DESC:FIELD OF THE INVENTION:
The present invention relates to a process for preparation of Riociguat (I).

The present invention also relates to process for purification of Riociguat (I).

BACKGROUND OF THE INVENTION:
Methyl-4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b] pyridin-3-yl] -5-pyrimidinyl (methyl) carbamate (herein Riociguat) structurally represented by Formula (I), also known as Adempas®, is an orally active drug used for treatment of Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH). It has a molecular formula of C20H19FN8O2 with molecular weight of 422.42.

US7173037 (US’037) describes method for preparation of Riociguat (I) as depicted in Scheme –1. US’037 involves use of Reverse Phase HPLC method for purification of Riociguat with an overall yield of 24.0%.

J. Mittendorf et al., Chem. Med. Chem 2009, 4, 853-865, describes an alternative method to the process described in Scheme -1, wherein the trisamino compound (V) is isolated as trihydrochloride and the HCl-free base is then generated by extraction with NaHCO3 solution and the free base is reacted with methylchloroformate in pyridine solvent to provide compound of formula (VI). J. Mittendorf also involves use of flash chromatography method for purification of the intermediates and Riociguat with an overall yield of 24%.

The process described in US’037 and J. Mittendorf et al poses the following limitations:
1) process is not feasible at industrial scale as it results in less yield;
2) process involves use of hazardous and pyrophoric base sodium hydride; and moisture sensitive and expensive LiHMDS for methylation reaction which makes the process less user friendly;
3) pyridine used for the condensation reaction (step –c) is carcinogenic and industrially not preferable;
4) involves use of expensive preparative RP-HPLC method and flash chromatography for purification of the intermediates and crude Riociguat which is expensive, time consuming and not industrially feasible;
5) isolation of trisamino compound (V) as a trihydrochloride involves use of acid-proof industrial plant, which is industrially not feasible.
6) Use of highly flammable diethylether for purification of intermediate compound (VI) is not user friendly and feasible at industrial scale.

Hence, one of the objective of the present invention is to provide an improved process for preparation of Riociguat, thereby providing a solution to substantially eliminate the problems associated with the prior arts. Another objective of the present invention is to provide a comparatively simple purification method, which is suitable for large-scale production such that the process is safe, labor friendly and, resulting in high yield and purity of the product.

OBJECTS OF THE PRESENT INVENTION:
The primary object of the present invention is to provide an improved process for preparation of Riociguat (I), which is efficient, economic, simple, and industrially viable.

Yet another object of the present invention is to provide an industrially feasible process for purification of Riociguat (I).

Yet another object of the present invention is to provide an industrially feasible process for purification of intermediates of Riociguat (I).

Yet another object of the present invention is to provide a process for preparation crystalline form Modification-I of Riociguat (I).

BRIEF DESCRIPTION OF DRAWING:
Figure - 1: X-ray powder diffraction ('XRD') pattern of crystalline form modification-I of Riociguat (I).

DETAILED DESCRIPTION OF THE INVENTION:
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having", means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims.

In one of the embodiments, the present invention provides a process for preparation of Riociguat (I), the said process comprising:
a. condensing HCl salt of compound of formula (II) with a compound of formula (III) in a suitable solvent and in presence of an alkali metal carbonate to provide a compound of formula (IV);

b. reducing the compound of formula (IV) in presence of a reducing agent under hydrogen pressure in a suitable solvent selected from dialkylformamides, cyclic amide, alcohol or mixtures thereof to provide a compound of formula (V);

c. condensing the compound of formula (V) with a methyl chloroformate in a suitable solvent and in presence an alkali metal carbonate to provide a compound of formula (VI); and

d. methylating the compound of formula (VI) using an iodo methane in a suitable solvent selected from ketone, nitriles or mixture thereof, in presence of an alkali metal hydroxides, and water to provide Riociguat of formula (I), and isolating and purifying Riociguat of formula (I).

Addition of water in step (d) helps to control the impurity observed at Relative Retention Time 1.47 by HPLC in Riociguat, which is further identified as compound of formula (IMP-A).

Compounds of formulae (IV), and (VI) obtained in steps (a) and (c) respectively, can be isolated from the reaction mass.

The suitable solvent used in step (a) is selected from aromatic hydrocarbon such as toluene or xylene; nitrile such as acetonitrile or propionitrile; alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol or t-butanol; ketone such as acetone, methyl isobutyl ketone, or ethyl methyl ketone; cyclic ether and substituted cyclic ethers, such as diethyl ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 1,4-dioxan, or 2-methyl tetrahydrofuran or mixture thereof.

The suitable solvent used in step (c) is selected from aromatic hydrocarbon such as toluene or xylene; nitrile such as acetonitrile or propionitrile; alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol or t-butanol; ketone such as acetone, methyl isobutyl ketone, or ethyl methyl ketone; cyclic ether and substituted cyclic ethers, such as diethyl ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 1,4-dioxan, or 2-methyl tetrahydrofuran; halogenated hydrocarbon such as dichloromethane, or dichloroethane; dialkylformamides such as dimethyl formamide or mixture thereof.

The reducing agent used in step (b) of the embodiment is selected from industrially customary Raney Nickel or Pt/carbon or Pd/carbon catalysts. Preferably, the reaction is carried out in most economic catalyst Raney Nickel.
Steps (a) and (b) of the embodiment are carried out at a temperature of 0°C to the reflux temperature of the solvent. Preferably, in the temperature range of 25°C to 150°C. More preferably, temperature is 50°C to 135°C.

Step (b) of the embodiment is carried out at pressure 2-90 bar, preferably 5-70 bar of hydrogen, over a period of 1-3 h.

Step (c) of the embodiment is carried out at a temperature of 0°C to the reflux temperature of the solvent. Preferably, in the temperature range of 0°C to 90°C. More preferably, temperature is 5°C to 45°C.

Step (d) of the embodiment is carried out at a temperature of 0°C to the reflux temperature of the solvent. Preferably, in the temperature range of 0°C to 50°C. More preferably, temperature is 0°C to 30°C.

Compound of the formula (IV) is isolated from the reaction mass of step (a), followed by optional purification, wherein the said process comprises the steps of:
i. adding water to the reaction mass, heating to 50° C to 55° C and cooling the reaction mass to 25° C to 30° C to obtain solid; and
ii. filtering the obtained solid, washing the obtained solid with water, methanol or mixture thereof, and drying to provide pure compound of formula (IV).

Compound of formula (IV) can be optionally purified by slurrying the obtained solid in step (ii) in alcohol, nitrile, water or mixture thereof; heating the resulting reaction mass to reflux temperature of the solvent; cooling the reaction mass to 25 °C to 35 °C; filtering, washing and drying the solid to provide pure compound of formula (IV).

Compound of the formula (V) is isolated from the reaction mass of step (b), followed by optional purification, wherein the said process comprises the steps of:
i. filtering the reaction mass of step (b) to remove the catalyst;
ii. concentrating filtrate under reduced pressure at a temperature of 50° C to 90° C to obtain residue, diluting the residue with suitable organic solvent, cooling the reaction mass to obtain solid, filtering and drying to provide compound of formula (V); and
iii. optionally treating the compound of formula (V) of step (ii) in a solvent, heating the obtained reaction mass to reflux temperature and cooling the reaction mass, filtering and drying to provide pure compound of formula (V).

The solvent used in steps (ii) and (iii) may be either same or different and is selected from the group comprising of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, pentane; aromatic hydrocarbons such as but not limited to toluene, xylene; dialkylformamides such as but not limited to dimethyl formamide; alcohols such as but not limited to methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, n-pentanol, ethylene glycol, diethylene glycol; ketones such as but not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone; dialkylsulfoxides such as but limited to dimethyl sulfoxide; dialkylacetamides such as but not limited to ?,?,-dimethyl acetamide; cyclic amide such as but not limited to N-methyl-2-pyrrolidone; nitriles such as but not limited to acetonitrile; water or mixtures thereof.

Compound of the formula (VI) is isolated from the reaction mass of step (c), followed by purification, wherein the said process comprises the steps of:
i. filtering the cooled reaction mass of step (c) to obtain solid containing compound of formula VI and alkali metal carbonate, washing the solid with acetone, dichloromethane or mixture thereof, slurrying obtained solid in dimethylformamide and water, heating, cooling and filtering the mixture to obtain crude compound of formula (VI); OR
i. quenching reaction mass of step (c) with water, extracting the compound (VI) into 2-methyl tetrahydrofuran, washing the organic layer with brine, concentrating the said separated organic layer to obtain residue, slurrying the residue in dimethylformamide and water, heating, cooling and filtering the mixture to obtain crude compound of formula (VI); and
ii. treating obtained crude compound of formula (VI) in dimethyl formamide and toluene, heating to reflux temperature of the solvent, cooling the reaction mass to obtain solid, filtering and washing the solid with toluene, and drying the obtained solid to provide pure compound of formula (VI).

Compound of the formula (I) is isolated from reaction mass of step (d) wherein the said isolation process comprises:
i. adding water to the reaction mass;
ii. concentrating the organic portion under reduced pressure to obtain slurry;
iii. diluting the obtained slurry of step (ii) in water, cooling to 10° C to 30° C; and
iv. filtering and washing the solid with water to obtain crude Riociguat (I).

Another embodiment of the present invention provides a process for purification of Riociguat (I), the said process comprising:
A. dissolving crude Riociguat (I) in N-methyl pyrrolidone (NMP) or N, N-Dimethylacaetamide (DMA) as a solvent ;
B. adding an anti-solvent to precipitate a solid, filtering and washing solid with the said anti-solvent to provide Riociguat (I) with purity of 99% by HPLC;
C. dissolving the Riociguat (I) obtained in step (B) in NMP or DMA;
D. adding an anti-solvent to the contents of (C) to precipitate a solid, filtering and washing solid with said anti-solvent to provide Riociguat (I) with purity of 99% by HPLC;
E. Decolorizing the obtained Riociguat (I) in step (D) in a solvent with activated charcoal, filtering charcoal and concentrating the solvent to provide residue of Riociguat (I) free from colored impurities; and
F. crystallizing the Riociguat (I) obtained in step (e) in a solvent, filtering and drying the obtained pure Riociguat Modification –I

Riociguat (I) may be either the crude Riociguat (I) obtained from the reaction mass of step (d) or may be obtained by any of the process known in the art.

The anti-solvent used in step (B) and (D) may be either same or different and is selected from the group comprising of hydrocarbons selected from hydrocarbons selected from cyclohexane, n-hexane, n-heptane, and pentane, aromatic hydrocarbons selected from benzene, toluene, xylene, naphthalene; ethers selected from methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether and di-methyl ether, methyl butyl ether; alcohols selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol; alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate; nitriles such as but not limited to acetonitrile; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride; water or mixture thereof. Preferably, the anti-solvent used in steps (B) is aromatic hydrocarbons such as toluene, and step (D) is water

The solvent used for the step (E) is an organic solvent selected from the group consisting of halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride; dialkylformamides such as but not limited to dimethyl formamide; alcohols such as but not limited to methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, n-pentanol; ketones such as but not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone; dialkylacetamides such as but not limited to ?,?,-dimethyl acetamide; cyclic amide such as N-methyl-2-pyrrolidone or mixtures thereof. Preferably the solvent is selected from halogenated aliphatic hydrocarbons such as dichloromethane, alcohol such as methanol or mixture thereof.

The solvent used for the step (F) is an organic solvent selected from the group consisting of alkyl acetate such as but not limited to ethyl acetate, isopropyl acetate; aromatic hydrocarbons such as but not limited to toluene, xylene, naphthalene; halogenated aliphatic hydrocarbons such as but not limited to are dichloromethane, chloroform, ethylene dichloride; cyclic ethers such as but not limited to tetrahydrofuran, 1,4-dioxane; substituted cyclic ethers such as but not limited to 2-methyl tetrahydrofuran; alcohols such as but not limited to methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, n-pentanol, ethylene glycol, diethylene glycol; esters; ketones such as but not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone; nitriles such as but not limited to acetonitrile; water or mixtures thereof. Preferably the solvent used for step (F) is selected from alcohol such as methanol, alkyl acetate such as but not limited to ethyl acetate or mixture thereof.

Pure Riociguat (I) obtained in step (F) is Modification –I polymorphic form having XRPD as depicted in Fig. 1.

Riociguat obtained from the process of the present invention is substantially free from process related impurities, by products, carry over impurities and degradation impurities. Riociguat obtained from the process of the present invention has a purity of at least 99.0% by HPLC.

BEST MODE OR EXAMPLES FOR WORKING OF THE INVENTION
The present invention is described in the examples given below; further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention.

EXAMPLE-1: 2-[1-(2-fluorobenzyl)-1H-pyrazolo [3, 4-b] pyridine-3-yl]-5-[(E) phenyldiazenyl] 4, 6-pyrimidinediamine (IV)
To a solution of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride (100.0 gm, 0.327 mol) in toluene (1000 ml) was added potassium carbonate (90.40 gm, 0.654 mol) at 25-30° C, followed by addition of [(E)-phenyldiazenyl]malononitrile (58.64 gm, 0.343 mol). The reaction mass was heated to 50-55° C and stirred for 3-8 hr. Progress of reaction was monitored by HPLC. Upon completion of reaction, purified water was added to this reaction mass at temperature 50-55° C and stirred for 45-60 minutes. The resulting suspension was gradually cooled to 25-30° C and reaction mass was maintained at 25-30° C for 60-90 min. Obtained solid was filtered, washed with purified water (200 ml) and followed by methanol (500 ml), suck dried and dried at 55-60°C to afford of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-[(E)phenyldiazenyl] 4,6-pyrimidinediamine. [Yield= 139.0gm (96.71%); Purity (HPLC)=99.30 %]
Melting point: 269-271 °C. (M + H)+/z= 440.0. 1H NMR (DMSO): d 9.18-9.21 (dd, 1 H), 8.64-8.66 (dd, 1H), 8.50 (bs, 2H), 8.00-8.03 (dd, 2H), 7.89 (bs, 2H), 7.46-7.50 (m, 2H), 7.33-7.42 (m, 3H), 7.21-7.28 (m, 1H), 7.08-7.20 (m, 2H). 13C NMR (DMSO): d 161.14, 160.62, 158.70, 158.32, 152.56, 150.86, 149.19, 141.13, 133.97, 129.93-130.12, 128.89-129.06, 124.65-124.67, 123.91-124.06, 121.99, 118.40, 115.63, 115.42, 115.08, 112.11, 44.15.

EXAMPLE-2: 2-[1-(2-fluorobenzyl)-1H-pyrazolo [3, 4-b] pyridin-3-yl] -4, 5, 6-pyrimidine triamine (V)
In pressure autoclave, 2-[1-(2-fluorobenzyl)-1H-pyrazolo [3, 4-b] pyridine-3-yl]-5-[(E) phenyldiazenyl] 4, 6-pyrimidinediamine (100.0 gm, 0.227 mol) was added in DMF (2000 ml), followed by addition of water, moist Raney/Nickel (50.0 gm) at 25-30°C. After inertization with nitrogen, hydrogenated at hydrogen pressure of 60 bar and internal temperature at 60-65° C for 1-3 hrs. Upon completion of reaction, the reaction mass was cooled to 25-30° C, venting and inertization, catalyst was filtered off and washed with DMF (100 ml). Filtrate was concentrated at 80-85°C under reduced pressure to produce 2-[1-(2-fluorobenzyl)-1H-pyrazolo [3, 4-b] pyridin-3-yl] -4, 5, 6-pyrimidine triamine as a crude residue. Obtained residue was slurried in toluene (1000 ml) at 70-75°C, stirred and maintained for 30 min. The resulting suspension was gradually cooled to 25-30° C and maintained reaction mass at 25-30°C for 45-60 min. Obtained solid was filtered, washed with toluene (100.0 ml), suck dried and dried at 55-60° c for 3-4 hrs. to afford 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl] -4,5,6-pyrimidine triamine. [Yield = 76.50 gm (96.0%); Purity (HPLC) = 99.0%]
Melting point: 239-245 °C. (M + H)+/z= 351.0. 1H NMR (DMSO): d 9.01-9.04 (dd, 1H), 8.55-8.57 (dd, 1H), 7.31-7.37 (m, 1H), 7.29-7.30 (m, 1H), 7.22-7.28 (t, 1H), 7.14-7.21 (m, 2H), 5.82 (s, 4H), 5.75 (s, 2H), 4.07 (s, 2H). 13C NMR (DMSO): d 161.15, 158.71, 151.34, 150.93, 149.01-148.86, 142.47, 133.95, 130.01-130.04, 129.74-129.81, 124.48-124.55, 124.33, 117.51, 115.55- 115.35, 114.43, 106.70, 43.77.

EXAMPLE-3a: Methyl 4, 6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3, 4-b] pyridin-3-yl]-5-pyrimidinylcarbamate (VI)
To a solution of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl] -4,5,6-pyrimidine triamine (100.0 gm, 0.285 mol) in acetonitrile (1000 ml) was added potassium carbonate (78.86 gm, 0.570 mol) at 5-10° C, followed by slow addition of Methyl chloroformate (54.0 gm, 0.570 mol) over a period of 30 minutes. Temperature of reaction mass was raised to 25-30° C and stirred for 2-6 hr. Upon completion of reaction, purified water was added to this reaction mass at temperature 25-30° C and product was extracted with 2-methyl tetrahydrofuran (1000 ml and 500 ml); further washed the organic layer with 10% w/v sodium chloride solution (1500 ml x 2). 2-methyl tetrahydrofuran was evaporated at below 60°C under reduced pressure to produce residue. Slurry was prepared of residue in DMF (400 ml) 65-70°C and water (500 ml) was added to slurry at 65-70 °C. The reaction mass cooled to 5-30 °C and maintained for 60 min. Filtered the obtained solid, washed solid with water (50 ml), suck dried the solid. The wet solid was dissolved in DMF (400 ml) at 65-70 °C and stirred for 5-10 min at 65-70 °C. Toluene (500 ml) was added to slurry at 65-70 °C. The reaction mass cooled to 5-30 °C. Maintained the reaction mass for 60 min at 5-30 °C. Filtered the obtained solid, washed solid with toluene (50 ml), suck dried the solid, suck dried and dried under vacuum at 55-60°C to afford highly pure Methyl 4, 6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate (VI). [Yield = 112 gm; Purity (HPLC) = 98.11 %]
Melting point: 204-208 °C, (M + H) +/z= 409.0. 1H NMR (DMSO): d 9.05-9.07 (dd, 1H), 8.56-8.60 (dd, 1H), 8.01 (s, 1H), 7.31-7.37 (m, 2H), 7.20-7.24 (t, 1H), 7.11-7.23 (t, 2H), 6.17 (s, 4H), 5.792 (s, 2H), 3.55-3.65 (m, 4H). 13C NMR (DMSO): d 161.11, 160.36, 158.67, 156.77, 155.19, 150.83, 149.01, 141.82, 133.91, 129.83-129.93, 124.62, 124.14-124.28, 117.96, 115.38-115.59, 114.69, 94.28, 51.77, 43.92.

EXAMPLE-3b: 2-[1-(2-fluorobenzyl)-1H-pyrazolo [3, 4-b] pyridin-3-yl] -4, 5, 6-pyrimidine triamine (V)
In pressure autoclave, 2-[1-(2-fluorobenzyl)-1H-pyrazolo [3, 4-b] pyridine-3-yl]-5-[(E) phenyldiazenyl] 4, 6-pyrimidinediamine (100.0 gm, 0.227 mol) was added in DMF (1200 ml), followed by activated Raney/Nickel (50.0 gm) at 25-30°C. After inerttization with nitrogen, hydrogenated at hydrogen pressure of 8-10 kg/cm2 and internal temperature at 60-65° C for 1-3 hrs. Upon completion of reaction, the reaction mass was cooled to 25-30° C, venting and inerttization, catalyst was filtered off and washed with DMF (100 ml). Filtrate was distilled out 75-80% at 80-85°C under reduced pressure and cooled the reaction mass to 60-65 ºC. Added purified water (1500 ml) to the reaction mass at 60-65 ºC and stirred for 25-30 min. The resulting suspension was gradually cooled to 25-30° C and maintained reaction mass at 25-30°C for 45-60 min. Obtained solid was filtered, washed with water (100.0 ml), suck dried and dried at 55-60°C for 3-4 hrs. to afford 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl] -4,5,6-pyrimidine triamine. [Yield = 74.94 gm (94.0%); Purity (HPLC) = 99.2%]

EXAMPLE-4a: Methyl 4, 6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3, 4-b] pyridin-3-yl]-5-pyrimidinylcarbamate (VI)
To a solution of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl] -4,5,6-pyrimidine triamine (100.0 gm, 0.285 mol) in acetone (1500 ml) and MDC (500 ml) was added anhydrous potassium carbonate (118.34 gm, 0.856mol) at 20-25° C, followed by slowly addition of Methyl chloroformate (74.17 gm, 0.785 mol) over a period of 30.0 minutes. Maintain reaction mass to 20-25° C and stirred for 2-6 hr. at 20-25° C and the progress of reaction was monitored by HPLC. After reaction completion, reaction mass Filtered the obtained solid, washed solid with MDC (50 ml), suck dried the solid. The wet solid was slurry in DMF (500 ml) at 50-55 °C and stirred for 5-10 min at 50-55 °C. Water (1000 ml) was added to slurry at 50-55 °C. The reaction mass cooled to 15-25 °C. Maintained the reaction mass for 60 min at 15-25 °C. Filtered the obtained solid, washed solid with water (50 ml), suck dried the solid, The wet solid was slurry in DMF (400 ml) at 50-55 °C and stirred for 5-10 min at 50-55 °C.Toluene (500 ml) was added to slurry at 50-55 °C. The reaction mass was cooled to 5-15 °C and maintained 60 min. Filtered the obtained solid, washed solid with toluene (50 ml), suck dried the solid, and dried under vacuum at 55-60°C to afford pure Methyl 4, 6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate ( VI ).
[Yield = 108.0 gm (92.65 %); Purity (HPLC) = 97.20 %]

EXAMPLE-4b: Methyl 4, 6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3, 4-b] pyridin-3-yl]-5-pyrimidinylcarbamate (VI)
To a solution of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl] -4,5,6-pyrimidine triamine (100.0 gm, 0.285 mol) in acetone (1500 ml) and methanol (500 ml) was added anhydrous potassium carbonate (118.34 gm, 0.856mol) at 20-25° C, followed by slowly addition of Methyl chloroformate (74.17 gm, 0.785 mol) over a period of 30.0 minutes. Maintain reaction mass to 20-25° C and stirred for 2-6 hr. at 20-25° C and the progress of reaction was monitored by HPLC. After reaction completion, reaction mass Filtered the obtained solid, washed solid with MDC (50 ml), suck dried the solid. The wet solid was slurry in DMF (500 ml) at 50-55 °C and stirred for 5-10 min at 50-55 °C. Water (1000 ml) was added to slurry at 50-55 °C. The reaction mass cooled to 15-25 °C. Maintained the reaction mass for 60 min at 15-25 °C. Filtered the obtained solid, washed solid with water (50 ml), suck dried the solid, The wet solid was slurry in DMF (400 ml) at 50-55 °C and stirred for 5-10 min at 50-55 °C.Toluene (500 ml) was added to slurry at 50-55 °C. The reaction mass was cooled to 5-15 °C and maintained 60 min.. Filtered the obtained solid, washed solid with toluene (50 ml), suck dried the solid, and dried under vacuum at 55-60°C to afford pure Methyl 4, 6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate ( VI ).
[Yield = 100.0 gm (85.68 %); Purity (HPLC) = 96.87 %]

Example-5a: Preparation of Riociguat (I)
To a solution of Methyl 4, 6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate (VI)(100.0 gm, 0.244 mol) in Acetone (4000 ml) and water (120 ml,), potassium hydroxide (27.48 gm, 0.367 mol), and methyl iodide (69.51 gm, 0.489 mol) was added at 5-10° C and the reaction mass was maintained at 5-10° C for 3-30 hr. Upon completion of reaction, water (400 ml) was added and the reaction mass was stirred for 30 min. at 25-30 °C. Acetone was distilled under vacuum below 50 °C, followed by addition of water (500 ml) to obtain obtained slurry, which was further stirred for 30-45 min. at 25-30 °C. Filtered the obtained solid, washed the solid with water (50 ml), suck dried to offered crude riociguat. [Yield= 94 gm; Purity (HPLC) = 97.19%]

Example-5b: Preparation of Riociguat (I)
To a solution of Methyl 4, 6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate (VI)(100.0 gm, 0.244 mol) in Acetone (4000 ml), NMP (100 ml) and water (300 ml) potassium hydroxide (27.48 gm, 0.367 mol), and methyl iodide (69.51 gm, 0.489 mol) was added at 5-10° C and the reaction mass was maintained at 5-10°C for 2-4 hr. Upon completion of reaction, water (400 ml) was added and the reaction mass was stirred for 30 min. at 25-30 °C. Acetone was distilled under vacuum below 50 °C, followed by addition of water (500 ml) to obtain obtained slurry, which was further stirred for 30-45 min. at 25-30 °C. Filtered the obtained solid, washed the solid with water (50 ml), suck dried to offered crude riociguat. [Yield= 91.96 gm; Purity (HPLC) = 97.89%]

Purification of Riociguat (I)
Riociguat crude (94.0 gm) wet solid was dissolved at 65-70°C in NMP (500 ml) and anti-solvent toluene (2000 ml) was added to reaction mass at 65-70 °C. The reaction mass cooled to 5-30 °C and maintained for 60 min. Filtered the obtained solid, washed solid with toluene (50 ml), suck dried the solid. The wet solid was dissolved in NMP (500 ml) at 65-70 °C and stirred for 5-10 min at 65-70 °C. Water (2000 ml) was added to reaction mass at 65-70 °C. The reaction mass cooled to 5-30°C. Maintained the reaction mass for 60 min at 5-30°C. Filtered the obtained solid, washed solid with water (50 ml), suck dried the solid. The mixture of dichloromethane (1500 ml) and methanol (1500 ml) was added to obtain solid followed by heating at 40-55°C. Activated charcoal (10 gm) was added. Maintained the reaction mass for 15-45 min at 40-55°C. Filtered the reaction mass to remove activated charcoal. Distilled out the solvent. The mixture of Ethyl acetate (150 ml) and methanol (150 ml) is added to obtained residue. The reaction mass heated to 50-60°C. Maintained the reaction mass for 60 min at 50-60°C. Cooled to 10-30 °C. The obtained solid was filtered, washed with methanol (50 ml), suck dried and dried under vacuum at 55-60°C to afford highly pure Riociguat (I). [Yield = 65 gm; Purity (HPLC) = 99.91%]
(M + H)+/z= 423.0. 1H NMR (DMSO): d 2.99 (s, 3 H), 3.52-3.65 (s, 3H), 5.79 (s, 2H), 6.35-6.37 (s, 4H), 7.06-7.13 (m, 2H), 7.19-7.24 (t, 1H), 7.31-7.37 (m, 2H), 8.58-8.60 (dd, 1H), 9.04-9.06 (dd, 1H). 13C NMR (DMSO): d 34.34, 43.88-43.92, 52.43-52.56, 99.37-100.32, 114.70, 115.35-115.56, 117.92, 124.14-124.60, 129.78, 129.86-129.89, 133.86, 141.77-141-84, 148.93, 150.84, 155.58-155.15, 157.24, 158.64, 159.56-159.85, 161.09

,CLAIMS:We claim:
1. A process for preparation of Riociguat (I), said process comprises:
a. condensing HCl salt of compound of formula (II) with a compound of formula (III) in a suitable solvent and in presence of an alkali metal carbonate to provide a compound of formula (IV);

b. reducing the compound of formula (IV) in presence of a reducing agent under hydrogen pressure in a suitable solvent selected from dialkylformamides, cyclic amide, alcohol or mixtures thereof to provide a compound of formula (V);

c. condensing the compound of formula (V) with a methyl chloroformate in a suitable solvent and in presence an alkali metal carbonate to provide a compound of formula (VI); and

d. methylating the compound of formula (VI) using an iodo methane in a suitable solvent selected from ketone, nitriles or mixture thereof, in presence of an alkali metal hydroxides, and water to provide Riociguat of formula (I), and isolating and purifying Riociguat of formula (I).

2. The process as claimed in claim 1, wherein the suitable solvent used in step (a) is selected from aromatic hydrocarbon such as toluene or xylene; nitrile such as acetonitrile or propionitrile; alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol or t-butanol; ketone such as acetone, methyl isobutyl ketone, or ethyl methyl ketone; cyclic ether and substituted cyclic ethers, such as diethyl ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 1,4-dioxan, or 2-methyl tetrahydrofuran or mixture thereof; and the suitable solvent used in step (c) is selected from aromatic hydrocarbon such as toluene or xylene; nitrile such as acetonitrile or propionitrile; alcohol such as methanol, ethanol, propanol, isopropanol, n-butanol or t-butanol; ketone such as acetone, methyl isobutyl ketone, or ethyl methyl ketone; cyclic ether and substituted cyclic ethers, such as diethyl ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 1,4-dioxan, or 2-methyl tetrahydrofuran; halogenated hydrocarbon such as dichloromethane, or dichloroethane; dialkylformamides such as dimethyl formamide or mixture thereof.

3. The process as claimed in claim 1, wherein the reducing agent used in step (b) is selected from Raney Nickel, Pt/carbon or Pd/carbon catalysts.

4. A process for purification of Riociguat (I), the said process comprises:
A. dissolving crude Riociguat (I) in N-methyl pyrrolidone (NMP) or N, N-Dimethylacaetamide (DMA) as a solvent ;
B. adding an anti-solvent to precipitate a solid, filtering and washing solid with the said anti-solvent to provide Riociguat (I) with purity of 99% by HPLC;
C. dissolving the Riociguat (I) obtained in step (B) in NMP or DMA;
D. adding an anti-solvent to the contents of (C) to precipitate a solid, filtering and washing solid with said anti-solvent to provide Riociguat (I) with purity of 99% by HPLC;
E. Decolorizing the obtained Riociguat (I) in step (D) in a solvent with activated charcoal, filtering charcoal and concentrating the solvent to provide residue of Riociguat (I) free from colored impurities; and
F. crystallizing the Riociguat (I) obtained in step (E) in a solvent, filtering and drying the obtained pure Riociguat Modification –I

5. The process as claimed in claim 4, wherein the anti-solvent used in steps (B) and (D) is selected from hydrocarbons such as cyclohexane, n-hexane, n-heptane, or pentane; aromatic hydrocarbons selected from benzene, toluene, xylene, or naphthalene; ethers selected from methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether, di-methyl ether, or methyl butyl ether; alcohols selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, or iso-butanol; alkyl acetate selected from ethyl acetate or isopropyl acetate; such as acetonitrile; halogenated aliphatic hydrocarbons selected from dichloromethane, chloroform or ethylene dichloride; water or mixture thereof.

6. The process as claimed in claim 4, wherein the solvent used in step (E) is an organic solvent selected from halogenated aliphatic hydrocarbons such as dichloromethane, chloroform, or ethylene dichloride; dialkylformamides such as dimethyl formamide; alcohols selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, or n-pentanol; ketones selected from acetone, methyl ethyl ketone, or methyl isobutyl ketone; dialkylacetamides such as ?,?,-dimethyl acetamide; cyclic amide such as N-methyl-2-pyrrolidone or mixtures thereof.

7. The process as claimed in claim 4, wherein the solvent used in step (F) is an organic solvent selected from alkyl acetate such as ethyl acetate or isopropyl acetate; aromatic hydrocarbons such as toluene, xylene or naphthalene; halogenated aliphatic hydrocarbons such as dichloromethane, chloroform, or ethylene dichloride; cyclic ethers such tetrahydrofuran, or 1,4-dioxane; substituted cyclic ethers such as 2-methyl tetrahydrofuran; alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, n-pentanol, ethylene glycol, or diethylene glycol; esters; ketones such as acetone, methyl ethyl ketone, or methyl isobutyl ketone; nitriles such as acetonitrile; water or mixtures thereof.