DESC:FIELD OF THE INVENTION:
The present invention relates to an efficient and industrially advantageous process for the preparation of Vadadustat or salts thereof.
The present invention also relates to a process for the preparation of Vadadustat intermediates namely {[3-chloro-5-(3-chlorophenyl)pyridine-2-carbonyl]amino}acetic acid of Formula-IV, {[5-(3-chlorophenyl)-3-methoxypyridine-2-carbonyl]amino}acetic acid of Formula-V and their use for the preparation of Vadadustat or salts thereof.
The present invention also relates to Vadadustat salt of Formula-VI, and process thereof.
BACKGROUND OF THE INVENTION:
Vadadustat is chemically known as [5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxamido]acetic acid, having the structure of Formula-I,

Formula-I
Vadadustat has been developed by Akebia Therapeutics Inc. and approved by Japanese pharmaceutical and medical device agency (PMDA) on June 29, 2020, under the proprietary name Vafseo®. Vadadustat is under Phase-III clinical trials in USA and Europe. Vadadustat is prolyl hydroxylase inhibitor, which may prevent diseases ameliorated by modulation of hypoxia-inducible factor (HIF) prolyl hydroxylase (e.g., peripheral vascular disease (PVD), coronary artery disease (CAD), heart failure, ischemia, hypoxia, and anemia). Vadadustat is useful for treating and preventing anemia secondary to or associated with chronic kidney disease (renal anemia).
US patent number US 7811595 (herein after US ‘595) first discloses Vadadustat. The process for the preparation of Vadadustat has been also disclosed by reacting 3,5-dichloro-2-cyanopyridine with benzyl alcohol in presence of sodium hydride to obtain 3,5-bis-benzyloxy-pyridine-2-carbonitrile, which on further reaction with sodium hydroxide in presence of methanol, followed by acidification using hydrochloric acid results into hydrochloride salt of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid. Resulting hydrochloric acid salt is then reacted with glycine methyl ester hydrochloride in presence of diisopropylethylamine, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-hydroxybenzotriazole to obtain [(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-acetic acid methyl ester. Resulting ester is then reduced by 10% palladium on carbon in presence of methanol to obtain [(3,5-dihydroxy-pyridine-2-carbonyl)-amino]-acetic acid methyl ester. The resulting compound is protected by using N-phenyltrifluoromethansulfonimide to obtain [(3-hydroxy-5-trifluoromethanesulfonyloxy-pyridine-2-carbonyl)-amino]-acetic acid methyl ester, which on further reaction with 3-chlorophenylboronic acid in presence of dioxane, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) and tripotassium phosphate followed by silica purification to obtain {[5-(3-chloro-phenyl)-3-hydroxy-pyridine-2-carbonyl]-amino}-acetic acid methyl ester having 53% yield. The resulting compound is hydrolysed using sodium hydroxide in presence of tetrahydrofuran to obtain Vadadustat having 64 % yield.
US ‘595 process requires catalyst 1-hydroxybenzotriazole (HOBT) in excess amount during the coupling of hydrochloric acid salt of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid with glycine methyl ester hydrochloride to obtain [(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-acetic acid methyl ester. Also, coupling reaction require longer reaction time. Generally, 1-hydroxybenzotriazole (HOBT) contains hydrazine moiety. Whenever, 1-hydroxybenzotriazole (HOBT) is used in any reaction, hydrazine moiety present may result into formation of potential genotoxic impurity in the product, which may carry forward in final Vadadustat API and may require additional purification to control the impurities which may result into low yield & purity of final Vadadustat API. Therefore, Vadadustat process as disclosed in US‘595 is not an attractive option to use for industrial scale as it requires longer reaction time, excess use of organic solvent, tedious work-up process, and results into lower yield & purity.
PCT publication number WO 2021117767 (herein after WO ‘767) discloses a process for the preparation of 2-[[3-chloro-5-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetic acid comprising reacting 3,5-dichloro-2-cyanopyridine with (3-chlorophenyl) boronic acid in presence of potassium carbonate, N,N-dimethylformamide and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) to obtain 3-chloro-5-(3-chlorophenyl) pyridine-2-carbonitrile. Resulting compound is then treated with sodium hydroxide in presence of ethanol to obtain 3-chloro-5-(3-chlorophenyl) pyridine-2-carboxylic acid. Resulting compound further reacts with glycine methyl ester hydrochloride in presence of 1-(3-dimethylaminopropyl))-3-ethylcarbodiimide hydrochloride (EDC·HCl), 1-hydroxybenzotriazole monohydrate (HOBt·H2O) and diisopropylethylamine to obtain 2-[[[3-chloro-5-(3-chlorophenyl)pyridin-2-yl]carbonyl]amino]acetic acid methyl ester. Resulting compound is hydrolysed by addition of aqueous sodium hydroxide followed by addition of hydrochloric acid to adjust the pH to 4 to obtain 2-[[3-chloro-5-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetic acid.
The major drawbacks of WO ‘767 process is use of catalyst 1-hydroxybenzotriazole (HOBT) during the coupling of 3-chloro-5-(3-chlorophenyl) pyridine-2-carboxylic acid with glycine methyl ester hydrochloride to obtain 2-[[[3-chloro-5-(3-chlorophenyl)pyridin-2-yl]carbonyl]amino]acetic acid methyl ester. Also, coupling reaction require longer reaction time. Generally, HOBT contains hydrazine moiety. Whenever, 1-hydroxybenzotriazole (HOBT) is used in any reaction, hydrazine moiety present may result into formation of potential genotoxic impurity in product, which may carry forward in 2-[[3-chloro-5-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetic acid and may requires additional purification to control the impurities which may affect low yield & purity of 2-[[3-chloro-5-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetic acid. Further WO ‘767 process of 2-[[3-chloro-5-(3-chlorophenyl)pyridine-2-carbonyl]amino]acetic acid is silent about purity. Therefore, process as disclosed in WO ‘767 is not an attractive option to use for industrial scale as it requires longer reaction time, excess use of organic solvents, tedious work-up process, and results into lower yield & purity.
The Chinese patent application number CN 105837502A (herein after CN ‘502) discloses a process for the preparation of Vadadustat comprising reacting 3,5-dichloro-2-pyridinecarboxylic acid with glycine methyl ester hydrochloride in presence of N,N-dimethylformamide, 1-hydroxybenzotriazole (HOBT) and 4-dimethylaminopyridine, followed by recrystallization in methanol to obtain 2-[[(3,5-dichloropyridin-2-yl)carbonyl]amino]acetic acid methyl ester. Resulting compound on further reaction with 3-chlorophenylboronic acid in presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) potassium carbonate and methyl tert-butyl ether results into 2-[[[3-chloro-5-(3-chlorophenyl)pyridin-2-yl]carbonyl]amino]acetic acid methyl ester. Resulting compound is then reacted with sodium methoxide in presence of methanol to obtain {[5-(3-chlorophenyl)-3-methoxypyridine-2-carbonyl]amino}acetic acid followed by reaction with hydrobromic acid solution, followed by recrystallization in mixture of ethyl acetate and n-hexane solvent to obtain Vadadustat.
The major disadvantage of CN ‘502 process is, it requires catalyst 1-hydroxybenzotriazole (HOBT) during the coupling reaction of 3,5-dichloro-2-pyridinecarboxylic acid with glycine methyl ester hydrochloride. Also, the process requires excess organic solvent. Generally, 1-hydroxybenzotriazole (HOBT) contains hydrazine moiety. Whenever, 1-hydroxybenzotriazole (HOBT) is used in any reaction, hydrazine moiety present may result into formation of potential genotoxic impurity in product, which may carry forward in final Vadadustat API and may require additional purification to control the impurities which may result into low yield & purity of final Vadadustat API. Therefore, Vadadustat process as disclosed in CN ‘502 is not an attractive option for large industrial scale as it requires longer reaction time, excess use of organic solvent, tedious work-up process, and results into lower yield & purity.
Chinese patent application number CN 111848505A (herein after as CN ‘505) discloses a process for the preparation of Vadadustat comprising reacting 5-(3-chlorophenyl)-3-methoxy-2-pyridinecarbonitrile with sodium hydroxide in presence of water followed by heating at 100°C for 4 hours, resulting mixture is then treated with hydrochloric acid to adjust pH of reaction mixture. Resulting mixture is filtered to obtain 5-(3-chlorophenyl)-3-methoxypyridine-2-carboxylic acid. Resulting compound is further treated with glycine in presence of 1,1'-carbonyldiimidazole, dimethyl sulfoxide and N,N-diisopropylethylamine to obtain {[5-(3-chlorophenyl)-3-methoxypyridine-2-carbonyl]amino}acetic acid. Resulting compound is then reacted with mixture of hydrochloric acid and acetic acid at 100°C for 24 hours to obtain Vadadustat.
The major drawbacks of CN ‘505 process is reaction completion require longer time, higher reaction temperature, use of excess volume of organic solvents. Further, during reaction many impurities are generated, which may carry forward in final Vadadustat API which may result into the lower yield and low purity. Therefore, process as disclosed in CN ‘505 is not an attractive option for large scale industrial production.
Another Chinese patent application number CN 111205222A (herein after CN ‘222) discloses a process for the preparation of Vadadustat comprising reacting 3,5-dihydroxy-2-pyridinecarboxylic acid with methanol in presence of sulfuric acid to obtain methyl 3,5-dihydroxy-2-pyridinecarboxylate. Resulting compound is reacted with N-phenyl-bis(trifluoromethanesulfonimide) in presence of diisopropylethylamine and methanol to obtain methyl 3-hydroxy-5-[[(trifluoromethyl)sulfonyl]oxy]-2-pyridinecarboxylate. Resulting compound is further reacted with 3-chlorophenylboronic acid in presence of [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), tripotassium phosphate and 1,4-dioxane at 90°C to obtain methyl 5-(3-chlorophenyl)-3-hydroxy-2-pyridinecarboxylate. Resulting compound is further reacted with glycine in presence of sodium methoxide in presence of methanol at 75°C to obtain Vadadustat.
The major drawbacks of CN ‘222 process are reaction completion require longer time, requires higher reaction temperature, use of excess volume of organic solvents. Further during reaction, many impurities are generated, which may carry forward in final Vadadustat API which may result into the lower yield and low purity. Therefore, process as disclosed in CN ‘222 is not an attractive option for large scale industrial production.
All the prior arts discussed above suffer from many disadvantages like tedious work up process, use of 1-hydroxybenzotriazole (HOBT) which may result into formation of potential genotoxic impurities, high temperature condition, require higher reaction temperature and longer time, use of excess reagent and solvents which may affect the overall yield as well as the purity of the final product. Therefore, there is an urgent need for an improved process for the preparation of Vadadustat or salt thereof having high purity and high yield which overcomes the drawbacks of the prior arts process.
The present inventors have developed an efficient process for the preparation of Vadadustat or salt thereof and its intermediates which offer advantages over the prior art processes in terms of high yield, high purity and less effluents and simple scalable procedure suitable for large scale industrial production of Vadadustat or salt thereof.
OBJECT OF THE INVENTION:
The main object of the present invention is to provide an efficient and industrially advantageous process for the preparation of Vadadustat of Formula-I or salt thereof having higher yield and purity.
Another object of the present invention is to provide an industrially advantageous process for the preparation of Vadadustat intermediates namely {[3-chloro-5-(3-chlorophenyl)pyridine-2-carbonyl]amino}acetic acid of Formula-IV, {[5-(3-chlorophenyl)-3-methoxypyridine-2-carbonyl]amino}acetic acid of Formula-V and their use for the preparation of Vadadustat or salt thereof.
One more object of the present invention is to provide Vadadustat salt of Formula-VI and process thereof.

SUMMARY OF INVENTION:
First aspect of the present invention is to provide a process for the preparation of Vadadustat of Formula-I or salt thereof,

Formula-I
comprising the steps of:
a) reacting compound of Formula-II,

Formula-II
with glycine of compound of Formula-III,

Formula-III
in presence of base to obtain compound of Formula-IV;

Formula-IV
b) converting compound of Formula-IV to compound of Formula-V,

Formula-V
by methoxy substitution reaction; and
c) converting compound of Formula-V to Vadadustat of Formula-I or salt thereof.
Second aspect of the present invention is to provide a process for the preparation of compound of Formula-IV,

Formula-IV
comprising reacting compound of Formula-II,

Formula-II
with glycine of compound of Formula-III,

Formula-III
in presence of base to obtain compound of Formula-IV.
Third aspect of the present invention is to provide a process for the preparation of compound of Formula-V,

Formula-V
comprising converting compound of Formula-IV,

Formula-IV
to compound of Formula-V by methoxy substitution reaction.
Fourth aspect of present invention is to provide a process for the preparation of Vadadustat of Formula-I or salt thereof,

Formula-I
comprising reacting compound of Formula-V,

Formula-V
with Lewis acid catalyst to obtain Vadadustat of Formula-I or salt thereof.
Fifth aspect of the present invention is to provide a Vadadustat salt of Formula-VI,

Formula-VI
“wherein, salt is selected from sodium, lithium, and calcium”
Sixth aspect of the present invention is to provide a process for the preparation of Vadadustat salt of Formula-VI,

Formula-VI
“wherein, salt is selected from sodium, lithium, and calcium”
comprising converting Vadadustat of Formula-I,

Formula-I
to Vadadustat salt of Formula-VI.
BRIEF DESCRIPTION OF DRAWINGS:
Figure 01: Illustrates the x-ray powder diffractogram (XRPD) of Vadadustat sodium salt.
Figure 02: Illustrates the x-ray powder diffractogram (XRPD) of Vadadustat lithium salt.
Figure 03: Illustrates the x-ray powder diffractogram (XRPD) of Vadadustat calcium salt.
Figure 04: Illustrates the Infrared spectroscopy (IR) of Vadadustat sodium salt.
Figure 05: Illustrates the Infrared spectroscopy (IR) of Vadadustat lithium salt.
Figure 06: Illustrates the Infrared spectroscopy (IR) of Vadadustat calcium salt.
DEFINITION:
All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25ºC and normal pressure unless otherwise designated.
All temperatures used herein are in degree Celsius unless specified otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements that may or may not be recited.
The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
The term "about", as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
DETAILED DESCRIPTION OF INVENTION:
While the following specification describes the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description and by studying the included examples.
The methods and materials of performing the present invention are described here.
The present invention provides a novel, efficient and industrially advantageous process for the preparation of Vadadustat compound of Formula-I or salt thereof.
According to first embodiment, the present invention provides a process for the preparation of Vadadustat of Formula-I or salt thereof,

Formula-I
comprising the steps of:
a) reacting compound of Formula-II,

Formula-II
with glycine of compound of Formula-III,

Formula-III
in presence of base to obtain compound of Formula-IV;

Formula-IV
b) converting compound of Formula-IV to compound of Formula-V,

Formula-V
by methoxy substitution reaction; and
c) converting compound of Formula-V to Vadadustat of Formula-I or salt thereof.
The compound of Formula-II and compound of Formula-III used as starting material for the preparation of Vadadustat of Formula-I can be prepared by processes known in the prior-art.
In the first embodiment of step a), the base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine, methylmorpholine, 1,4-diazabicyclo[2.2.2]octanetriethylenediamine (DABCO), 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), di-isopropylamine, di-butylamine, tert-butylethylamine, or mixture(s) thereof, preferably the base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
In the first embodiment of step a), the reaction of compound of Formula-II with compound of Formula-III can be carried out in presence of polar aprotic solvent selected from the group consisting of acetone, acetonitrile, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, N,N-dimethylacetamide, or mixture(s) thereof, preferably the solvent is dimethyl sulfoxide.
In the first embodiment of step a), the reaction of compound of Formula-II with compound of Formula-III can be carried out at temperature of 20°C to 100°C, preferably at temperature 40°C to 50°C.
In the first embodiment of step a), the reaction of compound of Formula-II with compound of Formula-III can be carried out for 2 hours to 24 hours, preferably for 16 hours to 18 hours.
After completion of reaction of compound Formula-II with compound of Formula-III, water followed by polar aprotic solvent can be added to the resulting reaction mixture at 20°C to 30°C. Acid can be added to resulting mixture to adjust the pH in the range of 1.5 to 2.5. Resulting mixture can be filtered to obtain crude compound of Formula II. The resulting crude can be purified using polar aprotic solvent by recrystallization method or by slurry wash to obtain pure compound Formula-IV.
The resulting compound of Formula-IV may have purity greater than 98.0 %, preferably the purity is greater than 99.0 % by HPLC (High-performance liquid chromatography).
In the first embodiment of step b), methoxy substitution reaction can be carried out using base selected from the group consisting of sodium methoxide, potassium methoxide, or mixture(s) thereof, preferably methoxy substitution reaction is carried out by sodium methoxide.
In the first embodiment of step b), methoxy substitution reaction can be carried out in presence of solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetamide, or mixture(s) thereof.
Alternatively, methoxy substitution reaction can be carried out using methanol in presence of base; wherein base is selected from group consisting of sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide or mixture(s) thereof.
In the first embodiment of step b) methoxy substitution reaction can be carried out at temperature about 40°C to about 70°C, preferably at temperature of 55°C to 65°C.
In the first embodiment of step b), methoxy substitution reaction can be carried at for 1 hour to 10 hours.
After completion of methoxy substitution reaction, resulting reaction mixture can be acidified at 0°C to 15°C to adjust the pH in the range of 1.5 to 2.5. Resulting reaction mixture can be filtered and can be washed with water to obtain crude. Resulting crude can be slurry washed with water followed by drying to obtain pure compound of Formula-V.
The resulting compound of Formula-V may have purity greater than 98.0 %, by HPLC (High-performance liquid chromatography).
The obtained compound of Formula-V can be converted to Vadadustat of Formula-I or salt thereof.
According to second embodiment, the present invention provides a process for the preparation of compound of Formula-IV,

Formula-IV
comprising reacting compound of Formula-II,

Formula-II
with glycine of compound of Formula-III,

Formula-III
in presence of base to obtain compound of Formula-IV;
In the second embodiment, the base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine, methylmorpholine, 1,4-diazabicyclo[2.2.2] octanetriethylenediamine (DABCO), 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), di-isopropylamine, di-butylamine, tert-butylethylamine, or mixture(s) thereof, preferably the base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
In the second embodiment, the reaction of compound of Formula-II with compound of Formula-III can be carried out in presence of polar aprotic solvent selected from the group consisting of acetone, acetonitrile, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, N,N-dimethylacetamide, or mixture(s) thereof, preferably the solvent is dimethyl sulfoxide.
In the second embodiment, the reaction of compound of Formula-II with compound of Formula-III can be carried out at temperature of 20°C to 100°C, preferably at temperature 40°C to 50°C.
In the second embodiment, the reaction of compound of Formula-II with compound of Formula-III can be carried out for 2 hours to 24 hours, preferably for 16 hours to 18 hours.
After completion of reaction of compound of Formula-II with compound of Formula-III, water followed by polar aprotic solvent can be added to the resulting reaction mixture at 20°C to 30°C. Acid can be added to resulting mixture to adjust the pH in the range of 1.5 to 2.5. Resulting mixture can be filtered to obtain crude. The resulting crude can be purified using polar aprotic solvent by recrystallization method or by slurry wash to obtain pure compound of Formula-IV.
The resulting compound of Formula-IV may have purity greater than 98.0 %, preferably greater than 99.0 % by HPLC (High-performance liquid chromatography).
According to third embodiment, the present invention provides a process for the preparation of compound of Formula-V,

Formula-V
comprising converting compound of Formula-IV,

Formula-IV
to compound of Formula-V by methoxy substitution reaction.
In the third embodiment, methoxy substitution reaction can be carried out using base selected from the group consisting of sodium methoxide, potassium methoxide, or mixture(s) thereof, preferably methoxy substitution reaction can be carried out by using sodium methoxide.
In the third embodiment, methoxy substitution reaction can be carried out in presence of solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetamide, or mixture(s) thereof.
Alternatively, methoxy substitution reaction can be carried out using methanol presence of base; wherein base selected from group consisting of sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide or mixture(s) thereof.
In the third embodiment, methoxy substitution reaction can be carried out at temperature about 40°C to about 70°C, preferably at temperature of 55°C to 65°C.
In the third embodiment, methoxy substitution reaction can be carried at for 1 hour to 10 hours.
After completion of methoxy substitution reaction, resulting reaction mixture can be acidified at 0°C to 15°C to adjust the pH in the range of 1.5 to 2.5. Resulting reaction mixture can be filtered and can be washed with water to obtain crude. Resulting crude can be slurry washed with water followed by drying to obtain pure compound of Formula-V.
The resulting compound of Formula-V may have purity greater than 98.0%, by HPLC (High-performance liquid chromatography).
According to fourth embodiment, the present invention provides a process for the preparation of Vadadustat of Formula-I or salt thereof,

Formula-I
comprising reacting compound of Formula-V,

Formula-V
with Lewis’s acid catalyst to obtain Vadadustat of Formula-I or salt thereof.
In the fourth embodiment, Lewis’s acid catalyst is selected from the group consisting of titanium chloride (TiCl4), Boron-trifluoride (BF3), tin chloride (SnCl4), zinc chloride (ZnCl2) and aluminium chloride (AlCl3), or mixture(s) thereof, preferably the catalyst is aluminium chloride (AlCl3).
In the fourth embodiment, reaction of compound of Formula-V with Lewis’s acid catalyst can be carried out in presence of polar aprotic solvent selected from the group consisting of acetone, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetamide, or mixture(s) thereof, preferably the solvent is dimethylacetamide.
In the fourth embodiment, reaction of compound of Formula-V with Lewis acid catalyst can be carried out at temperature about 20°C to 95°C, preferably at temperature 80°C to 90°C.
In the fourth embodiment, reaction of compound of Formula-V with Lewis acid catalyst can be carried out for 1 hour to 7 hours, preferably for 1 hour to 6 hours.
After completion, the reaction compound of Formula-V with Lewis acid catalyst, aqueous acid can be added to resulting reaction mixture at 25°C to 30°C followed by stirring of mixture for 2 hours to 3 hours. Resulting mixture can be filtered and dried to obtain Vadadustat of Formula-I. The obtained Vadadustat can be further converted to salt of Vadadustat.
The resulting Vadadustat compound of Formula-I may have purity greater than 99.0% by HPLC (High-performance liquid chromatography).
According to fifth embodiment, the present invention provides Vadadustat salt of Formula-VI,

Formula-VI
“wherein, salt is selected from sodium, lithium, and calcium”
According to sixth embodiment, present invention provides a process for the preparation of Vadadustat salt of Formula-VI,

Formula-VI
“wherein, salt is selected from sodium, lithium, and calcium”
comprising converting Vadadustat of Formula-I,

Formula-I
to Vadadustat salt of Formula-VI.
In the sixth embodiment, Vadadustat salt of Formula-VI can be prepared by reacting compound of Formula-I with base; wherein base is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, lithium hydroxide, lithium carbonate, calcium hydroxide and calcium carbonate.
In the sixth embodiment, reaction of Vadadustat of Formula-I with base can be carried out in presence of polar aprotic solvent is selected from the group consisting of acetone, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetamide, or water or mixture(s) thereof, preferably solvent is acetonitrile. The reaction can be carried out at 40°C to 80°C. After completion of reaction, resulting reaction mixture can be cooled to room temperature and can be stirred for 1 hour to 2 hours. Resulting solid can be filtered and dried to obtain Vadadustat salt of Formula-VI.
The resulting Vadadustat salt of Formula-VI may have purity greater than 99.0 %, preferably purity is 99.3 % by HPLC (High-performance liquid chromatography).
EXAMPLES:
The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.
Example 01: Preparation of compound of Formula-IV

Formula-II Formula-IV
To a stirred solution of dimethyl sulfoxide (160 ml), compound of Formula-II (80 gm) and glycine (31.9 gm) was added at 25°C to 35°C under nitrogen atmosphere. 1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU) (66.90 gm) was added to the resulting mixture at 10°C to 15°C. The resulting mixture was heated at 40°C to 45°C and stirred for 18 hours. After completion of reaction, purified water (160 ml) and methylene dichloride (80 ml) was added to the reaction mixture at 20°C to 30°C. The resulting mixture was then acidified using aqueous hydrochloric acid to adjust the pH to 2.0 at same temperature. Purified water (320 ml) was added to resulting mixture at 20°C to 30°C to precipitate a solid. The resulting solid was filtered and washed with purified water (2 x 80 mL). Methylene dichloride (400 ml) was added to resulting solid at 20°C to 30°C. The resulting mixture was stirred for 1 hour at 0°C to 5°C. Resulting mixture was filtered, washed with methylene dichloride (80 ml) and dried at 45°C to 50°C for 8 hours to obtain title compound (79.85 gm).
Yield: 86.08 % HPLC Purity: 99.11 %
Example 02: Preparation of compound of Formula-V

Formula-IV Formula-V
To a stirred solution of methanol (498 ml), sodium methoxide (82.8 gm) and dimethyl sulfoxide (1660 ml) was added at 25°C to 35ºC under nitrogen atmosphere. The resulting reaction mixture was stirred for 15 minutes at 25°C to 35°C and compound of Formula-IV (83 gm) was added at same temperature. The resulting reaction mixture was heated at 60°C to 65°C for 8 hours. The resulting reaction mixture was cooled at 0°C to 10°C. To the resulting reaction mixture 15% aqueous hydrochloric acid (350 ml) was added to adjust the pH to 2.0 of reaction mixture at 0°C to 10°C. Purified water (3220 ml) was added to the resulting mixture at 0°C to 10°C and further stirred for 6 hours at same temperature. The resulting mixture was filtered and washed with purified water (2 x 170 mL) to obtain a solid. Resulting solid was added to purified water (350 ml) and stirred for 1 hour at 25°C to 35°C. Resulting solid was then filtered, washed with purified water (2 x 150 mL) and dried for 12 hours at 50°C to 55°C to obtain title compound (59.9 gm).
Yield: 73.19 % HPLC Purity: 98.20 %
Example 03: Preparation of compound of Formula-I

Formula-V Formula-I
To a stirred solution of dimethyl acetamide (80 ml) and Compound of Formula-V (20 gm), aluminium chloride (12.48 gm) was added at 20°C to 30°C. Resulting mixture was stirred for 6 hours at 85°C to 90°C. After completion of reaction, aqueous hydrochloric acid (20 gm hydrochloric acid in 200 ml purified water) was added to mixture at 20°C to 30°C and further stirred for 3 hours at same temperature. The resulting mixture was filtered and washed with purified water (20 ml) to obtain crude. Purified water (80 ml) was added to crude and stirred for 1 hours at 25°C to 35°C. The resulting mixture was filtered, washed with purified water (20 ml) and dried at 60°C to 65°C for 12 hours to obtain title compound (15.8 gm).
Yield: 82.63 % HPLC Purity: 99.21 %
Example 04: Preparation of Vadadustat sodium

Formula-V Vadadustat sodium
To a stirred solution of dimethyl acetamide (160 ml), compound of Formula-V (40 gm) and aluminium chloride (18.29 gm) was added under nitrogen atmosphere at 25°C to 35º C. The resulting mixture was heated at 85°C to 90°C for 4 hours to 6 hours. After completion of reaction, aqueous hydrochloric acid (40 gm hydrochloric acid in 400 ml purified water) was added to resulting reaction mixture at 20°C to 30°C. Resulting mixture was extracted with Ethyl acetate (240 ml) to obtain aqueous and organic layer. Resulting aqueous layer was extracted with ethyl acetate (2 x 120 mL). All the obtained organic layers were combined and washed with brine solution. Resulting organic layer was distilled out at 45°C. Acetonitrile (800 ml) was added to the distilled mass followed by addition of aqueous sodium hydroxide (7.82 gm sodium hydroxide in 60 mL purified water) at 25°C to 30°C to obtain a mixture. Resulting mixture was stirred at 55°C to 60°C followed by cooling at 20°C to 30°C for 1 hour. The resulting mixture was filtered, washed with acetonitrile (80 ml) and dried at 50°C to 55°C for 12 hours to obtain title compound (38.73 gm).
Yield: 94.55% HPLC Purity: 99.38 %
Example 05: Preparation of Vadadustat of Formula-I
To a stirred solution of purified water (400 ml), Vadadustat sodium (38.0 gm) was added at 25°C to 35ºC. Resulting reaction mixture was acidified using conc. hydrochloric acid at 20°C to 30°C to adjust the pH to 2.0. Purified water (40 mL) was added to the resulting mixture and stirred for 1 hour at same temperature. The resulting mixture was filtered, washed with purified water (80 mL) and dried at 40°C to 45°C for 8 hours to obtain title compound (32.0 gm).
Yield: 90.0% HPLC Purity: 99.50 %
Example 06: Preparation of Vadadustat Sodium
To a stirred mixture of purified water (50 mL), sodium hydroxide (3.42 g) and acetone (250 mL), Vadadustat (25.0 g) was added at 25°C to 35°C. Resulting mixture was stirred for 15 minutes at same temperature. The resulting mixture was further heated to 50°C to 55°C and stirred for 120 minutes at the same temperature. The mixture was then cooled at 25°C to 35°C and stirred for 60 minutes. The resulting solid was filtered, washed with acetone (100 mL) and dried at 45°C to 50°C for 12 hours to obtain a tile compound (24.57 g).
Example 07: Preparation of Vadadustat Lithium
To a stirred mixture of purified water (20 mL), Lithium hydroxide (0.821 g) and acetone (100 mL), Vadadustat (10.0 g) was added at 25°C to 35°C. The resulting mixture was heated to 50°C to 55°C and stirred for 120 minutes at the same temperature. The mixture was then cooled at 25°C to 35°C and stirred for 60 minutes. The resulting solid was filtered, washed with acetone (40 mL) and dried at 45°C to 50°C for 12 hours to obtain a tile compound (8.8 g).
Example 08: Preparation of Vadadustat Calcium
To a stirred mixture of purified water (20 mL), Calcium hydroxide (2.54 g) and acetone (100 mL), Vadadustat (10.0 g) was added at 25°C to 35°C. Resulting mixture was stirred for 15 minutes at same temperature. The resulting mixture was further heated to 50°C to 55°C and stirred for 120 minutes at the same temperature. The mixture was then cooled at 25°C to 35°C and stirred for 60 minutes. The resulting solid was filtered, washed with acetone (40 mL) and dried at 45°C to 50°C for 12 hours to obtain a tile compound (10.24 g).

I / We Claim:
1. A process for the preparation of Vadadustat of Formula-I or salt thereof,

Formula-I
comprising the steps of:
a) reacting compound of Formula-II,

Formula-II
with glycine of compound of Formula-III,

Formula-III
in presence of base to obtain compound of Formula-IV;

Formula-IV
b) converting compound of Formula-IV to compound of Formula-V,

Formula-V
by methoxy substitution reaction; and
c) converting compound of Formula-V to Vadadustat of Formula-I or salt thereof.

2. The process as claimed in claim no. 01; wherein step a) is carried out using base selected from triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine, methylmorpholine, 1,4-diazabicyclo[2.2.2]octanetriethylenediamine (DABCO), 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), di-isopropylamine, di-butylamine, tert-butylethylamine in presence of polar aprotic solvent selected from acetone, acetonitrile, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, N,N-dimethylacetamide, or mixture(s) thereof .

3. The process as claimed in claim no. 01; wherein step b) methoxy substitution reaction is carried out using sodium methoxide or potassium methoxide in presence of solvent selected from methanol, ethanol, isopropanol, acetone, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetamide, or mixture(s) thereof at temperature 40°C to 70°C.

4. A process for the preparation of compound of Formula-IV,

Formula-IV
comprising reacting compound of Formula-II,

Formula-II
with glycine of compound of Formula-III,

Formula-III
in presence of base to obtain compound of Formula-IV.

Formula-IV
5. The process as claimed in claim no. 05; wherein reaction of compound of Formula II with glycine of compound of Formula-III is carried out using base selected from triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine, methylmorpholine, 1,4-diazabicyclo[2.2.2]octanetriethylenediamine (DABCO), 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), di-isopropylamine, di-butylamine, tert-butylethylamine in presence of polar aprotic solvent selected from acetone, acetonitrile, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, N,N-dimethylacetamide, or mixture(s) thereof.

6. The process as claimed in claim no. 05; wherein the reaction of compound of Formula-II with compound of Formula-III is carried out at temperature of 20°C to 100°C for 2 hours to 24 hours.

7. A process for the preparation of compound of Formula-V,

Formula-V
comprising converting compound of Formula-IV,

Formula-IV
to compound of Formula-V by methoxy substitution reaction.

8. The process as claimed in claim no. 08; wherein methoxy substitution reaction is carried out using base selected from sodium methoxide or potassium methoxide in presence of solvent selected from methanol, ethanol, isopropanol, acetone, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetamide, or mixture(s) thereof.

9. The process as claimed in claim no. 08; wherein methoxy substitution reaction is carried out at temperature about 40°C to about 70°C for 1 hour to 10 hours.

10. A process for the preparation of Vadadustat of Formula-I or salt thereof,

Formula-I
comprising reacting compound of Formula-V,

Formula-V
with Lewis acid catalyst to obtain Vadadustat of Formula-I or salt thereof.

11. The process as claimed in claim no. 11; wherein Lewis acid catalyst is selected from the group consisting of titanium chloride (TiCl4), Boron-trifluoride (BF3), tin chloride (SnCl4), zinc chloride (ZnCl2) and aluminium chloride (AlCl3).

12. The process as claimed in claim no. 11; wherein the reaction of compound of Formula-V with Lewis acid catalyst is carried out in presence of polar aprotic solvent selected from acetone, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetamide, or mixture(s) thereof.

13. The process as claimed in claim no. 11; wherein the reaction of compound of Formula-V with Lewis acid catalyst is carried out at temperature about 20°C to 95°C for 1 hours to 7 hours.

14. Vadadustat salt of Formula-VI,

Formula-VI
“wherein, salt is selected from sodium, lithium, and calcium”

15. A process for the preparation of Vadadustat salt of Formula-VI,

Formula-VI
“wherein, salt is selected from sodium, lithium, and calcium”
comprising converting Vadadustat of Formula-I,

Formula-I
to Vadadustat salt Formula-VI using base and solvent.

16. The process as claimed in claim no. 16; wherein base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, lithium hydroxide, lithium carbonate, calcium hydroxide, calcium carbonate and solvent is selected from acetone, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetamide, water or mixture(s) thereof.

Dated this 12th October 2023

Raju Sharma,
Sr. Manager-IPR,
Ami Lifesciences Pvt. Ltd
ABSTRACT
“A PROCESS FOR THE PREPARATION OF VADADUSTAT OR SALTS THEREOF”
The present invention relates to an efficient and industrially advantageous process for the preparation of Vadadustat of Formula-I or salt thereof.
The present invention also relates to a process for the preparation of Vadadustat intermediates namely {[3-chloro-5-(3-chlorophenyl)pyridine-2-carbonyl]amino}acetic acid of Formula-IV, {[5-(3-chlorophenyl)-3-methoxypyridine-2-carbonyl]amino}acetic acid of Formula-V and their use for the preparation of Vadadustat or salt thereof.
The present invention also relates to Vadadustat salt of Formula-VI, and process thereof.

Formula-I Formula-IV Formula-V

Formula-VI

Dated this 12th October 2023

Raju Sharma,
Sr. Manager-IPR,
Ami Lifesciences Pvt. Ltd

Ami Lifesciences Pvt. Ltd. Sheet 1 of 6

Figure 01

Dated this 12th October 2023

Raju Sharma,
Sr. Manager-IPR,
Ami Lifesciences Pvt. Ltd

Ami Lifesciences Pvt. Ltd. Sheet 2 of 6

Figure 02

Dated this 12th October 2023

Raju Sharma,
Sr. Manager-IPR,
Ami Lifesciences Pvt. Ltd

Ami Lifesciences Pvt. Ltd. Sheet 3 of 6

Figure 03

Dated this 12th October 2023

Raju Sharma,
Sr. Manager-IPR,
Ami Lifesciences Pvt. Ltd

Ami Lifesciences Pvt. Ltd. Sheet 4 of 6

Figure 04

Dated this 12th October 2023

Raju Sharma,
Sr. Manager-IPR,
Ami Lifesciences Pvt. Ltd

Ami Lifesciences Pvt. Ltd. Sheet 5 of 6

Figure 05

Dated this 12th October 2023

Raju Sharma,
Sr. Manager-IPR,
Ami Lifesciences Pvt. Ltd

Ami Lifesciences Pvt. Ltd. Sheet 6 of 6

Figure 06

Dated this 12th October 2023

Raju Sharma,
Sr. Manager-IPR,
Ami Lifesciences Pvt. Ltd

,CLAIMS:I / We Claim:
1. A process for the preparation of Vadadustat of Formula-I or salt thereof,

Formula-I
comprising the steps of:
a) reacting compound of Formula-II,

Formula-II
with glycine of compound of Formula-III,

Formula-III
in presence of base to obtain compound of Formula-IV;

Formula-IV
b) converting compound of Formula-IV to compound of Formula-V,

Formula-V
by methoxy substitution reaction; and
c) converting compound of Formula-V to Vadadustat of Formula-I or salt thereof.

2. The process as claimed in claim no. 01; wherein step a) is carried out using base selected from triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine, methylmorpholine, 1,4-diazabicyclo[2.2.2]octanetriethylenediamine (DABCO), 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), di-isopropylamine, di-butylamine, tert-butylethylamine in presence of polar aprotic solvent selected from acetone, acetonitrile, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, N,N-dimethylacetamide, or mixture(s) thereof .

3. The process as claimed in claim no. 01; wherein step b) methoxy substitution reaction is carried out using sodium methoxide or potassium methoxide in presence of solvent selected from methanol, ethanol, isopropanol, acetone, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetamide, or mixture(s) thereof at temperature 40°C to 70°C.

4. A process for the preparation of compound of Formula-IV,

Formula-IV
comprising reacting compound of Formula-II,

Formula-II
with glycine of compound of Formula-III,

Formula-III
in presence of base to obtain compound of Formula-IV.

Formula-IV
5. The process as claimed in claim no. 05; wherein reaction of compound of Formula II with glycine of compound of Formula-III is carried out using base selected from triethylamine, N,N-diisopropylethylamine, tripropylamine, tributylamine, methylmorpholine, 1,4-diazabicyclo[2.2.2]octanetriethylenediamine (DABCO), 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), di-isopropylamine, di-butylamine, tert-butylethylamine in presence of polar aprotic solvent selected from acetone, acetonitrile, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, N,N-dimethylacetamide, or mixture(s) thereof.

6. The process as claimed in claim no. 05; wherein the reaction of compound of Formula-II with compound of Formula-III is carried out at temperature of 20°C to 100°C for 2 hours to 24 hours.

7. A process for the preparation of compound of Formula-V,

Formula-V
comprising converting compound of Formula-IV,

Formula-IV
to compound of Formula-V by methoxy substitution reaction.

8. The process as claimed in claim no. 08; wherein methoxy substitution reaction is carried out using base selected from sodium methoxide or potassium methoxide in presence of solvent selected from methanol, ethanol, isopropanol, acetone, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetamide, or mixture(s) thereof.

9. The process as claimed in claim no. 08; wherein methoxy substitution reaction is carried out at temperature about 40°C to about 70°C for 1 hour to 10 hours.

10. A process for the preparation of Vadadustat of Formula-I or salt thereof,

Formula-I
comprising reacting compound of Formula-V,

Formula-V
with Lewis acid catalyst to obtain Vadadustat of Formula-I or salt thereof.

11. The process as claimed in claim no. 11; wherein Lewis acid catalyst is selected from the group consisting of titanium chloride (TiCl4), Boron-trifluoride (BF3), tin chloride (SnCl4), zinc chloride (ZnCl2) and aluminium chloride (AlCl3).

12. The process as claimed in claim no. 11; wherein the reaction of compound of Formula-V with Lewis acid catalyst is carried out in presence of polar aprotic solvent selected from acetone, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetamide, or mixture(s) thereof.

13. The process as claimed in claim no. 11; wherein the reaction of compound of Formula-V with Lewis acid catalyst is carried out at temperature about 20°C to 95°C for 1 hours to 7 hours.

14. Vadadustat salt of Formula-VI,

Formula-VI
“wherein, salt is selected from sodium, lithium, and calcium”

15. A process for the preparation of Vadadustat salt of Formula-VI,

Formula-VI
“wherein, salt is selected from sodium, lithium, and calcium”
comprising converting Vadadustat of Formula-I,

Formula-I
to Vadadustat salt Formula-VI using base and solvent.

16. The process as claimed in claim no. 16; wherein base is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, lithium hydroxide, lithium carbonate, calcium hydroxide, calcium carbonate and solvent is selected from acetone, acetonitrile, dichloromethane, dimethylformamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, dimethylacetamide, water or mixture(s) thereof.

Dated this 12th October 2023

Raju Sharma,
Sr. Manager-IPR,
Ami Lifesciences Pvt. Ltd