Field of the Invention:
The present invention relates to process for the preparation of methyl 4,6-diamino-2-
[l-(2-fluorobenzyl)-lH-pyra2olo[3J4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1, represented by the following structural formula:
Background of the Invention:
Riociguat, also known as methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1. Riociguat is the first of a new class of guanylatecyclase: (sGC) agonist, directly activates sGC and increases low levels of NO sensitivity, for treating pulmonary hypertension and chronic obstructive pulmonary hypertension.
WO 03/095451 describes the preparation of the compound of the formula-1. However, there are number of disadvantages associated with the process disclosed in WO 03/095451. The prior known described methods for the preparation of methyl 4,6-diamino-2-[l-(2-
fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 involve long reaction time, usage of hazardous reagents which leads to the formation of higher impurities and not suitable for commercial level process. Hence there is a need in the art to develop an efficient, cost effective, commercially viable and environmentally friendly process which provides compound of formula-1 with high yield and purity.
Brief description of the Invention:

The first aspect of the present invention is to provide an improved process for the
preparation of l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboxamide compound of formula-7.
The second aspect of the present invention is to provide a process for the preparation of l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboxainide compound of formula-7, comprising of reacting compound of formula-6 with a suitable amidating agent in presence of a suitable base in a suitable solvent to provide compound of formula-7.
the third aspect of the present invention is to provide a process for the purification of (E)-2-(H2-fluorol>enzyl>lH-^ diamine compound of formula-12.
The fourth aspect of the present invention is to provide a process for the purification of
2-(l-(2-fluorobenzyl)-lH-pyrazolo[3)4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine compound of formula-13.
The fifth aspect of the present invention, relates to novel crystalline form of methyl
4,6-diamino-2-(l-(2-fluorobenzyl)-lH-pyrazolo[354-b]pyridin-3-yl)pyrimidin-5-yl carbamate compound of formula-14, herein after designated as form R-I.
The sixth aspect of the present invention relates to novel crystalline form of methyl
4,6-diamino-2-(l-(2-fluorobenzyr)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl carbamate compound of formula-14, herein after designated as form R-II.
The seventh aspect of the present invention is to provide a process for the purification
of methyl 4,6-diamino-2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl carbamate compound of formula-14.
The eighth aspect of the present invention relates to novel crystalline form of methyl
4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula-1,.herein after designated as form M-I.

The ninth aspect of the present invention provides a process for the purification of
methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridinO-yl]-5-pyrimidinyl (methyl)carbamate compound of formula-1.
Brief description of Figures:
Figure 1: Illustrates the PXRD pattern of crystalline form R-I of methyl 4,6-diamino-2-(l-(2-
fluorobenzyl)-1 H-pyrazolo[354-b]pyridin-3-yl)pyrimidin-5-ylcarbamate compound of formula-14.
Figure 2: Illustrates the PXRD pattern of crystalline form R-II of methyl 4,6-diamino-2-(l-
(2-fluoroben2yl)-lH-pyrazolo[3,4-b]pyridin-3-yljpyrimidin-5-ylcarbamate compound of formula-14.
Figure 3: Illustrates the PXRD pattern of crystalline form M-I of methyl 4,6-diamino-2-[l-(2-
fluorobenzyl)-lH-pyrazolo[354-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1.
Detailed Description of Invention:
The term "suitable base" used herein'the present invention' until unless specified is selected from inorganic bases like "alkali metal hydroxides" such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the ' like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; ammonia; and organic bases such as triethyl amine, methyl amine, ethyl amine, 1,8-Diaza bicyclo[5.4.0]undec-7-ene (DBU), l,5-Diazabicyclo(4.3.0)non-5-ene (DBN), lithium diiso porpylamide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethylamino pyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methyl imidazole, 1,2,4-triazole, l,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.

As used herein ■ the term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methylcyclohexane, m-, o-, or p-xylene, and the like; "ether solvents" such as dimethoxy methane, 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, 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), dimethylfoi-mamide. (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloro methane, dichloroethane and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; -"nitrite solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanbl, n-propanol, isopropanoi, n-butanol, isobutanol, t-butanol, ethylene glycol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, diethylene glycol mono ethyl ether, cyclohexanol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.
The first aspect of the present invention provides an improved process for the preparation of l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboxamide compound of formula-7, comprising of the following steps:
a) Reacting (2-fluorobenzyl)hydrazine hydrochloric acid compound of formula-2a with sodium (Z)-l-cyano-3-ethoxy-3-oxoprop-l-en-2-olate compound of formula-3 in presence of suitable acid in a suitable solvent to provide ethyl 5-amino-l-(2-fluoro benzyl)-1 H-pyrazole-3-carboxylate compound of formula-4,
b) optionally, purifying the compound of formula-4 using a suitable solvent,
c) reacting the compound of formula-4 obtained in step-a) or b) with (E)-3-(dimethyl amino)acrylaldehyde compound of formula-5 in presence of a suitable acid in a suitable solvent to provide ethyl l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboxylate compound of formula-6,

d) reacting the compound of formula-6 .with a suitable amidating agent in presence of a suitable base in a suitable solvent to provide l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridine-3-carboxamide compound of formula-7.
Wherein,
In step-a) and c) the suitable acid is selected from trifluoro acetic acid;
in step-d) the suitable amidating agent is selected from formamide, ammonium carbamate,
ammonium formate, ammonium phosphate, ammonium acetate, ammonium fluoride,
ammonium bromide, ammonium chloride, ammonium iodide, ammonium iodate, ammonium
carbonate, ammonium citrate, ammonium chromate, ammonium clichromate, ammonium
■ - ■ ' ■ ■ *
hydroxide, ammonium lactate, ammonium nitrate, ammonium oxalate, ammonium sulfate, ammonium sulfide, ammonium tartrate, ammonium triflate, ammonium dihydrogen phosphate, urea, methyl carbamate, ethyl carbamate, propyl carbamate or t-butyl carbamate and alkyl or aryl amines; and the suitable base is selected from organic or inorganic base; in step-a) to step-d) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, nitrile solvents, chloro solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents and polar solvents like water or mixture thereof.
The preferred embodiment of the present invention provides an improved process for the preparation of l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboxamide compound of formula-7, comprising of the following steps:
a) Reacting (2-fluorobenzyl)hydrazine hydrochloric acid compound of formula-2a with sodium (Z)-l-cyano-3-ethoxy-3-oxoprop-l-en-2-olate compound of formula-3 in presence of trifluoro acetic acid in tetrahydrofuran to provide ethyl 5-amino-l-(2-fluorobenzyl)-lH-pyrazole-3-carboxylate compound of formula-4,
b) purifying the compound of formula-4 using methyl tertiary butyl ether,
c) reacting the compound of formula-4 obtained in step-a) or b) with (E)-3-(dimethyl amino)acrylaldehyde compound of formula-5 in presence of trifluoro acetic acid in
xylene to provide ethyl l-(2-fiuorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboxylate compound of formula-6,

d) reacting the compound of formula-6 with formamide in presence of sodium methoxide in a mixture of dimethyl formamide and water to provide l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboxamide compound of formula-7.
US6743798 Bl disclosed process for the preparation of compound of formula-6, by the reaction of compound of formula-4 with compound of formula-5 in the presence of trifluoro acetic acid with a reaction time of 3 days to provide compound of formula-6 with low yield and purity. Further, the said process involves the purification of compound of formula-6 by silica gel column chromatography, which is, tedious, time consuming and provides compound of formula-6 with low yield. Therefore, the said processes not suitable for commercial scale.
The aforementioned prior art process taking longer time intervals to complete the reaction, also requires tedious purifications which thereby increase the cost of the production. Hence, not suitable for commercial scale.
In order to overcome the problems associated with the prior art inventors of the present invention have carried out the reaction in various solvents like tetrahydrofuran, toluene & xylene as a reaction solvent. For toluene & tetrahydrofuran the reaction took longer hours to complete and the obtained compound of formula-6 also having low purity.
Surprisingly it was observed that when the reaction is carried out in Xylene the reaction was completed within 14 hours and provided the compound of formula-6 with high yield and purity.
The usage of xylene as a solvent reduced the reaction time intervals and provided the high pure compound which decreased the production cost and commercially viable.
The second aspect of the present invention provides a process for the preparation of 1-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]p)Tidine-3-carboxamide compound of formula-7, comprising of reacting ethyl l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboxylate

compound of formula-6 with a suitable amidating agent in presence of a suitable base in a suitable solvent to provide compound of formula-7.
Wherein, the suitable amidating agent, suitable base and suitable solvent are same as defined in step-d) of the first aspect of the present invention.
The preferred embodiment of the present invention provides a process for the preparation of l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboxamide compound of formula-7, comprising of reacting ethyl l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboxylate'compound of formula-6 with'formamide in presence of sodium methoxide in a mixture of dimethyl formamide and water to provide compound of formula-7.
US6743798 Bl discloses process for the preparation of compound of formula-7, by reacting compound of formula-6 with ammonia in the presence of methanol for 24 hours provides compound of formula-7 with low yield and purity and not commercially viable.
To overcome the problem with the prior art, inventors of the present invention have carried out the reaction in the presence of formamide, it was observed that the reaction was completed in shorter period less than 4 hours and provides the compound of formula-7 with higher yield and purity.
Hence when compared with the prior art process, the present process is simple, advantageous, less time consuming and commercially viable.
The third aspect of the present invention provides a process for the purification of (E)-
2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine compound of formula-12, comprising of:
a) Adding a suitable solvent to (E)-2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine,
b) stirring the reaction mixture,
c) filtering the solid to get pure (E)-2-(l-(2-fluorobenzyl)-lH-pyrazolo[354-b]pyridin-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine compound of formula-12.

Wherein, in step-a) the suitable solvent is same as defined in step-d) of the first aspect of the present invention.
The preferred embodiment of the present invention provides a process for the purification of (E)-2-(l-(2-fluorobenzyl)-lH-pyrazolo[354-b]pyridin-3-yl)-5-(phenyldiazenyl) pyrimidine-4,6-diamine compound of formula-12, comprising of:
a) Adding isopropanol to (E)-2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine,
b) stirring the reaction mixture,
c) filtering the solid to get pure (E)-2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridin-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine compound of formula-12.
The fourth aspect of the present invention provides a process for the purification of 2-(1 -(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4J5,6-triamine compound of formula-13, comprising of,
a) Adding a suitable solvent to. 2-(l-(2-fluorobenzyl)-lH-pyrazolo[3J4-b]pyridin-3-yl) pyrimidine-4,5,6-triamine, , b) heating the reaction mixture to a suitable temperature, • c) stirring the reaction mixture,
d) cooling the reaction mixture to a suitable temperature,
e) stirring the reaction mixture and filtering the solid to get pure 2-(l-(2-fluorobenzyl)-iH-pyrazolo[3,4-b]pyridin-3-yl) pyrimidine-4,5,6-triamine compound of formula-13.
Wherein
In step-a) the suitable solvent is same as defined in step-d) of the first aspect of the present invention;
in step-b) the suitable temperature is ranging from ambient temperature to reflux temperature of the solvent used in the reaction;
in step-d) the suitable temperature is ranging from 0°C to 30°C.

The preferred embodiment of. the .present invention provides a process for the purification of 2-(l-(2-fluorobenzyl)-lH-pyrazolo[3s4-b]pyridin-3-yI)pyrimidine-4,5,6-triamine compound of formula-13, comprising of,
a) Adding acetonitrile to 2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yI) pyrimidine-4,5,6-triamine,
b) heating the reaction mixture to 70-75°C,
c) stirring the reaction mixture,
d) cooling the reaction mixture to 25-30°C,
e) stirring the reaction'mixture and filtering the solid to get pure 2-(l-(2-fluoroberizyl)-lH-pyrazolo[3,4-b]pyridin-3-yl) pyrimidine-4,5,6-triamine-compound of formula-13.
The fifth aspect of the present invention provides a novel crystalline form R-I of methyl 4,6-diamino-2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl carbamate compound of formula-14, characterized by its powder X-ray diffraction pattern having peaks at 5.2, 7.0, 10.6, 12.8, 13.3, 14.4, 15.1, 15.8, 16.7, 18.0, 19.5, 21.0, 22.4, 25.3,
28.8, 30.3,-32.6 and 36,8 ±0.2 degrees two theta and P-XRD pattern was depicted in figure-1.
The sixth aspect of the present invention provides a novel crystalline form R-II of methyl 456-diamino-2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl carbamate compound of formula-14, characterized by its powder X-ray diffraction pattern having peaks at 4.4, 8.0, 9.0, .11.9, 12.7, 13.1, 14.1, 15.2, 15.9, 16.6, 17.3, 19.4, 20.8, 22.4,
22.9, 23.5, 25.0, 25.2, 25.7, 26.1, 27.2, 29.5, 30.3 and 32.5 ±0.2 degrees two theta and P-XRD
pattern was depicted in figure-2.
The seventh aspect of the present invention provides a process for the purification of
methyl 4,6-diamino-2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl carbamate compound of formula-14.
a) Adding a suitable solvent to methyl 4,6-diamino-2-(l-(2-fluorobenzyl)-lH-pyrazolo [3,4-b]pyridin-3-yl)pyrimidin-5-ylcarbamate,
b) heated the reaction mixture to a suitable temperature,
c) stirring the reaction mixture,
d) cooling the reaction mixture to a suitable temperature,

e) stirring the reaction mixture and filtering the solid to get pure methyl 4,6-diamino-2-
(l-(2-fluorobenzyl)-lH-pyrazolo[354-b]pyridin-3-yl)pyrimidin-5-ylcarbamate compound of formula-14.
Wherein,
In step-a) the suitable solvent is same as defined in first aspect of the present invention:
in step-b) the suitable temperature is ranging from ambient temperature to reflux temperature
of the solvent used in the reaction;
in step-d) the suitable temperature is ranging from 0°C to 30°C.
The preferred embodiment of present invention provides a process for the purification
of methyl 4,6-diamino-2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl carbamate compound of formula-14,
a) Adding a mixture of dimethyl formamide and ethyl acetate to methyl 4,6-diamino-2-
(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-ylcarbamate,
b) heating the reaction mixture to 70-75°C,
c) stirring the reaction mixture,
■* d) cooling the reaction mixture to 25T30°C,
;- e) stirring the reaction mixture and filtering the solid to get pure methyl 4,6-diamino-2-
(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-ylcarbamate compound of formula-14.
The eighth aspect of the present invention provides a novel crystalline form M-I of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula-1, characterized by its powder X-ray diffraction pattern having peaks at 7.7, 8.6, 11.0, 12.6, ■13.4, 14.1, 15.1, 16.1, 17.5, 18.4, 19.3,20.4,22.6, 23.9, 24.9, 25.6, 26.0, 29.1, 30.7 and 31.3 ±0.2 degrees two theta and P-XRD pattern as depicted in figure-3.
The ninth aspect of the present invention provides a process for the purification of methyl 4i6-diamino-2-[l-(2-iluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula-1, comprising of:

a) Adding a suitable solvent to methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1,
b) heating the reaction mixture to a suitable temperature,
c) stirring the reaction mixture,
d) optionally adding carbon to the reaction mixture,
e) cooling the reaction mixture to a suitable temperature,
f) optionally filtering the reaction mixture through hy-flow bed,
g) optionally adding a suitable solvent to the filtrate obtained in step-f),
h) stirring the reaction mixture and filtering the precipitated solid to get pure methyl 4,6-diamino-2-il-(2-fluorobe'nzyl)-lH-pyrazolb[3,4-b]pyridin.3-yl]-5-' pyrirhidinyl(methyl)carbamate compound of formula-1.
Vherein,
n step-a) and g) the suitable solvent is selected from alcohol solvents, ketone solvents, ester
olvents, chloro solvents, hydrocarbon solvents,-polar aprotic solvents, ether solvents and
iolar solvents like water or mixture thereof; .
i step-b) the suitable temperature is; ranging from. ambient temperature to the reflux
^mperature of the solvent used in the reaction;
i step'-e) the suitable temperature is ranging from 25-60°C.
The preferred embodiment of the present invention provides a process for the urification of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-yrimidinyl(methyl)carbamate compound of formula-1, comprising of:
a) Adding dimethyl acetamide to methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1,
b) heating the reaction mixture to 90-95°C,
c) stirring the reaction mixture,
d) adding carbon to the reaction mixture,
e) cooling the reaction mixture to 50-55°C, ^
f) filtering the reaction mixture through hy-flow bed,
g) adding ethyl acetate to the filtrate obtained in step-e),

h) stirring the reaction mixture and filtering the precipitated solid to get pure methyl 4,6-
diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula-1.
In another preferred embodiment of the present invention provides a process for the purification of methyl 4)6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1, comprising of:
a) Adding a mixture of dimethyl acetamide and ethyl acetate to methyl 4,6-diamino-2-[l-
(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate , compound of formula-1, ,
b) heating the reaction mixture to 90-95 °C,
c) stirring the reaction mixture,
d) cooling the reaction mixture to 25-30°C,
e) stirring the reaction mixture and filtering the precipitated solid to get pure methyl 4,6-
diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula-1.
Crystalline forms R-I and R-II of methyl 4,6-diamino-2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-ylcarbamate compound of formula-14 and crystalline form M-I of compound of formula-1 are useful in the preparation of pure methyl
4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula-1.
Methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-
pyrimidinyl(methyl)carbamate compound of formula-1 produced by the present invention can be further micronized or milled in a conventional techniques 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.

The methyl 456-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 obtained according to the present invention is having purity greater than 99.6 % by HPLC.
The methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 obtained according to the present inventions is stable for 9 months at accelerated and long term stability conditions.
P-XRD Method of Analysis:
PXRD analysis of compounds produced by the present invention were carried out using BRUKER D8 ADVANCE/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min. PSD method of Analysis:
Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.
HPLC Method of Analysis:
Methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4rb]pyridin-3-yl]-5-pyrimidinyl
(methyl)carbamate compound of formula-1:
Apparatus: A liquid chromatographic system is to be equipped with variable wavelength PDA-detector; Column: YMC triart CI8, 250 x 4.6 mm, 5 um 12 nm (or) equivalent; Wavelength: 210 nm; Column Temperature: 40°C; Injection volume: 10 uL; Diluent: Methanol : water (70:30 v/v); Needle wash: Diluent v/v; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Buffer : Methanol (60:30:10 v/v/v); Buffer: Transfer 2 ml of orthophosphoric acid (85%) into a 1000 ml of milli-Q-water, mix well and adjust pH to 4.0 with diluted NaOH solution. Filter through 0.22 p, filter paper and sonicate to degas it.
The process of the present invention can be represented schematically as follows: Scheme-A:

These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention,

Example-l: Preparation of (2-fluorobenzyl)hydrazine hydrochloric acid (Formula-2)
2-Fluoro benzyl chloride (100 gms) was slowly added to a pre-cooled solution of water (500 ml) and hydrazine hydrate (301.5 gms) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 4 hours at the same temperature. Dichloromethane was added to the reaction mixture at 25-30°C and stirred for 20 minutes at the same temperature. Both the organic, and aqueous layers were separated and extracted the aqueous layer using dichloromethane. Combined the organic layers and ethyl acetate-hydrochloric acid solution (260 ml) was added at 25-30° C and stirred for 4 hours at the same temperature. Filtered the precipitated solid and washed'with dichloromethane. To the obtained wet compound, isopropanol (600 ml) was added at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid and washed with isopropanol and dried to get the title compound. Yield: 56.5 gms; M.R: 102-108°C.
ExampIe-2: Preparation of Ethyl 5-amino-l-(2-fluorobenzyl)-lH-pyrazole-3-carboxylate (FormuIa-4)
Diethyl oxalate (50 gms) was added to a pre-cooled solution of methyl tertiary butyl ether (250 ml) at 10-15°C. Sodium methoxide (28.0 gms) was slowly added to the reaction mixture at 10-15°C. Raised the temperature of reaction mixture to 25-30°C and stirred for 20 minutes at the same temperature. Heated the reaction mixture to 50-55°C. Acetonitrile (28.05 ml) was added to the reaction mixture at 50-55°C under nitrogen atmosphere and stirred for 3 hours at the same temperature. Distilled off the solvent completely under reduced pressure. Tetrahydrofliran (250 ml) was added to the obtained compound at 25-30°C and stirred for 20 minutes at the same temperature. Cooled the reaction mixture to 10-15°C. Trifluoro acetic acid (39.0 gms) was slowly added to the reaction mixture at 10-15°C. Heated the reaction mixture to 25-30°C and stirred for 20 minutes at the same temperature. 2-Fluoro benzyl)hydrazine hydrochloric acid (60.4 gms) compound of formula-2 was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 4 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Water and ethyl acetate were

added to the reaction mixture at 25-30°C. Aqueous sodium carbonate solution was slowly added to the reaction mixture at.25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed and washed the bed with ethyl acetate. Both the organic and aqueous layers from the filtrate were separated and aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with water and followed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer and co-distilled with methyl tertiary butyl ether. To the obtained compound, methyl tertiary butyl ether (100 ml) was added at 50-55°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with methyl tertiary butyl ether and dried to get the title compound; Yield: 32.0 gms; M.R:; 127.0-13l:0°C.
Example-3: Preparation of l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboxamide (Fdrmuia-7)
A mixture of xylene (250 ml) and ethyl 5-amino-l-(2-fluorobenzyl)-lH-pyrazole-3-carboxylate (50 gms) compound of formula-4 were stirred for 20'minutes at 25-30°C under nitrogen atmosphere. (E)-3-(dimethylamino)acrylaldehyde (23.53 gms) was added to the reaction mixture at 25-30°C and stirred for 20 minutes at.the same temperature. Cooled the reaction mixture to 10-15°C. Trifluoro acetic acid (43.30 gms) was added to the reaction mixture at 10-15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 20 minutes at the same temperature. Heated the reaction mixture to 105-110°C and stirred for 10 hours at the same temperature. Cooled the reaction mixture to 40-45°C. Xylene and followed by water were added to the reaction mixture at 40-45°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed the bed with xylene. Both the organic and aqueous layers from filtrate were separated and extracted the aqueous layer with xylene. Combined the organic layers and aqueous sodium carbonate solution was added to it. Both the organic and aqueous layers were separated. Water was added to the organic layer at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer. Dimethyl formamide (75 ml) was added to the obtained compound at 25-30°C and stirred for 20 minutes at the same temperature. Cooled the reaction mixture to 5-

IO°C. Formamide (25.6'ml) was added to the"reaction mixture at 5-10°C and stirred for 20 minutes at the same temperature. Sodium methoxide (41 ml) was added to the reaction mixture at 5-10°C under nitrogen atmosphere. Raised the temperature of the reaction mixture to 25-30°C and stirred for 4 hours at the same temperature. Water (600 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 1lH-pyrazolo[3,4-b] pyridin-3-yl)pyrimidin-5-ylcarbamate(Formula-14)
A mixture of dimethyl formamide (70 ml) and ethyl acetate (280 ml) was added to methyl 4,6-diamino-2-(l-(2-fluoroberizyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl carbamate (100 gms) at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get the title

compound. Water (500 ml) was added to the obtained compound at 25-30°C and stirred for 2
hours at the same temperature. Filtered the solid, washed with water and dried to get the title
compound. Yield: 92.4 gms; M.R: 205-210°C; Purity by HPLC: 93.73%.
The P-XRD pattern of the obtained compound was disclosed in figure-2.
Example-10: Preparation of crystalline form M-I methyl 4,6-diamino-2-[l-(2-
fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yI]-5-pyrimidinyl(methyl)carbamate (Formula-1)
Methyl iodide (31.49 gms) was added to a pre-cooled solution of sodium hydroxide (11.75 grhs)and water (200 ml) at 0-5°C. A mixture of dimethyl sulfoxide (1000 ml) and methyl 4,6-diamirio-2-(l-(2-fluoroberizyl)-l^
carbamate (100 gms) was added to the reaction mixture at 0-5 °C and stirred for 30 minutes at the same temperature. Methyl iodide was slowly added to the reaction mixture at 0-5°C and stirred for 3 hours at the same temperature/Water was added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid and washed with water. To the obtained compound, water (1000 ml) was added at 25-30°C and stirred for 1 hour at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 60 gms; DMSO content: 149 ppm (RS/OVI) The P-XRD pattern of the obtained compound was disclosed in figure-3. Example-11: Purification of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methy])carbamate(FormuIa-l)
Dimethyl acetamide (300 ml) was added to the compound obtained in example-10 at 25-30°C. Heated the reaction mixture to 90-95°C and stirred for 45 minutes at the same temperature. Carbon (10 gms) was added to the reaction mixture at 90-95°C. Cooled the reaction mixture to 50-55°C. Filtered the reaction mixture through hy-flow bed and wash the bed with ethyl acetate. To the obtained filtrate, ethyl acetate (300 ml) was added at 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate to get the title compound. A mixture of dimethyl acetamide (100 ml) and ethyl acetate (100 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 90-95 °C and stirred tor 45 minutes at the same temperature. Cooled the reaction

mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Water (1000 ml) was added to the obtained compound at 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Methanol (200 ml) was added to the obtained compound at 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with methanol and dried to get the title compound. Yield: 55 gms; MR: 265-269°C; Purity by HPLC: 99.95%; Carbamate impurity: 0.01%; Des fluoro impurity: Not detected; Phenyl azomalononitrile impurity: Not detected; Dimethyl impurity: 0;02%; Diamine impurity: Not detected; HIUI: 0.03%.
Particle Size Distribution (PSD): D(0:1) is 11,0 urn; D(0.5) is 23.5 jini; D(0.9) is 46.3 urn; D[4.3] is 26.6 urn; The P-XRD pattern of the obtained compound was similar to the P-XRD pattern of Modification I disclosed in US2015/0376184A1.:
Example-12: Purification of methyl 4,6-diamino-2-[i-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridm-3-yl]-5-pyrimidinyl(methyl)carbamate (Formula-lJ
A mixture of ethyl acetate (40 ml) and N-methyl-2-pyrrolidone (20 ml) was added to methyl 4,6-diamino-2-[l-(2-fluorobenzyl)4H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate (10 gms) at 25-30°C. Heated the reaction mixture to 95-100°C and stirred for 2 hours at the same temperature. Filtered the reaction mixture through hy-flow bed. The obtained filtrate was further heated to 95-100°C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 20-25°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 7.2 gms.
Example-13: Preparation of l-(2-fluorobenzyI)-lH-pyrazolo[3,4-b]pyridine-3-carboxamide (Formula-7)
Dimethyl formamide (50 ml) was added to ethyl l-(2-fluorobenzyl)-lH-pyrazolo[3,4-bjpyridine-3-carboxylate (15 gms) at 25-30°C. Cooled the reaction mixture to 0-5°C. Formamide (12.8 gms) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Water was added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid and dried to get the title compound. Yield: 10.1 gms.

We Claim:
1. A process for the preparation of l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboxamide compound of formula-7, comprising of reacting ethyl l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboxylate compound of formula-6 with a suitable amidating agent in presence of a suitable base in a suitable solvent to provide compound offormula-7.
2. A process for the preparation of l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboxamide compound offormula-7, comprising of reacting ethyl l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboxylate compound of. formul.a-6 with formamide in presence of sodium methoxide in a mixture of dimethyl formamide and water to provide compound of formula-7.
3. An improved process for the preparation of l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridine-3-carboxamide compound offormula-7, comprising of the following steps:
a) Reacting (2-fluorobenzyl)hydrazine hydrochloric acid compound of formula-2a with
sodium (Z)-l-cyano-3-ethoxy-3-oxoprop-l-en-2-olate compound of formula-3 in the
. presence of suitable acid in a, suitable solvent to provide ethyl 5-amino-l-(2-fluorobenzyl)-lH-pyrazole-3-carboxylate compound of formula-4,
b) optionally, purifying the compound of formula-4 using a suitable solvent,
c) reacting compound of formula-4 with (E)-3-(dimethylamino)acrylaldehyde compound. of formula-5 in presence of a suitable acid in a suitable solvent to provide ethyl l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboxylate compound of formula-6,
d) reacting compound of formula-6 with a suitable amidating agent in presence of a suitable base in a suitable solvent to provide l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridine-3-carboxamide compound of formula-7.
Wherein in step-a) and c) the suitable acid is selected from trifluoro acetic acid; in step-a) to step-d) the suitable solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcoholic solvents, and polar solvents such as water or mixtures thereof.

. The process according to claims 1 or 3 wherein, the suitable amidating agent is selected from formamide, ammonium carbamate, ammonium formate, ammonium phosphate, ammonium acetate, ammonium fluoride, ammonium bromide, ammonium chloride, ammonium iodide, ammonium iodate, ammonium carbonate, ammonium citrate, ammonium chromate, ammonium dichromate, ammonium hydroxide, ammonium lactate, ammonium molybdate, ammonium nitrate, ammonium oxalate, ammonium sulfate, ammonium sulfide, ammonium tartrate, ammonium triflate, ammonium thiocyanate, ammonium dihydrogen phosphate, urea, methyl carbamate, ethyl carbamate, propyl carbamate or t-butyl carbamate and alkyl or aryl amines; preferably formamide; and the suitable base is selected from organic or inorganic base; the suitable solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcoholic solvents, arid polar solvents such as water or mixtures thereof.
i. An improved process for the preparation of l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridine-3-carboxamide compound of formula-7, comprising of the following steps:
a) Reacting (2-fluorobenzyl)hydrazine hydrochloric acid compound of formula-2a with
: sodium (Z)-l-cyano-3-ethoxy-3-oxoprop-l-en-2-olate compound of formula-3 in
' presence of trifluoro acetic acid in tetrahydrofuran to provide ethyl 5-amino-l-(2-
fluorobenzyl)-lH-pyrazole-3-carboxylate compound of formula-4,
b) purifying the compound of formula-4 using methyl tertiary butyl ether,.
c) reacting compound of formula-4 with (E)-3-(dimethylamino)acrylaldehyde compound
of formula-5 in presence of trifluoro acetic acid in xylene to provide ethyl l-(2-
m
fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboxylate compound of formula-6,
d) reacting compound of formula-6 with formamide in presence of sodium methoxide in
a mixture of dimethyl formamide and water to provide l-(2-fluorobenzyl)-lH-
pyrazolo[3,4-b]pyridine-3-carboxamide compound of formula-7.

6. Novel crystalline form M-I of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo [3,4-b] pyridin-3-yl]-5-pyrimidinyi(methyl)carbamate is characterized by P-XRD pattern as depicted in figure-3.
7. Novel crystalline forms of methyl 436-diamino-2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridin-3-yl)pyrimidin-5-ylcarbamate compound of formula-14, comprises of:

a) Crystalline form R-I of methyl 4,6-diamino-2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridin-3-yl)pyrimidin-5-ylcarbamate compound of formula-14, characterized by its powder X-ray diffraction pattern having peaks at 5.2,:7.0,.10.6, 12.8, 13.3, 14.4, 15.1, 15.8, 16.7,. 18.0, 19.5, 21.0, 22.4, 25,3, 28.8, 30.3, 32.6 and 36.8 ±0.2 degrees.two theta and P-XRD pattern as depicted in figure-1.
b) Crystalline form R-II of methyl 4,6-diamino-2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridin-3-yl)pyrimidin-5-ylcarbamate compound of formula-14, characterized by its powder X-ray diffraction pattern having peaks at 4.4, 8.0, 9.0, 11.9, 12.7, 13.1, 14.1, 15.2, 15.9, 16.6, 17.3, 19.4, 20.8, 22.4, 22.9, 23.5, 25.0, 25.2, 25.7, 26.1, 27.2,29.5, 30.3 and 32.5 ±0.2 degrees two theta and P-XRD pattern as depicted in figure-2.
8. A process for the purification of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo
[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1, comprising
of:
a) Adding a suitable solvent to methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1,
b) heating the reaction mixture to a suitable temperature,
c) stirring the reaction mixture,
d) optionally, treating the reaction mixture with carbon,
e) optionally, adding a suitable solvent to the filtrate obtained in step-d),
f) stirring the reaction mixture and filtering the precipitated solid to get pure methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula-1.

Wherein, in step-a) and e) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, chloro solvents, polar aprotic solvents, ether solvents and polar solvents like water or mixture thereof;
in step-b) the suitable temperature is ranging from ambient temperature to the reflux temperature of the solvent used in the reaction;
9. A process for the purification of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo
[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1, comprising
6f: ' . ■■..'■•■■
a) Adding dimethyl acetamide to methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1,
b) heating the reaction mixture to 90-95°C,
c) stirring the reaction mixture,
d) adding carbon to the reaction mixture,
e) cooling the reaction mixture to 50-55°C,
f) filtering the reaction mixture through hy-flow bed,
g) adding ethyl acetate to the filtrate obtained in step-f),
h) stirring the reaction mixture and filtering the precipitated solid to get pure methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula-1.
10. A process for the purification of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo
[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1, comprising
of:
a) Adding a mixture of N-methyl-2-pyrrolidone and ethyl acetate to methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) carbamate compound of formula-1,
b) heating the reaction mixture to 95-100°C,
c) stirring the reaction mixture,
d) cooling the reaction mixture to 25-30°C,

e) stirring the reaction mixture and filtering the precipitated solid to get pure methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula-1.