DESC:
FIELD OF THE INVENTION
The present invention relates to a field of pharmaceuticals, in particular to an improved process for the preparation of a crystalline form of desidustat substantially free from other crystalline forms.

BACKGROUND OF THE INVENTION
International (PCT) Publication No. WO 2014/102818 A1 discloses a series of quinolone compounds that are indicated to have inhibitory activity against Hypoxia-inducible factor (HIF) hydroxylases and to be useful in the treatment of conditions mediated by HIF prolyl hydroxylase including anemia. 2-(1-(Cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido) acetic acid (also referred to as “Desidustat”) is one of the compounds disclosed in International (PCT) Publication No. WO 2014/102818 A1. Desidustat has the chemical structure shown as a compound of Formula (I) below:

U.S. Patent No. 10,899,713 B2 discloses a process for the preparation of quinolone compounds, including the compound of Formula (I), and crystalline forms thereof.

International (PCT) Publication No. WO 2021/181360 A1 discloses various pharmaceutical salts of desidustat, like calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium etc. and pharmaceutical compositions thereof.

International (PCT) Publication No. WO 2022/195525 A1 discloses a process for the preparation of desidustat and crystalline forms thereof.

The solid form of a compound plays a pivotal role in the formulation of pharmaceutical compositions. For example, different forms of a compound can have different physical properties (e.g., stability, dissolution rate, density, etc.) relating to their suitability for use in pharmaceutical compositions. Different polymorphic forms can also show different behavior with respect to their dissolution properties, flow properties, particle size distribution and chemical stability. Thus, having a suitable polymorphic form with desired properties is an important prerequisite during drug development.

The present invention provides an improved process for the preparation of a crystalline form of desidustat as described herein and is substantially free from other crystalline forms. The process is robust, does not require any organic solvent and can consistently produce the specified crystalline form of the desidustat free from other crystalline forms. Thus, the present invention provides a green process for the preparation of a crystalline form of desidustat as described herein and is substantially free from other crystalline forms.

SUMMARY OF THE INVENTION
In one general aspect, the present invention provides a process for the preparation of a crystalline form of desidustat characterized by at least three X-ray powder diffraction peaks expressed in degree 2? selected from 8.0°, 8.9°, 10.6°, 11.3°, 16.1°, 25.5°, and 26.4°±0.2°, the process comprising:
(a) treating desidustat with an inorganic base in water to obtain a solution;
(b) adding an aqueous acid to the solution obtained at step (a); and
(c) obtaining the crystalline form of desidustat.

In another general aspect, the present invention provides a process for the preparation of a crystalline form of desidustat characterized by at least three X-ray powder diffraction peaks expressed in degree 2? selected from 8.0°, 8.9°, 10.6°, 11.3°, 16.1°, 25.5°, and 26.4°±0.2°, the process comprising:
(a) treating desidustat with an inorganic base in water to obtain a solution;
(b) heating the solution to a temperature of 40 °C to 60 °C;
(c) adding an aqueous acid to the solution followed by stirring;
(d) cooling to a temperature of 5 °C to 35 °C; and
(e) obtaining the crystalline form of the desidustat.

In another general aspect, the present invention provides a process for the preparation of a crystalline form of desidustat characterized by at least three X-ray powder diffraction peaks expressed in degree 2? selected from 8.0°, 8.9°, 10.6°, 11.3°, 16.1°, 25.5°, and 26.4° ± 0.2°, the process comprising:
(a) treating desidustat with sodium hydroxide in water to obtain a solution;
(b) heating the solution to a temperature of 40 °C to 60 °C;
(c) adding aqueous hydrochloric acid to the solution followed by stirring;
(d) cooling to a temperature of 5 °C to 35 °C; and
(e) obtaining the crystalline form of the desidustat.

In another general aspect, the present invention provides a process for the preparation of a crystalline form of desidustat characterized by at least three X-ray powder diffraction peaks expressed in degree 2? selected from 8.0°, 8.9°, 10.6°, 11.3°, 16.1°, 25.5°, and 26.4°±0.2°, the process comprising:
(a) reacting a compound of Formula II,

wherein R1 is C1-6 alkyl;
with an inorganic base in water to obtain a reaction mixture;
(b) stirring the reaction mixture to obtain a solution;
(c) adding an aqueous acid to the solution obtained at step (b); and
(d) obtaining the crystalline form of desidustat.

In another general aspect, the present invention provides a process for the preparation of a crystalline form of desidustat characterized by at least three X-ray powder diffraction peaks expressed in degree 2? selected from 8.0°, 8.9°, 10.6°, 11.3°, 16.1°, 25.5°, and 26.4°±0.2°, the process comprising:
(a) reacting a compound of Formula II,

wherein R1 is C1-6 alkyl;
with an inorganic base in water to obtain a reaction mixture;
(b) stirring the reaction mixture to obtain a solution;
(c) heating the solution to a temperature of 40 °C to 60 °C;
(d) adding an aqueous acid to the solution followed by stirring;
(e) cooling to a temperature of 5 °C to 35 °C; and
(f) obtaining the crystalline form of the desidustat.

The process of the present invention is a better alternative process that is economically viable and industrially scalable for preparing the specified crystalline form of desidustat free from other crystalline forms on consistent basis without the need of any organic solvent and uses only water as a solvent. Thus, the present invention provides a green process for the preparation of the specified crystalline form of desidustat.

BRIEF DESCRIPTION OF DRAWING
Figure 1. Powder X-ray diffraction pattern of crystalline desidustat as prepared in example 1 or example 2.

DETAILED DESCRIPTION OF THE INVENTION
The invention can further be understood in light of the description of the embodiments provided herein after. 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.

The following definitions are used in connection with present application, unless it is indicated otherwise.

In general, the terms “reacting” and “treating” are generally interchangeable and are used in their ordinary meaning as they are used in the field of the invention, unless defined specifically otherwise.

The terms “isolating”, “obtaining” and “purifying” are generally interchangeable, and include but not specifically limited to decantation, precipitation, extraction, filtration, evaporation, lyophilisation, spray drying, crystallization, recrystallization or chromatographic operations.

The term “alkyl”’ as used herein, unless otherwise specifically described, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, one or more of which may be substituted with hetero atom(s) independently selected from nitrogen, oxygen, and sulfur. The non-limiting examples of alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, etc.

The numerical in phrases like “C1- 6alkyl”, refers that there are 1 to 6 carbon atoms in the alky chain.

The term “substantially free from any other crystalline form” as used herein refers to the said crystalline Form comprises less than about 1%, more preferably less than about 0.5%, most preferably less than about 0.1% of the other crystalline form. In particular, the other crystalline form is absent. The content of other crystalline form can be measured by using X-ray powder diffraction.

The term "aqueous acid" as used herein refers to an aqueous solution of acid as described herein in the specification. Alternatively, aqueous acid can also refers to an aqueous solution of acid formed in-situ in the reaction mixture by adding water soluble acid as described herein to the reaction mixture having water as one of the solvent.

In general, desidustat 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 U.S. Patent No. 10,899,713 B2 which is incorporated herein by reference.

In general, the compound of Formula II 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 U.S. Patent No. 10,899,713 B2 which is incorporated herein by reference.

In general, the present invention provides a process for the preparation of a crystalline form of desidustat characterized by at least three X-ray powder diffraction peaks expressed in degree 2? selected from 8.0°, 8.9°, 10.6°, 11.3°, 16.1°, 25.5°, and 26.4°±0.2°.

In one embodiment, the present invention provides a process for the preparation of a crystalline form of desidustat characterized by the X-ray powder diffraction peaks expressed in degree 2? at 8.0°, 8.9°, 10.6°, 11.3°, 16.1°, 25.5°, and 26.4°±0.2°.

In another embodiment, the present invention provides a process for the preparation of a crystalline form of desidustat characterized by the X-ray powder diffraction peaks expressed in degree 2? at 8.0°, 8.9°, 11.3° and 25.5°±0.2°.

In another embodiment, the present invention provides a process for the preparation of a crystalline form of desidustat characterized by at least three X-ray powder diffraction peaks expressed in degree 2? selected from 8.0°, 8.9°, 10.6°, 11.3°, 16.1°, 25.5°, and 26.4°±0.2° and is substantially free from any other crystalline form.

In another embodiment, the present invention provides a process for the preparation of a crystalline form of desidustat characterized by X-ray powder diffraction pattern substantially as same as depicted in Figure 1.

Thus, in one general aspect, the present invention provides a process for the preparation of a crystalline form of desidustat characterized by at least three X-ray powder diffraction peaks expressed in degree 2? selected from 8.0°, 8.9°, 10.6°, 11.3°, 16.1°, 25.5°, and 26.4° ± 0.2°, the process comprising:
(a) treating desidustat with an inorganic base in water to obtain a solution;
(b) adding an aqueous acid to the solution obtained at step (a); and
(c) obtaining the crystalline form of desidustat.
In general, the inorganic base at step (a) is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, cesium carbonate, calcium hydroxide, and calcium carbonate. In particular, the base is sodium hydroxide.

In general, the desidustat can be treated with the inorganic base in water at a temperature of 10 °C to 40 °C, in particular, at a temperature of 25 °C to 40 °C. The resultant reaction mixture then can be stirred to form the solution or optionally it can be further filtered to obtain the solution.

In general, the aqueous acid at step (b) is selected from hydrochloric acid, sulfuric acid, and nitric acid. In particular, the aqueous acid is hydrochloric acid.

In one embodiment of the above aspect, the solution at step (a) was heated to a temperature of 40 °C to 60 °C before the addition of aqueous acid.

The present inventors have found that the addition of aqueous acid to the solution of step (a) at a temperature of 40 °C to 60 °C is critical to obtain the crystalline form of desidustat as herein mentioned substantially free from other crystalline forms on consistent basis.

In particular, the solution at step (a) was heated to a temperature of 45 °C to 60 °C before the addition of aqueous acid. More particularly, the solution at step (a) was heated to a temperature of 45 °C to 55 °C before the addition of aqueous acid.

In another embodiment, the solution at step (a) was heated to a temperature of 45 °C to 50 °C before the addition of aqueous acid.

In another embodiment, the aqueous acid at step (b) of the above process is added in a quantity such that the pH of the reaction mixture is adjusted to less than 2.
In general, after the addition of acid, the resultant reaction mixture is stirred for a time ranging from 1 h to 12 h, in particular, for 1 h to 2 h, more particularly, for 90 min. Then it is cooled to a temperature of 5 °C to 35 °C. The resultant crystalline form can be obtained 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 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 another general aspect, the present invention provides a process for the preparation of a crystalline form of desidustat characterized by at least three X-ray powder diffraction peaks expressed in degree 2? selected from 8.0°, 8.9°, 10.6°, 11.3°, 16.1°, 25.5°, and 26.4°±0.2°, the process comprising:
(a) treating desidustat with an inorganic base in water to obtain a solution;
(b) heating the solution to a temperature of 40 °C to 60 °C;
(c) adding an aqueous acid to the solution followed by stirring;
(d) cooling to a temperature of 5 °C to 35 °C; and
(e) obtaining the crystalline form of the desidustat.

In general, the inorganic base at step (a) of the above process is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, cesium carbonate, calcium hydroxide, and calcium carbonate. In particular, the inorganic base is sodium hydroxide.

In general, desidustat can be treated with the inorganic base in water as per step (a) of the above process, at a temperature of 10 °C to 40 °C, in particular, at a temperature of 25 °C to 40 °C. The solution can be stirred, and, optionally it can be further filtered to obtain the solution.

In general, the temperature of the solution formed at step (a) is raised to a temperature of 40 °C to 60 °C; in particular, to a temperature of 45 °C to 60 °C, more particularly, to a temperature of 45 °C to 55 °C, still more particularly to a temperature of 45°C to 50°C.

In general, the aqueous acid at step (c) of the above process is selected from hydrochloric acid, sulfuric acid, and nitric acid. In particular, the acid is hydrochloric acid.

In one embodiment of the above aspect, the aqueous acid is added in a quantity such that the pH of the reaction mixture is adjusted to less than 2.

In general, after the addition of the aqueous acid, the reaction mixture is stirred for a time ranging from 1 h to 12 h, in particular, for 1 h to 2 h, more particularly, for 90 min. Then it is cooled to a temperature of 5 °C to 35 °C. The resultant crystalline form can be obtained 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 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 another embodiment of the above aspect, the process of the present invention does not involve use of organic solvent.

In another embodiment of the above aspect, the obtained crystalline form of the desidustat is substantially free of other crystalline forms.

In another general aspect, the present invention provides a process for the preparation of a crystalline form of desidustat characterized by at least three X-ray powder diffraction peaks expressed in degree 2? selected from 8.0°, 8.9°, 10.6°, 11.3°, 16.1°, 25.5°, and 26.4°±0.2°, the process comprising:
(a) treating desidustat with sodium hydroxide in water to obtain a solution;
(b) heating the solution to a temperature of 40 °C to 60 °C;
(c) adding aqueous hydrochloric acid to the solution followed by stirring;
(d) cooling to a temperature of 5 °C to 35 °C; and
(e) obtaining the crystalline form of the desidustat.

In another general aspect, the present invention provides a process for the preparation of a crystalline form of desidustat characterized by at least three X-ray powder diffraction peaks expressed in degree 2? selected from 8.0°, 8.9°, 10.6°, 11.3°, 16.1°, 25.5°, and 26.4°±0.2°, the process comprising:
(a) reacting a compound of Formula II,

wherein R1 is C1-6 alkyl;
with an inorganic base in water to obtain a reaction mixture;
(b) stirring the reaction mixture to obtain a solution;
(c) adding an aqueous acid to the solution obtained at step (b); and
(d) obtaining the crystalline form of desidustat.

In general, the inorganic base at step (a) of the above process is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, cesium carbonate, calcium hydroxide and calcium carbonate. In particular, the base is sodium hydroxide.

In one embodiment of the above aspect, R1 in the compound of Formula II at step (a) is selected from methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, 2-butyl and isobutyl. In particular, the R1 in the compound of Formula II is ethyl.

In general, the compound of Formula II can be reacted with the inorganic base in water at a temperature of 10 °C to 40 °C, in particular, at a temperature of 25 °C to 40 °C. The resultant reaction mixture then can be stirred for a time sufficient to cause the hydrolysis of the compound of Formula II, in particular, for 30 min. to 3 hrs. The resultant reaction mixture thus formed can optionally be filtered to obtain a solution.

In general, the aqueous acid at step (c) is selected from hydrochloric acid, sulfuric acid, and nitric acid. In particular, the aqueous acid is hydrochloric acid.

In one embodiment of the above aspect, the solution obtained at step (b) of the above process is heated to a temperature of 40 °C to 60 °C before the addition of an aqueous acid.

In another embodiment, the solution obtained at step (b) was heated to a temperature of 45 °C to 55 °C before the addition of an aqueous acid.

In another embodiment, the solution obtained at step (b) was heated to a temperature of 45 °C to 50 °C before the addition of an aqueous acid.

In another embodiment, the aqueous acid at step (c) of the above process is added in a quantity such that the pH of the reaction mixture is adjusted to less than 2.

In general, after the addition of aqueous acid, the resultant reaction mixture is stirred for a time ranging from 1 h to 12 h, in particular, for 1 h to 2 h, more particularly for 90 min. Then it is cooled to a temperature of 5 °C to 35 °C. The resultant crystalline form thus formed can be obtained 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 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 another general aspect, the present invention provides a process for the preparation of a crystalline form of desidustat characterized by at least three X-ray powder diffraction peaks expressed in degree 2? selected from 8.0°, 8.9°, 10.6°, 11.3°, 16.1°, 25.5°, and 26.4°±0.2°, the process comprising:
(a) reacting a compound of Formula II,

wherein R1 is C1-6 alkyl;
with an inorganic base in water to obtain a reaction mixture;
(b) stirring the reaction mixture to obtain a solution;
(c) heating the solution to a temperature of 40 °C to 60 °C;
(d) adding an aqueous acid to the solution followed by stirring;
(e) cooling to a temperature of 5 °C to 35 °C; and
(f) obtaining the crystalline form of the desidustat.

In general, the inorganic base at step (a) of the above process is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, cesium carbonate, calcium hydroxide and calcium carbonate. In particular, the base is sodium hydroxide.

In one embodiment of the above aspect, R1 in the compound of Formula II at step (a) is selected from methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, 2-butyl and isobutyl. In particular, the R1 in the compound of Formula II is ethyl.

In general, the compound of Formula II can be reacted with the inorganic base in water at a temperature of 10 °C to 40 °C, in particular, at a temperature of 25 °C to 40 °C. The resultant reaction mixture then can be stirred for a time sufficient to cause the hydrolysis of the compound of Formula II, in particular, for 30 min. to 3 hrs. The resultant reaction mixture thus formed can optionally be filtered to obtain a solution.

In general, the aqueous acid at step (d) is selected from hydrochloric acid, sulfuric acid, and nitric acid. In particular, the aqueous acid is hydrochloric acid.

In one embodiment of the above aspect, the solution obtained at step (b) of the above process is heated to a temperature of 40 °C to 60 °C before the addition of an aqueous acid.

In another embodiment of the above aspect, the solution obtained at step (b) of the above process is heated to a temperature of 45 °C to 55 °C before the addition of an aqueous acid.

In another embodiment, the solution obtained at step (b) is heated to a temperature of 45 °C to 50 °C before the addition of an aqueous acid.

In another embodiment, the aqueous acid at step (d) of the above process is added in a quantity such that the pH of the reaction mixture is adjusted to less than 2.

In general, after the addition of aqueous acid, the resultant reaction mixture is stirred for a time ranging from 1 h to 12 h, in particular, for 1 h to 2 h, more particularly, for 90 min. Then it is cooled to a temperature of 5 °C to 35 °C. The resultant crystalline form thus formed can be obtained 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 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 another general aspect, the present invention provides a process for the preparation of a crystalline form of desidustat characterized by at least three X-ray powder diffraction peaks expressed in degree 2? selected from 8.0°, 8.9°, 10.6°, 11.3°, 16.1°, 25.5°, and 26.4° ± 0.2°, the process comprising:
(a) reacting a compound of Formula II,

wherein R1 is ethyl;
with sodium hydroxide in water to obtain a reaction mixture;
(b) stirring the reaction mixture to obtain a solution;
(c) heating the solution to a temperature of 40 °C to 60 °C;
(d) adding an aqueous hydrochloric acid to the solution followed by stirring;
(e) cooling to a temperature of 5 °C to 35 °C; and
(f) obtaining the crystalline form of the desidustat.

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 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. 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:
Characterization by X-Ray Powder Diffraction
The X-ray powder diffraction spectrum was measured under the following experimental conditions:
Instrument: X-Ray Diffractometer, PW3050/60, Make: PANalytical.
X-Ray : Cu K alpha radiation
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° rad
Time per step : 67.575s
Scan mode : Continuous

Example 1. Preparation of crystalline form of desidustat
Into a mixture of 110 g (0.305 mol) ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate and 1210 mL water, under stirring a solution of sodium hydroxide (30.5 g; 0.76 mol) prepared in 330 mL water was added at 25-40 °C temperature. Reaction was stirred for 2 hours at same temperature and was monitored by high performance liquid chromatography (HPLC) for completion. After reaction complies, it was filtered and washed with 220 mL of water. Additional 2860 mL water was charged under stirring and reaction mass was heated to 45-50 °C. A solution of ~15% aqueous diluted hydrochloric acid in water was added to reaction mass to made pH below 2 and stirred at 45-50 °C for 90 minutes. Reaction mass was cooled to 25-35 °C and stirred for 60 minutes. The reaction mass was filtered followed by washing with water (550 mL x 4 times). Wet cake was dried at 30-40 °C using fluidized bed dryer (FBD) to obtain the crystalline form of the desidustat with 95-98% yield.
X-ray powder diffraction pattern is as set forth in Figure 1.

Example 2. Preparation of crystalline form of desidustat
Into a mixture of 100 g (0.30 mol) desidustat and 1100 mL water under stirring a solution of sodium hydroxide (27.68 g; 0.69 mol) prepared in 300 mL water was added at 25-40 °C temperature. Reaction was stirred for 30 minutes at the same temperature. Then it was filtered and washed with 200 mL water. Additional 2600 mL water was charged under stirring and reaction mass was heated to 45-50 °C. A solution of ~15% aqueous diluted hydrochloric acid in water was added to reaction mass to made pH below 2 and stirred at 45-50 °C for 90 minutes. Reaction mass was cooled to 25-35 °C and stirred for 60 minutes. The reaction mass was filtered followed by washing with water (500 ml x 4 times). The wet cake was dried at 30-40 °C using fluidized bed dryer (FBD) to obtain the crystalline form of desidustat with 90-98% yield.
X-ray powder diffraction pattern is as set forth in Figure 1.

While the invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.


,CLAIMS:We Claim:

1. A process for the preparation of a crystalline form of desidustat characterized by at least three X-ray powder diffraction peaks expressed in degree 2? selected from 8.0°, 8.9°, 10.6°, 11.3°, 16.1°, 25.5°, and 26.4°±0.2°, the process comprising:
(a) treating desidustat with an inorganic base in water to obtain a solution;
(b) adding an aqueous acid to the solution obtained at step (a); and
(c) obtaining the crystalline form of desidustat.

2. The process as claimed in claim 1, wherein the solution at step (a) was heated to a temperature of 40 °C to 60 °C before the addition of the aqueous acid.

3. The process as claimed in claim 1, wherein the inorganic base at step (a) is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, cesium carbonate, calcium hydroxide, and calcium carbonate.

4. The process as claimed in claim 1, wherein the aqueous acid at step (b) is selected from hydrochloric acid, sulfuric acid, and nitric acid.

5. The process as claimed in claim 1, wherein the aqueous acid is added in a quantity such that the pH of the reaction mixture is adjusted to less than 2.

6. A process for the preparation of a crystalline form of desidustat characterized by at least three X-ray powder diffraction peaks expressed in degree 2? selected from 8.0°, 8.9°, 10.6°, 11.3°, 16.1°, 25.5°, and 26.4°±0.2°, the process comprising:
(a) treating desidustat with an inorganic base in water to obtain a solution;
(b) heating the solution to a temperature of 40 °C to 60 °C;
(c) adding an aqueous acid to the solution followed by stirring;
(d) cooling to a temperature of 5 °C to 35 °C; and
(e) obtaining the crystalline form of the desidustat.

7. The process as claimed in claim 6, wherein the inorganic base at step (a) is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, cesium carbonate, calcium hydroxide, and calcium carbonate; and the acid at step (b) is selected from hydrochloric acid, sulfuric acid, and nitric acid.

8. The process as claimed in claim 6, wherein the aqueous acid is added in a quantity such that the pH of the reaction mixture is adjusted to less than 2.

9. The process as claimed in claim 6, wherein the obtained crystalline form of the desidustat is substantially free of other crystalline forms.

10. A process for the preparation of a crystalline form of desidustat characterized by at least three X-ray powder diffraction peaks expressed in degree 2? selected from 8.0°, 8.9°, 10.6°, 11.3°, 16.1°, 25.5°, and 26.4°±0.2°, the process comprising:
(a) reacting a compound of Formula II,

wherein R1 is C1-6 alkyl;
with an inorganic base in water to obtain a reaction mixture;
(b) stirring the reaction mixture to obtain a solution;
(c) heating the solution to a temperature of 40 °C to 60 °C;
(d) adding an aqueous acid to the solution followed by stirring;
(e) cooling to a temperature of 5 °C to 35 °C; and
(f) obtaining the crystalline form of the desidustat.

Dated this the 16th day of April 2024.

(HARIHARAN SUBRAMANIAM)
IN/PA-93
of SUBRAMANIAM & ASSOCIATES
Attorneys for the applicants