C and filtered the solid and washed with water and dried to get the title compound. Yield: 8.0 g.
Example-29: Purification of the compound of formula-I (crystalline form I)
A round bottom flask was charged with compound-I (10 g), dimethyl sulfoxide (30 mL) and heated to 70-80°C, and stirred for 45 min at same temperature. Charge activated carbon and stirred for 45 min and filtered through hyflo and washed with ethyl acetate (20 mL). The filtrated solution was heated to 70-80°C and charged with a solution of oxalic acid (7.3 g in 200 ml of ethyl acetate) and stirred for 30 min at same temperature. Cooled the reaction mixture to 25-35°C and stirred for 1 hr, filtered the reaction mixture and washed with ethyl acetate. The resulting wet compound was charged into a suspension of dimethyl sulfoxide, aq. sodium bicarbonate (12 g in 200 mL), crystalline form-I seeding material and stirred for 5 hr at 25-35°C. Filtered the obtained compound and washed with water. The obtained wet compound was again charged into a solution of aq. sodium bicarbonate and stirred for 5 hr 25-35°C and filtered the solid and washed with water and dried to get the title compound. Yield: 8.0 g.
Example-30: Purification of the compound of formula-I (crystalline form I)
A round bottom flask was charged with compound-I (10 g), dimethyl sulfoxide (30 mL) and heated to 70-80°C, and stirred for 45 min at same temperature. Charge activated carbon and stirred for 45 min and filtered through hyflo and washed with ethyl acetate (20 mL). The filtrated solution was heated to 70-80°C and charged with a solution of oxalic acid (7.3 g in 200 ml of ethyl acetate) and stirred for 30 min at same temperature. Cooled the reaction
mixture to 25-35°C and stirred for 1 hr, filtered the reaction mixture and washed with ethyl acetate. The resulting wet compound was charged into a suspension of dimethyl sulfoxide, ethanol, aq. sodium bicarbonate (12 g in 200 mL), crystalline form-I seeding material and stirred for 5 hr at 25-35°C. Filtered the obtained compound and washed with water. The obtained wet compound was again charged into a solution of aq. sodium bicarbonate and stirred for 5 hr 25-35°C and filtered the solid and washed with water and dried to get the title compound. Yield: 8.0 g.

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

Formula-I
a) Reacting 2, 6-dichloro-5-fluoronicotinonitrile in presence of suitable reagent, solvent to provide compound of formula-1,

Formula-1
b) reacting of compound of formula-1 in presence of suitable reagent, solvent to provide compound of formula-2,

Formula-2 Formula-3
c)reacting the compound obtained in step-b) with suitable reagent, solvent to provide compound of formula-3,
d) optionally reacting the compound 2,6-dichloro-5-fluoronicotinonitrile with suitable reagent, solvent to provide compound of formula-3,
e) reacting the compound obtained in step-c) or d) with suitable reagent, solvent to provide compound of formula-4,
f) reacting the compound obtained in step-e) with suitable reagent, solvent to provide compound of formula-5 (X : Cl/ Br/ I),

Formula-4 Formula-5
g) reacting the compound obtained in step-f) with suitable reagent, solvent to provide compound of formula-6 (X : Cl/ Br/ I),

Formula-6 Formula-7
h) reacting the compound obtained in step-g) with suitable reagent, solvent to provide compound of formula-7
i) reacting the compound obtained in step-h) with suitable reagent, solvent to provide compound of formula-8 or salts thereof,

Formula-8
j) reacting the compound obtained in step-i) with suitable reagent, solvent to provide compound of formula-9 or salts thereof,
k)reacting the compound obtained in step-j) with suitable reagent, solvent to provide compound of formula-10 or salts thereof,

Formula-9 Formula-10
l)reacting the compound obtained in step-k) with suitable reagent, solvent to provide compound of formula-I or salts thereof,
m) optionally purifying the compound obtained in the above steps with suitable acid, base in suitable solvent to provide the pure compound,
2. A process for preparation of compound of formula I according to claim 1 wherein in step-a) the suitable reagents are selected from sulfuric acid, wherein in step-b), d) the suitable reagents are selected from zinc, iron, acetic acid, ammonium chloride, hydrochloride and any mixture thereof, wherein in step-c) the suitable reagents are selected from phosphorous oxychloride, trifluoro acetic anhydride, organic base and any mixture thereof, wherein in step-e) the suitable reagents are selected from hydrazine hydrate, aqueous hydrazine hydrate, wherein in step-f) the suitable reagents are selected from boron trifluoride etherate, isoamyl nitrite, tert-butyl nitrite, NaI, NaBr, NaCl, CuI, CuBr, CuCl, sulfuric acid, hydrochloric acid, sodium nitrite, trifluoro methane sulphonic acid and nitric acid or mixture thereof, wherein in step-g) the suitable reagents are selected from 2-fluorobenzyl chloride, 2-fluorobenzyl bromide, 2-fluoro benzyl iodide, 2-fluoro benzyl tosylate, 2-fluoro benzyl mesylate / 2-fluoro benzyl sulfonate, organic base, inorganic base and any mixture thereof.
wherein in step-h) the suitable reagents are selected from CuCN, NaCN, KCN, Zn(CN)2, K4Fe(CN)6, ligands are selected from tBuXPhos Pd(dba)3, palladium catalyst, Pa(OAc)2 , palladium tetrakis, Pa(OH)2, tBuXPhos, Xphos, , triphenyl phosphine,; ammonium chloride, acetic acid, HCl, HBr, trifluoroacetic acid, organic bases such as sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium t-butoxide, triethylamine and any mixture thereof; wherein in step-i) the suitable reagents are selected from aniline, malononitrile, sodium nitrite, Con. HCl, sodium acetate, potassium acetate, organic base, inorganic base and any mixture thereof. wherein in step-j) the suitable reagents are selected from Pd/C, hydrogen gas, Raney nickel, ammonium chloride, acetic acid, zinc, iron, ammonium acetate, ammonium formate and any mixture thereof. wherein in step-k) the suitable reagents are selected from methylchloro formate, organic base, inorganic base, organic acid, inorganic acid, and any mixture thereof.
3. An improved process for the preparation of vericiguat compound of formula- I,
Comprising of:
a) Reacting 2, 6-dichloro-5-fluoronicotinonitrile in presence of Con. sulfuric acid to provide compound of formula-1,

Formula-1
b) reacting of compound of formula-1 with zinc, ammonium chloride in methanol to provide compound of formula-2,

Formula-2 Formula-3
c)reacting the compound obtained in step-b) with phosphorous chloride, triethylamine in dichloromethane to provide compound of formula-3,
e) reacting the compound obtained in step-c) hydrazine hydrate to provide compound of formula-4,

Formula-4 Formula-5a
f) reacting the compound obtained in step-e) with sodium nitrite, sulfuric acid, sodium iodide, copper iodide in water to provide compound of formula-5a,
g) reacting the compound obtained in step-f) with 2-fluorobenzyl chloride in presence of potassium carbonate in DMF to provide compound of formula-6a,

Formula-6a Formula-7
h) reacting the compound obtained in step-g) with copper cyanide in DMF to provide compound of formula-7,
i) reacting the compound obtained in step-h) with sodium methoxide, ammonium chloride in methanol, acetic acid to provide compound of formula-8a

Formula-8a
j) reacting the compound obtained in step-i) with 2-(phenyldiazenyl) malononitrile in presence of potassium carbonate in toluene to provide compound of formula-9,
k) reacting the compound obtained in step-j) with palladium carbon under hydrogen gas atmosphere in DMF to provide compound of formula-10,
l) reacting to the compound obtained in step-k) with methyl chloroformate in presence of sodium carbonate in water, tetrahydrofuran to provide compound of formula-I .
m) treating the compound obtained in step-i) in DMSO with oxalic acid and acetone or ethyl acetate to provide vericiguat oxalate salt,
n) basifying the compound obtained in step-m) with ammonia or sodium bi carbonate in water and to provide pure compound-I
4. An improved process for crystalline from I of compound of formula-I
Comprising of:
a) dissolving the compound of formula-I in DMSO,
b) adding the solution obtained in step-a) to oxalic acid in acetone or ethyl acetate,
c) isolating the compound obtained in step-b) as vericiguat oxalic acid salt,
d) treating the compound obtained in step-c) with ammonia or sodium carbonate in water to get pure compound of formula-I.
e) optionally, treating the compound obtained in step-c) with mixture of DMSO and aqueous sodium bicarbonate solution or mixture of DMSO, ethanol and aqueous sodium bicarbonate, or mixture of ethanol and aqueous sodium bicarbonate solution to provide pure crystalline form I.
5. An improved process for crystalline from I of compound of formula-I
Comprising of:
a) dissolving the compound of formula-I in suitable solvent,
b) adding the solution obtained in step-a) to suitable acid alone or in suitable solvent
c) isolating the compound obtained in step-b) as vericiguat acid addition salt,
d) treating the compound obtained in step-c) with suitable base to get pure crystalline form I of compound of formula-I.
e) optionally treating the compound obtained in step-c) with a mixture of polar solvent and / or alcohol solvent with aqueous base solution to provide pure crystalline form I of compound of formula-I.
6. A process for crystalline form I of compound of formula I according to claim 1, 6 wherein in 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; 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; organic base, inorganic base, and mixture thereof, suitable temperature 0 -150°C.
7. Vericiguat according to the preceding claims is having particle size distribution of D90 <300 µm, D50 <150 µm. D10 <75 µm.
8. Vericiguat 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.