WO2017025981A1

WO2017025981A1 - Process for the preparation of methyl 4,6-diamino-2-[l-(2-fhiorobenzvr)-lh-pyrazolo i3,4-blpvridin-3-vn-5-pyrimidinyl(methvl)carbamate and its polymorphs thereof

Info

Publication number: WO2017025981A1
Application number: PCT/IN2016/000213
Authority: WO
Inventors: Srinivasan THIRULMALAI RAJAN
Original assignee: Msn Laboratories Private Limited; ESWARAIH, Sajja; Venkata Panakala Rao, Gogulapati; RAJESHAM, Boge
Priority date: 2015-08-13
Filing date: 2016-08-12
Publication date: 2017-02-16

Abstract

The present invention relates to process for the preparation of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate and its polymorphs thereof compound of formula-1, represented by the following structure.

Description

Process for the preparation of methyl 4,6-diamino-2-[l-(2-fhiorobenzyr)-lH-pyrazolo i3,4-blpyridin-3-vn-5-pyrimidinyl(methyl)carbamate and its polymorphs thereof

Related Applications:

This application claims the benefit of priority of our Indian patent application numbers 4221 /CHE/2015 filed on 13^th Aug. 2015 and 6594/CHE/2015 filed on 9^th Dec. 2015 which are incorporated herein by reference.

Field of the Invention:

The present invention relates to an improved process for the preparation of methyl 4,6- diamino-2 [ 1 -(2-fluorobenzyl)- 1

carbamate compound of formula- 1 , represented by the following structural formula:

Formula- 1

The present invention also relates to novel crystalline forms 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.

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 the formation of higher impurity and not suitable for the 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. US Patent No. 7173037 B2 (herein after referred as US'037) discloses methyl 4,6- diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyr

carbamate compound of formula- 1 and process for its preparation. The said US'037 patent does not discuss about its polymorphic form. WO2014/128109 Al claims crystalline modification I, modification II, mono-DMSO solvate, sesqui-DMSO solvate, ¼ ethyl acetate solvate and^; amorphous forms of methyl 4,6- di amino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3 -yl] -5 -pyrimidinyl

(methyl)carbamate compound of formula- 1. WO2015/055124 Al claims crystalline Form I, Form II, Form III and Form IV and amorphous forms of methyl 4,6-diamino-2-[ 1 -(2-fluorobenzyl)- lH-pyrazolo [3, 4-b]pyridin-3- yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1.

WO2016/113415 Al claims crystalline forms of methyl acetate solvate, hemi-ethyl acetate solvate and 2-butanone solvate of methyl 4,6-diamino-2-[l -(2-fluorobenzyl)- 1H- pyrazolo[3.4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1.

The crystalline form of a drug compound may have different chemical and physical properties, including appearances, melting point, chemical reactivity, apparent solubility, dissolution rate, stability, optical and mechanical properties, vapor pressure and density. These properties may have a direct effect on the ability to process and/or manufacture the drug compound and the drug product, as well as on drug product stability, dissolution, and bioavailability. Thus the crystalline forms of the compound of formula- 1 may affect the quality, safety, and efficacy of a drug product comprising the compound of formula- 1.

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-carboxamide 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-( l-(2-fluorobenzyl)- 1

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 is to provide a novel crystalline form of methyl 4,6-diamino-2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-y carbamate compound of formula- 14, herein after designated as form R-I. The sixth aspect of the present invention is to provide a novel crystalline form 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, 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 is to provide a novel crystalline form of methyl 4,6-diamino-2-[l-(2-fluorobeiizyl)-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]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula- 1. The tenth aspect of the present invention is to provide an improved process 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.

The eleventh aspect of the present invention is to provide a process for the preparation of methyl 4,6-diamino-2-[l-(2-iluorobenzyl)-l H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate, compound of formula- 1 comprising of reacting^, methyl 4,6-diamino-2- [ l - (2-flμorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate compound of formula- 14 with methyl iodide in presence of suitable inorganic base in a suitable solvent to provide compound of formula- 1 , with a proviso that the base is not NaH or LiHMDS.

The twelfth aspect of the present invention is to provide a process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl carbamate compound of formula- 14, comprising of reacting 2-[ 1 -(2-fluorobenzyl)- 111- pyrazolo[3,4-b]pyridin-3-yl]pyrimidinetrianiine formula-13 with methyl chloroformate in presence of a base in a suitable; solvent to provide compound of formula- 14, with a proviso that the base is not pyridine.

The thirteenth aspect of the present^' invention is to provide a process for the preparation ,_. of 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidinetriamine compound of formula-13, comprising of:

a) Reacting 1 -(2-fluorobenzyl)- 1 H-pyrazolo [3 ,4rb]pyridine-3 -carboximidamide compound of formula- 10 with 2-(phenyldiazenyl)malononitrile compound of formula- 11 in presence of sodium formate in a suitable solvent to provide 2-[l-(2-fluoro benzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)phenyldiazenyl]4,6-pyrimidinediamine compound of formula- 12,

b) reducing the compound of formula- 12 with a suitable reducing agent in a suitable solvent to provide 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine triamine compound of formula-13. The fourteenth aspect of the present invention is to provide a 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-] , herein after designated as form-M. The fifteenth aspect of the present invention is to provide a process for the preparation of crystalline form-M 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.

The sixteenth aspect of the present invention is to provide a 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 foimula-1, herein after designated as form-S. ^{^}

The seventeenth aspect of the present invention is to provide a process for the preparation of crystalline form-S of methyl 4,6-diamiho-2-[l-(2-fluorobenzyl)-lH-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1.

The eighteenth aspect of the present invention is to provide an improved process 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.

Brief description of Figures:

Figure 1: Illustrates the PXRD pattern of novel crystalline form R-I of methyl 4,6-diamino-2- (1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-ylcarbamate compound of formula- 14.

Figure 2: Illustrates the PXRD pattern of novel 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.

Figure 3: Illustrates the PXRD pattern of 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.

Figure 4: Illustrates the PXRD pattern of novel crystalline form-M 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. Figure 5: Illustrates the DSC thermogram of novel crystalline form-M 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.

Figure 6: Illustrates the PXRD pattern of novel crystalline form-S 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.

Figure 7: Illustrates the DSC thermogram of novel crystalline form-S of methyl 4,6-diamino- 2-[l-(2-iluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1. ^{' ;} - :

Figure 8: Illustrates the PXRD pattern of crystalline form-A of methyl 4,6-diamino-2-[ 1 -(2- fluorobenzyl)- 1 H-pyrazol0[3,4^Lb]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1 obtained according to reference example- 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, irf-, 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, 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 dimethyl acetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N- methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloro methane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; "nitrile solvents" such as acetonitrile, propidnitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butariol, 2-nitroethanol, 2- fluoroethanol, 2,2,2-trifluor0ethanol, ethylene glycol, 2-metHoxyethanol, 1, 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 term suitable "reducing agent" is selected from Fe, Fe in acidic media like NH₄C1 , ammonium acetate or HCl or acetic acid, Sn in acidic media like HCl, Zn dust, Zn in acidic media like NH₄C1, ammonium acetate or acetic acid, stannous chloride (SnCfe), NaBH₄, LiAlH₄, LiBH₄, diborane, borane-THF complex, hydrazine hydrate, hydrogenation catalysts such as Rhodium, sulfides, alkali metal dithionite, alkali metal dithionate and sodium amalgam. 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)hydfazine 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 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 1 -(2- fluoro benzyl)- lH-pyrazolo[3,4-b]pyridine-3-carboxylate compound of formula-6, d) reacting compound of formula-6 in-situ 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 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 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; 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, 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)rl-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 1 -(2-fluoro benzyl)- 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.

US6743798 Bl disclosed the 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 lower yield and purity. Further, the said process involves the purification of compound of formula-6 by silica gel column chromatography which is tedious and time consuming and provides compound of fqrmula-6 with lower yield. . The aforementioned prior art process taking longer time intervals to complete the'' reaction, also requires tedious column 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-fiuorobenzyl)-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 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 the process for the preparation of compound of formula-7, by reacting compound of formula-6 with ammonia in methanol which requires longer hours maintenance to complete the reaction to provide compound of formula-7 with lower yield and purity and further such process is not suitable for commercially scale.

The inventors of the present in vehtion observed that the time intervals of the reaction was drastically reduced when the reaction is performed in presence of formamide arid provides better yield and purity. Hence this process is highly advantageous when compared over the prior art process.

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[3,4-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[3,4-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)- 1 H-pyrazolo[3 ,4-b]pyridin-3 -yl)pyrimidine-4,5 ,6-triamine compound of formula- 13, comprising of,

a) Adding a suitable solvent to 2-(l -(2-fluorobenzyl)- lH-pyrazolo [3 ,4-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)- lH-pyrazolo[3,4-b]pyridin-3-yl) pyrimidine-4,5,6-triarriine compound of formula- 13.

Wherein,

In step-a) the suitable solvent is selected from nitrile solvents, ether solvents, ketone solvents, hydrocarbon solvents, chloro solvents and polar solvent like water or mixture thereof;

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-( 1 -(2-fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl)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-yl) 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 an

f) d filtering the solid to get pure 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 provides a novel crystalline form R-I of methyl 4,6-diamino-2-( 1 -(2-fluorobenzyl)- 1 H-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 as depicted in figure-1.

The sixth aspect of the present invention provides a novel crystalline form R-II 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 4.4, 8.0, 9.0, 1 1.9, 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.

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-bjpyridin-3-yl)pyrimidin-5-yl carbamate compound of formula-14.

a) Adding a suitable solvent to methyl 4,6-diamino-2-(l -(2-fluorobenzyl)- 1 H-pyrazolo

[3,4-b]pyridin_^3-yl)pyrimidin-5-ylcarbamate,

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 methyl 4,6-diamino-2- ( 1 -(2-fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl)pyrimidin-5-ylcarbamate compound of formu la- 14. 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 25°C 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- 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 methyl 4,6-diamino-2- (l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyfidin-3-yl)pyrimidin-5-ylcarbamate compound of formula- 14.

The eighth aspect of the present invention provides a crystalline form M-I of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimid

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 4,6-diamino-2-[l -(2-fIuorobenzyl)- 1 H-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]-5Tpyrimidinyl(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-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula- 1.

Wherein,

In step-a) and g) 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 25°C to the reflux temperature of the solvent used in the reaction;

in step-e) the suitable temperature is ranging from 25-55°C.

. _.,. , The preferred embodiment of the present invention provides a process for the purification of methyl 4,6-diamino-2-[l ^-fluorobenzy^-lH-pyrazolotS^-bJpyridin-S-ylJ-S- pyrimidinyl(methyl)carbamate compound of formula- 1, comprising of:

a) Adding dimethyl acetamide to methyl 4,6-diamino-2-[l-(2-fluorobenzyl)- 1 H-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- [ 1 -(2-fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl] -5 -pyrimidiny 1 (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)carbarnate compound of formula- 1 , comprising of: a) Adding a mixture of dimethyl acetarnide 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. ^:

Novel 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 novel crystalline form M-I of compound of formula- 1 are useful in the preparation of pure methyl 4,6-diariiino-2-[l-(2-fluor0behzyl)-l H-pyrazolo[3,4-b]pyridin-3-yl^

carbamate compound of formula- 1.

_.. . The tenth aspect of the present invention provides an improved process 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 , comprising of:

a) Reacting .l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide compound of formula- 10 with 2-(phenyldiazenyl)malononitrile compound of formula- 1 1 in presence of sodium formate in a suitable solvent to provide 2- [l-(2-fluoro benzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)phenyldiazenyl]4,6-pyrimidinediamine compound of formula- 12,

b) reducing the compound of formula- 12 with a suitable reducing agent in a suitable solvent to provide 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine triamine compound of formula-13,

c) reacting the compound of formula-13 with methyl chloroformate in presence of base in a suitable solvent to provide compound of formula-14, with a proviso that the base in not pyridine,

d) reacting the compound of formula-14 with methyl iodide (or) dimethyl sulfate in presence of suitable base in a suitable solvent to provide methyl 4,6-diamino-2-[l-(2- fluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1, with a proviso that the base is not NaH or LiHMDS, e) optionally, purifying the compound of formula- 1 using a suitable solvent to provide pure compound of formula- 1.

Wherein,

in step-b) the suitable reducing agents is selected from Fe, Fe in acidic media like NH₄C1, ammonium acetate or HCl or acetic acid, Sn in acidic media like HCl, Zn dust, Zn in acidic media like NH₄CI, ammonium acetate or acetic acid, stannous chloride (SnCl₂), NaBH₄. LiAlH₄, LiBH₄, diborane, borane-THF complex, hydrazine hydrate, hydrogenation catalysts such as Rhodium, sulfides, alkali metal dithionite, alkali metal dithionate and sodium amalgam and the like; preferably Zn-ammonium acetate;

in step-c) the suitable base is selected from organic or inorganic base;

in step-d) the suitable base is selected from inorganic base;

in step-a) to step-e) the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, polar aprotic solvents, nitrile solvents, ester solyents, polar aprotic solvents, hydrocarbon solvent, ether solvents and polar solvent like water or mixture thereof. The preferred embodiment of the present invention provides an improved process 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, comprising of:

a) Reacting l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide compound of formula- 10 with 2-(phenyldiazehyl)malononitrile compound of formula- 1 1 in presence of sodium formate in dimethyl formamide to provide 2-[l-(2-fluoro benzy])rl H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)phenyldiazenyl]4,6-pyrimidine diamine compound of formula- 12,

b) reducing the compound of formula- 12 with zinc and ammonium acetate in methanol to provide 2- [ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3 -yl]pyrimidinetriamine compound of formula- 13,

c) reacting the compound of formula- 13 with methyl chloroformate in presence of sodium hydroxide in isopropanol to provide compound of formula- 14, d) reacting the compound of formula- 14 with methyl iodide in presence of sodium hydroxide in a mixture of water and dimethyl sulfoxide to provide methyl 4,6- diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula- 1.

US7173037 B2 discloses the reduction of 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridin-3-yl]-5-[(E)phenyldiazenyl]4,6-pyrimidinediamine compound of formula-12 using Raney nickel in presence of water and DMF. The reaction requires longer hours maintenance to provide 2-[i-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimid compound of formula- 13.

WO2001/083490 Al discloses the reduction of compound of formula-12 using zinc dust in presence of strong acids like hydrochloric acid. When the inventors of the present invention have repeated the same process, they have found that the compound of formula- 13 is obtained with low yield and purity.

US8492544 B2 discloses the reduction of compound of formula-4 using pd/c i the presence of high boiling solvents like DMF, DMA and NMP in autoclave to provide compound of formula-5. As it is known that palladium is expensive reagent. Usage of high boiling solvents and autoclave pressure reactions are not suggestible for large scale production.

When the inventors of the present invention have carried out the reduction of compound of formula-4 using zinc and neutral base like ammonium acetate in presence of methanol, surprisingly they the time cycle of the reaction has reduced drastically and the reaction was carried out at ambient temperatures conditions. Moreover the said reagent is cheaper when compared to the regular reducing agents like Pd/C and Raney Nickel.

The eleventh aspect of the present invention provides a process 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 comprising of reacting methyl 4,6-diamino-2-[l- (2-fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl] -5-pyrimidinylcarbamate compound of formula- 14 with methyl iodide (or) dimethyl sulfate in presence of a suitable base in a suitable solvent to provide methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3- yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1, with a proviso that the base is not NaH or LiHMDS. Wherein, the suitable base is selected from inorganic base and suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, polar aprotic solvents, nitrile solvents, ester solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents and polar solvent like water or mixture thereof. The preferred embodiment of the present invention provides a process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-l H-pyrazolo[3,4-b]pyridin-3-yl]-5- pyrimidinyl(methyl)carbamate compound of formula- 1 comprising of reacting methyl 4,6- diamino-2-[l -(2-fluorober^yl)-l H-pyrazolo

compound of formula-14 with methyl iodide in presence of sodium hydroxide in a mixture of water and dimethyl sulfoxide to provide methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH- pyrazolo[3,4-h]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1.

US7173037 B2 discloses process for the preparation of compound of formula-1, by reacting compound of formula- 14 with methyl iodide in the presence of bases like sodium hydride (or) LiHMDS.

When the inventors of the present invention, had carried out the same reaction, they found that the yields and purity of compound of formula-1 was very low. Moreover, NaH or LiHMDS are not easy to handle in the laboratory as well as on commercial scale process.

Further, there are disadvantages of using sodium hydride i.e., its high cost, inflammability and liberation of large amounts of inflammable hydrogen while contacted with water. In order to overcome the problem associated with the prior art process, the present inventors had carried out the reaction in the presence of simple hydroxide base such as sodium hydroxide, it is observed that the yield and purity of final compound of formula-1 has been increased when compared to prior art process. Moreover, sodium hydroxide is cheaper, easily to handling in the laboratory as well as on commercial scale up. Hence, the present invention is cost effective, avoids toxic reagents and more advantageous when compared Over the prior art process. The twelfth aspect of the present invention provides a process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]p> idin-3-yl]-5-pyrimidinyl carbamate compound of formula- 14, comprising of reacting 2-[l-(2-fluorobenzyl)-lH- pyrazolo[3,4-b]pyridin-3-yl]pyrimidinetriamine compound of formula- 1.3 with methyl chloroformate in presence of base in a suitable solvent to provide the compound of formula- 14, with a proviso that the base is not pyridine.

Wherein, the base is selected from organic or inorganic base and the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, polar aprotic solvents, nitrile solvents, ester solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents and polar solvent like water or mixture thereof.

The preferred embodiment of the present invention provides a process for the preparation of methyl- 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5- pyrimidinylcarbamate compound of formula- 14, comprising of reacting 2-[l-(2-fluorobenzyl) -lH-pyrazolo[3,4-b]pyridiri-3-yl]py imidinetriamine compound of formula-13 with methyl chloroformate in presence of aqueous sodium hydroxide in isopropanol to provide compound of formula- 14.

Prior reported processes disclosed the process for the preparation of compound of formula- 14 in the presence of pyridine. As pyridine is a carcinogenic substance and further due to its piercing odor, not easy to handle in the laboratory as well on commercial scale.

Whereas, the present invention involves the usage of base like sodium hydroxide making the process economically as well as eco-friendly viable when compared over the prior art process.

The thirteenth aspect of the present invention provides a process for the preparation of

2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3 -yl]pyrimidinetriamine compound of formula-13, comprising of: a) Reacting l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide compound of formula- 10 with 2-(phenyldiazenyl)malononitrile compound of formula- 1 1 in presence of sodium formate in a suitable solvent to provide 2-[l -(2-fluoro benzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)phenyldiazenyl]4,6-pyrimidinediamine compound of formula- 12,

b) reducing the compound of formula- 12 with a suitable reducing agent in a suitable solvent to provide 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine triamine compound of formula-13. Wherein,

in step-b) the suitable reducing agents is same as defined in step-b) of the tenth aspect of the present invention;

in step-a) & b) the suitable solvent is selected form alcohol solvents, chloro solvents, ketone solvents, polar aprotic solvents, . nitrile solvents, ester solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents and polar solvents like water or mixture thereof.

The preferred embodiment, of the present invention provides a process for the preparation of 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidinetriamine compound of formula-13, comprising of:

a) Reacting l-(2-flUorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide compound of formula- 10 with 2-(phenyldiazenyl)malononitrile compound of formula-

1 1 in presence of sodium formate in dimethyl formamide to provide 2-[l-(2-fluoro benzyl)- lH-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)phenyldiazenyl]4,6-pyrimidine diamine compound of formula- 12,

b) reducing the compound of formula- 12 with zinc and ammonium acetate in methanol to provide 2-[l-(2-fluorobe.nzyl)-l H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidinetriamine compound of formula-13.

The fourteenth aspect of the present invention provides a novel crystalline form-M of methyl 4,6-diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-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 7.1, 8.2, 8.6, 10.8, 12.9, 13.5, 14.2, 15.4, 17.7, 19.2, 20.1 , 23.3, 24.1 , 25.0 and 26.5 ±0.2 degrees two theta.

The crystalline form-M 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 is further characterized by its powder X-ray diffraction pattern having peaks at 13.1, 16.2, 19.5, 20.7, 22.8, 26.0, 27.5, 27.8, 29.0, 29.8 and 31.6 ±0.2 degrees two theta.

The crystalline form-M 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 is further characterized: by powder X-ray diffraction pattern as depicted in figure-4 and differential scanning calorimetry (DSC) thermogram as depicted in figure-5 respectively.

^■ The fifteenth aspect_. of the present invention provides a process for the preparation of crystalline form-M 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) Dissolving methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3- yl]-5-pyrimidihyl(methyl)carbamate compound of formula-1 in a suitable solvent, b) adding the solution obtained in step-a) to a suitable solvent at a suitable temperature, c) stirring- the reaction mixture,

d) adding a suitable solvent to the reaction mixture at a suitable temperature,

e) stirring the reaction mixture and filtering the precipitated solid to get crystalline form- M 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.

Wherein,

in step-a), b) and d) suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents and polar solvents like water or mixture thereof;

in step-b) the suitable temperature is ranging from -50°C to 25-30°C; _;

in step-d) the suitable temperature is ranging from 0°C to 25-30°C.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M 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) Dissolving 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 dimethyl acetamide, b) adding the solution obtained in step-a) to methyl tertiary butyl ether at -50°C, c) stirring the reaction mixture,

d) adding acetone to the reaction mixture at -20°C,

e) stirring the reaction mixture and filtering the precipitated solid to get crystalline form- M 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 ;

The another preferred embodiment of the present invention provides a process for the preparation of crystalline form-M 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) Dissolving 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 dimethyl acetamide, b) adding the solution obtained in step-a) to toluene at -50°C,

c) stirring the reaction mixture,

d) adding acetone to the reaction mixture at -20°C,

The another preferred embodiment of the present invention provides process for the preparation of crystalline form-M 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) Dissolving 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 dimethyl acetamide, b) adding the solution obtained in step-a) to a mixture of acetone and water at -30°C, c) stirring the reaction mixture,

d) adding methyl tertiary butyl ether and followed by n-heptane to the reaction mixture at 25-30°C, e) stirring the reaction mixture and filtering the precipitated solid to get crystalline form- M 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. The sixteenth aspect of the present invention provides a novel crystalline form-S of methyl 4,6-diamino-2- [ 1 -(2-fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl] -5-pyrimidiny 1 (methyl)carbamate compound of formula- 1, characterized by its powder X-ray diffraction pattern having peaks at 6.7, 8.0, 8.2, 11.2, 11.8, 13.2, 13.5, 14.3, 15.4, 15.9, 16.4, 17.7, 19.4, 20.2, 21.5, 23.4, 24.2, 25.1, 25.5, 26.6, 27.9 and 28.6 ±0.2 degrees two theta.

The crystalline form-S of methyl 4,6-diamino-2-[l -(2-fluorobenzyl)- lH-pyrazolo[3 ,4- b]pyridin-3-yl]'-5-pyrimidiriyl(methyl)carbamate compound of formula- 1 is further characterized by its powder X-ray diffraction pattern having peaks at 7.1, 8.6, 8.9, 10.6, 18.1, 22.9, 29.0, 29.8, 30.9, 32.1, 32.7, 34.4 and 35.9 ±0.2 degrees two theta.

The crystalline form-S of methyl 4,6-diamino-2-[l -(2-fluorobenzyl)- 1 H-pyrazolo [3,4- b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1 is further characterized by powder X-ray diffraction pattern as depicted in figure-6 and differential scanning calorimetry (DSC) thermogram as depicted in figure-7.

The seventeenth aspect of the present invention provides a process for the preparation of crystalline form-S 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) Dissolving 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 a suitable solvent, b) adding the solution obtained in step-a) to a suitable solvent at a suitable temperature, c) cooling the reaction mixture to a suitable temperature,

d) stirring the reaction mixture and filtering the precipitated solid to get crystalline form- S 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.

Wherein,

in step-a) and b) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents and polar solvents like water or mixture thereof;

in step-b) the suitable temperature was ranging from -30°C to 20°C.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-S 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) Dissolving 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 dimethyl acetamide, b) adding the solution obtained in step-a) to water at a 0°C to 5°C,

c) cooling the reaction mixture to -30°C,

d) stirring the reaction mixture and filtering the precipitated solid to get crystalline form- S of methyl 4,6-diamino-2-il-(2-fluorobenzyl)ⁱlH-pyrazolo[3,4-b]pyndin-3-yl]-5- pyrimidinyl(methyl)carbamate compound of formula- 1.

The eighteenth aspect of the present invention provides an improved process for.? the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo [3,4-b]pyridin-3-yi]-5- pyrimidinyl(methyl)carbamate compound of formula-1, 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)- 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 obtained in step-a) or b) with (E)-3-(dimethylamino) acrylaldehyde compound of formula-5 in presence of a suitable acid in a suitable solvent to provide ethyl l-(2-fluoro benzyl)-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,

e) reacting the compound of formula-7 with trifluoro acetic anhydride in presence of a suitable base in a suitable solvent to provide l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridine-3-carbonitrile compound of formula-8, f) treating the compound of formula-8 in-situ with a suitable base in presence of a suitable solvent to provide methyl l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3- carbimidate compound of formula-9,

g) reacting the compound of formula-9 with ammonium chloride in a suitable solvent and then treating the obtained compound with a suitable acid to provide acid addition salt of compound of general formula- 10, .

h) reacting the acid addition salt of compound of general formula- 10 with (E)-2- (phenyldiazenyl)malononitrile compound of formula- 11 in presence of sodium formate in a suitable solvent to provide (E)-2-( 1 -(2-fluorobcnzyl)- 1 H-pyrazolo[3 ,4-b] pyridih-3 ⁱyl)-5-(phenyldiazenyl)pyrimidine-4i6ⁱdiamine compound' of formula- 12, i) optionally, purifying the compound of formula- 12,

j) reducing the compound of formula- 12 with a suitable reducing agent in a suitable solvent and then treating the obtained compound with suitable hydrochloric acid source to provide hydrochloride salt of 2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridin-3-yl)pyrimidine-4,5,6-triamine compound of formula- 13a,

k) treating the compound of formula- 13a with a suitable base to provide free base of compound of formula- 13,

1) optionally, purifying the compound of formula- 13 using a suitable solvent, m) reacting the compound of formula- 13 with methyl chloroformate in presence of a suitable base in a suitable solvent to provide methyl 4,6-diamino-2-(l-(2-fluoro benzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3-yl)pyrimidin-5-ylcarbamate compound of formula- 14,

n) optionally, purifying the compound of formula- 14 using a suitable solvent, o) reacting the compound of formula- 14 with methyl iodide (or) dimethyl sulfate in presence of a suitable base in a suitable solvent to provide methyl 4,6-diamino-2-[l-

(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1,

p) purifying the compound of formula- 1 using a suitable solvent to provide 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 c) the suitable acid is trifluoro acetic acid;

in step-d), e), f), k), m) and o) the suitable base is selected from organic or in organic base; in step-d) the suitable amidating agent is same as defined in step-d) of the first aspect of the present invention;

in step-g) the suitable acid is selected from hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, fumaric acid, malic acid, maleic acid, tartaric acid, succinic acid and mandelic acid;

in step-j) the suitable reducing agent is selected from same as defined in step-b) of the tenth aspect of the present invention and suitable hydrochloric acid source is selected from HCl, aqueous HCl, IPA-HC1, ethyl acctate-HCl, HCl gas;

in step-a) to p) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, nitrile solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, chloro solvents and polar solvents like water or mixture thereof.

The preferred embodiment of the present invention provides an improved process 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 , 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 tert-butyl ether,

c) reacting compound of formula-4 of step-a) or b) with (E)-3-(dimethylamino) acrylaldehyde compound of formula- 5 in presence of trifluoro acetic acid in xylene 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 formamide in presence of sodium methoxide in a mixture of water and dimethyl formamide to provide l-(2-fluorobenzyl)-lH- pyrazolo[3,4-b]pyridine-3-carboxamide compound of formula-7,

e) reacting the compound of formula-7 v/ith trifluoro acetic anhydride in presence of a triethyl amine and dimethylamino pyridine in tetrahydrofuran to provide 1 -(2-fluoro benzyl)- lH-pyrazolo [3 ,4-b]pyridine-3-carbonitrile compound of formula-8, f) treating the compound of formula-8 in-situ with sodium methoxide in a mixture of methanol and water to provide methyl l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine- 3-carbimidate compound of formula-9,

g) reacting the compound of formula-9 with ammonium chloride in isopropanol and then treating the obtained compound with aqueous hydrochloric acid to provide 1 -(2-fluoro benzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride compound of formula- 1 Oa,

h) reacting the compound of formula- 10a with (E)-2-(phenyldiazenyl)malononitrile compound of formula- 11 in presence of sodium formate in toluene to provide (E)-2- ( 1 -(2-fluoroberizyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl)-5 -(phenyldiazenyl)pyrirnidine- 4,6-diamine compound of formula- 12,

i) purifying the compound of formula- 12 using isopropanol,

j) reducing the compound of formula- 12 of step-h) or i) with zinc dust in presence of ammonium acetate in a mixture of methanol and tetrahydrofuran and then treating the obtained compound with aqueous hydrochloric acid to provide 2-(l-(2-fluorobenzyl)- lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine hydrochloride compound of formula- 13 a,

k) treating the compound of formula- 13a with aqueous sodium carbonate to provide 2-(l- (2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine compound of formula- 13,

1) purifying the compound of formula- 13 using acetonitrile,

m) reacting the compound of formula- 13 with methyl chloroformate in presence of aqueous sodium carbonate in tetrahydrofuran to provide methyl 4,6-diamino-2-(l-(2- fluorobenzy 1) - 1 H-pyrazolo [3 ,4-b] pyridin- 3 -y l)pyr imidin- 5 -y lcarbamate co mpound o f formula- 14,

n) purifying the compound of formula- 14 using a mixture of dimethyl formamide and ethyl acetate, followed by water slurry,

o) reacting the compound of formula- 14 of step-m) or n) with methyl iodide (or) dimethyl sulfate in presence of aqueous sodium hydroxide in dimethyl sulfoxide to provide methyl 4,6-diamino-2-[l-(2-fluoroberizyl)-l H-pyrazolo[3,4-b]pyridin-3-yl]-5- pyrimidinyl(methyl)carbamate compound of formula- 1,

p) purifying the compound of formula- using dimethyl acetamide and ethyl acetate followed by water and methanol slurry to provide 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 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 produced by the present invention call be further iiiicronized or milled in a conventional techniques to get the desired' particle size to achieve ¹ 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 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 invention is having purity greater than 99.5 % 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 at room temperature conditions.

The present invention also encompasses pharmaceutical compositions comprising compound of formula- 1 or salts thereof of the present invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

The inventors of the present invention have in-toto repeated the process disclosed in example-8 of US7173037B2 and the obtained solid methyl 4,6-diamino-2-[l-(2-fluoro benzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1 was characterized by P-XRD and the same has been designated herein as Form- A. The present invention provides methyl 4,6-diamino-2-[l-(2-fluoro benzyl)- 1H- pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1 substantially free of impurities. In particular, the term "substantially free" refers to the compound having the impurities less than 0.1% preferably less than 0.05% and more preferably less tha 0.02% by HPLC. Particularly the present invention provides compound of formula- 1 having "triamine impurity", "phenylazo malononitrile impurity" and "diamine impurity" in not detected levels (measured as area percentage by HPLC).

The P-XRD pattern of the crystalline form-A of methyl 4,6-diamino-2-[l -(2-fluoro ben/.yl)-l H-pyrazolof3,4-bJpyridin-3-yl ]-5-pyrimidinyl(methyl)carbamate compound of formula- 1 is depicted in figure-8.

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.

DSC method of Analysis: Differential scanning calorirhetric (DSC) analysis was performed with QI O V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10° per minute.

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-pyrazoIo[3,4-b]pyridin-3-yI]-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 CI 8, 250 x 4.6 mm, 5 μπι 12 nm (or) equivalent; Wavelength: 210 nm; Column Temperature: 40°C; Injection volume: 10 μΐ; 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 μ filter paper and sonicate to degas it.

The process of the present invention can be represented schematically as follows: Scheme-A:

10a = Hydrochloric acid

13a = Hydrochloric acid

Formula-l Formula- 14

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 (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.

Example-2: Preparation of Ethyl 5-amino-l-(2-fluorobenzyI)-lH-pyrazole-3-carboxylate 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. Tetrahydrofuran (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-Fluorobenzyl) 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 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: 127.0-131.0°C.

Example-3: Preparation of l-(2-fluorobenzyI)-lH-pyrazolo[3,4-b]pyridine-3- carboxamide (Formula- 7)

A mixture of xylene (250 ml) and ethyl 5-amino-l-(2-fluorobenzyl)-lH-pyrazole-3- earboxylate (50 gms) compound of formula-4 were stirred for 20 minutes at 25-30°C under nitrogen atmosphere. ^;(E)-3-(dimethylamin0)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. Trifiuoro 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 105-1 10°C and stirred for ^" 10 hours at the same temperature. Cooled the reaction mixture to 40-45°C. Xylene and followed by water was added to the reaction mixture at 40-45°C and stirred for 20 minutes at ? the same temperature. Filtered the reaction mixture through hy-flow bed and washed the bed with xylene. Both the organic and aqueous layers 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 5-10°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 minutes at the same temperature. Cooled the reaction mixture to 10-15°C and stirred for 4 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.

Yield: 22.0 gms; M.R: 165-170°C.

Example-4: Preparation of methyl l-(2-fluorobenzyl)-lH-pyrazoIo[3,4-b]pyridine-3- carbimidate (Formula-9)

A mixture of tetrahydrofuran (700 ml) and l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridine-3-carboxamide (100 gms) compound of formula-7 were stirred for 15 minutes at 25- 30°C under nitrogen atmosphere. Dimethyl amino pyridine (13.5 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 0-5°C. Triethyl amine (93.4 gms) was added to the reaction mixture at 0- 5°C and stirred for 15 minutes at the same temperature. Trifluoro acetic anhydride (132.1 1 gms) was slowly added to the reaction mixture at 0-5°C and stirred for 8 hours at the same temperature under nitrogen atmosphere. Aqueous sodium carbonate solution was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25- 30°C. Ethyl acetate 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 aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with water and distilled off the solvent completely from the reactio mixture under reduced pressure and co- distilled with methanol. To the obtained compound, methanol (500 ml) was added at 5-10°C.

Sodium methoxide solution (26.8 gms) was slowly added to the reaction mixture at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 5 hours at the same temperature. Cooled the reaction mixture to 0-5°C. 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, washed with water and dried to get the title compound. Yield: 78.66 gms; M.R: 120-125°C.

Excample-5: Preparation of l-(2-fluorobenzyI)-lH-pyrazolo[3,4-b]pyridine-3- carboximidamide hydrochloric acid (Formula-lOa)

A mixture of isopropanol (300 ml) and methyl l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridine-3-carbimidate (50 gms) were stirred for 20 minutes at 25-30°C. Ammonium chloride (19 gms) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 80- 85°C and stirred for 6 hours at the same temperature. Cooled the reaction mixture to 0-5°C. Aqueous hydrochloric acid (25 ml) was slowly added to the reaction mixture at 0-5°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound. Yield: 36.35 gms; M.R: 187^oC-190°C.

Exaraple-6: Preparation of (E)-2-(l-(2-fluorobenzyl)-lH-pyrazoIo[3,4-b]pyridin-3-yl)-5- (phenyldiazenyl)pyrimidine-4,6-diamine (FormuIa-12)

A mixture of toluene (350 ml), l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3- carboximidamide hydrochloric acid (50 gms) compound of formula- 10a and 2- (phenyldiazenyl)malononitrile (30.61 gms) were stirred for 15 minutes at 25-30°C. Sodium formate (13.35 gms) was added to the reaction mixture at 25-30°C. Raised the temperature of the reaction mixture to 105-1 10°C and stirred for 10 hours at the same temperature. Cooled the reaction mixture to 50-55°C. Water was added to the reaction mixture at 50-55°C and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hour at the same temperature. Filtered the reaction mixture and washed with toluene. To the obtained compound, isopropanol (250 ml) was added at 25-30°C and stirred for 2 hours⁵ at the same temperature. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: 63.0 gms; M;R: 250.1-255.2°C; Purity by HPLC: 98.09%.

Example-7: Preparation of 2-(l-(2-fluorobenzyI)-lH-pyrazolo[3,4-b]pyridin-3-yI) pyrimidine-4,5,6-triamine (Formula-13)

A mixture of methanol (250 ml) and tetrahydrofuran (250 ml) was added to (E)-2-(l- (2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)-5-(j)henyldiazenyl)pyrimidine-4,6-diamine (100 gms) compound of formula-12 at 25-30°C. Cooled the reaction mixture to 5-10°C. Ammonium acetate (70.14 gms) was added to the reaction mixture at 5-10°C and stirred for 15 minutes at the same temperature. Zinc dust (36.35 gms) was slowly added to the reaction mixture at 5-10°C and stirred for 2 hour at the same temperature. Filtered the reaction mixture through hy-flow bed and washed the bed with methanol. To the obtained filtrate, water was slowly added at 25-30°C and stirred for 1 hour at the same temperature. Aqueous hydrochloric acid solution was slowly added to the reaction mixture, at 25-30°C and stirred for 1 hour 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. Aqueous sodium carbonate solution was slowly added to the reaction mixture at 25-30°C and stirred for 1 hour at the same temperature. Filtered the solid and washed with water. Acetonitrile (400 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered precipitated solid, washed with acetonitrile and dried to get the title compound. Yield: 55.0 gms; MR: 195-200°C; Purity by HPLC: 95.40%

Examplc-8: Preparation of crystalline form R-I of methyl 4,6-diamino-2-(l-(2-fluoro bettzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-ylcarbamate (Formula-14)

Tetrahydrofuran (700 ml) was added to a pre-cooled solution of water (80 ml) and sodium carbonate (45.53 gms) at 0-5°C. 2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3- yl)pyrimidine-4,5,6-triainine (100 gms) compound of formula- 13 at 0-5°C and stirred for 20 minutes at the same temperature. Methyl chloroformatc (32.36 gms) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 10-15°C and stirred for 4 hours at the same temperature. Water was added to the reaction mixture at 10- ί 5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 6 hours at the ^' ^' same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 98.0 gms; The P-XRD pattern of the obtained compound was disclosed in figure- 1. ExampIe-9: Preparation of crystalline form R-II methyl 4,6-diamino-2-(l-(2- fluorobenzyl)-lH-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-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl carbamate (100 gms) at 25-30°C. Raised the temperature of 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.

The P-XRD pattern of the obtained compound was similar to the P-XRD pattern of figure- 19 disclosed in US2012/01316183 Al .

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; MR: 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-ylJ-5-pyrimidinyl(methyl)carbamate

(Formula-1)

Methyl iodide (31.49 gms) was added to a pre-cooled solution of sodium hydroxide (11.75 gms) and water (200 ml) at 0-5°C. A mixture of dimethyl sulfoxide (1000 ml) and methyl 4,6-diamino-2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4~b]pyridin-3-yl)pyrimidin-5-yl 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 arid 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: 60.0 gms; Purity by HPLC: 94.48%; DMSO content: 149 ppm (by 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-pyrimidinyI(methyl)carbamate (Formula-1)

Dimethyl acetamide (300 ml) was added to the compound obtained in example-10 at^■ 25-30°C. Raised the temperature of 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 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, 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: 55.0 gms; M.R: 265-269°C; Purity by HPLC: 99.97%; Carbamate impurity: 0.01%; Des fluoro impurity: Not detected; Phenyl azomalononitrile impurity: Not detected; Dimethyl impurity: 0.01%; Diamine impurity: Not detected; HIUI: 0.03%;

Particle Size Distribution (PSD): D(0.1) is 1 1.0 μιη; D(0.5) is 23.5 μηι; D(0.9) is 46.3 μι^η; D[4.3] is 26.6 μπι; After Micronization: D(0.1) is 2.18 μιη; D(0.5) is 4.71 μιη; D(0.9) is 8.97 μπι; D[4.3] is 5.19 μπι; The P-XRD pattern of the obtained compound was similar to the P- XRD pattern of figure- 1 disclosed in US2015/0376184A1.

Example- 12: Purification of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4- b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (Formula-1)

A mixture of ethyl acetate (40 ml) and N-methylpyrrolidone (20 ml) was added to methyl 4,6-diamino-2-[l-(2-fluoi benzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate (10 gms) at 25-30°C. Raised the temperature of 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. Water (10 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 (20 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: 7.2 gms; Particle Size Distribution (PSD): D(0.1) is 4.63 μπι; D(0.5) is 27.6 μιη; D(0.9) is 96.5 μπι; D[4.3] is 47.9 μηι; After Micronization: D(0.1) is 1.97 μιη; D(0.5) is 4.26 μm; D(0.9) is 9.99 μm; D[4.3] is 5.45 μm.

Example-13: Prepar ation of 2-[l-(2-fluorobenzyI)-lH-pyrazolo[3,4-b]pyridin-3-yI]-5- [(E)phenyldiazenyl]4,6-pyrimidinediamine (Formula-12)

Sodium formate (0.64 gms) and dimethyl formamide (30 ml) were added to l-(2- fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (3 gms) at 25-30°C and stirred for 15 minutes at the same temperature. 2-(phenyldiazenyl)malononitrile (1.89 gms) was added to the reaction mixture at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 105-110°C and stirred for 5 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C. Water was slowly added to the reaction mixture at 25-30°C and stirred for 1 hour at the same temperature. Ethyl acetate was added to the reaction mixture and stirred for 10 minutes. Both the organic and aqueous layers were separated and aqueous layer was extracted with ethyl acetate. Combined organic layers and washed with 10% sodium chloride solution. Distilled off the solvent from the organic layer to get the title compound. Yield: 3.0 gms.

Example-14: Preparation of 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3j4-b]pyridin-3-yl]-5- [(E)pHenyldiazenyl]4,6-pyrimidinediamine (Formiila-12)

Sodium formate (0.64 gms) and toluene (400 ml) were added to 1 -(2-fliiOrobenzyl)- lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (50 gms) at 25-30°C and stirred for 15 minutes at the same temperature. 2-(phenyldiazehyl)malorionitrile (1.89 gms) was added to the reaction mixture at 25-30°C and stirred for 10 minutes . at the same temperature. Heated the reaction mixture to 105-1 10°C and stirred for 8 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with toluene. To the obtained wet solid, water (250 ml) was added at 25-30°C and stirred for 1 hour at the same temperature. Filtered the solid, washed with water and then followed with cyclohexane and dried to get the title compound. Yield: 63.0 gms; MR: 295-303°C.

Example-15: Preparation of 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl] pyrimidinetriamine hydrochloride (Formula-13a)

Methanol (40 ml) and zinc (1.48 gms) were added to 2-[l-(2-fluorobenzyl)-lH- pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)phenyldiazenyl]4,6-pyrimidinediamine (5 gms) at 25-30°C and stirred for 10 minutes at the same temperature. Ammonium acetate (4.39 gms) was added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. After completion of the reaction, filtered the reaction mixture through hy-flow bed. Distilled off the solvent from the filtrate under reduced pressure. Water was added to the obtained compound and adjusted the pH of the reaction mixture to 1-2 using 50% hydrochloric acid solution. Stirred the reaction mixture for 1 hour at 25-30°C. Filtered the solid and washed with water. To the obtained wet compound, ethyl acetate (50 ml) was added at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hour at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get the title compound.

Yield: 3.0 gms; M.R: 170-175°C.

Example-16: Preparation of methyl 4,6-diamino-2-[J-(2-fluorobenzyl)-lH-pyrazoIo[3,4- b]pyridin-3-yl]-5-pyrimidinyIcarbamate (Formula-14)

Aqueous sodium hydroxide solution {sodium hydroxide (0.69 gms) in water (10 ml)} was added to a mixture of isopropanol (100 ml) and 2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3 ,4- b]pyridin-3-yl|pyrimidinetriamine (5 gms) at 25-30°C and stirred for 10 minutes at the same temperature. Methyl chloro formate (1.61 gms) and isopropanol (5 ml) were slowly added to the reaction mixture at 25-30°C and stirred for f ½ hour at the same temperature. After completion of the reaction, distilled off the solvent from the reaction mixture under reduced pressure. Water was added to the obtained solid at 25-30°C and stirred for 1 hour at the same temperature. Filtered the solid and washed with water. To the obtained wet solid, ethyl acetate (50 ml) was added at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hour at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get the " title compound. Yield: 4.0 gms.

Example-17: Preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo [3,4- b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (Formula-1)

Dimethyl sulfoxide (250 ml) was added to a pre-cooled solution of aqueous sodium hydroxide at 0-5°C and stirred for 10 minutes. A mixture of methyl 4,6-diamino-2-[l-(2- fluorobenzyl)-lH"pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate (50 gms), dimethyl sulfoxide (500 ml) was slowly added to the reaction mixture at 0-5 °C and stirred for 30 minutes at the same temperature. Methyl iodide (17.5 gms) was slowly added to the reaction mixture at 0-5°C and stirred for 2 hours at the same temperature. After completion of the reaction, water was slowly added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated compound, washed with water and dried to get the title compound. Yield: 45.30 gms; Melting point: 267.1 °C; Purity by HPLC: 99.8%. Example-18: Preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4- b]pyridin-3-yl]-5-pyrimidinyI(methyl)carbamate (Formula-!)

Methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5- pynmidinylcarbamate (100 gms) and dimethyl sulfoxide (1000 ml) was added to a pre-cooled mixture of sodium hydroxide (1 1.75 gms) and water (200 ml) at 0-5°C and stirred for 30 minutes at the same temperature. Dimethyl sulphate (23.67 gms) 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, washed with water. To the obtained wet compound, water was added at 25-30°C arid stirred for 1 hour at the same temperature.' Filtered the solid, washed with water arid dried to get the title compound.

Yield: 60.5 gms.

Exairiple-19: Preparation of crystalline Form-M of methyl 4,6-diamino-2-[l-(2-fluoro benzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (Formula-1) Dimethyl acetamide (70 ml) was added to methyl 4,6-diamino-2-[l -(2-fluoro benzyl)- lH-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (500 mg) at 25-30°C arid^' stirred for 10 minutes at the same temperature. The reaction mixture was added to a pre-^': cooled methyl tert-butyl ether (30 ml) at -45°C to -50°C and stirred for 10 minutes at the same temperature. Slowly raised the temperature of the reaction mixture to -10°C to -5°C. Acetone (10 ml) was added to the reaction mixture at -10°C to -5°C. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 20 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 400 mg.

The P-XRD pattern of the obtained compound is depicted in figure-4 and DSC is depicted in figure-5.

Example-20: Preparation of crystalline Form-M of methyl 4,6-diamino-2-[l-(2- fluorobenzyl)-lH-pyrazolo(3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate

(Formula-1)

Dimethyl acetamide (70 ml) was added to methyl 4,6-diamino-2-[l - (2-fluorobenzyl)- lH-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (500 mg) at 25-30°C and stirred for 10 minutes at the same temperature. The reaction mixture was added to a pre- cooled toluene at -45°C to -50°C and stirred for 10 minutes at the same temperature. Slowly raised the temperature of the reaction mixture to -10°C to -5°C. Acetone (10 ml) was added to the reaction mixture at -10°C to -5°C. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 30 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 350 mg.

Example-21: Preparation of crystalline Form-M of methyl 4,6-diamino-2-[l-(2- fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-p^

(Formula-1)

Dimethyl acetamide (10 ml) was added to methyl 4,6-diamino-2-[l-(2-fluoro benzyl)- lH-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (300 mg) at 25-30°C and stirred for 10 minutes at the same temperature. The reaction mixture was added to pre-cooled aqueous acetone at -30°C to -35°C and stirred for 10 minutes at the same temperature. Slowl raised the temperature of the reaction mixture to -20°C to -15°C. Methyl tertiary butyl ether (50 ml) and followed by n-Heptane (50 ml) were added to the reaction mixture at -20°C to - 15°C. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 20^' minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 220 mg.

Example-22: Preparation of crystalline Form-S of methyl 4,6-diamino-2-[l-(2- fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate

(Formula-1)

Dimethyl acetamide (70 ml) was added to methyl 4,6-diamino-2-[l-(2-fluorobenzyl)- lH-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (500 mg) at 25-30°C and stirred for 10 minutes at the same temperature. The reaction mixture was cooled to 0°C to 5°C and water was added at the same temperature. Further, cooled the reaction mixture to -25°C to -30°C and stirred for 20 minutes at the same temperature. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 30 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 400 mg.

The P-XRD pattern of the obtained compound is depicted in figure-6 and DSC is depicted in figure-7.

Example-23: Preparation of ethyl l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3- carboxylate (Formula-6)

A mixture of xylene (125 ml) and ethyl 5-amino-l-(2-fluorobenzyl)-lH-pyrazole-3- carboxylate (25.0 gms) compound of formula-4 were stirred for 20 minutes at 25-30°C under nitrogen atmosphere. (E)-3-(dimethylamino)acrylaldehyde (1 1.75 gms) was added to the reaction mixture' at 25-30°G and stirred for 20 minutes at the same temperature. Cooled the reaction mixture to 10-15°C. Trifluoro acetic acid (21.65 gms) was added to the reaction mixture at 10-1 °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 105-1 10°C and stirred for 12 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Water was added to the reaction mixture at 25-30°C. Filtered the reaction mixture through hy-flow bed and washed the bed with xylene. Both the organic and aqueous layers were separated arid extracted the aqueous layer with xylene. Combined the organic layers and aqueous sodiiim 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. Silicon dioxide was added to the organic layer and stirred for 15 minutes at 25-30°C. Filtered the reaction mixture through hy-flow bed and washed the bed with xylene. Distilled off the solvent completely from the organic layer to get the title compound. Yield: 16.0 gms.

ExampIe-24: Preparation of l-(2-fluorobenzyl)-lH-pyrazoIo[3,4-b]pyridine-3- carboxamide (Formula-7)

Dimethyl formamide (50 ml) was added to ethyl l-(2-fluorobenzyl)-lH-pyrazolo[3,4- b]pyridine-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, washed with water and dried to get the title compound. Yield: 10.1 gms.

Example-25: Preparation of hydrochloric acid salt of 2-(l-(2-fluorobenzyl)-lH-pyrazolo

[3,4-b]pyridin-3-yl) pyrimidine-4,5,6-triamine (Formula-13a)

(E)-2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)-5-(phenyldiazenyl) pyrimidine-4,6-diamine (40 gms), dimethyl formamide (240 ml) and 10% Pd/C were added to autoclave under nitrogen atmosphere and applied 4.0 kg/cm² hydrogen pressure. The reaction mixture was heated to 60-65 °C and stirred for 8 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture through hy-flow bed and washed the bed with dimethyl formamide. Distilled off the solvent from the filtrate and co-distilled with isopropanol. To the obtained compound, water was added at 25-30°C. Aqueous hydrochloric acid solution was added to the reaction mixture at 25-30°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: 25.8 gms; Purity by HPLC: 95.5%.

Example-26: Purification of (E)-2-(l-(2-fluorobenzyI)-lH-pyrazolo[3,4-b]pyridin-3-yI)-5- (phenyldiazeriyl)pyrimidine-4,6-diamine (FormuIa-12)

A mixture of (E)-2-(l-(2-flu0robenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)-5-(phenyldiazenyl) pyrimidine-4,6-diamine (50 gms) and dimethyl formamide (500 ml) were heated to 85-90°C. Basic carbon and silica were added to the reaction mixture at 85-90°C and stirred for 30 minutes at. the same temperature. Filtered the reaction mixture through hy-flow bed ¾nd washed the bed with dimethyl formamide. To the obtained filtrate, water (1000 ml) was slowly added at 25-30°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: 45.0 gms; Purity by HPLC: 98.5%; Assay by HPLC: 98%.

Example-27: Preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazoIo[3,4- b]pyridin-3-yl]-5-pyrimidinylcarbamate (Formula-14)

Aqueous sodium hydroxide solution {sodium hydroxide (0.69 gms) in water (10 ml)} was added to a mixture of Dimethyl formamide (100 ml) and 2-[l-(2-fluorobenzyl)-lH- pyrazolo[3,4-b]pyridin-3-yl]pyrimidinetriamine (5 gms) at 25-30°C and stirred for 10 minutes at the same temperature. Methyl chloroformate (1.61 gms) and Dimethyl formamide (5 ml) were slowly added to the reaction mixture at 25-30°C and stirred for 1 ½ hour at the same temperature. After completion of the reaction, distilled off the solvent from the reaction mixture under reduced pressure. Water was added to the obtained solid at 25-30°C and stirred for 1 hour at the same temperature. Filtered the solid and washed with water. To the obtained wet solid, ethyl acetate (50 ml) was added at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 4.1 gms.

Reference example-1: Preparation of methyl 4,6-diamino-2-[l-(2-fluoro benzyl)-lH- pyrazolo [3,4-b]pyridih-3-yI]-5-pynmidinyl(methyl)carbaniate (Formula-l)

! Methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-l I I-pyrazolof3,4-b]pyridin-3-yl]-5- pyrimidinylcarbamate 20.0 g (49.0 m mol) is dissolved in tetrahydrofuran (257 ml) and cooled to 0°C. Lithium bis(trimethylsilyl)amide solution 53.9 ml (49 0 m mol of a 1M solution in tetrahydrofuran) was added drop wise over the course of 15 minutes. After stirring at 0°C for 20 minutes, iodomethane 6.95 g (53.9 m mol) was added. After one hour, the mixture is allowed to warm to room temperature, and the reaction is stopped by adding saturated aqueous ammonium chloride solution. The phases are separated. The aqueous phase is extracted several times with ethyl acetate and dichloromethane. The combined organic phases are concentrated in vacuo. The residue obtained in this way is suspended in a mixture of dichloromethane and tetrahydrofuran (1 : 1). The insoluble crystals are filtered off with suction and taken up in methanol. The mixture is refluxed for one hour. After cooling, the precipitate which has separated out is filtered off. The red solid obtained in this way is suspended in a mixture of dioxane and dichloromethane (1 : 1) 100 ml and, while boiling, methanol (20 ml) was added until a clear solution forms. Activated carbon is added, and the mixture is boiled briefly and filtered hot through kieselguhr. The solution obtained in this way is evaporated to dryness. The suspension after taking up in methanol is stirred at room temperature for one hour. The white crystals are filtered off with suction. Yield: 14.8 gms. The P-XRD pattern of the obtained compound was depicted in figure-8.

Claims

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 of formula-7.

2. 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)- lH-pyrazole-3 -carboxylase 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 xylene to provide ethyl l-(2-fluoro benzyl)- 1 H-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.

3. The process, according to claim-2, wherein

in step-a) and c) the suitable acid is trifluoro acetic acid;

in step-a) to step-d) the suitable solvent is selected from hydrocarbon solvents, ether solvents, nitrile solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcoholic solvents, and polar solvents such as water or mixtures thereof.

4. The process according to claims- 1 (or) 2 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 and suitable base is selected from organic or inorganic base; and the suitable solvent is selected from hydrocarbon solvents, ether solvents, nitrile solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcoholic solvents, and polar solvents such as water or mixtures thereof.

A process for . the preparation of l-(2-fluorobenzyl) H-pyrazolo[3,4-b]pyridine-3- carboxamide compound of formula-7, comprising of reacting ethyl l-(2-fluoroberizyl)- 1 H-pyrazolo [3, 4-b]pyridine'3-carboxylate compound of formula-6 with formamide in presence of sodium niethoxide in a mixture of dimethyl formamide and water to provide compound of formula-7.

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 fbrmula-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-fluoro benzyl)-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.

7. 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 is characterized by P-XRD pattern as depicted in figure-3.

8. Novel 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.

9. Novel 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.

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 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-e) or f),

h) stirring the reaction mixture and filtering the precipitated solid to get pure methyl 4,6- diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl] -5 -pyrimidinyl (methyl)carbamate compound of formula- 1. Wherein, in step-a) and g) the suitable solvent is selected from polar aprotic solvents selected from dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, -N- methylpyrrolidone and ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate or their mixtures thereof;

in step-b) the suitable temperature is ranging from ambient temperature to the reflux temperature of the solvent used in the reaction;

in step-e) the suitable temperature is ranging from 25-55°C.

11. A process for the purification of methyl 4,6-diamino-2-[ 1 -(2 -fluorohenzyl)-l H-pyrazolo

[3 ,4-b]pyridin-3-yl]-5-pyrimidinyl(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-f),

h) stirring the reaction mixture and filtering the precipitated solid to 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.

12. 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-[ 1 - (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-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl] -5-pyrimidinyl (methyl)carbamate compound of formula- 1.

13. A process for the purification of methyl 4,6-diamino-2-[l -(2-fluorobenzyl)- 1 H-pyrazolo

a) Adding a mixture of N-methylpyrrolidone and ethyl acetate to methyl 4,6-diamino-2- [1 -(2-fluorobenzyl)- lHrpyr

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- [ 1 -(2-fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl] -5-pyrimidinyl (methyl)carbamate compound of formula- 1.

14. A process for the purification of methyl 4,6-diamino-2-(l -(2-fluorobenzyl)- 1 H-pyrazolo

[3,4-b]pyridin-3-yl)pyrimidin--5-ylcarbariiate compound of formula- 14.

[3,4-b]pyridin-3-yl)pyrimidin-5-ylcarbamate,

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 methyl 4,6-diamino-2- (l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-ylcarbamate compound of formula-14.

15. The process according to claim- 14, wherein, In step-a) the suitable solvent is selected from pola aprotic solvents selected from dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N-methylpyrrolidone and ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate or mixture thereof;

in step-b) the suitable temperature is ranging from 25°C to reflux temperature of the solvent used in the reaction;

in step-d) the suitable temperature is ranging from 0°C to 30°C.

16. A process for the purification of methyl 4,6-diamino-2-( 1 ~(2-fluorobenzyl)- 1 H-pyrazolo f3,4-b]pyridin-3-yl)pyrimidin-5-ylcarbamate compound of formula- 14,

a) Adding a mixture of dimethyl formamide and ethyl acetate to methyl 4,6-diamino-2- (1 -(2-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-ylcarbaiiiate, b) heating the reaction mixture to 70-75°C,

c) stirring the reaction mixture,

d) cooling the reaction mixture to 25-30°C,

e) stin'ing the reaction mixture and filtering the solid to get pure methyl 4,6-diamino-2- ( 1 -(2^fluorobenzyl)- 1 H-pyrazolo [3, 4-b]pyridin-3-yl)pyfimidin-5-ylcarbamate compound of formula- 14.

17. An improved process for the preparation of methyl 4,6-diamino-2-[l-(2-lluorobenzyl)-lH- pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 , comprising of:

a) Reacting l-(2-fluoro benzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide compound of formula- 10 with 2-(phenyldiazenyl)malononitrile compound of formula-11 in presence of sodium formate in a suitable solvent to provide 2-[l-(2- fluorobenzy 1)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl] -5- [(E)phenyldiazenyl]4,6-pyrimidine diamine compound of formula- 12,

b) reducing the compound of formula- 12 with a suitable reducing agent in a suitable solvent to provide 2-[l-(2-iluoiObenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine triamine compound of formula-13, c) reacting the compound of formula- 13 with methyl chloro formate in presence of a base in a suitable solvent to provide compound of formula- 14, with a proviso that the base in not pyridine,

d) reacting the compound of formula- 14 with methyl iodide (or) dimethyl sulfate in ■ presence of inorganic base in a suitable solvent to provide methyl 4,6-diamino-2-[l-

(2-fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl] -5 -pyrimidinyl(methyl)carbamate compound of formula- 1, with a proviso that the base is not NaH or LiHMDA.

18. The process according to claim- 17 wherein, ,

in step-b) the suitable reducing agent is selected from Fe, Fe in acidic media like NH₄C 1 , ammonium acetate or HCl or acetic acid, Sn in acidic media like HCl, Zn dust, Zn in acidic media like NH₄C1, ammonium acetate, or acetic acid, stannous chloride (SnCl₂), NaBILt, LiAlILi, LiBIl₄, diborane, borane-TIIF complex, hydrazine hydrate, hydrogenation catalysts such as Rhodium, sulfides, alkali metal dithionite, alkali metal dithionate and sodium amalgam and the, like- in step-c) the suitable base is selected from organic (or) inorganic base;

in step-d) the suitable inorganic base is selected from alkali metal hydroxides; alkali metal alkoxides; alkali metal carbonates; alkali metal bicarbonates; preferably alkali metal hydroxides;

in step-a) to step-d) the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, polar aprotic solvents, nitrile solvents, ester solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents and polar solvent like water or mixture thereof.

19. An improved process 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 , comprising of:

a) Reacting l-(2-fluorobsnzyl)-l H-pyrazolo [3 ,4-b]pyridine-3-carboximidamide compound of formula- 10 with 2-(phenyldiazenyl)malononitrile compound of formula- 1 1 in presence of sodium formate in dimethyl formamide to provide 2-[l-(2- fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)phenyldiazenyl]4,6-pyrimidine diamine compound of formula- 12,

a) reducing the compound of formula- 12 with zinc in presence of ammonium acetate in methanol to provide 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine triamine compound of formula-13,

b) reacting compound of formula-13 with methyl chloroformate in presence of sodium hydroxide in isopropanol to provide compound of formula- 14,

c) reacting the compound of formula- 14 with methyl iodide in the presence of sodium hydroxide in dimethyl sulfoxide to provide methyl 4,6-diamino-2-[l -(2-fluorobenzyl)- iH-pyraz0lo[3,4-bipyridih-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1.

20. A process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH- pyrazol0[3,4-b]pyridin-3-yl]-5-pyrimidihyl(methyl)carbamate compound of formula- 1, comprising of reacting methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridin-3-yl]-5-pyrimidinylcarbamate compound of formula-14 with methyl iodide (or) dimethyl sulfate in presence of a suitable inorganic base in a suitable solvent to provide methyl 4,6-diamino-2-[l -(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula- 1 , with a proviso that the base is not NaH or LiHMDA.

21. The process according to claim-20 wherein, the suitable inorganic base is selected from alkali metal hydroxides; alkali metal alkoxides; alkali metal carbonates; alkali metal bicarbonates; preferably alkali metal hydroxides; and suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, polar aprotic solvents, nitrile solvents, ester solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents and polar solvent like water or mixture thereof.

22. A process 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, comprising of reacting methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridin-3-yl]-5-pyrimidinylcarbamate compound of formula- 14 with methyl iodide in presence of sodium hydroxide in dimethyl sulfoxide to provide methyl 4,6-diamino-2-[l- (2-fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl]-5 -pyrimidinyl(methyl)carbamate compound of formula- 1.

23. A process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH- pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate compound of formula-14, comprising of reacting 2- [l r(2-fluorobenzyl)-l H-pyrazolo [3 ,4-b]pyridin-3-yl]pyrimidine triamine compound of formula- 13 with methyl chloroformate in presence of base in a suitable solvent to provide the compound of formula-14, with a proviso that the base is not pyridine.

24. The process according to claim-23 wherein, the base is selected from organic or inorganic base and suitable solvent is alcohol solvents, chloro solvents, ketone solvents, polar aprotic solvents, nitrile solvents, ester solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents and polar solvent like water or mixture thereof.

25. A process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH- pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate compound of formula-14, comprising of reacting 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine triamine compound of formula- 13 with methyl chloroformate in presence of aqueous sodium hydroxide in isopropanol to provide compound of formula-14.

26. A process for the preparation of 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl] pyrimidinetriamine compound of formula-13, comprising of:

a) Reacting l-(2-fluorobenzyl)-l H-pyrazolo [3, 4-b]pyridine-3-carboximidamide compound of formula- 10 with 2-(phenyldiazenyl)malononitrile compound of formula- 11 in presence of sodium formate in dimethyl formamide to provide 2-[l-(2- fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)phenyldiazenyl]4,6-pyrimidine diamine compound of formula- 12, b) reducing the compound of formula- 12 with zinc in presence of ammonium acetate in methanol to provide 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3- yl]pyrimidinetriamine compound of formula- 13.

27. Novel crystalline form-M 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 7.1, 8.2, 8.6, 10.8, 12.9, 13.1, 13.5, 14.2, 15.4, 16.2, 17.7, 19.2, 19.5, 20.1, 20.7, 22.8, 23.3, 24.1, 25.0, 26.0, 26.5, 27.5, 27.8, 29.0. 29.8 and 31.6 ±0.2 degrees two theta and P-XRD pattern as depicted in figure-4.

28. A process for the preparation of novel crystalline form-M of methyl 4,6-diamino-2-[l-(2- fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl] -5-pyrimidinyl(methyl)carbamate compound of formula- 1, comprising of:

a) Dissolving methyl 4,6-diamino-2- [ 1 -(2-fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridih-3 - yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1 in a suitable solvent, b) adding the solution obtained in step-a) to a suitable solvent at a suitable temperature^', c) stirring the reaction mixture,

d) adding a suitable solvent to the reaction mixture at a suitable temperature,

e) stirring the reaction mixture,

f) filtering the precipitated solid and drying to get crystalline form-M of methyl 4,6- diamino-2- [ 1 -(2-fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl] -5-pyrimidinyl (methyl)carbamate compound of formula-1.

29. The process according to claim-28 wherein,

in step-b) the suitable temperature is ranging from -50°C to 25-30°C;

in step-d) the suitable temperature is ranging from 0°C to 25-30°C.

30. A process for the preparation of novel crystalline form-M 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) Dissolving 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 dimethyl acetamide, b) adding the solution obtained in step-a) to methyl tertiary butyl ether at -50°C, c) stirring the reaction mixture,

d) adding acetone to the reaction mixture at -20°C

e) stirring the reaction mixture,

f) filtering the precipitated solid and drying to get crystalline form-M of methyl 4,6- diamino-2- [ 1 -(2-fiuorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -y 1] -5 -pyrimidiny 1 (mcthyl)carbamate compound of formula- 1.

31. A process for the preparation of novel crystalline form-M of methyl 4,6-diamino-2-[l-(2- fluorobenzyl)- 1 H-pyrazol0[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula- 1, comprising of,

a) Dissolving methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl] -5-pyrimidinyl(methyl)carbarnate compound of formula- 1 in dimethyl acetamide, b) adding the solution obtained in step-a) to toluene at -50°C,

c) stirring the reaction mixture,

d) adding acetone to the reaction mixture at -20°C

e) stirring the reaction mixture,

f) filtering the precipitated solid and drying to get crystalline form-M of methyl 4,6- diamino-2- [ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3-yl] -5 -pyrimidiny 1 (methyl)carbamate compound of formula- 1.

32. A process for the preparation of novel crystalline form-M of methyl 4,6-diamino-2-[l-(2- fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-y]]-5-pyrimidinyl(methyl)carbamate compound of formula- 1 , comprising of,

a) Dissolving 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 dimethyl acetamide, b) adding the solution obtained in step-a) to a mixture of acetone and water at -30°C, c) stirring the reaction mixture,

d) adding methyl tertiary butyl ether and followed by n-heptane to the reaction mixture at 25-30°C,

e) stirring the reaction mixture,

f) filtering the precipitated solid and drying to get crystalline form-M of methyl 4,6- diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl] -5-pyrimidinyl (methyl)carbamate compound of formula- 1.

33. Novel crystalline form-S of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridin-S-ylJ-S-pyrimidinylimethy carbamate compound of formula- 1 , Characterized by its powder X-ray diffraction pattern having peaks at 6.7, 7.1, 8.0, 8.2, 8.6, 8.9, 10.6, 11.2, 11.8, 13.2, 13.5, 14.3, 15.4, 15.9, 16.4, 17.7, 18.1, 19.4, 20.2, 21.5, 22.9, 23.4, 24.2, 25.1, 25.5, 26.6, 27.9, 28.6, 29.0, 29.8, 30.9, 32.1, 32.7, 34.4 and 35.9 ±0.2 degrees two theta and P-XRD pattern was as depicted in figure-6.

34. A process for the preparation of crystalline form-S of methyl 4,6-diamino-2-[l-(2- fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl] -5 -pyrimidinyl(methyl)carbamate compound of formula-1, comprising of:

a) Dissolving 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 a suitable solvent, b) adding the solution obtained in step-a) to a suitable solvent at a suitable temperature, c) cooling the reaction mixture to a suitable temperature,

d) stirring the reaction mixture,

e) filtering the precipitated solid and drying to get crystalline form-S 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.

35. The process according to claim-34 wherein,

in step-b) the suitable temperature was ranging from -30°C to 20°C.

36. A process for the preparation of crystalline form-S 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) Dissolving 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 dimethyl acetamide, b) adding the solution obtained in-step-a) to water at a 0°C to 5°C,

c) cooling the reaction mixture to -30°C,

d) stirring the reaction mixture,

e) filtering the precipitated solid and / drying to get crystalline form-S of methyl 4,6- diamino-2-[l-(2-fluorobenzyl)-l H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)carbamate compound of formula- 1.

37. Novel crystalline forms M, S and 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 are useful in the preparation of pure compound of formula-1.

38. Methyl 4,6-diamino-2- [ 1 -(2-fluorobenzyl)- 1 H-pyrazolo [3 ,4-b]pyridin-3 -yl] -5 -pyrimidinyl (methyl)carbamate compound of formula-1 obtained according to any of the preceding claims having particle size distribution of D90 less than 150 μπι, preferably less than 100 m; more preferably 50 μιη.

39. Novel crystalline forms of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridin-3-ylj 5-pyrimidinyl(methyl)carbamate obtained according to any of the preceding claims are useful for the preparation of pharmaceutical composition.

40. A pharmaceutical composition comprising methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH- pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate and a pharmaceutically acceptable carrier or diluent.

41. 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-fluprobenzyl)-lH-pyrazolo[3,4-b]pyridin-3- yl)-5-(phenyldiazenyl)pyrimidine-4,6-dianiine compound of formula- 12.

Wherein, in step-a) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, riitrile solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents and polar solvents like water or mixture thereof.

42. A process for the purification of (E)-2-(l-(2-fluordbenzyl)-lH-pyrazolo[3,4-b]pyridin-3- yl)-5-(phenyldiazenyl) pyrimidine-4,6-diamine compound of formula- 12, comprising of: a) Adding isopiopanol 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.

43. A process for the purification of 2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl) P3'rimidine-4,5,6-tri amine compound of formula- 13, comprising of,

a) Adding a suitable solvent to 2-(l -(2-fluorobenzyl)-lH-pyrazolo[3,4-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)- lH-pyrazolo[3,4-b]pyridin-3-yl) pyrimidine-4,5,6-triamine compound of formula-13.

Wherein

in step-d) the suitable temperature is ranging from 0°C to 30°C.

44. A process for the purification of 2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl) pyrimidine-4,5,6-tfiarnine compound of formula- 13, comprising of,

a) Adding acetonitrile to 2-(l-(2-flUorobenzyl)-lH-pyfazolo[3,4-b]pyridin-3-yl) 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-fluorobenzyl)- 1 H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidine-4,5,6-triamine compound of formula- 13.

45. 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 to provide compound of formula-7.

46. A process for the preparation of ethyl l-(2-fluoro benzyl)- IH-pyrazolo [3, 4-b]pyridine-3- carboxylate compound of formula-6, comprising of reacting ethyl 5-amino-l-(2-fluoro benzyl)- lH-pyrazole-3-carboxyiate compound , of formula-4 with (E)-3-(dimethylamino) acrylaldehyde compound of formula-5 in presence of trifluoroacetic acid in xylene to provide compound of formula-6.

47. A process for the preparation of 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl] pyrimidinetriamine compound of formula- 13, comprising of reducing 2-[l-(2-fluoro beiizyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)phenyldiazenyl]4,6-pyrimidinediamine compound of formula- 12 with zinc in presence of ammonium acetate to provide compound of formula- 13.

48. Methyl 4,6-diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3 -yl] -5 -pyrimidinyl (methyl)carbamate compound of formula- 1 obtained according to any of the preceding claims having dimethyl impurity less than 0.05% as measured by I IPLC.

49. Methyl 4,6-diamino-2-[ 1 -(2-fluorobenzyl)- 1 H-pyrazolo[3 ,4-b]pyridin-3-yl] -5-pyrimidinyl (methyl)carbamate compound of formula- 1 obtained according to any of the preceding claims is free of 'iriamine impurity", "phenylazo malononitrile impurity" and "diamine impurity".

50. 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 preceding claims having purity greater than 99.9%; preferably 99.95%; more preferably 99.98% as measured by HPLC.