Field of the Invention:

700147807
700147807

The present invention relates to an improved process for the preparation of methyl 4,6-
diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3s4-b]pyridin-3-yl]-5-pyrimidinyl(methyl) 5 carbamate compound of formula-1, represented by the following structural formula:


H3c,

10
15
20

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, hazardous reagents which leads to higher impurity formation and therefore increased production cost. Hence there is a need in the art to develop an efficient, cost effective, commercially viable and environmentally friendly process which provides compound of formula-1 with high yield and purity.

Brief description of the Invention:
The first aspect of the present invention is to provide an improved process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-5 pyrimidinyl(methyl)carbamate compound of formula-1.
The second 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 (methyl)carbamate compound of formula-1 comprising of reacting methyl 4,6-diamino-2-[l-0 (2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate compound of formula-6 with methyl iodide in the presence of inorganic base in a suitable solvent to provide compound of formula-1.
The third 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-6, comprising of reacting 2-[l-(2-fluorobenzyl)-lH-
pyrazolo[3,4-b]pyridin-3-yl]pyrimidinetriamine formula-5 with methyl chloroformate in the
presence of base in a suitable solvent to provide compound of formula-6.
) The fourth 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-5, comprising of:
a) Reacting 1 -(2-fluorobenzyl)-l H-pyrazolo[3,4-b]pyridine-3-carboximidamide
compound-of formula-3 with 2-(phenyldiazenyl)malononitrile compound of formula-2
in the presence of sodium formate in a suitable solvent to provide 2-[l-(2-
fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)phenyldiazenyl]4,6-pyrimidine diamine compound of formula-4,
b) reducing the compound of formula-4 with a suitable reducing agent in a suitable
solvent to provide 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine
30 triamine compound of formula-5.
3
,YE UT OFFP^E^^TFFfW^^

Detailed Description of Invention:
The present invention provides to 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) 5 carbamate compound of formula-1.
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, n-pentane, cycloheptane, methylcyclohexane, m-, o-, or p-xylene and the like; "ether solvents" such as 10 dimethoxymethane, tetrahydroruran, 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 15 dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, 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, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, 20 ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanoI, 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. 25
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 30 bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and
PAT EMI OFFICE dffEW^fAir zir6-^er3rr^&ir6- ^T^B^

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-Diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-Diazabicyclo(4.3.0)non-5-ene (DBN), lithium dioisoporpylamide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropyl amine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethyl aminopyridine, morpholine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methylimidazole, 1,2,4-triazole, 1,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.

10
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 HCl or 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 15 dithionate and sodium amalgam.
The first 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:
20 a) Reacting l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide
compound of formula-3 with 2-(phenyldiazenyl)malononitrile compound of formula-2
in presence of sodium formate in a suitable solvent to provide 2-[l-(2-fluorobenzyl)-
4-b]pyridin-3-yl]-5-pyrimidinylcarbamate compound of formula-6 with methyl iodide in presence of sodium hydroxide in dimethyl sulfoxide to provide methyl 4,6-diamino-2-[l -(2-fluorobenzyl)- lH-pyrazolo[3,4-b]pyridin-3-20 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-6 with methyl iodide in the presence of bases like sodium
hydride (or) LiHMDS.
25 ■.-..'
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.
30
8
PATFMT G'FFtCF CHEMRAJ- lb'/f8'rtti & '12-0^: "--■ -

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, and as a consequence, the necessity of keeping strictly anhydrous reaction medium.
5 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 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 handle in the laboratory as well as on commercial scale up. Hence, the present invention is
10 cost effective, avoids toxic reagents and more advantageous when compared over the prior art
process.1 • . > , .
The third aspect of the present invention provides a process for the preparation of methyl 4,6-diamino-2-[l-(2-fluorqber^ 15 carbamate compound of formula-6, comprising, of reacting 2-[l -(2-fluorobenzyl)-1 H-pyrazolo [3,4-b]pyridin-3-yl]pyrimidinetriamine compound of formula-5 with methyl chloroformate in presence of a suitable base in a suitable solvent to provide the compound of formula-6.
Wherein, the base is selected from organic or inorganic base and suitable solvent is 20 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 25 preparation of methyl 4,6-diamino-2-[ 1 -(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate compound of formula-6, comprising of reacting 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidinetriamine compound of formula-5 with methyl chloroformate in presence of aqueous sodium hydroxide in isopropanol to provide compound of formula-6. 30
PATENT 'OFFICE CTFErTO^F"-" T7^:W8 ~^WWt ^-^TT^-B 4

Prior reported processes disclosed the process for the preparation of compound of formula-6 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.
5 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.
The fourth aspect of the present invention provides a process for the preparation of 2-
10 n^2-fluorober^yl)-lH-pyrazolo[3,4-b^ compound of
formula-5, comprising of:
a) Reacting 1 -(2-fluorobenzyl)-1 H-pyrazolo[3,4-b]pyridine-3-carboximidamide
compound of formula-3 with 2-(phenyldiazenyl)malononitrile compound of formula-2
in presence of sodium formate in a suitable solvent to provide 2-[l-(2-fluorobenzyl)-
15 1H-Pyr^olo[3,4-b]pyridin.3-yl]-5-[(E)phenyldiazenyl]4,6-pyrimidinediamine
compound of formula-4,
b) reducing the compound of formula-4 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-5.
20
Wherein,
in step-b) the 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 NH4CI, ammonium acetate or acetic acid, stannous chloride (SnCl2), NaBH4, 25 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;
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, 30 hydrocarbon solvents, ether solvents and polar solvent like water or mixture thereof.
10

The preferred embodiment of the present invention provides a process for the
preparation of 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3J4-b]pyridin-3-yl]pyrimidinetriamine compound of formula-5, comprising of:
a) Reacting l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide with 2-
5 (phenyldiazenyl)malononitrile in presence of sodium formate in dimethyl formamide
to provide 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)phenyl diazenyl]4,6-pyrimidinediamine compound of forinula-4,
b) reducing the compound of formula-4 with zinc and ammonium acetate in methanol to
provide 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidinetriamine
10 compound of formula-5.
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. 15
Methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-
pyrimidinyl(methyl)carbamate compound of formula-1 produced by the present invention can be further micronized or milled in a conventional techniques to get the desired particle size to achieve desired- solubility profile based on different forms of pharmaceutical composition 20 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.
HPLC Method of Analysis:
25 Methyl 4,6-diamino-2-[l-(2-fluorobenzyI)-lH-pyrazolo[3,4-b]pyridin-3-yI]-5-pyrimidinyl (methyl)carbamate compound of formula-l:
Apparatus: A liquid chromatographic system is to be equipped with variable
wavelength PDA-detector; Column: Symmetry CI8, 150 x 4.6 mm, 3.5 urn (or) equivalent;
Wavelength: 210 nm; Column Temperature: 40°C; Injection volume: 5 uL; Diluent: Methanol
30 v/v; Needle wash: Diluent v/v; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile
phase-B: Acetonitrile: Methanol : Water (90:05:05) v/v/v; Buffer: First filter 1000 ml of milli-
11
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Q-water through 0.45 urn nylon membrane filter paper and transfer accurately 1.0 ml perchloric acid (70%). Mix well and sonicate to degas it.
The process of the present invention can be represented schematically as follows:
5 Scheme-I:



Formula-2

Formula-3

Toluene
HCOONa

H,N

N^N-Ph
Zn dust, MeOH Ammonium acetate
^X^

Formula-4

Formula-5

t

NaOH, IPA, water Methyl chloro formate



CHjI/DimethylsuIfate DMSO
NaOH

Formula-l

Formula-6

10
15

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-[l-(2-fluorobenzyl)-lH-pyrazoIo[3,4-b]pyridin-3-yI]-5-[(E)phenyl diazenyl]4,6-pyrimidinediamine (Formula-4)

12

Sodium formate (0.64 gms) and dimethyl formamide (30 ml) were added to l-(2-
fluorobenzyl)-lH-pyrazolo[3s4-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.
5 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
10 organic layers and washed with 10% sodium chloride solution. Distilled off the solvent from
the organic layer to get the title compound. Yield: 3 gms.
Example-2:
Preparation of 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)phenyl 15 diazenyl]4,6-pyrimidinediamine (Formula-4)
Sodium formate (0.64 gms) and toluene (400 ml) were added to l-(2-fluorobenzyI>
lH-pyrazolo[3,4-b]pyridine-3-carboximidamide (50 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
20 the reaction mixture to 105-110°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
25 compound. Yield: 63 gms; M.R: 295-303°C. Example-3:
Preparation of 2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]pyrimidinetriamine (Formula-5)
Methanol (40 ml) and zinc (1.48 gms) were added to 2-[l-(2-fluorobenzyl)-lH-
30 pyrazolo[3J4-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
13

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 hyflow 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. 5 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. 10 Yield: 3 gms; M.R: 170-175°C.
Example-4:
Preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate (FormuIa-6)
15 Aqueous sodium hydroxide solution {sodium hydroxide (0.69 gms) in water (10 ml)}
was added to a mixture of isopropanol (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 isopropanol (5 ml) were slowly added to the reaction mixture at 25-30°C and stirred for 1 V2 hour at the same temperature. After
20 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
25 hour at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 4 gms.
ExampIe-5:
Preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo [3,4-b]pyridin-3-30 yl]-5-pyrimidinyl(methyI)carbamate(Formula-l)
14

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
5 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. ■ • ■■ <
10 Yield: 45.30 gms; Melting point: 267.1°C; Purity by HPLC: 99.8%. Example-6:
Preparation of methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyI)carbamate (Formula-1)
Methyl 4,6-diamino-2-[l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-
15 pyrimidinylcarbamate (100 gms) and dimethyl sulfoxide (1000 ml) was added to a pre-cooled mixture of sodium hydroxide (11.75 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 20 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 and stirred for 1 hour at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 60.5 gms.
25
30
15

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700147808
w „. . : 700147808
We Claim:
1. 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 2-(phenyldiazenyl)malononitrile compound of formula-2 with l-(2-
fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide compound of formula-
3 in presence of sodium formate in a suitable solvent to provide 2-[l-(2-fluorobenzyl)-
lH-pyrazolo[3J4-b]pyridin-3-yl]-5-[(E)phenyldiazenyl]4,6-pyrimidinediamine compound of formula-4,
b) reducing the compound of formula-4 with a suitable reducing agent in a suitable
■ solvent to provide 2-[l-(2-fluoroben2yl)-lH-pyra2olo[3,4-b]pyridin-3-yl]pyrimidine triamine compound of formula-5,
c) reacting the compound of formula-5 with methyl chloroformate in presence of a suitable base in a suitable solvent to provide compound of formula-6, with a proviso that the base is not pyridine,
d) reacting the compound of formula-6 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)-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1", with a proviso that the base is not LiHMDS or NaH,
e) optionally, purifying the compound of formula-1 using a suitable solvent to provide
pure compound of formula-1.
. The process according to claim-1 wherein,. in step-b) the 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 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; in step-c) the suitable base is selected from organic or inorganic base;
16

in step-d) the suitable inorganic base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates and alkali metal alkoxides; preferably alkali metal hydroxides;
in step-a) to step-e) the suitable solvent is selected from alcohol solvents, chloro solvents,
5 ketone solvents, polar aprotic solvents, nitrile solvents, ester solvents, polar aprotic
solvents, hydrocarbon solvents, ether solvents and polar solvent like water or mixture thereof.
3. An improved process for the preparation of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-
10 Pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate compound of formula-1,
comprising of:
a) Reacting 2-(phenyldiazenyl)malononitrile compound of formula-2 with, l-(2-
fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-carboximidamide compound of formula-
3 in presence of sodium formate in dimethyl formamide- to provide 2-[l-(2-
15 fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl]-54(E)phenyldiazenyl]4,6-pyrimidine
diamine compound of formula-4,
b) reducing the compound of formula-4 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-5,
20 c) reacting compound of formula-5 with methyl chloroformate in presence of sodium
hydroxide in isopropanol to provide compound of formula-6,
d) reacting the compound of formula-6 with methyl iodide in the presence of sodium
hydroxide in 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
25 formula-1.

£ o
10
4. 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]
LU
x 30 pyridin-3-yl]-5-pyrimidinylcarbamate compound of formula-6 with methyl iodide (or)
CN dimethyl sulfate in presence of a suitable inorganic base in a suitable solvent to provide

io
CO
CO CO
I
3