1
F O R M 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. –
NOVEL SALT OF SUBSTITUTED 5-FLUORO-1H-
PYRAZOLOPYRIDINES AND ITS USES
2. Applicant(s)
(a) NAME : TORRENT PHARMACEUTICALS LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : Torrent House, Off Ashram Road, Near Dinesh Hall,
Gujarat 380 009, Ahmedabad
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which
it is to be performed :
2
FIELD OF THE INVENTION
The present invention provides a novel 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-
pyrazolo [3, 4-b] pyridine-3-carboximidamide formate compound of formula (IV)5
and process for the preparation thereof.
The present invention further provides for the use of compound of formula (IV) for
the preparation of vericiguat compound of formula I.
The present invention also relates to a process for the preparation of vericiguat
Modification form II, vericiguat Modification form III, vericiguat monohydrate and10
dihydrate.
BACKGROUND OF THE INVENTION
The compound of the formula (I) acts as a stimulator of soluble guanylate cyclase
and can be used as an agent for prophylaxis and/or treatment of cardiovascular15
disorders, for example for treatment of hypertension and heart failure, including
chronic heart failure, heart failure with reduced ejection fraction (HFrEF), and heart
failure with preserved ejection fraction (HFpEF), stable and unstable angina
pectoris, peripheral and cardiac vascular disorders, of arrythmias, for treatment of
thromboembolic disorders and ischaemias such as myocardial infarction, stroke,20
transitory and ischaemic attacks, peripheral perfusion disorders, prevention of
restenoses such as after thrombosis therapy, percutaneous transluminal angioplasty
(PTA), percutaneous transluminal coronary angioplasty (PTCA), bypass, and for
treatment of arteriosclerosis, asthmatic disorders and diseases of the urogenital
system, for example prostate hypertrophy, erectile dysfunction, female sexual25
dysfunction, osteoporosis, glaucoma, pulmonary hypertension, gastroparesis,
scleroderma and incontinence.
US 8,420,656 (also referred to herein as "the '656 patent") describes a process for
preparing vericiguat (Refer Scheme 1 to 3 of "the '656 patent"). The Scheme 230
3
specifically discloses use of ammonium chloride and acetic acid for the preparation
of 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-pyrazolo [3, 4-b] pyridine-3-
carboximidamide acetate. The disclosed process involves tedious workup process
and affords low yield.
5
US 8,802,847 and US 10,633,356 (also referred to herein as "the ‘847 " and " the
‘356 ") specifically discloses use of ammonium chloride for the preparation of 5-
fluoro-1-[(2-fluorophenyl) methyl]-1H-pyrazolo [3, 4-b] pyridine-3-
carboximidamide hydrochloride, but also results in low yield. The ‘847 also
discloses the compound of formula (I) may exist in various crystal forms, hydrates10
and solvates thereof. However, the US ‘847 and ‘356 dose not discloses the process
for the preparation of Form II, III, monohydrate and dihydrate.
WO 2021254981 A1 also discloses use of ammonium chloride for the preparation
of 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-pyrazolo [3, 4-b] pyridine-3-15
carboximidamide hydrochloride, but with low yield.
The prior art processes for the preparation of vericiguat and its intermediates
discloses tedious methods like column chromatography, multiple extractions, with
low yield and quality.20
The inventors of a present invention have developed cost effective, non and or less
tedious process resulting in high yield.
The inventors of a present invention have also developed a simple, safe, efficient,25
economical, industrially feasible and scalable process for the preparation of
vericiguat and its intermediates.
4
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a novel 5-fluoro-1-[(2-fluorophenyl)
methyl]-1H-pyrazolo [3, 4-b] pyridine-3-carboximidamide formate compound of
formula (IV).
5
In another aspect, the present invention provides use of compound of formula (IV)
for the preparation of vericiguat compound of formula I.
In still another aspect, the present invention provides a novel process for preparing
a compound of formula (IV), comprising reacting compound of formula (III) in10
presence of ammonium formate in an alcohol and base to form a compound of
formula (IV).
In another aspect, the present invention provides a process for the preparation of
vericiguat compound of formula I comprises converting a compound of formula IV15
to vericiguat compound of formula I.
In another aspect, the present invention provides a process for preparation of
vericiguat modification form II comprising;
a) providing solution of vericiguat or solvate thereof in a solvent;20
b) adding a solvent;
c) isolating vericiguat modification Form II.
In another aspect, the present invention provides a process for preparation of
vericiguat modification form II comprising;25
I) providing a wet vericiguat or solvate thereof;
II) isolating vericiguat modification Form II.
5
In another aspect, a process for preparation of wet vericiguat or solvate thereof of
step (I) as used in above aspect comprises;
i) providing a solution of vericiguat or solvate thereof in a solvent;
ii) combining a solvent to form wet solid after filtration;
iii) providing a wet solid from the wet solid of step ii in a solvent.5
iv) providing a wet vericiguat or solvate thereof from the wet solid of step
iii in a solvent.
In another aspect, the present invention provides a process for preparation of
vericiguat modification form III comprising;10
a) providing a suspension of vericiguat or solvate thereof in a solvent;
b) heating the solution;
c) isolating vericiguat modification Form III.
In another aspect, the present invention provides a process for preparation of15
vericiguat monohydrate comprising;
a) providing a solution of vericiguat or solvate thereof in a solvent;
b) adding a mixture of solvent;
d) isolating vericiguat monohydrate.
20
In another aspect, the present invention provides a process for preparation of
vericiguat dihydrate comprising;
a) providing a solution of vericiguat or solvate thereof in a solvent;
b) adding a solvent;
c) isolating vericiguat dihydrate.25
BRIEF DESCRIPTION OF THE FIGURES
Figure 1: X-ray diffraction pattern (XRD) of vericiguat Modification form II.
6
Figure 2: X-ray diffraction pattern (XRD) of 5-fluoro-1-[(2-fluorophenyl) methyl]-
1H-pyrazolo [3, 4-b] pyridine-3-carboximidamide formate compound of formula
(IV).
Figure 3: X-ray diffraction pattern (XRD) of vericiguat as per Example 21.5
DESCRIPTION OF THE EMBODIMENTS
The term "solution" as used herein means an appropriate mixture for purposes
disclosed herein of one or more solutes in one or more solvents. Solution
encompasses homogeneous mixtures as well as heterogeneous mixtures, such as10
slurries or other suspension mixtures having insoluble (not dissolved) material.
The present invention provides a novel compound of formula (IV).
In another aspect, the present invention provides use of compound of formula (IV)
for the preparation of compound of formula I.15
The present invention further provides a novel compound of formula (IV)
characterized in that the x-ray diffraction of the compound exhibits peak maxima
of 2 theta angle at 6.0,10.7,12.0,14.9,17.5,18.7, 20.1,22.8,22.9,24.6,25.0, 25.0,
25.5, 27.3, 27.4 ± 0.2.20
The present invention further provides a compound of formula (IV) as shown by
the x-ray diffraction pattern of FIG. 2.
The present invention provides a novel process for preparing a compound of25
formula (IV), comprising reacting a compound of formula (III) in presence of
ammonium formate in an alcohol and base to form a compound of formula (IV).
7
Ammonium formate may be used in an amount of 1 to 10 moles equivalent, suitably
1 to 3 moles equivalent, more preferably 1or 2 or 3 moles equivalent. The reaction
temperature may be usually 0 °C to 40 °C, preferably 30 °C and the reaction
temperature may be further raised to the reflux temperature of the solvent used. It
may be suitable to conduct stirring for 1 to 10 hours, more suitably about 1 or 35
hours.
The alcohol solvent is selected form methanol, ethanol, n-propanol, isopropanol, n-
butanol or tert-butanol and mixtures thereof, preferably methanol.
10
The base may be selected from sodium methoxide or sodium ethoxide, preferably
sodium methoxide.
After cooling, the compound of formula (IV) (wet) can be isolated by using
techniques such as, evaporation and/or filtration with or without gravity or suction,15
from the mass to obtain the desired product, and optionally the solid (wet) can be
washed with a solvent. The compound of formula (IV) can be isolated by
evaporating solvent and/or filtration. The solvent used for evaporation and/or
filtration or washing may be selected from methanol, ethanol, n-propanol,
isopropanol, butanol, ethyl acetate, methylenechloride, ethylenedichloride, water or20
mixture thereof.
The compound of formula (IV) after isolation can be dried at suitable temperature,
at atmospheric or reduced pressure, for about 1-50 hours, or longer, using drying
equipment, such as a tray dryer or vacuum oven. Drying temperature and time will25
be sufficient to achieve desired product. The temperature may be 30 °C to 70 °C,
preferably 45°C to 55 °C for about 7 to 12 hours.
8
The present invention provides a novel process for the preparation of vericiguat
compound of formula I comprising converting a compound of formula IV to
vericiguat compound of formula I.
The scheme I illustrates individual reaction steps of present invention and illustrated5
by the way of examples.
Vericiguat or solvate thereof for the preparation of modification form II, III,
monohydrate and dihydrate can be synthesized by the process of the present
invention or may be obtained by any of the methods known in the literature.10
The present invention provides a process for preparation of vericiguat modification
form II comprising;
a) providing a solution of vericiguat or solvate thereof in a solvent;
b) adding a solvent;15
c) isolating vericiguat modification Form II.
In one embodiment, vericiguat solvate may be selected from Vericiguat dimethyl
sulfoxide, Vericiguat di-dimethyl sulfoxide and dimethylacetamide (DMAc),
preferably vericiguat di-dimethyl sulfoxide solvate.20
Vericiguat or solvate thereof, preferably vericiguat di-dimethyl sulfoxide solvate
of step (a) may be dissolved in a solvent to form a solution.
The solvent for step (a) is selected from N-methyl pyrrolidone, N,N-25
dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide
(DMAc), preferably dimethylacetamide.
9
Vericiguat or solvate thereof, preferably vericiguat di-dimethyl sulfoxide may be
dissolved or obtained in the solvent at a temperature of about 5°C to the reflux
temperature of the solvent. In another embodiment, Vericiguat or solvate thereof
may be dissolved or obtained in the solvent, preferably dimethylacetamide, at 25 to
35°C and the temperature may be further raised at 55 to 65 °C or 70 to 80 °C.5
After cooling below 5 °C, preferably at 3 °C , the solvent (antisolvent for
precipitation) of step (b) may be selected form methyl acetate, ethyl acetate,
chloroform, methylenechloride, ethylenedichloride, or mixture thereof, preferably
ethyl acetate or methylenechloride.10
After step b), the reaction mass of step (b) can be further isolated by filtration with
or without gravity or suction, the obtained wet reaction mass can be washed with a
solvent of step (b) and further suck dried to obtain vericiguat wet solid.
15
After washing, Vericiguat modification Form II can be isolated by drying vericiguat
wet solid at suitable temperature ranges from 30 °C to 70 °C, preferably 45° C to
55 °C, more preferably 50 °C. The drying is perform using vacuum oven (Vacuum
Tray dryer).
20
The present invention provides a process for preparation of vericiguat modification
form II comprising;
I) providing a wet vericiguat or solvate thereof;
II) isolating vericiguat modification Form II.
25
Vericiguat or solvate thereof of step I) may be wet or dry solid. Vericiguat or solvate
thereof may be selected form wet vericiguat solid. Wet Vericiguat solid comprises
dimethylacetamide (DMAc) and ethyl acetate.
10
Vericiguat modification Form II can be isolated by drying wet vericiguat or solvate
thereof at suitable temperature ranges from 50 °C to 90 °C, preferably 75 °C, for 15
to 24 hours, preferably 18 hours. The drying is performed using fluidized bed dryer
or vacuum oven (Vacuum Tray dryer).
5
In further embodiment, the process for preparation of a wet vericiguat or solvate
thereof, as used in above aspect of step (I) comprising;
i) providing a solution of vericiguat or solvate thereof in a solvent;
ii) combining a solvent to form wet solid;
iii) providing a wet solid from the wet solid of step ii in solvent.10
iv) providing a wet vericiguat or solvate thereof from the wet solid of step
iii in a solvent.
The solvate may be vericiguat dimethyl sulfoxide, Vericiguat di-dimethyl sulfoxide
solvate.15
The vericiguat or solvate thereof of step (i) may be dissolved in a solvent to form a
solution or suspension, preferably solution.
The solvent of step (i) is selected from N-methyl pyrrolidone, N,N-20
dimethylformamide (DMF), dimethylacetamide (DMAc); or mixtures thereof,
preferably dimethylacetamide.
The Vericiguat or its solvate, preferably Vericiguat di-dimethyl sulfoxide solvate
may be dissolved or obtained in the solvent, preferably dimethylacetamide at a25
temperature of about 5°C to the reflux temperature of the solvent used, preferably
25 to 35°C and temperature may be further raised at 70 °C to 80 °C, preferably
75°C, followed by filtration and washing with hot solvent, preferably
dimethylacetamide (DMAc).
11
After filtration, reaction mass may be cooled below 5 °C, preferably at 0 °C. After
cooling, the solvent of step (ii) is selected from chloroform, methylenechloride,
ethylenedichloride, or mixture thereof, preferably methylenechloride.
5
After precipitation, the step (ii) further includes filtration of reaction mass of step
(ii) and further dried to obtain wet solid. The wet solid comprises of vericiguat or
solvate thereof, preferably wet solid of vericiguat, more preferably wet solid of
vericiguat comprising methylene chloride and dimethylacetamide.
10
Step iii) provides a wet solid from the wet solid of step ii) in a solvent. The solvent
for step iii) is selected from ester, preferably ethyl acetate.
The vericiguat wet soild of step ii) mixed in a solvent under stirring to form a
suspension. Vericiguat wet solid of step ii mixed under stirring in a solvent i.e. ethyl15
acetate to form a suspension at a temperature of about 5°C to the reflux temperature
of the solvent, preferably at 30 to 35°C, more preferably 33°C and stirred for 1 to 6
hours, preferably 2 to 3 hours.
The reaction mass of step iii) can be further isolated by using filtration with or20
without gravity or suction to obtain wet solid. The obtained wet solid can be washed
with a solvent of step iii) and further suck dried to obtain wet solid. The wet solid
comprises vericiguat or solvate thereof. The obtained wet vericiguat or its solvate
comprising ethyl acetate and dimethylacetamide.
25
Step iv) provides a wet solid from the wet solid of step iii) in a solvent. The solvent
for step iv) is selected from ester, preferably ethyl acetate.
12
The wet vericiguat or solvate thereof of step iii) is mixed under stirring in a solvent
to form a suspension.
Vericiguat or solvate thereof i.e. vericiguat wet solid may be mixed under stirring
in a solvent i.e. ethyl acetate to form a suspension at a temperature of about 5°C to5
the reflux temperature of the solvent, preferably at 30 to 35°C, more preferably
33°C and stirred for 1 to 6 hours, preferably 2 to 3 hours.
After formation of suspension, the reaction mass (suspension) can be further filtered
with or without gravity or suction, the obtained wet solid can be washed with a10
solvent of step iv) and further suck dried to obtain wet solid. The wet solid
comprises vericiguat or solvate thereof. The obtained wet vericiguat or its solvate
comprising dimethylacetamide (DMAc) and ethyl acetate.
In one aspect, the present invention provides a process for preparation of vericiguat15
modification form III comprising;
a) providing a suspension of vericiguat or solvate thereof in a solvent
b) heating the solution
c) isolating vericiguat modification Form III.
20
The solvate may be Vericiguat dimethyl sulfoxide, Vericiguat di-dimethyl
sulfoxide solvate, dimethylacetamide (DMAc). The solvate may be Vericiguat di-
dimethyl sulfoxide solvate.
The vericiguat or solvate thereof of step (a) may be mixed in a solvent to form a25
solution or suspension, preferably suspension.
13
The solvent for step (a) is selected from alcohol. The alcohol may be selected form
methanol, ethanol, n-propanol, isopropanol, butanol, or mixture thereof; preferably
methanol.
In another embodiment, the Vericiguat or solvate thereof, preferably Vericiguat di-5
dimethyl sulfoxide is heated or obtained in the solvent, preferably methanol, at a
temperature of about to the reflux temperature of the solvent used.
After cooling, the obtained wet solid containing vericiguat modification Form III
can be isolated by filtration with or without gravity or suction, and further the solid10
can be washed with a solvent of step (a). After washing, Vericiguat modification
Form III can be further isolated by drying using vacuum oven (Vacuum Tray dryer),
at suitable temperature such as 30 °C to 70 °C, preferably 45°C to 55 °C, preferably
50 °C for about 5 to 10 hours, preferably about 8 hours.
15
In one aspect, the present invention provides a process for preparation of vericiguat
monohydrate comprising;
a) providing a solution of vericiguat or solvate thereof in a solvent
b) adding a mixture of solvent
c) isolating vericiguat monohydrate.20
The vericiguat of step (a) may be dissolved in a solvent to form a solution or
suspension, preferably solution.
In one embodiment, the solvent of step (a) includes acid such as formic acid.25
The solution of step a) may be filtered through hyflow bed. The hyflobed may be
washed with formic acid.
14
The solvent used in step (c) includes a mixture of liquor ammonia and water. The
solvent of step (a) is added to step (b). The solvent of step (a) is added to step (b) at
a temperature below 4 °C, preferably at 2 °C.
Vericiguat monohydrate of step (c) can be isolated by filtration with or without5
gravity or suction, and the solid can be washed with a solvent such as water. After
washing, vericiguat monohydrate after isolation can be dried at suitable
temperature, using a tray dryer, Drying temperatures will be sufficient to achieve
desired product. The drying temperature may be at room temperature.
10
In one aspect, the present invention provides a process for preparation of vericiguat
dihydrate comprising;
a) providing a solution of vericiguat or solvate thereof in a solvent
b) adding a solvent
c) isolating vericiguat dihydrate.15
In one embodiment, the vericiguat or solvate thereof, preferably vericiguat may be
mixed or obtained in the solvent at a temperature of about 20 °C to 35°C
temperature of the solvent used, and more preferably at about 27 °C to form a
solution or suspension, preferably suspension.20
In another embodiment, the solvent for step (a) is selected from methanol, ethanol,
n-propanol, isopropanol, butanol or mixture thereof, preferably methanol.
The solvent used in step (b), can be added at about 27 ± 3 °C. The solvent used in25
step (b) include an aqueous ammonia.
Vericiguat dihydrate of step (c) can be isolated by using filtration with or without
gravity or suction, and the solid can be washed with a solvent such as methanol.
15
After washing, Vericiguat dihydrate after isolation can be dried at suitable
temperature, using vacuum oven (Vacuum Tray dryer). Drying temperature will be
sufficient to achieve desired product. The temperature may be at 30 to 70°C,
preferably 45 to 55 °C.5
N NH
N
F
I
5-fluoro-3-iodo-1H-pyrazolo
[3,4-b]pyridine (IIa)
N N
N
F
I
F
5-fluoro-1-[(2-fluorophenyl)methyl]-
3-iodo-1H-pyrazolo[3,4-b]pyridine (II)
N N
N
F
CN
F
5-fluoro-1-[(2-fluorophenyl)methyl]-1H-
pyrazolo[3,4-b]pyridine-3-carbonitrile
(III)
N N
N
F
C
F
NH2
NH
5-fluoro-1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]
pyridine-3-carboximidamide (IV')
N
N
NC
NC
N
N N
F
F
N
N
NH2
NH2
N
N
2-5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo
3,4-bpyridin-3-yl)-5-(E)-phenyldiazenylpyrimidine-4,6-
diamine (VI)
N N
N
F
F
N
N
NH2
NH2
NH2
2-{5-fluoro-1-[(2-fluorophenyl)methyl]-1H-pyrazolo
[3,4-b]pyridin-3-yl}pyrimidine-4,5,6-triamine (VII)
N N
N
F
F
N
N
NH2
NH2
NH
O
O
CH3
Methyl-(4,6-diamino-2-{5-fluoro-1-[(2-fluorophenyl)methyl]
-1H-pyrazolo[3,4-b]pyridin-3-yl}pyrimidin-5-yl)carbamate (I) or Di-DMSO
solvate (Ia)
N N
N
F
F
N
N
NH2
NH2
NH
O
O
CH3
Vericiguat (I)
(V)
NH2
(Va)
HCl (IVa) OR HCOOH (IV)
Scheme I
The present invention is further illustrated by the following examples which is10
provided merely to be exemplary of the invention and do not limit the scope of the
invention. Certain modification and equivalents will be apparent to those skilled in
the art and are intended to be included within the scope of the present invention.
EXAMPLES:15
Example 1: Preparation of 5-fluoro-1-[(2-fluorophenyl) methyl]-3-iodo-1H-
pyrazolo[3,4-b]pyridine (II)
16
1000 ml of dimethylfumarate was charged into round bottom flask & charged 200.0
gm of 5-fluoro-3-iodo-1H-pyrazolo [3,4-b]pyridine. Reaction mass was stirred to
get clear solution at 25 °C. 235.37 gm of cesium carbonate was charged in reaction
mass and stirred at 25°C. 136.55 gm of 2-fluoro benzyl bromide was charged and5
stirred the reaction mass at 25±5°C and further stirred for 2 hrs at 25 °C. 6000.0 ml
of water was charged in the reaction mass maintaining temperature at 25±5°C.
Reaction mass was stirred for 45-60 min at 25 °C. Reaction mass was filtered and
1000 ml of water wash was given to wet solid. The solid was suck dried well and
unload the wet cake. The wet solid was charged in 3200 ml of isopropyl alcohol10
and raise reaction temperature at 83 °C. Reaction was stirred and maintained at
83°C for 30-45 min. Heating was stopped and cooled the reaction mass at 25 °C.
Reaction mass was stirred at 25°C for 45-60 min. Reaction mass was filtered and
suck dried well. Unload the wet solid, wet wt. 218 gm. Wet product was dried in
vacuum tray dryer at 50 °C for 8.0 hours. Dry weight of 5-fluoro-1-[(2-15
fluorophenyl)methyl]-3-iodo-1H-pyrazolo[3,4-b]pyridine- 210 gm.
Example 2: Preparation of 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-
pyrazolo[3,4-b]pyridine-3-carbonitrile (III)
1500.0 ml of dimethyl fumarate was charged into round bottom flask & charged20
200.0 gm of 5-Fluoro-1(2-fluorobenzyl)-3-iodo-1H-pyrazolo [3,4-b]Pyridine.
Reaction mass was stirred at 30°C. 62.74 gm of copper cyanide was charged in
reaction mass and reaction temperature was raised at 152°C. Reaction mass was
stirred at 152°C for 3.0 hrs. Heating was stopped and cooled the reaction mass at
30°C. Reaction mass was charged into solution of 1140.0 ml of aqueous ammonia25
and 6800.0 mL of water at 25 °C. Reaction mass was stirred for 10-15 min at 30°C.
Reaction mass was extracted with 2000 ml of ethyl acetate. Organic layer was
separated and aqueous layer was again extracted with 2000 ml of ethyl acetate.
Organic layer was separated and aqueous layer was discarded. Organic layer was
17
filtered on hyflobed and the bed was washed with organic layer, followed by
washing with 1000 ml of ethyl acetate. Combined filtrate and washed with 1000 ml
of 2% Ethylene diamine tetra acetic acid solution at 30°C, followed by washing
with 1000 ml of 10% sodium chloride solution. The organic layer was dried on
60.0gm of sodium sulphate. Sodium sulphate was removed by filtration and5
washed with 1000 ml of ethyl acetate. Ethyl acetate was distilled out completely
under vacuum at 52°C. Residue was co-distilled with 400 ml of n-heptane under
vacuum at 52±3°C followed by co-distilled with 400 ml of heptane under vacuum
at 52°C. 400 ml of heptane was charged in residue and stirred for 30-45 minute at
52°C. Heating was stopped and cooled the reaction mass at 20°C. Reaction mass10
was stirred for 30-45 minute at 20 °C. Reaction mass was filtered and washed 200
ml of heptane wash was given to wet solid, suck dried well and unload the wet solid
wet wt. -148.0 gm. Wet solid was dried under vacuum at 50±3°C for 10 hours. Dry
wt: 130.0 gm.
15
Example 3: Preparation of 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-pyrazolo
[3,4-b]pyridine-3-carboximidamide formate (IV)
1000.0 ml of methanol was charged in the round bottom flask. 10.0 gm of sodium
methoxide was charged in reaction mass at 30°C. The reaction mass was stirred for
10-20 minute at 30°C. 50.0 gm of 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-20
pyrazolo [3,4-b]pyridine-3-carbonitrile was charged in reaction mass. The reaction
mass was stirred for 3.0 hours at 30°C. 35.02 gm of ammonium formate was added
in reaction mass at 30°C. The reaction temperature was raised at 63°C, stirred and
maintained reaction mass at 63°C.The reaction mass was cooled below 55°C
temperature. The reaction mass was distilled under vacuum below 55°C. After25
distillation, degassing the residue under vacuum below 55°C for 20-30 minute.
100.0 ml of ethyl acetate was charged in residue and stirred it at 52°C. Ethyl acetate
was distilled out completely under vacuum below 55°C. 100.0 ml of ethyl acetate
was charged in residue and stirred it at 52°C. Ethyl acetate was distilled out
18
completely under vacuum below 55°C. Degassed the residue under vacuum
completely below 55°C. 500.0 ml of methylene chloride was charged in residue
below 55°C. The reaction mass was stirred at reflux temperature at 42°C. After
heating, the reaction was cooled at 27 °C. The reaction mass was stirred for 30-45
minute at 27 °C. The reaction mass was filtered and washed the wet cake with 100.05
ml of methylene chloride. Suck dried the wet cake well. 100.0 gm of wet solid was
charged in 500.0 ml of water. The reaction mass was stirred for 30-45 minute at 30
°C. The reaction mass was filtered and washed the wet solid with 100.0 ml of water.
Suck dried the wet solid well. Unload the wet solid wet wt. - 100.0 gm. wet solid
was dried in air tray dryer for 8-10 hours at 50°C. Unload the dry solid Dry wt. -10
58.0 gm (96.83%).
Example 4: Preparation of 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-pyrazolo
[3, 4-b]pyridine-3-carboximidamide formate (IV)
1250.0 ml of methanol was charged in the round bottom flask. 55.0 gm of sodium15
methoxide was charged in reaction mass at 30 °C. The reaction mass was stirred for
10-20 minute at 30 °C. 250.0 gm of 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-
pyrazolo [3,4-b]pyridine-3-carbonitrile was charged in reaction mass. The reaction
mass was stirred for 3.0 hours at 30 °C. 175.0 gm of ammonium formate was added
in reaction mass at 30°C. The reaction temperature was raised at 63 °C, stirred and20
maintained reaction mass at 63 °C. The reaction mass was cooled below 30 °C
temperature. The reaction mass was stirred for 1.0 hour at 30 °C. Filtered the
reaction mass and slurry wash with 250.0 ml of chilled methanol. 320.0 gm of wet
solid was charged in 1250.0 ml of water. The reaction mass was stirred for 1 hour
at 30 °C. The reaction mass was filtered and washed the wet solid with 250.0 ml of25
water. Suck dried the wet solid well. Unload the wet solid wet wt. 440.0 gm. wet
solid dried in air tray dryer for 10-12 hours at 50°C. Unload the dry solid. Dry wt.
- 290.0 gm (96.83%).
19
Example 5 : Preparation of 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-pyrazolo
[3, 4-b]pyridine-3-carboximidamide hydrochloride (IVa)
2400.0 ml of methanol was charged in the round bottom flask. 23.99 gm of sodium
methoxide was charged in reaction mass at 30±3°C. The reaction mass was stirred
for 10-20 minute at 30°C. 120.0 gm of 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-5
pyrazolo [3, 4-b] pyridine-3-carbonitrile was charged in reaction mass. The reaction
mass was stirred for 3.0 hours at 30 °C. 28.51 gm of ammonium chloride was
charged in reaction mass at 30 °C. The reaction temperature was raised at 63±3°C,
stirred and maintained reaction mass at 63°C and cooled the reaction mass below
55°C temperature. The reaction mass was distilled under vacuum below 55°C. After10
distillation, degassed the residue under vacuum below 55°C for 20-30 min. 240.0
ml of Ethyl acetate was added in residue and stirred it at 52°C. Ethyl acetate was
distilled out completely under vacuum below 55°C. 240.0 ml of Ethyl acetate was
charged in residue and stirred it at 52°C. Ethyl acetate was distilled out completely
under vacuum below 55°C. Degassed the residue under vacuum completely below15
55° C. 1200 ml of methylene chloride was charged in residue below 55°C. The
reaction mass was stirred at reflux temperature at 42°C. The reaction was cooled at
27°C. The reaction mass was stirred for 30-45 minute at 27°C. The reaction mass
was filtered and washed the wet cake with 120.0 ml of methylene chloride. Suck
dried the wet cake well. Unloaded the wet cake wet wt.:- 154.0 gm. 154.0 gm of20
wet solid was charged with 1200.0 ml of water. The reaction mass was stirred for
30-45 min at 30°C. The reaction mass was filtered and the wet solid was washed
with 240 ml of water. Suck dried the wet solid well. Unloaded the wet solid wet
wt.:- 145.0 gm. Wet solid was dried in air tray dryer for 8-10 hours at 50°C.
Unloaded the dry solid. Dry wt.:- 103.0 gm (71.65%).25
Example 6 : Preparation of 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-pyrazolo
[3, 4-b] pyridine-3-carboximidamide hydrochloride (IVa)
20
2400.0 ml of methanol was added in the round bottom flask. 23.99 gm of sodium
methoxide was added in reaction mass at 30°C. The reaction mass was added for
10-20 minute at 30°C. 120.0 gm of 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-
pyrazolo [3, 4-b] pyridine-3-carbonitrile was added in reaction mass. The reaction
mass was stirred for 3.0 hours at 30°C. 71.27 gm of ammonium chloride was added5
in reaction mass at 30°C and raised reaction temperature at 63°C., stirred and
maintained reaction mass at 63°C.The reaction mass was cooled below 55°C
temperature. The reaction mass was distilled under vacuum below 55°C. After
distillation, degassed the residue under vacuum below 55°C for 20-30 minute. 240.0
ml of ethyl acetate was added in residue and stirred it at 52°C. Distilled out ethyl10
acetate completely under vacuum below 55°C. 240.0 ml of ethyl acetate was
charged in residue and stir it at 52°C. Ethyl acetate was completely distilled out
under vacuum below 55° C. Degassed the residue under vacuum completely below
55°C. 1200 ml of methylene chloride was charged in residue below 55°C. Stirred
the reaction mass at reflux temperature i.e. 42°C. The reaction was cooled at 27°C.15
The reaction mass was stirred for 30-45 minute at 27°C. The reaction mass was
filtered and washed the wet cake with 240.0 ml of methylene chloride. Suck dried
the wet cake well. Unloaded the wet cake wet wt.:- 232.0 gm. 232.0 gm of wet solid
was charged with 1200.0 ml of water. The reaction mass was stirred for 30-45
minute at 30°C. The reaction mass was filtered and washed the wet solid with 24020
ml of water. Suck dried the wet solid well. Unloaded the wet solid wet wt.:- 170.0
gm. Wet solid was dried in air tray dryer for 8-10 hours at 50°C. Unloaded the dry
solid. Dry wt.:- 116.0 gm (80.69%).
Example 7 : Preparation of 2-5-Fluoro-1-(2-fluorobenzyl)-1H-pyrazolo [3, 4-25
b] pyridin-3-yl)-5-1(E)-phenyldiazenylpyrimidine-4, 6-diamine (VI)
a) Preparation of [(E)-phenyldiazenyl]malanonitrile] (V)
28.26 ml aniline was charged with 864 ml of water stirred it at 30±5°C. The reacti
on mass was cooled at 0-5°C. The aqueous solution of hydrochloric acid (56.18 ml
21
of Conc. HCl diluted with 60.0 ml of water) was added slowly in reaction mass. T
he reaction mass was stirred for 5-15 minute at 0-5°C. Sodium nitrite solution was
added (21.36 gm of sodium nitrite dissolve in 159.0 ml of water) slowly by additi
on funnel to control temperature at 0-5°C. The reaction mass was stirred for 5-15m
in. at 0-5°C. Sodium acetate solution (32.23 gm of sodium acetate dissolve in 159.5
0 ml of water) was added slowly by addition funnel to control temperature at 0-5°
C. The reaction mass was stirred for 10-20 min. at 0-5°C. Malononitrile solution (
20.45 gm of malononitrile dissolve in 90.0 ml of methanol) was slowly added by a
ddition funnel to control temperature at 0-5°C.. The reaction mass was stirred for 1
.50 ±0.30 min.at 0-5°C. The reaction mass was filtered and suck dried well. The w10
et cake was washed with 150.0 ml of chilled water. The wet cake was washed with
100.0 ml of chilled toluene. Suck dried the wet solid well and unloaded the wet so
lid. Unloaded the wet solid wet wt.-70.0 gm [(E)-phenyldiazenyl] malononitrile (Y
ellowish colour product).
15
b) Preparation of [(E)-phenyldiazenyl]malanonitrile] (V)
320.20 ml aniline was charged with 5040 ml of water stirred it at 30 ±5°C. The rea
ction mass was cooled at 0-5°C. The aqueous solution of hydrochloric acid (618.4
0 ml of Conc. HCl diluted with 700.0 ml of water) was added slowly in reaction m
ass. The reaction mass was stirred for 30 minute at 0-5°C. Sodium nitrite solution20
was added (242.1 gm of sodium nitrite dissolve in 1852 ml of water) slowly by ad
dition funnel to control temperature at 0-5°C. The reaction mass was stirred for 30
minute at 0-5°C. Sodium acetate solution (363.6 gm of sodium acetate dissolve in
1852.0 ml of water) was added slowly by addition funnel to control temperature a
t 0-5°C. The reaction mass was stirred for 30 min. at 0-5°C. Malononitrile solution25
(231.7 gm of malononitrile dissolve in 1050.0 ml of Methanol) was slowly added
by addition funnel to control temperature at 0-5°C. . The reaction mass was stirred
for 2 hours at 0-5°C. The reaction mass was filtered and suck dried well. The wet
cake was washed with 700.0 ml of chilled water. 1075.0 gm of wet solid was charg
22
ed in 3500.0 ml of water. The reaction mass was stirred for 1 hour at below 30°C.
The reaction mass was filtered and washed the wet solid with 1400.0 ml of water.
Suck dried the wet solid well. 1038.0 gm of wet solid was charged in 1800.0 ml of
toluene. The reaction temperature was raised at 45°C. The reaction mass was stirr
ed for 1 hour at 45°C. The reaction mass was cooled below 30°C temperature. The5
reaction mass was filtered and washed the wet solid with 400.0 ml of toluene. Suc
k dried the wet solid well. Unload the wet solid, wet wt. 800.0 gm. wet solid dried
in vacuum tray dryer for 8-12 hours at 40°C. Unload the dry solid, Dry wt. - 512.0
gm.
10
c) Condensation of 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-pyrazolo [3,4-b]p
yridine-3-carboximidamide hydrochloride (IVa) and [(E)-phenyldiazenyl]mal
ononitrile] (V)
120.0 gm of 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-pyrazolo [3,4-b]pyridine-3-15
carboximidamide hydrochloride was charged with 600.0 ml of dimethylformamide
and stirred it at 30 °C. The reaction mass temperature was raised at 87°C. 77.50 ml
of triethyl amine was slowly added in reaction mass at 87°C. [(E)-
phenyldiazenyl]malononitrile (190.0 gm) was dissolve in 600.0 ml of
dimethylfumarate (Weight of solution 660.0 gm) at 27°C. [(E)-phenyldiazenyl]20
malononitrile solution was slowly added in reaction mass at 87°C. After addition
raised reaction mass temperature at 100°C. Reaction mass was stirred and
maintained for 4-5 hours at 100°C. Heating was stopped and cooled the reaction
mass at 27°C.3600.0 ml of cool water was slowly added in reaction mass to control
temp at 25°C. The reaction mass was cooled at 3°C. Reaction mass was stirred and25
maintained at 3°C for 45-60 minute. Reaction mass was filtered and washed to wet
solid with 600.0 ml of chilled water. Suck dried well. 120.0 ml of chilled methanol
wash was given to wet solid and suck dried well. Unloaded the wet solid wet wt.:-
23
180 gm. wet solid was dried in air tray dryer at 50°C for 6.0 hours. Unloaded the
solid Dry wt.:- 132.0 gm (77.85%).
d) Condensation of 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-pyrazolo [3, 4-b]
pyridine-3-carboximidamide formate (IV) with [(E)-phenyldiazenyl] malanon5
itrile] (V)
60.0 gm of 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-pyrazolo [3,4-b]pyridine-3-
carboximidamide formate was charged with 300.0 ml of dimethylformamide and
stirred it at 30 °C. The reaction mass temperature was raised at 87°C. 38.75 ml of10
triethyl amine was slowly added in reaction mass at 87°C. (E)-Phenyldiazenyl]
malononitrile (80.0 gm) was dissolved in 300.0 ml of dimethylformamide at
27±3°C. (E)-Phenyldiazenyl] malononitrile solution was slowly added in reaction
mass at 87 °C. After addition, raised reaction mass temperature at 100°C. Reaction
mass was stirred and maintained for 4-5 hours at 100°C. Heating was stopped and15
the reaction mass was cooled at 27°C. 1800.0 ml of cool water was slowly added in
reaction mass to control temp at 25°C. The reaction mass was cooled at 3 °C.
Reaction mass was stirred and maintained at 3°C for 45-60 minute. Reaction mass
was filtered and washed to wet solid with 600.0 ml of chilled water. Suck dried
well. 60.0 ml of chilled methanol wash was given to wet solid and suck dried well.20
Unloaded the wet solid wet wt. - 89.0 gm. Wet solid was dried in air tray dryer at
50°C. The solid was dried at 50°C till to get constant weight. A constant weight
was obtained after 6.0 hours drying at 50 °C and heating was stopped. Unload the
solid Dry wt. - 78.0 gm (92%).
25
e) Condensation of 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-pyrazolo [3,4-b]p
yridine-3-carboximidamide formate (IV) and [(E)-phenyldiazenyl]malononitr
ile] (V)
24
2000.0 ml of Toluene was charged in the round bottom flask. 150.0 gm of 5-fluoro-
1-(2-fluorpbenzyl)-1H-pyrazolo(3,4-b)pyridine-3-carboximidamidamide formate
was charged in reaction mass. 136.81 gm of potassium carbonate was charged in
reaction mass. The reaction mass was stirred for 10-15 minute at 30°C. 91.90 gm
of (E)-phenyldiazenyl]malanonitrile was charged in reaction mass. The reaction5
temperature was raised at 55°C, stirred and maintained reaction mass at 55°C for
4-6 hours. The reaction mass was cooled below 35°C temperature. 1500 ml of water
was charged in reaction mass. The reaction mass was stirred for 1.0 hour at 30-
35°C. Filtered the reaction mass and slurry washed with 450.0 ml of methanol to
get wet solid. 280.0 gm of wet solid was charged in 1200.0 ml of10
Dimethylformamide. The reaction temperature was raised at 115°C, stirred and
maintained reaction mass at 115°C for 1 hour. The reaction mass was cooled below
35°C temperature. The reaction mass was stirred for 1 hour at below 35°C. The
reaction mass was filtered and washed the wet solid with 150.0 ml of methanol.
230.0 gm of wet solid was charged in 750.0 ml of water. The reaction mass was15
stirred for 1 hour at below 35°C. The reaction mass was filtered and washed the wet
solid with 150.0 ml of methanol and 300 ml of water. Suck dried the wet solid well.
Unload the wet solid wet wt. 310.0 gm. 310.0 gm of wet solid was charged in 750.0
ml of water. The reaction mass was stirred for 1 hour at below 35°C. The reaction
mass was filtered and washed the wet solid with 150.0 ml of methanol and 300 ml20
of water. Suck dried the wet solid well. Unload the wet solid wet wt. 262.0 gm. wet
solid dried in air tray dryer for 8-12 hours at 50°C. Unload the dry solid Dry wt. -
190.0 gm (92.32%).
Example 8: Preparation of 2-{5-fluoro-1-[(2-fluorophenyl) methyl]-1H-25
pyrazolo[3,4-b] pyridin-3-yl}pyrimidine-4,5,6-triamine(VII)
78.0 gm of 2,-5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b] pyridin-3-yl)-5-
1(E)-phenyldiazenylpyrimidine-4,6-diamine was charged with 780.0 ml of
Dimethylformamide in 2.0 L pressure vessel. 7.8 gm of palladium carbon catalyst
25
was charged in reaction. The reaction mass was hydrogenated at 60-65°C under 28-
35 Kg/Cm2 Hydrogen atom for 8-10 hour. Heating was stopped and reaction mass
was cooled to room temperature. The reaction mass was hold with nitrogen gas at
30 °C in reactor for overnight. Unloaded the reaction mass from reactor and reactor
was washed with 70.0 ml of Dimethylformamide and washing was added to the5
reaction mass. Reaction mass was filtered through hyflow bed (Hyflow bed was
prepared with 15.0 gm Hyflow powder in 100 ml of ethyl acetate). Hyflow bed was
washed with 70.0 ml of Dimethylformamide and suck dried well. Filtrate was taken
in 5.0 Litre round bottom flask and cooled to 22°C. 2730.0 ml of water was slowly
added in reaction mass (clear solution) at 22±3°C. Reaction mass was stirred and10
maintained for 45-60 min at 22±3°C. Reaction mass was filtered and washed with
390.0 ml of water. Filtered solid was suck dried well and unloaded the wet solid
wet wt. - 72.0 gram. Arranged 2.0 Litre of 4.0 neck round bottom flask equipped
with stirrer, thermopocket, condenser in a water bath. 720.0 ml of toluene was
charged in 2.0 litre of 4 neck round bottom flask. 72.0 gm of crude wet solid was15
charged and stirred. The reaction temperature was raised at 55°C. Reaction mass
was stirred and maintained at 55 °C for 45-60 minute. Heating was stopped and
cooled the reaction mass at 27±3°C. Reaction mass was stirred and maintained for
45 to 60 minute at 27°C. Reaction mass was filtered and washed with 144.0 ml of
toluene and suck dried well for 25-30 minute. Unloaded the solid wet wt.- 70.020
gram. Wet solid was dried in vacuum tray dryer for 8.0 hours at 50°C. Unload the
solid Dry wt. - 50.0 Gm (80.64%).
Example 9 : Preparation of 2-{5-fluoro-1-[(2-fluorophenyl) methyl]-1H-
pyrazolo[3,4-b] pyridin-3-yl}pyrimidine-4,5,6-triamine (VII)25
50.0 gm of 2,-5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b] pyridin-3-yl)-5-
1(E)-phenyldiazenylpyrimidine-4,6-diamine was charged with 1000.0 ml of
dimethylformamide in 2.0 L pressure vessel. 2.5 gm of wet palladium carbon
catalyst was charged in reaction. The reaction mass was hydrogenated at 60-65°C
26
under 8-10 Kg/Cm2 hydrogen atom for 8-10 hrs. Heating was stopped and reaction
mass was cooled to 50°C. The reaction mass was hold with nitrogen gas. Reaction
mass was filtered through hyflow bed (Hyflow bed was prepared with 15.0 gm
Hyflow powder in 50 ml of dimethylformamide). Hyflow bed was washed with
100.0 ml of hot dimethylformamide and suck dried well. Cleared filtrate was taken5
in 2.0 litre round bottom flask and distilled the reaction mass completely under
vacuum at about 60-80 °C. Charged 50 ml of dimethylformamide in reaction mass
and reaction mass was stirred and maintained at 75 °C for 30 minute. Heating was
stopped and cooled the reaction mass at 27°C. Reaction mass was stirred and
maintained for 1 hour at 27°C. Reaction mass was filtered and washed with 25 ml10
of dimethylformamide and suck dried well. Unloaded the solid wet wt.- 70.0 gm.
Wet solid was dried in vacuum tray dryer for 10.0 hours at 65°C. Unload the solid,
Dry wt. - 45.0 gm. 250.0 ml of isopropyl: water (25 ml: 225 ml) was charged in 500
ml of 4 neck round bottom flask. 45.0 gm of dry solid was charged and raised the
reaction mass temperature to 83±3°C. Stirred and maintained the reaction mass for15
1.5 hour at 83±3°C. Heating was stopped and cooled the reaction mass at 27±3°C.
Reaction mass was stirred and maintained for 45 to 60 minute at 27°C. Reaction
mass was filtered and washed with 100.0 ml of water and suck dried well. Unloaded
the solid wet wt.- 50.0 gm. Wet solid was dried in vacuum tray dryer for 10-12
hours at 65°C. Unload the solid Dry wt. - 37.0 gm (91.9%).20
Example 10: Preparation of methyl (4, 6-diamino-2-{5-fluoro-1-[(2-
fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}pyrimidin-5-
yl)carbamate Di-DMSO solvate (I and Ia)
20.0 2-{5-fluoro-1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}25
pyrimidine-4,5,6-triamine was charged with 200.0 ml of isopropyl alcohol. The
reaction mass was stirred at 30°C. The reaction temperature was raised to 40 °C.
5.85 ml of methyl chloroformate was added in reaction mass by addition funnel to
control temperature at 40 °C. The reaction mass was stirred and maintained at 40°C
27
for 4 hours. The reaction mass temperature was raised to 50°C. 50.0 ml of methanol
was charged in reaction and maintain at 50 °C. 13.09 ml of triethyl amine was added
in reaction by addition funnel to control temperature at 50 °C. After addition of
triethyl amine, stirred and maintained the reaction mass for 45-60 minute at 50 °C.
Stopped heating and cooled the reaction mass at 27°C. The reaction mass was5
stirred and maintain for 45-60 minute, at 27°C. The reaction mass was filtered and
suck dried well. The wet cake was washed with 40.0 ml of methanol. Suck dried
well and wet solid wet wt-45.0 gm. The wet solid was dried in vacuum tray dryer
at 50 °C for 8-10 hours. 22.00 gm of above solid was charged with 40.0 ml of
dimethylsulfoxide. The reaction mass was stirred at 30°C for 5-10 minute. 68.0 ml10
of ethyl acetate was charged in reaction mass. The reaction mass was raised at
temperature 85°C. 1.5 gm (5%) activated carbon was charged in reaction mass
during heating of reaction mass. Stirred and maintained reaction mass for 20-30
minute at 85°C. The reaction mass was filtered through hyflow bed (12.0 gm
Hyflow powder in 40.0 ml Ethyl acetate) and the bed was washed with 40 ml of hot15
ethyl acetate. The filtrate was added into preheated 240.0 ml of ethyl acetate at
47°C. Stirred and maintained reaction mass for 50-60 minute at 47°C. The reaction
mass was cooled within 65 minute up to at 27°C. The reaction mass was cooled
within 65 minute to 0-5°C. Stirred and maintained reaction mass for 45-60 minute
at 0-5°C. The reaction mass was filtered and washed with 26.0 ml x 2 of ethyl20
acetate and suck dried well. Unload the wet solid wt. = 32.0 gm. The wet solid was
dried in vacuum tray dryer at 50°C for 8-10 hours. Unload the solid Dry wt- 15.00
gm (47.5%).
Example 11: Preparation of methyl (4,6-diamino-2-{5-fluoro-1-[(2-25
fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}pyrimidin-5-
yl)carbamate Di-DMSO solvate (I and Ia)
80.0 2-{5-fluoro-1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}
pyrimidine-4,5,6-triamine was charged with 800.0 ml of isopropyl alcohol. The
28
reaction mass was stirred at 30°C. The reaction temperature was raised to 40 °C.
23.55 ml of methyl chloroformate was added in reaction mass by addition funnel to
control temperature at 40 °C. Raised the reaction temperature at 65°C.The reaction
mass was stirred and maintained at 63 ±3°C for 12 hours. 200.0 ml of methanol was
charged in reaction and maintain at 65±3°C for 1 hour. Stirred and maintained the5
reaction mass for 45-60 minute at 65±3°C. Stopped heating and cooled the reaction
mass at 27°C. The reaction mass was stirred and maintain for 45-60 minute at 27°C.
The reaction mass was filtered and washed with 160 ml of isopropyl alcohol. Suck
dried well, wet wt. 150.0 gm. The wet solid was dried in vacuum tray dryer at 75
°C for 8-10 hours, dry wt. 96.0 gm. 163.2 ml of dimethylsulphoxide and 96.0 gm10
dry solid was charged in round bottom flask. The reaction temperature was raised
at 75 °C. 44.91 ml of diisopropyl ethylamine was added in reaction by addition
funnel at 75°C. After addition of diisopropyl ethylamine, stirred and maintained the
reaction mass for 30 minute at 75°C. 4.8 gm activated carbon was charged in
reaction mass during heating of reaction mass. Stirred and maintained reaction mass15
for 30 minute at 75°C. The reaction mass was filtered through hyflow bed (38.4 gm
Hyflow powder in 100.0 ml dimethylsulphoxide) and the bed was washed with 28.8
ml of hot dimethylsulphoxide. Charged the clear filtered reaction mass into round
bottom flask. Cooled the reaction mass at 30°C. 672.0 ml of ethyl acetate was added
in reaction mass at 30°C. Stirred and maintained reaction mass for 30 minute at20
30°C. Raised the reaction mass temperature at 45°C. Stirred and maintained
reaction mass for 45 minute at 45°C.The reaction mass was cooled at 30°C. Stirred
and maintained reaction mass for 60 minute at 30°C. The reaction mass was cooled
at 0°C. Stirred and maintained reaction mass for 60 minute at 0°C. The reaction
mass was filtered and washed with 96.0 ml x 2 of ethyl acetate and suck dried well.25
Unload the wet solid wt. = 92.0 gm. The wet solid was dried in vacuum tray dryer
at 75°C for 8-10 hours. Unload the solid Dry wt- 80.00 gm.
29
Example 12: Preparation of Vericiguat Polymorph-I
320.0 ml of ethyl acetate was charged into the round bottom flask.14.0 gm of methyl
(4,6-diamino-2-{5-fluoro-1-[(2-fluorophenyl]-1H-pyrazolo[3,4-b]pyridine-3-
yl}pyrimidin-5-yl)carbamate Di dimethylsulphoxide solvate was charged in5
reaction at 27 °C. 77 ml of ethanol was added in reaction at 27°C. The reaction
temperature was raised up to reflux at 72 °C. Reaction mass was stirred and
maintained at reflux 72 °C. Heating was stopped after 16.0 hours, maintained and
cooled the reaction at 27 °C. The reaction mass was stirred at 27°C for 25-30
minutes. Reaction mass was filtered and suck dried well. Wet cake was washed10
with 27 ml of ethyl acetate. Unloaded the wet solid wet wt.- 14.70 gm. Wet solid
was dried in vacuum tray dryer at 50 °C for 8-10 hours. Unload the dry solid Dry
wt.- 10.1 gm (98.56%).
Example 13: Preparation of polymorph modification form II of Vericiguat15
15.0 gm Vericiguat didimethylsulphoxide solvate was charged in 75.0 ml of
dimethylacetamide in the round bottom flask at 30°C. Reaction mass was stirred
for 10.0 minutes at 30°C. Raised the reaction temperature to 60°C, stirred and
maintained the reaction mass at 60°C for 10 minute. The reaction mass was cooled
to 3°C. 375.0 ml of ethyl acetate was added slowly to the reaction mass at 3°C.20
Reaction mass was stirred for 30 minutes. Reaction mass was filtered and washed
with 75.0 ml of ethyl acetate and suck dried well. Unloaded the wet solid wt. - 10.90
gm. Wet solid was dried in vacuum tray dryer for at 50 °C. Unload the solid Dry
wt- 8.6 gm.
25
Example 14 : Preparation of polymorph modification form II of Vericiguat
14.0 gm Vericiguat didimethylsulphoxide solvate was charged in 70.0 ml of
dimethylacetamide in the round bottom flask at 27 °C. Reaction mass was stirred
for 5.0 minutes at 27°C.The reaction temperature was raised to 75°C,stirred and
30
maintained the reaction mass at 75°C for 15-20 minute. The reaction mass was
slowly cooled to 3 °C. Slowly added 350.0 ml of ethyl acetate to the reaction mass
at 3°C. Reaction mass was stirred for 30-45 minutes. Reaction mass was filtered
and washed with 70.0 ml of ethyl acetate and suck dried well. Unloaded the wet
solid wt. - 12.5 gm. Wet solid dried in vacuum tray dryer for at 50°C. Unload the5
solid Dry wt- 8.0 gm.
Example 15: Preparation of polymorph modification form-II of Vericiguat
15.0 gm Vericiguat didimethylsulphoxide solvate was charged in 60.0 ml of
dimethylacetamide in the round bottom flask at 30°C. Reaction mass was stirred10
for 10.0 minutes at 30°C. The reaction temperature was raised to 75°C, stirred and
maintained the reaction mass at 75°C for 10 minute and the reaction mass was
cooled to 3°C. 375.0 ml of methylene dichloride was added to the reaction mass at
3°C. Reaction mass was stirred for 60 minutes. Reaction mass was filtered and
washed with 75.0 ml of methylene dichloride and suck dried well. Unloaded the15
wet solid wt.- 10.3 gm. Wet solid dried in vacuum tray dryer for at 50°C. Unload
the solid Dry wt- 7.3 gm.
Example 16 : Preparation of polymorph modification Form-II of Vericiguat
14.0 gm Vericiguat didimethylsulphoxide solvate was charged in 70.0 ml of20
dimethylacetamide in the round bottom flask at 27°C. Reaction mass was stirred
for 5.0 minutes at 27°C.The reaction temperature was raised to 75°C, stirred and
maintained the reaction mass at 75°C for 15-20 minute. The reaction mass was
slowly cooled to 3°C. 350.0 ml of methlenechloride was added to the reaction mass
at 3°C. Reaction mass was stirred for 30-45 minutes. Reaction mass was filtered25
and washed with 70.0 ml of methlenechloride and suck dried well. Unloaded the
wet solid wt. - 12.5 gm. Wet solid was dried in vacuum tray dryer for at 50°C.
Unload the solid Dry wt- 8.5 gm.
31
Example 17: Preparation of polymorph modification Form-II of Vericiguat
80.0 gm Vericiguat didimethylsulphoxide solvate was charged in 300.0 ml of
dimethylacetamide in the round bottom flask at 30°C. Reaction mass was stirred
for 10.0 minutes at 30°C. Raise the reaction temperature to 75 °C, stirred and
maintained the reaction mass at 75 °C for 30 minute. Fine filtered the reaction and5
wash with 20.0 ml hot dimethylacetamide. Charged clear filtrate in to round bottom
flask. The reaction mass was cooled to 0°C. 2000.0 ml of methylene chloride was
added slowly to the reaction mass at 0°C. Reaction mass was stirred for 1-2 hours
at 0°C. Reaction mass was filtered and washed with 240.0 ml of methylene chloride.
Suck dried well. wet solid wt.180.0 gm. 180.0 gm wet solid and 1200.0 ml of ethyl10
acetate was charged in to round bottom flask. Reaction mass was stirred for 2-3
hours at 33°C. Reaction mass was filtered and washed with 160.0 ml of ethyl
acetate. Suck dried well. Unloaded the wet solid wt. 164.0 gm. 164.0 gm wet solid
and 1200.0 ml of ethyl acetate was charged in to round bottom flask. Reaction mass
was stirred for 2-3 hours at 33°C. Reaction mass was filtered and washed with 160.015
ml of ethyl acetate. Suck dried well. Unloaded the wet solid wt. 150.0 gm Wet solid
was dried in vacuum tray dryer for at 75 °C for 18 hours. Unload the solid, dry wt-
85.0 gm.
Example 18: Preparation of polymorph modification Form-III of Vericiguat20
10.0 g of Vericiguat didimethylsulphoxide solvate mixed in 250.0 ml of methanol
at 27°C. Heated to reflux and maintained under reflux for 14 hours. The reaction
mass was cooled to 27°C and filtered the solid. The solid was washed with 30 ml
of methanol. Wet wt: 11.0 g. Dried the solid in vacuum tray dryer at 50 °C for 8
hours. Dry wt: 8.0 gm.25
Example 19: Preparation of Vericiguat Monohydrate
2.0 gm of Vericiguat was dissolved in 6.0 ml of formic acid. The solution was
filtered through hyflow bed and the bed was washed with 2.0 ml of formic acid.
32
Mixture of 25.0 ml of liquor ammonia and 60.0 ml of water was added in the formic
acid solution at 2°C and stirred at 2°C for 10 minute. The solid was filtered and
washed with 60 ml of water, dried in air tray dryer at room temperature. Dry wt:
2.20 gm.
5
Example 20: Preparation of Vericiguat Dihydrate
2.0 gm of Vericiguat was dissolved in 16.0 ml of methanol at 27 °C. 0.8 ml of
aqueous ammonia solution was slowly added to the reaction mass at 27°C. Reaction
mass was stirred for 3.0 hours at 27°C. The solution was filtered and washed with
4.0 ml of methanol and dried in vacuum tray dryer at 50°C. Dry wt: 1.10 gm.10
Example 21: Preparation of Vericiguat (I)
15.0 gm 2-{5-fluoro-1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-
yl}pyrimidine-4,5,6-triamine was charged in 285.0 ml of pyridine and stirred at
30°C under N2 atmosphere. The reaction mass was cooled at 0-5°C under N215
atmosphere. 3.15 ml of methylchloroformate in methylene dichloride was slowly
added in reaction mass to control temperature at 0-5°C.Reaction mass was stirred
and maintained at 0-5°C under N2 atmosphere. After 1.0 hours, maintaining at 0-5
°C the reaction mass temperature was raised to 25 °C and further maintained for
15 hours at 25 °C. The reaction mass distilled out under reduced pressure. 50 ml20
toluene was added to reaction mass and distilled out at 40 °C. 10 ml toluene was
added and distilled out at 40 °C. 10 ml toluene was again added and distilled out
at 40°C. 20 ml ethanol/water 1:1 (20 ml) was added to residue at 30°C. The
reaction mass was stirred for 30 minute at 30°C. The reaction mass was filtered at
30°C and washed with ethanol: ethyl acetate mixture. Unload the solid (4.7gm)25
and stirred in diethyl ether at 30 °C for 30 minute. The reaction mass was filtered
and washed with diethyl ether. Unload the solid and dried under vacuum at 40°C.
Dry wt: 14.9 gm.
30
33
WE CLAIM :
1. 5-fluoro-1-[(2-fluorophenyl) methyl]-1H-pyrazolo [3, 4-b] pyridine-3-
carboximidamide formate compound of formula (IV).5
2. The compound of claim 1, wherein the x-ray diffraction of the compound
exhibits peak maxima of 2 theta angle at
6.0,10.7,12.0,14.9,17.5,18.7,20.1,22.8,22.9,24.6,25.0, 25.0, 25.5, 27.3, 27.4 ±
0.2.10
3. Use of compound of formula (IV) for the preparation of vericiguat compound
of formula I.
4. A process for preparing a compound formula (IV), comprising reacting a15
compound of formula (III) in presence of ammonium formate in an alcohol and
base to form a compound of formula (IV).
5. The process according to claim 4, wherein the alcohol is selected from
methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol and20
mixtures thereof.
6. The process according to claim 4 further comprises base selected form sodium
methoxide, sodium ethoxide.
25
7. A process for preparing a vericiguat compound formula (I) comprises
converting a compound of formula IV to vericiguat compound of formula I.
8. A process for preparation of vericiguat modification form II comprising;
a) providing a solution of vericiguat or solvate thereof in a solvent;30
34
b) adding a solvent;
c) isolating vericiguat modification Form II.
9. The process according to claim 8, wherein the solvent of step (a) is selected
from N-methyl pyrrolidone, N,N-dimethylformamide (DMF),5
dimethylsulfoxide (DMSO), dimethylacetamide (DMAc); or mixture thereof,
preferably dimethylacetamide.
10. The process according to claim 8, wherein the solvent of step b) is selected from
methyl acetate, ethyl acetate, chloroform, methylenechloride,10
ethylenedichloride, or mixture thereof, preferably ethyl acetate or
methylenechloride.
11. The process according to claim 8, wherein vericiguat solvate of step a) is
selected from Vericiguat dimethyl sulfoxide, Vericiguat di-dimethyl sulfoxide15
solvate and dimethylacetamide (DMAc), preferably vericiguat
didimethylsulphoxide solvate.
12. A process for preparation of vericiguat modification form II comprising;
I) providing a wet vericiguat or solvate thereof;20
II) isolating vericiguat modification Form II.
13. The process according to claim 12, wherein wet vericiguat or solvate thereof
comprising dimethylacetamide (DMAc) and ethyl acetate.
25
14. The process according to claim 12, wherein the drying temperature at which
vericiguat modification Form II is isolated in the range of from 50 °C to 90 °C,
preferably 75 °C.
35
15. A process according to claim 12, wherein preparation of wet Vericiguat or
solvate thereof of step (I) comprising;
v) providing a solution of vericiguat or solvate thereof in a solvent;
vi) combining a solvent to form wet solid;5
vii) providing a wet solid from the wet solid of step ii in a solvent.
viii) providing a wet vericiguat or solvate thereof from the wet solid of step
iii in a solvent.
16. The process according to claim 15, wherein the solvent of step i) is selected10
from N-methyl pyrrolidone, N,N-dimethylformamide (DMF),
dimethylacetamide (DMAc); or mixtures thereof, preferably
dimethylacetamide.
17. The process according to claim 15, wherein vericiguat solvate of step I) is15
selected from vericiguat dimethyl sulfoxide, Vericiguat di-dimethyl sulfoxide
solvate.
18. The process according to claim 15, wherein solvent of step (ii) is selected form
chloroform, methylenechloride, ethylenedichloride, or mixture thereof,20
preferably methylenechloride.
19. The process according to claim 15, wherein solvent of step iii) and iv) is selected
form ester, wherein ester is selected form ethyl acetate.
25
20. A process for preparation of vericiguat modification form III comprising;
a) providing a suspension of vericiguat or solvate thereof in a solvent;
b) heating the solution;
c) isolating vericiguat modification Form III.
36
21. The process according to claim 20, wherein the solvent of step a) is selected
from alcohol, wherein alcohol is selected from methanol, ethanol, n-propanol,
isopropanol, butanol or mixture thereof, preferably methanol.
22. The process according to claim 20, wherein heating the solution of step b) to5
the reflux temperature of the solvent used.
23. The process according to claim 20, wherein vericiguat solvate of step a) is
selected from vericiguat didimethylsulphoxide solvate.
10
24. The process according to claim 20, wherein a drying temperature at which
vericiguat modification form III is isolated in the range of from 30°C to 70 °C,
preferably 45 to 55 °C, more preferably 50 °C.
25. A process for preparation of vericiguat monohydrate comprising;15
a) providing a solution of vericiguat or solvate thereof in a solvent;
b) adding mixture of solvent;
c) isolating vericiguat monohydrate.
26. The process according to claim 25, wherein the solvent of step (a) comprises20
formic acid.
27. The process according to claim 25, wherein the solvent of step (c) comprises a
mixture of liquor ammonia and water.
25
28. The process according to claim 25, wherein the solvent of step (a) is added to
(b) at below 4 °C, preferably at 2 °C.
29. The process according to claim 25, wherein the drying temperature at which
vericiguat monohydrate is isolated at room temperature.30
37
30. A process for preparation of vericiguat dihydrate comprising;
a) providing a solution of vericiguat or solvate thereof in a solvent
b) adding a solvent;
c) isolating vericiguat dihydrate.5
31. The process according to claim 30, wherein the solvent of step (a) is selected
from methanol, ethanol, n-propanol, isopropanol, butanol or mixture thereof,
preferably methanol.
10
32. The according to claim 30, wherein the solvent of step (b) is selected from
aqueous ammonia.
33. The process according to claim 30, wherein the solvents of step (b) is added at
27± 3 °C.15
34. The process according to claim 30, wherein step a) provides suspension.
35. The process according to claim 30, wherein the drying temperature at which
vericiguat dihydrate is isolated in the range of from 30°C to 70 °C, preferably20
45 to 55 °C.