DESC:
FIELD OF THE INVENTION

The present invention relates to a process for preparation of Voxelotor. The present invention also relates to process for preparing intermediate useful in the preparation of voxelotor. In particular, the present invention relates to a solid-state form of intermediate of voxelotor. The present invention also relates to an improved process for preparing voxelotor.

BACKGROUND AND THE PRIOR ART

The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.

Voxelotor is allosteric modulators of hemoglobin. It is used in the treatment of sickle cell disease (SCD) in adults and pediatric patients 12 years of age and older. Its chemical name is (2-Hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)metho- xy)benzaldehyde having the structure of Formula (I)

U.S. Patent No. 9,018,210 B2 discloses the compound voxelotor and provides its process for preparation.

U.S. Patent No. 9,447,071 B2 relates to ansolvate crystalline form of voxelotor.

PCT Pub. No. WO 2020/127924 A1 and WO 2020/127945 A1 relates to process for preparing voxelotor and intermediates thereof.
Though several processes for the preparation of voxelotor and intermediates thereof have been disclosed, they require many synthetic steps and give rise to the desired product in low yield.

It is therefore necessary to develop a new process for obtaining voxelotor as well as key intermediates in its synthesis which overcome all or part of the problems associated with the known processes belonging to the state of the art.

In view of the above art, there is provided an improved process for preparing voxelotor.

In particular there is provided a process for preparing intermediate useful in the preparation of voxelotor.

SUMMARY OF THE INVENTION

In one general aspect, there is provided a process for the preparation of Voxelotor of Formula (I),

comprising the steps of:
(a) reacting a compound of Formula (A) with a compound of Formula (B) to obtain a compound of Formula (C);

(b) converting a compound of Formula (C) to a compound of Formula (D) and reacting a compound of Formula (D) with a compound of Formula (E) to obtain compound of formula (F)

or converting a compound of Formula (C) to a compound of Formula (D) and reacting a compound of Formula (D) with a compound of Formula (G) to directly obtain voxelotor;

(c) converting a compound of Formula (F) to voxelotor.


In another general aspect, there is provided a solid state form of an acid addition salt of compound of Formula (C)

wherein X may be selected from hydrochloric acid, hydrobromic acid and sulfuric acid. The acid addition salt of compound of Formula (C) may be a mono or di acid salt.

In another general aspect, there is provided a solid state form of an acid addition salt of compound of Formula (C) having purity greater than 99.5% as measured by HPLC.

In another general aspect, there is provided a solid state form of an acid addition salt of compound of Formula (C) having water content less than 0.5%.

In another general aspect, there is provided a process for preparation of solid state form of compound of Formula (C),

comprising the steps of:
(a) reacting a compound of Formula (A) with a compound of Formula (B) to obtain a compound of Formula (C);
(b) converting compound of Formula (C) into an acid addition salt;
(c) isolating solid state form of an acid addition salt of compound of Formula (C).

In another general aspect, there is provided voxelotor having purity greater than 99.9% as measured by HPLC.

In another general aspect, there is provided voxelotor having water content less than 0.5%.

BRIEF DESCRIPTON OF THE ACCOMPANYING DRAWINGS

FIG. 1: X-ray powder diffractogram (XRPD) of hydrochloride salt of a compound of Formula (C).

DETAILED DESCRIPTION OF THE INVENTION

The aforementioned objectives of the present invention are fulfilled by one or more of the processes described herein.

While the invention has been described in terms of its specific embodiments, the description, in no way, intends to limit the scope of the present invention to the specifically described embodiments only; equivalents and variants thereof which are apparently obvious to those skilled in the art are also included within the scope of the present invention. The description does not include detailed description of conventional methods used in the field of the invention; such conventional methods are the ones well known to those of ordinary skill in the art either because they are normally practiced routinely by the skilled artisan in the field of the invention and/or are described in detail in various publications – physical as well digital.

The terms ‘reacting’, ‘contacting’ 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 term ‘converting’ means reacting the compound to which it refers to with another compound and/or reagent; and/or subjecting it to condition(s) wherein it transforms to another compound as a result of such treatment.
The terms ‘isolating’, ‘obtaining’ and ‘purifying’ are generally interchangeable and include, but not limited to, decantation, filtration, extraction, evaporation, crystallization, recrystallization and chromatographic operations.

The term ‘substantially’ defines "to a large extent only that is comprised which is specified". The boundaries of the term substantially is therefore to be drawn where the essential characteristics of the specified subject-matter ceased. The scope of the term substantially is therefore interpreted as being identical to that of consisting essentially of.

The expressions that recite a range of values “between” two values include the endpoints. Terms such as “about” and “generally” are to be construed as modifying a term or value to which they are attached such that the term or the value is not absolute. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

The product(s) obtained may further be purified to obtain them in purer form.

The product(s) obtained may further be dried additionally to achieve desired level of moisture and/or residual solvents.

The product(s) obtained may further be converted to any other physical forms thereof, which includes but not specifically limited to polymorph(s), salt(s), solvate(s), hydrate(s), co-crystal(s) or solid dispersion(s); and crystalline or amorphous forms thereof.

The product(s) obtained may further be subjected to physical processing which includes, but not limited to, pressing, crushing, triturating, milling or grinding to adjust the particle size of the product(s) to desired levels.

The product(s) obtained may further be combined with pharmaceutically acceptable career to obtain a pharmaceutical composition comprising voxelotor of the invention and pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutical composition may be in the form of solid or liquid dosage forms and may have immediate release or modified release characteristics. The dosage forms include but not limited to tablet, capsule, powder, granules, solution, suspension, emulsion, elixir or cream.

In one general aspect, there is provided a process for the preparation of Voxelotor of Formula (I),

comprising the steps of:
(a) reacting a compound of Formula (A) with a compound of Formula (B) to obtain an acid addition salt of compound of Formula (C);

wherein x may be selected from hydrochloric acid, hydrobromic acid and sulfuric acid.

(b) converting a compound of Formula (C) to a compound of Formula (D) and reacting a compound of Formula (D) with a compound of Formula (E) to obtain compound of formula (F)

or converting a compound of Formula (C) to a compound of Formula (D) and reacting a compound of Formula (D) with a compound of Formula (G) to directly obtain voxelotor;

(c) converting a compound of Formula (F) to voxelotor.


The compound of Formula (A) can be reacted with compound of Formula (B) by using a catalyst in presence of a base in one or more solvents to obtain compound of Formula (C).

The catalyst may be selected from Palladium scavenger being used in Suzuki coupling. The catalyst may be selected from Pd(PPh3)4, PdCl2(PPh3)4, PdCl2(dppf) and PdCl2(dppe).

The base may be selected from an organic or inorganic base. An organic base may be selected from diisopropylethylamine, diisopropylamine, triethylamine, diethylamine, piperidine, morpholine, pyridine, DBU and DABCO. The inorganic base comprises of an alkali and alkaline metal hydroxide and carbonate, in particular the suitable alkali metal hydroxide comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide and carbonate comprises of sodium carbonate, potassium carbonate and cesium carbonate.

In general, the solvent comprises one or more of C1-4 alcohols, C2-6 esters, ketones, halogenated hydrocarbons, polar aprotic solvents, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, or mixtures thereof.

In general, the C1-4 alcohol is selected from methanol, ethanol, n-propanol, isopropanol, and n-butanol; the C2-6 ester is selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; the ketone is selected from acetone, methyl ethyl ketone, and methyl isobutyl ketone; the halogenated hydrocarbon is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene; and the polar aprotic solvent is selected from dimethylformamide, dimethylsulfoxide and N-methylpyrrolidone or mixture thereof.

The compound of Formula (C) may be hydrochloride salt, hydrobromide salt and sulfate salt. The salt may be a mono acid or di acid salt. The preferred salt for compound of Formula (C) is hydrochloride salt.

The compound of Formula (C) may be reacted with thionyl chloride in presence of a base in one or more solvents to obtain a compound of Formula (D).

The compound of formula (D) may not be isolated and directly converted to voxelotor by reacting with a compound of formula (G) in presence of a base in one or more solvents.

Alternatively, compound of formula (D) may be reacted with a compound of Formula (E) in presence of a base in one or more solvents to obtain a compound of Formula (F).

The compound of formula (F) may be converted to voxelotor in presence of an acid, base and one or more solvents.

The conversion of compound of Formula (F) to voxelotor may be performed using an inorganic acid comprises of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.

The conversion of compound of Formula (F) to voxelotor may be performed using the solvent comprises one or more of C1-4 alcohols, C2-6 esters, ketones, halogenated hydrocarbons, polar aprotic solvents, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, water or mixtures thereof.

The preferred solvent for the conversion of compound of Formula (F) to voxelotor may be water.

The conversion of compound of Formula (F) to voxelotor may be performed at lower temperature i.e. less than 250C.

In another general aspect, there is provided a solid state form of an acid addition salt of compound of Formula (C)

wherein X may be selected from hydrochloric acid, hydrobromic acid and sulfuric acid. The acid addition salt of compound of Formula (C) may be a mono or di acid salt.

In another general aspect, there is provided a solid state form of hydrochloride salt of compound of Formula (C)

In another general aspect, solid state form of hydrochloride salt of compound of Formula (C) may be characterized by X-ray powder diffractogram (XPRD).

In another general aspect, solid state form of hydrochloride salt of compound of Formula (C) may be characterized by X-ray powder diffractogram (XPRD) as depicted in FIG. 1

In another general aspect, solid state form of hydrochloride salt of compound of Formula (C) is characterized by XRPD pattern having characteristic peaks at about 9.9, 13.0, 14.4, 16.4, 17.6, 20.3, 22.6, 23.2, 25.6, 27.5 and 29.3 ±0.2 degrees 2-theta.

In another general aspect, hydrochloride salt of compound of Formula (C) is having purity greater than 99.5% as measured by HPLC.

In another general aspect, hydrochloride salt of compound of Formula (C) is substantially free from impurities designated as pyrazole dimer impurity of Formula (1), triphenyl phosphine oxide impurity of Formula (2) and 1-(propan-2-yl)-1H-pyrazole impurity of Formula (3)

In another general aspect, there is provided hydrochloride salt of compound of Formula (C) having pyrazole dimer impurity of Formula (1) less than 0.5%.

In another general aspect, there is provided hydrochloride salt of compound of Formula (C) having pyrazole dimer impurity of Formula (1) less than 0.1%.

In another general aspect, there is provided hydrochloride salt of compound of Formula (C) having pyrazole dimer impurity of Formula (1) in not detected amount.

In another general aspect, there is provided hydrochloride salt of compound of Formula (C) having triphenyl phosphine oxide impurity of Formula (2) less than 0.5%.

In another general aspect, there is provided hydrochloride salt of compound of Formula (C) having triphenyl phosphine oxide impurity of Formula (2) less than 0.1%.

In another general aspect, there is provided hydrochloride salt of compound of Formula (C) having triphenyl phosphine oxide impurity of Formula (2) in not detected amount.

In another general aspect, there is provided hydrochloride salt of compound of Formula (C) having 1-(propan-2-yl)-1H-pyrazole impurity of Formula (3) less than 0.5%.

In another general aspect, there is provided hydrochloride salt of compound of Formula (C) having 1-(propan-2-yl)-1H-pyrazole impurity of Formula (3) less than 0.1%.

In another general aspect, there is provided hydrochloride salt of compound of Formula (C) having 1-(propan-2-yl)-1H-pyrazole impurity of Formula (3) in not detected amount.

In another general aspect, there is provided hydrochloride salt of compound of Formula (C) having water content is less than 0.5%.

In another general aspect, there is provided a process for preparation of solid state form of an acid addition salt of compound of Formula (C),

comprising the steps of:
(a) reacting a compound of Formula (A) with a compound of Formula (B) to obtain a compound of Formula (C);
(b) converting compound of Formula (C) into an acid addition salt;
(c) isolating solid state form of an acid addition salt of compound of Formula (C).

In another general aspect, there is provided a process for preparation of solid state form of hydrochloride salt of compound of Formula (C)

comprising the steps of:
(a) reacting a compound of Formula (A) with a compound of Formula (B) to obtain a compound of Formula (C);
(b) converting compound of formula (C) into hydrochloride salt;
(c) isolating solid state form of hydrochloride salt of compound of Formula (C).

The compound of Formula (A) can be reacted with compound of Formula (B) by using a catalyst in presence of a base in one or more solvents to obtain compound of Formula (C).

The catalyst may be selected from Palladium scavenger being used in Suzuki coupling.

The catalyst may be selected from Pd(PPh3)4, PdCl2(PPh3)4, PdCl2(dppf) and PdCl2(dppe).

The base may be selected from an organic or inorganic base.

In general, the solvent comprises one or more of C1-4 alcohols, C2-6 esters, ketones, halogenated hydrocarbons, polar aprotic solvents, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, or mixtures thereof.

In another general aspect, there is provided a solid state form of hydrobromide salt of compound of Formula (C)

In another general aspect, there is provided a solid state form of sulfate salt of compound of Formula (C)

In another general aspect, there is provided a process for preparation of solid state form of hydrobromide salt of compound of Formula (C)

comprising the steps of:
(a) reacting a compound of Formula (A) with a compound of Formula (B) to obtain a compound of Formula (C);
(b) converting compound of formula (C) into hydrobromide salt;
(c) isolating solid state form of hydrobromide salt of compound of Formula (C).
The reaction of compound of Formula (A) with compound of Formula (B) may be performed by using a catalyst in presence of a base in one or more solvents to obtain compound of Formula (C).

The catalyst may be selected from Palladium scavenger being used in Suzuki coupling. The catalyst may be selected from Pd(PPh3)4, PdCl2(PPh3)4, PdCl2(dppf) and PdCl2(dppe).

The base may be selected from an organic or inorganic base.

The solvent may be selected from one or more of C1-4 alcohols, C2-6 esters, ketones, halogenated hydrocarbons, polar aprotic solvents, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, or mixtures thereof.

In another general aspect, there is provided a process for the preparation of voxelotor of Formula (I),

comprising the steps of:
(a) reacting a compound of Formula (A) with a compound of Formula (B) to obtain a hydrochloride salt of compound of Formula (C);

(b) converting hydrochloride salt of compound of Formula (C) to a compound of Formula (D) and reacting a compound of Formula (D) with a compound of Formula (E) to obtain compound of formula (F)

(c) converting a compound of Formula (F) to voxelotor.

The compound of Formula (A) can be reacted with compound of Formula (B) by using a catalyst in presence of a base in one or more solvents to obtain compound of Formula (C).

The catalyst may be selected from Palladium scavenger being used in Suzuki coupling.

The catalyst may be selected from Pd(PPh3)4, PdCl2(PPh3)4, PdCl2(dppf) and PdCl2(dppe).

The base may be selected from an organic or inorganic base.

The solvent may be selected from one or more of C1-4 alcohols, C2-6 esters, ketones, halogenated hydrocarbons, polar aprotic solvents, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, or mixtures thereof.

The hydrochloride salt of compound of Formula (C) may be reacted with thionyl chloride in one or more solvents to obtain a compound of Formula (D).

The compound of formula (D) may not be isolated and directly reacted with a compound of Formula (E) in presence of a base in one or more solvents to obtain a compound of Formula (F).

The compound of formula (F) may be converted to voxelotor in presence of an acid and one or more solvents.

The conversion of compound of Formula (F) to voxelotor may be performed using an inorganic acid comprises of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.

The conversion of compound of Formula (F) to voxelotor may be performed using the solvent comprises one or more of C1-4 alcohols, C2-6 esters, ketones, halogenated hydrocarbons, polar aprotic solvents, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, water or mixtures thereof.

The preferred solvent for the conversion of compound of Formula (F) to voxelotor may be water.

The conversion of compound of Formula (F) to voxelotor may be performed at lower temperature i.e. less than 250C. The preferred temperature for the conversion of compound of Formula (F) to voxelotor is 15 to 200C.

In another general aspect, there is provided voxelotor substantially free from impurities designated as pyrazole dimer impurity of Formula (1), triphenyl phosphine oxide impurity of Formula (2) and 1-(propan-2-yl)-1H-pyrazole impurity of Formula (3)

In another general aspect, there is provided voxelotor having pyrazole dimer impurity of Formula (1) less than 0.5%.

In another general aspect, there is provided voxelotor having pyrazole dimer impurity of Formula (1) less than 0.1%.

In another general aspect, there is provided voxelotor having pyrazole dimer impurity of Formula (1) in not detected amount, wherein limit of detection is 0.02% by HPLC.

In another general aspect, there is provided voxelotor having triphenyl phosphine oxide impurity of Formula (2) less than 0.5%.

In another general aspect, there is provided voxelotor having triphenyl phosphine oxide impurity of Formula (2) less than 0.1%.

In another general aspect, there is provided voxelotor having triphenyl phosphine oxide impurity of Formula (2) in not detected amount, wherein limit of detection is 0.02% by HPLC.

In another general aspect, there is provided voxelotor having 1-(propan-2-yl)-1H-pyrazole impurity of Formula (3) less than 0.5%.

In another general aspect, there is provided voxelotor having 1-(propan-2-yl)-1H-pyrazole impurity of Formula (3) less than 0.1%.

In another general aspect, there is provided voxelotor having 1-(propan-2-yl)-1H-pyrazole impurity of Formula (3) in not detected amount, wherein limit of detection is 0.02% by HPLC.

In another general aspect, there is provided a process for the preparation of voxelotor as depicted in Scheme-1.

The present invention is further illustrated by the following examples which are provided merely to exemplify the invention and do not limit the scope of it.
EXAMPLES:
Example-1: Preparation of hydrochloride salt of compound of Formula (C)

(2-chloropyridin-3-yl)methanol compound of Formula (A) (100 g), 1-(propan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole compound of Formula (B) (205 g) and 1,4-dioxane (750 ml) were added to a 3000 ml RBF at 25 to 35 °C. Further, Potassium carbonate (290 g) and process water (250 ml) were added followed by addition of tetrakis (triphenylphosphine) palladium (24.0 g) and stirred. The reaction mass was heated at 80 to 90 °C and stirred for 60 minutes. After completion of reaction, product was extracted in dichloromethane and solvent was distilled out and acetone (500 ml) and hydrochloric acid in isopropyl alcohol was added at 25 to 35 °C. Reaction mass was stirred for 30 min. and product was isolated by filtration to obtain hydrochloride salt of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl] methanol.

Example-2: Preparation of compound of Formula (F)

Hydrochloride salt of [2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl] methanol compound of Formula (C) (100 g) and dichloromethane (450 ml) were added to a 1000 ml RBF at 25 to 35 °C. The reaction mass was flushed with dichloromethane (50 ml) followed by addition of thionyl chloride (110 g). The reaction mass was stirred for 2 hours and pH of reaction mass was adjusted to neutral and organic layer was separated and distilled out below 50°C to give residue compound of Formula (D). The residue compound of Formula (D) was cooled to 25 to 35 °C and treated with N,N-dimethyl acetamide (250 ml), 2-hydroxy-6-(methoxymethoxy)benzaldehyde compound of formula (E) (65 g) and potassium carbonate (75 g). The reaction mass was heated and stirred for 120 minutes. The reaction mass was cooled to 25 to 35 °C. The reaction mass was filtered and washed with water (2 x 100 ml) and dried under vacuum for 30 to 60 minutes to obtain 2-(methoxymethoxy)-6-({2-[1-(propan-2-yl)-1H-pyrazol-5-yl] phenyl}methoxy) benzaldehyde compound of Formula (F).
Example-3: Preparation of Voxelotor
2-(Methoxymethoxy)-6-({2-[1-(propan-2-yl)-1H-pyrazol-5-yl]phenyl}methoxy)benzal- dehyde compound of Formula (F) (100 g) and process water (450 ml) were added to a 1000 ml RBF. The reaction mass was flushed with process water (50 ml) and Conc. hydrochloric acid (~35 %) was added. The reaction mass was stirred below 25°C for 4 hours. Then neutral pH was adjusted by addition of sodium hydroxide solution. The reaction mass was stirred for 30 minutes. The reaction mass was filtered and washed with process water (2 x 100 ml) and dried under vacuum to obtain voxelotor.
Example-4: Preparation of voxelotor API
Conc. HCl (45 ml) was added in to the mixture of 2-hydroxy-6-({2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl}methoxy)benzaldehyde (Voxelotor Technical) (100 g) and methyl ethyl ketone (400 ml). Reaction mass was stirred for 30 minutes at 25 to 35°C. Filtration was carried out and wet cake was washed with methyl ethyl ketone. Further wet cake was charged in process water (500 ml) in to 1 litter RBF. This reaction mass was stirred for 60 minutes at 25 to 35°C. Finally solid was filtered and wet cake was washed with water and dried in vacuum dryer to obtain Voxelotor API.

,CLAIMS:We Claim:
1. A process for the preparation of Voxelotor of Formula (I),

comprising the steps of:
(a) reacting a compound of Formula (A) with a compound of Formula (B) using a catalyst in the presence of a base in one or more solvents to obtain an acid addition salt of compound of Formula (C);

wherein x may be selected from hydrochloric acid, hydrobromic acid, and sulfuric acid;
(b) converting the compound of Formula (C) to a compound of Formula (D) and reacting the compound of Formula (D) with a compound of Formula (E) in the presence of a base in one or more solvents to obtain compound of formula (F); and

(c) converting the compound of Formula (F) to voxelotor of compound of Formula (I); or converting the compound of Formula (C) to a compound of Formula (D) and reacting the compound of Formula (D) with a compound of Formula (G) in the presence of a base in one or more solvents to directly obtain voxelotor of compound of Formula (I).

2. The process as claimed in claim 1, wherein the catalyst may be selected from Pd(PPh3)4, PdCl2(PPh3)4, PdCl2(dppf), and PdCl2(dppe).

3. The process as claimed in claim 1, wherein the base may be selected from an organic or inorganic base.

4. The process as claimed in claim 3, wherein the organic base may be selected from diisopropylethylamine, diisopropylamine, triethylamine, diethylamine, piperidine, morpholine, pyridine, DBU, and DABCO.

5. The process as claimed in claim 3, wherein inorganic base may be selected from an alkali and alkaline metal hydroxides and carbonates, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.

6. The process as claimed in claim 1, wherein the solvent may be selected from one or more of C1-4 alcohols, C2-6 esters, ketones, halogenated hydrocarbons, polar aprotic solvents, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, or mixtures thereof.

7. The process as claimed in claim 1, wherein voxelotor is substantially free from impurities designated as pyrazole dimer impurity of Formula (1), triphenyl phosphine oxide impurity of Formula (2), and 1-(propan-2-yl)-1H-pyrazole impurity of Formula (3)

8. The process as claimed in claim 1, wherein the impurities designated as pyrazole dimer impurity of Formula (1), triphenyl phosphine oxide impurity of Formula (2), and 1-(propan-2-yl)-1H-pyrazole impurity of Formula (3) are less than less than 0.5% in voxelotor by HPLC.

9. The process as claimed in claim 1, wherein the impurities designated as pyrazole dimer impurity of Formula (1), triphenyl phosphine oxide impurity of Formula (2), and 1-(propan-2-yl)-1H-pyrazole impurity of Formula (3) are less than 0.1% in voxelotor by HPLC.

10. The process as claimed in claim 1, wherein the impurities designated as pyrazole dimer impurity of Formula (1), triphenyl phosphine oxide impurity of Formula (2), and 1-(propan-2-yl)-1H-pyrazole impurity of Formula (3) are in not detected amount in voxelotor, wherein limit of detection is 0.02% by HPLC.

Dated this 14th day of July 2022.

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