DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of a crystalline form of a triaminopyrimidine compound as described herein. In particular, the invention relates to an improved process for the preparation of crystalline Form II of the triaminopyrimidine compound substantially free from other crystalline forms as described herein.

BACKGROUND OF THE INVENTION
International (PCT) Publication No. WO 2015/165660 A1 (the WO '660) discloses triaminopyrimidine compounds, intermediates, pharmaceutical compositions and methods for use for preventing or treating malaria, wherein one of the triaminopyrimidine compound disclosed is a compound of Formula I as represented below:

The WO '660 discloses a process for the preparation of compound of Formula I and intermediates thereof.
International (PCT) Publication No. WO 2019/049021 A1 (WO ‘021) discloses a process for the preparation of compound of Formula I and crystalline Form I and Form II of the compound of Formula I.
The present invention provides a process for the preparation of crystalline Form II of triaminopyrimidine compound of Formula I. Particularly, the present invention provides an improved process for the preparation of crystalline Form II of triaminopyrimidine compound of Formula I, which is substantially free from other crystalline forms of the compound of Formula I. The process of the present invention is robust, scalable and reproducible for the large scale production and can provide the crystalline Form II of the compound of Formula I substantially free from other crystalline forms on consistent basis with certainty.

SUMMARY OF THE INVENTION
In one general aspect, the present invention provides a process for the preparation of a crystalline Form II of compound of Formula I,

characterized by x-ray powder diffraction pattern having peaks expressed in 2? at 13.8°, 21.9°, and 23.7° ±0.2°, the process comprising:
crystallizing the compound of Formula I from one or more solvents selected from:
(i) ethyl acetate, dichloromethane, chloroform, or a mixture thereof; or
(ii) a mixture of two solvents, wherein one of the solvent is acetonitrile, and the other solvent is selected from dichloromethane, ethyl acetate, and chloroform.
In another general aspect, the present invention provides a process for the preparation of a crystalline Form II of compound of Formula I,

characterized by x-ray powder diffraction pattern having peaks expressed in 2? at 13.8°, 21.9°, and 23.7° ±0.2°, the process comprising:
(a) heating a mixture of the compound of Formula I and one or more solvents to obtain a solution, wherein the one or more solvents are selected from:
(i) ethyl acetate, dichloromethane, chloroform, or a mixture thereof; or
(ii) a mixture of two solvents, wherein one of the solvent is acetonitrile, and the other solvent is selected from dichloromethane, ethyl acetate, and chloroform; and
(b) cooling the solution to obtain the crystalline Form II of the compound of Formula I.
The process of the present invention is a better alternative process that is economically viable and industrially scalable for preparing the crystalline Form II of the compound of Formula I free from other crystalline forms on consistent basis with certainty.

BRIEF DESCRIPTION OF DRAWING:
FIG. 1: X-ray powder diffraction pattern (XRPD) of Form II of compound of Formula I obtained from a mixture of dichloromethane and acetonitrile.
FIG. 2: XRPD of Form II of compound of Formula I obtained from a mixture of dichloromethane and acetonitrile.
FIG. 3: XRPD of Form II of compound of Formula I obtained from a mixture of chloroform and acetonitrile.
FIG. 4: XRPD of Form II of compound of Formula I obtained from a mixture of ethyl acetate and acetonitrile.
FIG. 5: XRPD of Form II of compound of Formula I obtained from a mixture of methanol and acetonitrile.
FIG. 6: XRPD of Form II of compound of Formula I obtained from ethyl acetate.
FIG. 7: XRPD of Form II of compound of Formula I obtained from methanol.
FIG. 8: XRPD of Form II of compound of Formula I obtained from ethanol.
FIG. 9: XRPD of Form II of compound of Formula I obtained from methyl ethyl ketone.
FIG. 10: XRPD of Form II of compound of Formula I obtained from acetone.

DETAILED DESCRIPTION OF THE INVENTION
The invention can be further understood in light of the description of the embodiments provided hereinafter. It is to be understood that the description, in no way, is intended to limit the scope of the invention to the expressly specified embodiments only. The equivalents and variants thereof or trivial modifications thereof which are apparently obvious to those skilled in the art, are also intended to be included within the scope of the present invention.
Detailed description of routine and conventional unit operations, which are easily understood by the skilled artisan, are not included herein. Such routine unit operations are to be construed as ordinarily understood and as routinely practiced by the person skilled in the field of the invention, unless otherwise specifically described.
All ranges recited herein include the endpoints, including those that recite a range “between” two values. Terms such as “about”, “generally”, “substantially,” and the like are to be construed as modifying a term or value such that it is not an absolute. This includes, at least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
Optionally, the solution, prior to any solid formation, can be filtered to remove any undissolved solids, solid impurities prior to removal of the solvent. Any filtration system and filtration techniques known in the art can be used.

The following definitions are used in connection with present application, unless it is indicated otherwise.
In general, the term “reacting” is used in their ordinary meaning as they are used in the field of the invention, unless defined specifically otherwise.
The terms “isolating”, or “obtaining” are generally interchangeable, and include but not specifically limited to decantation, filtration, or centrifugation.
The term “substantially free from any other crystalline form” as used herein refers to the said crystalline Form comprises less than about 1%, particularly less than about 0.5%, more particularly less than about 0.1% of the other crystalline form. In particular, the other crystalline form is absent. The content of other crystalline forms can be measured by x-ray powder diffraction.
The term "crystallizing" as used herein refers to a process comprising: heating a mixture of a starting material and one or more solvents to a suitable temperature, for example a temperature of between about 10 °C below and above the reflux temperature of the solvent, to obtain a solution, and cooling the solution to a temperature of about 0 °C to about 35 °C.
In general, triaminopyrimidine compound of Formula I to be used as the starting material may be prepared by the known methods reported in the prior art, for example, by using the process as disclosed in the WO 2015/165660 A1 and WO 2019/049021 A1 which is incorporated herein as reference. The triaminopyrimidine compound of Formula I to be used as the starting material in the process of the present invention may be in the form of crude obtained directly from any process for its synthesis or may be in the purified form.
In general, the present invention provides a process for the preparation of a crystalline Form II of the compound of Formula I characterized by x-ray powder diffraction pattern having peaks expressed in 2? at 13.8°, 21.9°, and 23.7° ±0.2°. In general, the crystalline Form II of the compound of Formula I is further characterized by x-ray powder diffraction pattern having peaks expressed in 2? at 8.3°, 12.1°, 13.8°, 21.9°, and 23.7°± 0.2°.
Thus, in one general aspect, the present invention provides a process for the preparation of a crystalline Form II of compound of Formula I, characterized by x-ray powder diffraction pattern having peaks expressed in 2? at 13.8°, 21.9°, and 23.7° ±0.2°, the process comprising:
crystallizing the compound of Formula I from one or more solvents selected from:
(i) ethyl acetate, dichloromethane, chloroform, or a mixture thereof; or
(ii) a mixture of two solvents, wherein one of the solvent is acetonitrile, and the other solvent is selected from dichloromethane, ethyl acetate, and chloroform.
In one embodiment, the one or more solvents is selected from ethyl acetate, dichloromethane, chloroform, or a mixture thereof. In particular, the solvent is dichloromethane. More particularly, the solvent is ethyl acetate.
In another embodiment, the solvent is a mixture of two solvents comprising acetonitrile as one of the solvent and the other solvent is selected from dichloromethane, ethyl acetate, and chloroform.
In another embodiment, the solvent is a mixture of acetonitrile and dichloromethane. In another embodiment, the solvent is a mixture of acetonitrile and ethyl acetate. In yet another embodiment, the solvent is a mixture of acetonitrile and chloroform
In another embodiment, the solvent is a mixture of two solvents, wherein the one of the solvent is acetonitrile, and the other solvent is selected from dichloromethane, ethyl acetate, and chloroform; and the solvents are used in a ratio of 5: 1 to 12: 1 v/v respectively. In particular, the solvents are used in a ratio of 5: 1, 5: 2, 6:1, 7: 1, 8: 1, 9: 1, 9: 2, 10: 1, 11: 1, 11: 2 or 12: 1 v/v respectively. More particularly, the solvents are used in a ratio of 9: 1 v/v, or 9: 2 v/v respectively. For example, when the one or more solvents used at step (a) is a mixture of acetonitrile and dichloromethane, the solvents can be used in a ratio of 5:1 to 12: 1 v/v respectively.
In another embodiment, the one or more solvents for the crystallization is a mixture of acetonitrile and dichloromethane, and used in a ratio of 9:1 v/v respectively. In another embodiment, the solvent is a mixture of acetonitrile and ethyl acetate, and used in a ratio of 9:2 v/v respectively. In yet another embodiment, the solvent is a mixture of acetonitrile and chloroform, and used in a ratio of 9: 1 v/v respectively.
In general, the mixture of the compound of Formula I and one or more solvents are heated at a temperature ranging from about 50 °C to reflux temperature of the solvent, to obtain a solution. Optionally, the reaction mixture can be stirred at this temperature for a time sufficient to obtain a solution. The solution then can be gradually cooled to a temperature of about 0 °C to about 35 °C to obtain a suspension. Optionally, the suspension can be stirred at this temperature for a time sufficient to cause complete crystallization. The crystalline Form II thus formed can be isolated by following the processes known to skilled artisans such as filtration, centrifugation, or decantation, etc.
In another general aspect, the present invention provides a process for the preparation of a crystalline Form II of compound of Formula I, characterized by x-ray powder diffraction pattern having peaks expressed in 2? at 13.8°, 21.9°, and 23.7° ±0.2°, the process comprising:
(a) heating a mixture of the compound of Formula I and one or more solvents to obtain a solution, wherein the one or more solvents are selected from:
(i) ethyl acetate, dichloromethane, chloroform, or a mixture thereof; or
(ii) a mixture of two solvents, wherein the one of the solvent is acetonitrile, and the other solvent is selected from dichloromethane, ethyl acetate, and chloroform; and
(b) cooling the solution to obtain the crystalline Form II of compound of Formula I.
In one embodiment of the above aspect, the process of the present invention further comprises optionally seeding the solution obtained at step (a) while cooling, with the crystalline Form II of compound of Formula I.
In another embodiment, the one or more solvents at step (a) is selected from ethyl acetate, dichloromethane, chloroform, or a mixture thereof. In particular, the solvent is ethyl acetate.
In another embodiment, the solvent at step (a), is a mixture of two solvents comprising acetonitrile as one of the solvent and the other solvent is selected from dichloromethane, ethyl acetate and chloroform.
In another embodiment, the solvent is a mixture of acetonitrile and dichloromethane. In another embodiment, the solvent is a mixture of acetonitrile and ethyl acetate. In yet another embodiment, the solvent is a mixture of acetonitrile and chloroform.
In general, the one or more solvents at step (a), is used in an amount of 5 volumes to 50 volumes of the quantity of the compound of Formula I. In particular, the solvent is used in an amount of 10 volumes to 30 volumes of the quantity of the compound of Formula I. More particularly, the solvent is used in an amount of 10 volumes to 20 volumes of the quantity of the compound of Formula I. For example, when the quantity of the compound of Formula I used in step (a) is 1 g, the solvent can be used in an amount ranging from 5 mL to 50 mL.
In general, when the solvent used at step (a) is a mixture of two solvents, wherein one of the solvent is acetonitrile and the other solvent is selected from dichloromethane, ethyl acetate and chloroform; the solvents can used in a ratio of 5: 1 to 12: 1 v/v respectively (acetonitrile: other solvent). Particularly, the solvents can be used in a ratio of 5: 1, 5: 2, 6:1, 7: 1, 8: 1, 9: 1, 9: 2, 10: 1, 11:1, 11: 2, or 12: 1 v/v respectively. More particularly, the solvents can be used in a ratio of 9: 1 v/v or 9: 2 v/v respectively. For example, when the one or more solvents used at step (a) is a mixture of acetonitrile and dichloromethane, the solvents can be used in a ratio of 5:1 to 12: 1 v/v respectively.
In another embodiment, the one or more solvents at step (a), is a mixture of acetonitrile and dichloromethane, and used in a ratio of 9:1 v/v respectively. In another embodiment, the solvent is a mixture of acetonitrile and ethyl acetate, and used in a ratio of 9:2 v/v respectively. In yet another embodiment, the solvent is a mixture of acetonitrile and chloroform, and used in a ratio of 9: 1 v/v respectively.
In another embodiment, the one or more solvents at step (a) is a mixture of two solvents comprising acetonitrile as one of the solvent and the other solvent is selected from dichloromethane, ethyl acetate, and chloroform; and the combined solvents are used in an amount of about 20 volumes to the compound of Formula I; and further used in a ratio of 9: 1 v/v, or 9: 2 v/v (acetonitrile: other solvent) respectively.
In another embodiment, the solvent at step (a) is ethyl acetate and is used in an amount ranging from 10 volumes to 20 volumes of the quantity of the compound of Formula I, particularly, 10 volumes to 15 volumes of the quantity of the compound of Formula I.
In general, the mixture of the compound of Formula I and one or more solvents at step (a) is heated at a temperature of about 50 °C to the reflux temperature of the solvent. In particular, the mixture is heated at a temperature of about 50 °C to about 85 °C, more particularly, at a temperature of about 70 °C to about 80 °C. The mixture can be stirred at this temperature for a time sufficient to obtain the solution of compound of Formula I. Particularly, the mixture can be stirred at this temperature for a time ranging from 10 minutes to 2 hours, more particularly, for a time ranging from 30 minutes to 1 hour.
In general, the process of the present invention comprises optionally seeding the solution obtained at step (a) while cooling with the crystalline Form II of the compound of Formula I. Particularly, the seed is added at a temperature of about 40 °C to about 70 °C. More particularly, the seed is added at a temperature of about 60 °C to about 70 °C.
In another embodiment, the solution at step (b) is cooled to a temperature of about 0 °C to about 35 °C with stirring. Particularly, the solution is cooled to a temperature of about 25 °C to about 35 °C to obtain a reaction mass. The reaction mass can be stirred at this temperature for a time sufficient to cause complete crystallization of crystalline Form II of compound of Formula I. Particularly, the reaction mass can be stirred at this temperature for a time ranging from 15 minutes to 2 hours, more particularly for a time ranging from 30 minutes to 1 hour.
In another embodiment, the solvent at step (a) is ethyl acetate and the process further comprises cooling the solution obtained at step (a) and stirring for a period of 1 hour or more, to obtain the crystalline Form II of compound of Formula I. In particular, it was stirred for a period of 1 hour to 2 hours.
The resultant crystalline Form II of compound of Formula I can be isolated by following the processes known to a person skilled in the art such as filtration, decantation, centrifugation, etc. The crystalline form thus obtained can further be washed with a suitable solvent and further dried to achieve desired level of moisture using the well-known techniques such as using fluidized bed dryer, vacuum tray dryer, rotocone vacuum dryer, steam tray dryer, etc.
In one embodiment, the obtained crystalline Form II of the compound of Formula I is substantially free from other crystalline forms of the compound of Formula I.

In another embodiment, the obtained crystalline Form II of the compound of Formula I is having a purity 99% or more by area percentage of high-performance liquid chromatography (HPLC) and is substantially free from any other crystalline forms of the compound of Formula I.

In another general aspect, the present invention provides a process for the preparation of a crystalline Form II of compound of Formula I, characterized by x-ray powder diffraction pattern having peaks expressed in 2? at 13.8°, 21.9°, and 23.7° ±0.2°, the process comprising:
(a) reacting a compound of Formula II

with formaldehyde in the presence of a suitable reducing agent in dichloromethane at a temperature of about 25 °C to about 35 °C to obtain a reaction mixture;
(b) adding water to the reaction mixture;
(c) basifying the reaction mixture;
(d) separating the organic layer and concentrating under reduced pressure to obtain a residue;
(e) adding a mixture of acetonitrile and dichloromethane to the residue to obtain a reaction mixture;
(f) heating the reaction mixture obtained at step (e) at a temperature of about 70 °C to about 85 °C to obtain a solution;
(g) cooling the solution to a temperature of about 60 °C to about 68 °C and seeding with the crystalline Form II of the compound of Formula I;
(h) further cooling to a temperature of about 5 °C to about 35 °C; and
(i) obtaining the crystalline Form II of the compound of Formula I.
In general, a suitable reducing agent at step (a) is selected from sodium cyanoborohydri- de, sodium triacetoxyborohydride, lithium aluminium hydride, and sodium borohydride. In particular, the reducing agent is sodium triacetoxyborohydride.
In general, basifying the reaction mixture at step (c) can be carried out by the addition of an aqueous solution of a base selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and sodium hydroxide to achieve a pH of 8 to 9.
In general, the mixture of acetonitrile and dichloromethane at step (e) is used in a ratio of 5:1 to 12:1 v/v respectively. In particular, the acetonitrile and dichloromethane are used in a ratio of 9: 1 v/v respectively.
In general, the compound of Formula II used as starting material in the above process can be obtained by following the process as reported in prior art, such as WO 2019/049021 A1.
In another general aspect, the present invention provides a process for the preparation of a crystalline Form II of compound of Formula I, characterized by x-ray powder diffraction pattern having peaks expressed in 2? at 13.8°, 21.9°, and 23.7° ±0.2°, the process comprising:
(a) heating a mixture of the compound of Formula I and one or more solvents at a temperature of about 50 °C to about 90 °C, for about 15 minutes to 2 hours to obtain a solution, wherein the one or more solvents are selected from:
(i) methanol, ethanol, methyl ethyl ketone, acetone, or a mixture thereof; or
(ii) a mixture of acetonitrile and methanol; and wherein the solvents are used in an amount of 5 volumes to 50 volumes of the quantity of the compound of Formula I;
(b) cooling the solution obtained at step (a) to a temperature of about 5 °C to 35 °C to obtain a suspension;
(c) stirring the suspension at a temperature of about 5 °C to 35 °C for 20 minutes to 2 hours; and
(d) obtaining the crystalline Form II of the compound of Formula I.
In general, the one or more solvents at step (a), is used in an amount of 5 volumes to 50 volumes of the quantity of the compound of Formula I. Particularly, the solvent is used in an amount of 5 volumes to 30 volumes of the quantity of the compound of Formula I. More particularly, the solvent is used in an amount of 10 volumes to 20 volumes of the quantity of the compound of Formula I.
In one embodiment of the above aspect, the solvent at step (a) is methanol and is used in an amount ranging from 5 volumes to 20 volumes of the quantity of the compound of Formula I, particularly, in amount 5 volumes to 10 volumes of the quantity of the compound of Formula I.
In another embodiment of the above aspect, the solvent at step (a) is ethanol and is used in an amount ranging from 5 volumes to 20 volumes of the quantity of the compound of Formula I, particularly, in amount 5 volumes to 10 volumes of the quantity of the compound of Formula I.
In another embodiment of the above aspect, the solvent at step (a) is acetone and is used in an amount ranging from 10 volumes to 40 volumes of the quantity of the compound of Formula I, particularly, in amount 25 volumes to 35 volumes of the quantity of the compound of Formula I.
In another embodiment of the above aspect, the solvent at step (a) is methyl ethyl ketone and is used in an amount ranging from 5 volumes to 20 volumes of the quantity of the compound of Formula I, particularly, in an amount 5 volumes to 10 volumes of the quantity of the compound of Formula I.
In another embodiment of the above aspect, the solvent at step (a) is a mixture of acetonitrile and methanol, and is used in a ratio of 5: 1 to 12: 1 v/v respectively; particularly in a ratio of 9: 1 v/v respectively.
In general, the suspension at step (c) is stirred for a time ranging from 20 minutes to 2 hours; particularly for a time ranging from 30 minutes to 2 hours, more particularly, for a time ranging from 30 minutes to 1 hour.
The present invention is further illustrated by the following examples which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in various publications.
Examples:
Instrumental Details
Characterization by X-Ray Powder Diffraction
The x-ray powder diffraction spectrum was measured under the following experimental conditions:
Instrument : X-Ray Diffractometer, EMPYREAN, Make: PANalytical.
X-Ray : Cu K alpha radiation (wavelength 1.54 Å)
Tension : 45KV
Current : 40mA
Divergence slit : Automatic
Incident beam side
Off set : 0.000
Anti-scatter slit : ½°
Receiving slit : None
Detector : PIXcel1D-Medipix3
Mode : Scanning line detector (1D)
Method parameter
Start position : 2°2?
End position : 40°2?
Step size : 0.02°
Time per step : 67.575
Scan mode : Continuous

Example-1: Preparation of crystalline Form II of triaminopyrimidine compound I from a mixture of dichloromethane and acetonitrile.
Into a Round bottom flask (RBF), 27 L of dichloromethane was added at 25 to 35 °C with constant stirring. To this, 2.98 Kg of (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3-methylpiperazin-1yl)pyrimidine-2,4-diamine was added followed by addition of 1.07 kg of formaldehyde solution. The reaction mixture was allowed to cool at 15 to 20 °C. To this mixture 2.1 Kg of sodium triacetoxyborohydride (STAB) was added followed by washing with 3L of dichloromethane. The resultant reaction mixture was stirred for 2 hours at 25 to 35 °C. Further 15L of water was added to the reaction mixture. The pH was adjusted from 8 to 9 using 20% w/v sodium carbonate solution followed by stirring for 15 mins. The reaction mixture was allowed to stand, and the aqueous layer was separated from the organic layer. To the aqueous layer, 6 L of dichloromethane was added and stirred for 15 mins. The layers were allowed to stand and separated. The aqueous layer was discarded, and the organic layer was combined with the first batch of organic layer. To this combined organic layer 149 g of activated charcoal was added and stirred for 30 mins. The reaction mass was filtered, and the solid residue was washed with 6 L of dichloromethane. The solvent was distilled out to give a syrupy mass. To this mass 8.95 L of acetonitrile was added and the reaction mass was stirred for 10-15 mins. Again, the solvent was distilled out to give a syrupy mass. To this mixture 6 L dichloromethane and 53.6 L acetonitrile was added. The reaction mixture was heated at 70 to 80 °C with constant stirring for 30 mins. The reaction was allowed to cool at 64 to 68 °C followed by addition of seed crystal of crystalline Form II of the compound of Formula I. The reaction was further cooled at 25 to 35 °C with constant stirring for 1 hour. The reaction mixture was filtered, and the solid residue was washed with acetonitrile to obtain the product. Yield 75%.
X-ray powder diffraction pattern is as set forth in Figure 1.
Example-2: Preparation of crystalline Form II of triaminopyrimidine compound of Formula I from a mixture of dichloromethane and acetonitrile
Into a Round bottom flask (RBF), 1g of the compound of Formula I in 2 ml of dichloromethane and 18 ml of acetonitrile were added. The reaction mixture was heated at 75 to 85 °C with constant stirring for 15 min. The reaction mass was allowed to cool at 25 to 35 °C and stirred for 1 hr. The reaction mass was filtered, and the solid residue was washed with 2 ml of acetonitrile to obtain the product.
X-ray powder diffraction pattern is as set forth in Figure 2.
Example-3: Preparation of crystalline Form II of triaminopyrimidine compound of Formula I from a mixture of chloroform and acetonitrile
Into a Round bottom flask (RBF), 1 g of the compound of Formula I in 18 ml of acetonitrile and 2 ml of chloroform were added. The reaction mixture was heated at 75 to 85 °C with constant stirring for 1 hour. The reaction mass was allowed to cool at 25 to 35 °C and stirred for 1 h. The reaction mass was filtered, and the solid residue was washed with 2 ml of acetonitrile to obtain the product.
X-ray powder diffraction pattern is as set forth in Figure 3.

Example-4: Preparation of crystalline Form II of triaminopyrimidine compound of Formula I from a mixture of ethyl acetate and acetonitrile
Into a Round bottom flask (RBF), 1g of compound of Formula I in 18 ml of acetonitrile and 4 ml of ethyl acetate were added. The reaction mixture was heated at 75 to 85 °C with constant stirring for 1 hour. The reaction mass was allowed to cool at 25 to 35 °C and stirred for 1 h. The reaction mass was filtered, and the solid residue was washed with 2 ml of acetonitrile to obtain the product.
X-ray powder diffraction pattern is as set forth in Figure 4.

Example-5: Preparation of crystalline Form II of triaminopyrimidine compound of Formula I from methanol and acetonitrile
Into a Round bottom flask (RBF), 36ml dichloromethane was added at 25 to 35 °C with constant stirring. To this, 4g of (R)-N2-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-N4-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(3-methylpiperazin-1yl)pyrimidine-2,4-diamine was added followed by addition of 1.43 g of formaldehyde solution. The reaction mixture was allowed to cool at 15 °C to 20 °C. To this mixture 2.81 g of sodium triacetoxyborohydride (STAB) was added. The reaction mixture was stirred for 2 hours at 25 to 35 °C. Further, 20 ml of water was added to the reaction mixture. The pH was adjusted from 8 to 9 using 20% w/v sodium carbonate solution followed by stirring for 15 mins. The reaction mixture was allowed to stand, and the aqueous layer was separated from the organic layer. To the aqueous layer, 8 ml of dichloromethane was added, and the reaction mixture was stirred for 15 mins. The layers were allowed to stand and separated. The aqueous layer was discarded, and the organic layer was combined with the first batch of organic layer. To this combined organic layer 200 mg of activated charcoal was added and stirred for 30 mins. The reaction mixture was filtered, and the solid residue was washed with 8 ml of dichloromethane. The solvent was distilled out to give a syrupy mass. To this reaction mass 15 ml of methanol was added and the reaction was stirred for 10-15 mins. Again, the solvent was distilled out to give a syrupy mass. To this reaction mass 6 ml of methanol was added and heated at 65 °C, then 54 ml of acetonitrile was added, and heating was continued at 70 to 80 °C with constant stirring for 30 mins. The reaction mass was allowed to cool at 25 to 35 °C with constant stirring for 1 hour. The reaction mass was then filtered, and the solid residue was washed with acetonitrile to obtain the product.
X-ray powder diffraction pattern is as set forth in Figure 5.

Example-6: Preparation of crystalline Form II of triaminopyrimidine compound of Formula I from ethyl acetate
Into a Round bottom flask (RBF), 1 g of compound of Formula I in 13 ml of ethyl acetate was added. The reaction mixture was heated at 75 to 80 °C with constant stirring to get clear reaction mass. The clear reaction mass was allowed to cool at 25 to 35 °C and stirred for 1 h. The reaction mass was filtered, and the solid was washed with 2 ml of ethyl acetate to obtain the product (Yield:71 %).
X-ray powder diffraction pattern is as set forth in Figure 6.

Example-7: Preparation of crystalline Form II of triaminopyrimidine compound of Formula I from methanol
Into a Round bottom flask (RBF), 1 g of compound of Formula I in 6 ml of methanol was added. The reaction mixture was heated at 60 to 65 °C with constant stirring to get clear reaction mass. The clear reaction mass was allowed to cool at 25 to 35 °C and stirred for 25-30 mins. The reaction mass was then filtered, and the solid was washed with 2 ml of methanol to obtain the product (Yield: 62%).
X-ray powder diffraction pattern is as set forth in Figure 7.

Example-8: Preparation of crystalline Form II of triaminopyrimidine compound of Formula I from ethanol
Into a Round bottom flask (RBF), 1 g of compound of Formula I in 6 ml of ethanol was added. The reaction mixture was heated at 75 to 80 °C with constant stirring to get clear reaction mass. The clear reaction mass was allowed to cool at 25 to 35 °C and stirred for 45 mins. The reaction mass was filtered, and the solid was washed with 2 ml of ethanol to obtain the product (Yield: 67%).
X-ray powder diffraction pattern is as set forth in Figure 8.
Example-9: Preparation of crystalline Form II of triaminopyrimidine compound of Formula I from methyl ethyl ketone
Into a Round bottom flask (RBF), 1 g of compound of Formula I in 6 ml of methyl ethyl ketone was added. The reaction mixture was heated at 80 to 85 °C with constant stirring to get clear reaction mass. The clear reaction mass was allowed to cool at 25 to 35 °C and stirred for 1 h. The reaction mass was filtered, and the solid was washed with 2 ml of methyl ethyl ketone to obtain the product (Yield: 69%).
X-ray powder diffraction pattern is as set forth in Figure 9.
Example-10: Preparation of crystalline Form II of triaminopyrimidine compound of Formula I from acetone
Into a Round bottom flask (RBF), 1 g of compound of Formula I in 30 ml of acetone was added. The reaction mixture was heated at 55 to 60 °C with constant stirring to get clear reaction mass. The clear reaction mass was allowed to cool at 25 to 35 °C and stirred for 1 h. The reaction mass was filtered, and the solid was washed with 2 ml of acetone to obtain the product (Yield-58%).
X-ray powder diffraction pattern is as set forth in Figure 10.
Example-11. Preparation of crystalline Form II of triaminopyrimidine compound of Formula I from ethyl acetate
Into a Round bottom flask (RBF), 1 g of compound of Formula I in 10 ml of ethyl acetate was added. The reaction mixture was heated at 75 to 85 °C with constant stirring to get clear reaction mass. The clear reaction mass was allowed to cool at 0 to 5 °C and stirred for 1 h. The reaction mass was filtered, and the solid was washed with 2 ml of ethyl acetate to obtain the product (Yield:78 %)
X-ray powder diffraction pattern is as set forth in Figure 6.
While the present invention has been described in terms of a few specific embodiments, certain modifications, and equivalents thereof, will be apparent to those skilled in the art, and are to be included within the scope of the invention.

,CLAIMS:We Claim:

1. A process for the preparation of a crystalline Form II of compound of Formula I,

characterized by x-ray powder diffraction pattern having peaks expressed in 2? at 13.8°, 21.9°, and 23.7°±0.2°, the process comprising:
crystallizing the compound of Formula I from one or more solvents selected from:
(i) ethyl acetate, dichloromethane, chloroform, or a mixture thereof; or
(ii) a mixture of two solvents, wherein one of the solvent is acetonitrile, and the other solvent is selected from dichloromethane, ethyl acetate, and chloroform.

2. A process for the preparation of a crystalline Form II of compound of Formula I,

characterized by x-ray powder diffraction pattern having peaks expressed in 2? at 13.8°, 21.9°, and 23.7°±0.2°, the process comprising:
(a) heating a mixture of the compound of Formula I and one or more solvents to obtain a solution, wherein the one or more solvents are selected from:
(i) ethyl acetate, dichloromethane, chloroform, or a mixture thereof; or
(ii) a mixture of two solvents, wherein one of the solvent is acetonitrile, and the other solvent is selected from dichloromethane, ethyl acetate, and chloroform; and
(b) cooling the solution to obtain the crystalline Form II of compound of Formula I.

3. The process as claimed in claim 2, wherein the process further comprises optionally seeding the solution obtained at step (a) while cooling, with the crystalline Form II of compound of Formula I.

4. The process as claimed in claim 2, wherein the solvent is used in an amount of 5 volumes to 50 volumes of the quantity of compound of Formula I.

5. The process as claimed in claim 2, wherein the solvent is a mixture of two solvents, comprising acetonitrile as one of the solvents and the other solvent is selected from dichloromethane, ethyl acetate, and chloroform, and the solvents are used in a ratio of 5: 1 to 12: 1 v/v respectively.

6. The process as claimed in claim 2, wherein the solvent is ethyl acetate and the process further comprises cooling the solution obtained at step (a) and stirring for a period of 1 hour or more, to obtain the crystalline Form II of compound of Formula I.

7. The process as claimed in claim 2, wherein the mixture of compound of Formula I and one or more solvents is heated at a temperature ranging from about 50 °C to the reflux temperature of the solvent.

8. The process as claimed in claim 2, wherein the solution at step (b) is cooled to a temperature of about 0 °C to 35 °C with stirring.

9. A process for the preparation of a crystalline Form II of compound of Formula I,

characterized by x-ray powder diffraction pattern having peaks expressed in 2? at 13.8°, 21.9°, and 23.7° ±0.2°, the process comprising:
(a) reacting a compound of Formula II,

with formaldehyde in the presence of a suitable reducing agent in dichloromethane at a temperature of about 25 ° to about 35 °C to obtain a reaction mixture;
(b) adding water to the reaction mixture;
(c) basifying the reaction mixture;
(d) separating the organic layer and concentrating under reduced pressure to obtain a residue;
(e) adding a mixture of acetonitrile and dichloromethane to the residue to obtain a reaction mixture;
(f) heating the reaction mixture obtained at step (e) at a temperature of about 70 °C to about 85 °C to obtain a solution;
(g) cooling the solution to a temperature of about 60 °C to about 68 °C and seeding with the crystalline Form II of compound of Formula I;
(h) further cooling to a temperature of about 5 °C to 35 °C; and
(i) obtaining the crystalline Form II of the compound of Formula I.

10. A process for the preparation of a crystalline Form II of compound of Formula I,

characterized by x-ray powder diffraction pattern having peaks expressed in 2? at 13.8°, 21.9°, and 23.7°±0.2°, the process comprising:
(a) heating a mixture of the compound of Formula I and one or more solvents at a temperature of about 50 °C to about 90 °C, for about 15 minutes to 2 hours to obtain a solution, wherein the one or more solvents are selected from:
(i) methanol, ethanol, methyl ethyl ketone, acetone, or a mixture thereof; or
(ii) a mixture of acetonitrile and methanol; wherein the solvents are used in an amount of 5 volumes to 50 volumes of the quantity of the compound of Formula I;
(b) cooling the solution obtained at step (a) to a temperature of about 5 °C to 35 °C to obtain a suspension;
(c) stirring the suspension at a temperature of about 5 °C to 35 °C for 20 minutes to 2 hours; and
(d) obtaining the crystalline Form II of the compound of Formula I.

Dated this 21st day of August 2024.

(HARIHARAN SUBRAMANIAM)
IN/PA-93
Of SUBRAMANIAM & ASSOCIATES
ATTORNEYS FOR THE APPLICANTS