DESC:FIELD OF THE INVENTION
Present invention relates to a process for obtaining pure polymorphic form I of quinolone based compound of formula (I). The present invention also relates to process for obtaining pure polymorphic form II of formula (I).
BACKGROUND OF THE INVENTION
The compound of formula (I) has been disclosed for the first time in WO2014102818, known for Hypoxia-inducible factor (HIF) inhibitors having utility in any disease state where ischemia hypoxia and/or anemia plays a role.

Formula (I)
US patent number US10899713 disclosed the process for the preparation of compound of formula (I) and its crystalline form as well.

To research new polymorphic form with significantly better stability, biological efficacy and other required physicochemical properties is a continuing goal of chemists. Some form may turn out to be more efficacious. As an active pharmaceutical substance it is also required that the pharmaceutical substance should also meet the necessities of using it for the preparation of a pharmaceutical composition and so the compound should exhibit desired physicochemical properties to be incorporated in a pharmaceutical composition. Scientists of the present invention have identified that polymorphic form I and form II of compound of formula (I) gets contaminated by another polymorphic form that created difficulty in developing pharmaceutical composition of compound of formula (I) therefore it is essential to obtain pure polymorphic form and further to be developed for pharmaceutical composition.
Present invention provides a process to overcome difficulty in obtaining pure polymorphic form I and form II of compound of formula (I), individually. By using the process for preparation of polymorphic form I and polymorphic form II of the present invention can be obtained in pure forms.
EMBODIMENT OF THE PRESENT INVENTION
In one embodiment, present invention provides a process for obtaining pure polymorphic form I and form II of compound of formula (I).
In another embodiment, present invention provides a process for obtaining at least 95%, more preferably atleast 98 % pure polymorphic form I of compound of formula (I).
In another embodiment, present invention provides a process for obtaining at least 95%, more preferably atleast 98 % pure polymorphic form II of compound of formula (I).
In yet another embodiment, present invention provides a process for conversion of form I to form II of formula (I).
DESCRIPTION OF FIGURES
Figure 1: Powder X-ray diffraction (XRD) pattern of crystalline form I of compound of Formula (I) as prepared in example 1.
Figure 2: Powder X-ray diffraction (XRD) pattern of crystalline form II of compound of Formula (I) as prepared in example 3.
Figure 3: Powder X-ray diffraction (XRD) pattern of mixture of crystalline forms I and II of compound of Formula (I) as prepared in example 5.
DETAILED DESCRIPTION OF THE INVENTION
The terms ‘dissolving’, ‘contacting’, ‘slurring’, ‘stirring’, and ‘mixing’ are interchangeable terms and doesn’t affect the scope of the present invention.
The terms ‘isolating’, ‘obtaining’ and ‘purifying’ are generally interchangeable, and include but not specifically limited to decantation, extraction, filtration, evaporation, lyophilisation, spray drying, crystallization, recrystallization or chromatographic operations.
The term “pharmaceutically acceptable” as used herein means useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and is acceptable for veterinary or human pharmaceutical use.
The term "pharmaceutical composition" as used herein means a drug product comprising the active ingredient(s) & pharmaceutically acceptable excipient(s), as well as any product, which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients including an active ingredient.
In one general aspect, present invention provides a process for obtaining pure polymorphic form I and form II of compound of formula (I).
In an embodiment pure polymorphic form I and form II of compound of formula (I) are present in crystalline forms.
Compound of formula (I) required for the preparation of new crystalline forms can be synthesized by the process disclosed in US patent no. US 10899713.
In one specific embodiment, the process for preparing substantially pure polymorphic form I of compound of formula (I) comprising following steps:
The process comprises following steps:
i. dissolving glycine coupled product of compound of formula (I) in one or more solvent; stirring the reaction mass for 5-10 minutes at suitable temperature;

Formula (I)
ii. preparing sodium hydroxide solution is by dissolving sodium hydroxide in water and adding it to the solution of step (i) within time period of 10 minutes wherein temperature maintained between 30-40oC;
iii. stirring the reaction mass for about 30 minutes wherein temperature maintained between 30-40oC; filtering the reaction mass and dilute it with water at 25-35oC;
iv. heating the diluted solution to temperature about 40-50oC; drop wise adding 50% hydrochloric acid solution to heated diluted solution of step (vii) within 15 minutes, wherein temperature should be maintained between 43-50 oC;
v. stirring the reaction mass for 1 hour at temperature between 43-50oC; cooling down the reaction mass to 30-35oC and solid is filtered and washed with water for four times and obtained product dried under fan dryer.
Temperature plays very crucial role in process for the development of pure polymorphic form. In one specific embodiment, the process for the preparation for polymorphic form I requires heating of the diluted solution between 40-50oC for step (vii) to step (ix).
In yet another embodiment, the product obtained by above explained process of polymorphic form I of compound of formula (I), substantially free of any contamination of other polymorphs.
In one preferred embodiment, the product obtained by above process is at least 98% pure polymorphic form I of compound of formula (I).
In another preferred embodiment, the product obtained by above process is at least 95% pure polymorphic form I of compound of formula (I).
In another embodiment, present invention provide process for the preparing substantially pure polymorphic form II of compound of formula (I).
The process comprises following steps:
i. dissolving glycine coupled product of compound of formula (I) in one or more solvent; stirring the reaction mass for 5-10 minutes at 25-35oC temperature;

Formula (I)
ii. preparing sodium hydroxide solution is by dissolving sodium hydroxide in water and adding it to the solution of step (i) within time period of 10 minutes wherein temperature maintained between 30-40oC;
iii. stirring the reaction mass for about 30 minutes wherein temperature maintained between 30-40oC; filtering the reaction mass and dilute it with water at 25-35oC;
iv. cooling the diluted solution of step (iii) at temperature 0-5oC; drop wise adding 50% hydrochloric acid solution to heated diluted solution of step (vii) within 15 minutes, wherein temperature should be maintained between 0-5oC;
v. stirring the reaction mass for 1 hour at temperature between 0-5oC; solid obtained, is filtered and washed with water for four times and obtained product dried under fan dryer.
In one specific embodiment, the process for obtaining substantially pure polymorphic form II requires cooling temperature to be maintained between 0-5oC for steps (vii) to step (ix).
It will be appreciated that a skilled person may modify/alter these processes suitably in an obvious manner and such obvious alternations/modifications are considered included within the scope of the present application.
Analytical methods:

XRD: The complete X-ray powder spectrum was recorded using a BP/AR/XRPD-02/345 X-Ray Powder Diffractometer model using Copper radiation. Step Size0.030 °, TPS76.80 s, Divergent Slit0.300 °, Antiscatter Slit3.000 mm, DetectorLYNXEYE (1D mode) Cu40.0 kV40.0 mA.
The process described in the present invention is exemplified further in the following examples which are provided for illustration only and should not be construed to limit the scope of the invention in any way.
Example 1: Preparation of crystalline form I of formula I
A mixture of Compound of formula (I) (50 g), Methanol (350 mL) and water (200 mL) was stirred for 5-10 minutes at 25-35oC. Sodium hydroxide (13.9 g in 150 mL water) was added in 10 min at 30-40oC. Reaction mass was stirred for 30 minutes at 30-40oC. Filtered the reaction mixture to get clear solution. Diluted with water (1400 mL) at 25-35oC. Heat reaction mass at 43-50oC. Hydrochloric acid solution (50%, 100 mL) was added slowly dropwise in below 15 min. at 43-50 oC. Stirred it for 1 hour at 43-50oC. Cooled to 30-35oC and Solid was filtered and washed with water (4 x 250 mL). Wet cake was dried in fan dryer to obtain polymorphic form I; 42.5 g (yield 92%). The XRPD pattern is depicted in Figure 1.
Example 2: Preparation of crystalline form I of formula I
A mixture of Glycine coupled product (50 g), Methanol (350 mL) and water (200 mL) was stirred for 5-10 minutes at 25-35 oC. Sodium hydroxide (13.9 g in 150 mL water) was added in 10 min at 30-40 oC. Reaction mass was stirred for 30 minutes at 30-40 oC. Filtered the reaction mixture to get clear solution. Diluted with water (1400 mL) at 25-35 oC. Heat reaction mass at 43-50 oC. Hydrochloric acid solution (50%, 100 mL) was added slowly dropwise in below 15 min. at 43-50 oC. Stirred it for 1 hour at 43-50 oC. Cooled to 30-35 oC and Solid was filtered and washed with water (4 x 250 mL). Wet cake was dried in fan dryer to obtain crystalline Form I : 42.5 g (yield 92%). The XRPD pattern is depicted in Figure 1.
Example 3: Preparation of crystalline form II of formula I
A mixture of Compound of formula (I) (5 g), Methanol (35 mL) and water (20 mL) was stirred for 5-10 minutes at 25-35 oC. Sodium hydroxide (1.38 g in 15 mL water) was added in 10 min at 30-40 oC. Reaction mass was stirred for 30 minutes at 30-40 oC. Filtered the reaction mixture to get clear solution. Diluted with water (140 mL) at 30-40 oC. Cool to 0-5 oC. Hydrochloric acid solution (50%, 10 mL) was added slowly dropwise in below 15 min. at 0-5 oC. Stirred it for 1 hour at 0-5 oC. Solid was filtered and washed with water (4 x 25 mL). Wet cake was then dried in fan dryer to obtain polymorphic form II : 4.1 g (yield 89%). The XRPD pattern is depicted in Figure 2.
Example 4: Preparation of crystalline form II of formula I
A mixture of Glycine coupled product (5 g), Methanol (35 mL) and water (20 mL) was stirred for 5-10 minutes at 25-35 oC. Sodium hydroxide (1.38 g in 15 mL) water was added in 10 min at 30-40 oC. Reaction mass was stirred for 30 minutes at 30-40 oC. Filtered the reaction mixture to get clear solution. Diluted with water (140 mL) at 30-40 oC. Cool to 0-5 oC. Hydrochloric acid solution (50%, 10 mL) was added slowly dropwise in below 15 min. at 0-5 oC. Stirred it for 1 hour at 0-5 oC. Solid was filtered and washed with water (4 x 25 mL) . Wet cake was then dried in fan dryer to obtain crystalline compound Form II : 4.1 g (yield 89%). The XRPD pattern is depicted in Figure 2.
Example 5: Preparation of crystalline form II of formula I
A mixture of Compound of formula (I) (5 g), Methanol (35 mL) and water (20 mL) was stirred for 5-10 minutes at 25-35 oC. Sodium hydroxide (1.38 g in 15 mL water) was added in 10 min at 30-40 oC. Reaction mass was stirred for 30 minutes at 30-40 oC. Filtered the reaction mixture to get clear solution. Diluted with water (140 mL) at 30-40 oC. Cool to 10-30 oC. Hydrochloric acid solution (50%, 10 mL) was added slowly dropwise in below 15 min. at 10-30 oC. Stirred it for 1 hour at 10-30 oC. Solid was filtered and washed with water (4 x 25 mL). Wet cake was then dried in fan dryer to obtain polymorphic mixture: 4.19 g (yield 91%). The XRPD pattern is depicted in Figure 3.
Example 6: Preparation of crystalline form II of formula I
A mixture of Glycine coupled product (10 g) and water (40 mL) was stirred for 10 minutes at 25-35 oC. Sodium hydroxide (2.77 g in 30 mL water) was added in 5-10 min at 25-35 oC. Reaction mass was stirred for 30 minutes at 25-35 oC. Filtered the reaction mixture to get clear solution. Diluted with water (280 mL) at 25-35 oC. Hydrochloric acid solution (50%, 20 mL) was added slowly in one lot at 25-35 oC. Stirred it for 1 hour at 25-35 oC. Solid was filtered and washed with water (4 x 30 mL). Wet cake was then dried in fan dryer to obtain polymorphic form II: 8.1 g (yield 88%). The XRPD pattern is depicted in Figure 2.
Example 7: Process for conversion of Form I to Form II of formula I: (100 g) was added to a mixture of methanol (400 mL) and methylene dichloride (800 mL) at 25-35 °C. The temperature of the reaction mixture was raised to 40-60 °C and then methylene dichloride was distilled off from the reaction mixture up to 60 °C. The reaction mass was cooled to 25-35 °C and stirred for 1 hour. The reaction mass was then filtered under suction and washed with methanol (50 mL). Wet cake was then dried at 50-80 °C for till constant weight to obtain crystalline Form II: 95 g (yield 95%). The XRPD pattern is depicted in Figure 2.
Pharmaceutical analysis of synthesized compounds:
It has been observed during formulation development of Compound of formula (I) that tablet could not achieve appropriate hardness due to contamination of polymorphic form II in polymorphic form I. Therefor it was desirable to obtain a pure polymorphic form during synthesis only.
Provided below is analysis of hardness of tablets formulated using the active pharmaceutical ingredients obtained from Examples 1 and 3. It explains that targeted hardness has been achieved with lesser compression force for polymorph of example 1, whereas for the mixture of polymorphs of example 3, it is difficult to achieve hardness of tablet even on higher compression force.
Example No. Target hardness Hardness (kp) Compression force (kN)
Example 1 3.0 kp
(1.5 kp – 4.5 kp) Min : 3.0
Max : 4.0 Min : 3.9
Max : 5.1
Example 3 3.0 kp
(1.5 kp – 4.5 kp) Min : 1.7
Max : 2.2 Min : 3.0
Max : 11.0
Min : 1.7
Max : 2.5 Min : 4.0
Max : 11.0

,CLAIMS:We claim:
1. A process for obtaining pure polymorphic form I and form II of compound of formula (I)

Formula (I)
2. The process as claimed in claim 1. wherein pure polymorphic form I and form II are present in crystalline forms.
3. The process as claimed in claim 1 and 2, wherein polymorphic form I having a powder X-ray diffraction pattern as shown in figure 1.
4. The process as claimed in claim 1 and claim 2, wherein polymorphic form II having a powder X-ray diffraction pattern as shown in figure 2.
5. A process for preparing substantially pure polymorphic form I as claimed in claim 1 and 2 comprising following steps:
(a) dissolving glycine coupled product of compound of formula (I) in one or more solvent; stirring the reaction mass for 5-10 minutes at suitable temperature;
(b) preparing sodium hydroxide solution is by dissolving sodium hydroxide in water and adding it to the solution of step (i) within time period of 10 minutes wherein temperature maintained between 30-40oC;
(c) stirring the reaction mass for about 30 minutes wherein temperature maintained between 30-40oC; filtering the reaction mass and dilute it with water at 25-35oC;
(d) heating the diluted solution to temperature about 40-50oC; drop wise adding 50% hydrochloric acid solution to heated diluted solution of step (vii) within 15 minutes, wherein temperature should be maintained between 43-50 oC;
(e) stirring the reaction mass for 1 hour at temperature between 43-50oC; cooling down the reaction mass to 30-35oC and solid is filtered and washed with water for four times and obtained product dried under fan dryer.
6. A process for preparing substantially pure polymorphic form II as claimed in claim 1 and 2 comprising following steps:
(a) dissolving glycine coupled product of compound of formula (I) in one or more solvent; stirring the reaction mass for 5-10 minutes at 25-35oC temperature;
(b) preparing sodium hydroxide solution is by dissolving sodium hydroxide in water and adding it to the solution of step (i) within time period of 10 minutes wherein temperature maintained between 30-40oC;
(c) stirring the reaction mass for about 30 minutes wherein temperature maintained between 30-40oC; filtering the reaction mass and dilute it with water at 25-35oC;
(d) cooling the diluted solution of step (iii) at temperature 0-5oC; drop wise adding 50% hydrochloric acid solution to heated diluted solution of step (vii) within 15 minutes, wherein temperature should be maintained between 0-5oC;
(e) stirring the reaction mass for 1 hour at temperature between 0-5oC; solid obtained, is filtered and washed with water for four times and obtained product dried under fan dryer.
7. The process as claimed in claim 5 and 6, wherein one or more solvent used in step (a) is alcohol selected from methanol, ethanol, isopropanol, butanol, 1,2-dimethoxy ethanol, 2-methoxy ethanol, 2-ethoxy ethanol and ethylene glycol; esters selected from ethyl acetate and isopropyl acetate; chlorinated solvents selected from chloroform, dichloromethane; acetonitrile, hydrocarbons selected from toluene, xylene, chlorobenzene, ketones selected from acetone, methyl ethyl ketone, ethers selected from diethyl ether, 1,4-dioxane, DIPE, MTBE, THF, aprotic polar solvents selected from DMF, DMSO, DMA, water and their suitable mixtures.

Dated this the 16th day of June 2023.

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