DESC:FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Roxadustat of formula I.

The present invention also relates to process for the preparation of Roxadustat Intermediates.

BACKGROUND OF THE INVENTION

Roxadustat (FG-4592) is chemically known as [(4-Hydroxy-1-methyl-7-phenoxy-iso quinoline-3-carbonyl)-amino]-acetic acid. It is an oral small molecule inhibitor of HIF prolyl hydroxylases, or HIF-PHs, is approved for treatment of anemia patients which chronic kidney disease (CDK).

Roxadustat was first disclosed in US 7323475 B2.

Several process for preparation of Roxadustat of formula I and its intermediates have been disclosed in US 7323475 B2, US 9206134 B2, WO 2014014834 A2, WO 2018072662 A1 and IN 201741002896 A.
In view of the importance of treating and preventing disorders associated with HIF, including anemia in chronic kidney disease, it would be desirable and of paramount importance to have a process for the preparation of Roxadustat of formula I, by employing inexpensive, readily available, easy to handle reagents. It would also be desirable to have a process that can be readily scaled up and which does not require a special purification step, thereby making it more suitable for industrial scale preparation.

Summary of the Invention

The present invention provides a cost effective, novel and an efficient process for the preparation of Roxadustat of formula I and Roxadustat intermediate of formula Ia with higher yields and purity.

In one aspect, the present invention provides an improved process for the preparation of Roxadustat having the structural formula I, which comprises:

i) reacting isoquinoline compound of formula II

with 1,3-dibromohydantoin in the presence of suitable solvent to give crude compound formula III;

ii) purification of crude compound of formula III in the presence suitable solvent and persulfate salt to give pure compound of formula III;
iii) reacting pure compound of formula III with methyl boric acid and palladium catalyst in the presence of suitable base and solvent to give crude compound of formula IV;

iv) purification of crude compound of formula IV in the presence of suitable solvent and metal hydroxide solution to give pure compound of formula IV;
v) coupling of pure compounds of formula IV with compound of formula V

in the presence of coupling reagent and suitable base and solvent to give benzyl derivative compound of formula Ia;

vi) deprotection of benzyl derivative compound of formula Ia with deprotecting agent in suitable solvent to give compound of formula I.

In one aspect, the present invention provides an improved process for the preparation of Roxadustat having the structural formula I, which comprises:

i) reacting isoquinoline compound of formula II

with 1,3-dibromohydantoin in the presence of suitable solvent to give crude compound formula III;

ii) purification of crude compound of formula III in the presence suitable solvent and persulfate salt to give pure compound of formula III;
iii) reacting pure compound of formula III with Grignard reagent and ferrous catalyst in the presence of suitable base and solvent to give crude compound of formula IV;

iv) purification of crude compound of formula IV in the presence of suitable solvent and metal hydroxide solution to give pure compound of formula IV;
v) coupling of pure compounds of formula IV with compound of formula V

in the presence of coupling reagent and suitable base and solvent to give benzyl derivative compound of formula Ia;

vi) deprotection of benzyl derivative compound of formula Ia with deprotecting agent in suitable solvent to give compound of formula I.

In another aspect, the present invention provides a process for the purification of compound of formula III,

which comprises:
dissolving crude compound of formula III in the presence of suitable solvent and persulfate salt to give pure compound of formula III.

In another aspect, the present invention provides an improved process for the preparation of Roxadustat intermediate having the structural formula IV,

which comprises:
reacting pure compound of formula III with methyl boric acid and Palladium catalyst in the presence of suitable solvent and base to give crude compound of formula IV.

In another aspect, the present invention provides an improved process for the preparation of Roxadustat intermediate having the structural formula IV,

which comprises:
reacting pure compound of formula III with Grignard reagent and ferrous catalyst in the presence of suitable solvent and base to give crude compound of formula IV.

In another aspect, the present invention provides a process for the purification of compound of formula IV,

which comprises:
dissolving crude compound of formula IV in the presence of suitable solvent and metal hydroxide solution to give pure compound of formula IV.

In another aspect, the present invention provides an improved process for the preparation of Roxadustat intermediate having the structural formula Ia,

which comprises:
coupling of compounds of formula IV

with compound of formula V

in the presence of coupling reagent and suitable base and solvent to give benzyl derivate compound of formula Ia.

Detailed Description of the Invention

Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:

The term "solvent” means hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; “ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dimethoxyethane, diethoxyethane, dibutoxyethane, tetrahydrofuran, 1,4-dioxane and the like; “ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; “polar-aprotic solvents” such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcohol solvents” such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, ethane-1,2-diol, propane-1,2-diol, alkyl ethers of ethylene glycol or propylene glycol selected from but not limited to ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol mono-n-butyl ether and the like; “polar solvents” such as water; formic acid, acetic acid, 2-Methoxyethanol or mixtures thereof.

The term "Base” means alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; “alkali metal amides” such as sodium amide, potassium amide, lithium amide and the like; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; ammonia; “organic bases” like “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; Potassium tri phosphate; dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, triisopropyl amine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine, imidazole, N-methylimidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), N-methylmorpholine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine and the like; “organolithium bases” such as methyl lithium, n-butyl lithium, lithium diisopropylamide and the like; “organosilicon bases” such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide and the like or their mixtures. Preferably Potassium tri phosphate.

Accordingly, the present invention provides an improved process for the preparation of Roxadustat having the structural formula I.

The main embodiment of the present invention provides an improved process for the preparation of Roxadustat having the structural formula as shown in the Scheme-I given below.

Scheme-I
In stage-I), reacting isoquinoline compound of formula II with 1,3-Dibromo-5,5-Dimethylhydantoin in the presence of suitable solvent to give compound formula III.

Solvent used in the reaction is selected from the group consisting of hydrocarbon solvents; nitrile solvents; ether solvents; ester solvents; polar-aprotic solvents; chloro solvents; ketone solvents; nitrile solvents; alcohol solvents; polar solvents. Preferably acetonitrile and dimethylformamide.

The reaction temperature may range from 20 °C to 40 °C and preferably at a temperature in the range from 25 °C to 30 °C. The duration of the reaction may range from 2 to 4 hours, preferably for a period of 3 hours.

In Stage-II), purification of crude compound of formula III in the presence of Solvent and persulfate salt to give pure compound of formula III.

Solvent used in the reaction is selected from the group consisting of hydrocarbon solvents; nitrile solvents; ether solvents; ester solvents; polar-aprotic solvents; chloro solvents; ketone solvents; nitrile solvents; alcohol solvents; polar solvents. Preferably Dichloromethane.

Persulfate salts used in the reaction is selected from the group consisting of Sodium peroxomonosulfate (Na2SO5) Potassium peroxymonosulfate (KHSO5), Sodium persulfate (sodium peroxydisulfate) (Na2S2O8) Ammonium persulfate (ammonium peroxydisulfate) ((NH4)2S2O8), Potassium persulfate (potassium peroxydisulfate) (K2S2O8) and sodium thiosulfate (Na2S2O3). Preferably sodium thiosulfate (Na2S2O3).

The reaction temperature may range from 20 °C to 40 °C and preferably at a temperature in the range from 25 °C to 30 °C. The duration of the reaction may range from 20 to 45 minutes. Preferably for a period of 30 minutes.

In stage-III), reacting compound of formula III with methyl boric acid and Palladium catalyst in the presence of base and solvent to give crude compound of formula IV.

Solvent used in the reaction is selected from the group consisting of hydrocarbon solvents; nitrile solvents; ether solvents; ester solvents; polar-aprotic solvents; chloro solvents; ketone solvents; nitrile solvents; alcohol solvents or polar solvents. Preferably 2-Methoxyethanol.
Base used in the reaction is selected from the group consisting of inorganic bases, organic base; alkali metal bicarbonates; alkali metal hydroxides; alkali metal hydrides; alkali metal amides; alkali metal and alkali earth metal salts of acetic acid; organolithium bases or organosilicon bases. Preferably Potassium tri phosphate.

Palladium catalyst used in the reaction is selected from the group consisting of Tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), Bis(triphenylphosphine) palladium(II) dichloride (PdCl2(PPh3)2), Palladium(II) acetate (Pd(OAc)2), Tris(dibenzylideneacetone)dipalladium(0)-chloroform (Pd2(dba)3•CHCl3) or Tetrakis(triphenylphosphine)-palladium. Preferably Tetrakis(triphenylphosphine) palladium.

The reaction temperature may range from 80 °C to 110 °C and preferably at a temperature in the range from 90 to 105 °C, more preferably 95°C to 100°C. The duration of the reaction may range from 10 to 16 hours, preferably for a period of 12 to 14 hours.

In stage-IIIa), reacting compound of formula III with grignard reagent and ferrous catalyst in the presence of base and solvent to give crude compound of formula IV.

Solvent used in the reaction is selected from the group consisting of hydrocarbon solvents; nitrile solvents; ether solvents; ester solvents; polar-aprotic solvents; chloro solvents; ketone solvents; nitrile solvents; alcohol solvents or polar solvents. Preferably Tetrahydrofuran.

Base used in the reaction is selected from the group consisting of inorganic bases, organic base; alkali metal bicarbonates; alkali metal hydroxides; alkali metal hydrides; alkali metal amides; alkali metal and alkali earth metal salts of acetic acid; organolithium bases or organosilicon bases. Preferably N-Methyl-2-pyrrolidone.

Ferrous Catalyst used in the reaction is Fe(acac)3 (Tris(acetylacetonato)iron(III)).

The reaction temperature may range from 0 to 20 °C and preferably at a temperature in the range from 10 °C to 15 °C, more preferably 5 °C to 10 °C. The duration of the reaction may range from 6 to 10 hours, preferably for a period of 8 hours.

In stage-IV), purification of crude compound of formula IV in the presence of suitable solvent and Metal hydroxide solution to give pure compound of formula IV.

Metal hydroxide solution used in the reaction is selected from the group consisting of Sodium hydroxide, Potassium hydroxide and Lithium hydroxide. Preferably Sodium hydroxide solution.

Solvent used in the reaction is selected from the group consisting of hydrocarbon solvents; nitrile solvents; ether solvents; ester solvents; polar-aprotic solvents; chloro solvents; ketone solvents; nitrile solvents; alcohol solvents; polar solvents. Preferably Dimethylsulfoxide.

The reaction temperature may range from 20 °C to 40 °C and preferably at a temperature in the range from 25 °C to 35 °C, more preferably 25 °C to 30 °C. The duration of the reaction may range from 20 to 40 minutes, preferably for a period of 30 minutes.

In stage-V), coupling the compound of formula IV with compound of formula V in the presence of coupling reagents, suitable solvent and suitable base to give benzyl derivative compound of formula Ia.

Solvent used in the reaction is selected from the group consisting of hydrocarbon solvents; nitrile solvents; ether solvents; ester solvents; polar-aprotic solvents; chloro solvents; ketone solvents; nitrile solvents; alcohol solvents or polar solvents. Preferably dichloromethane and methanol.

Base used in the reaction is selected from the group consisting of inorganic bases, organic base; alkali metal bicarbonates; alkali metal hydroxides; alkali metal hydrides; alkali metal amides; alkali metal and alkali earth metal salts of acetic acid; organolithium bases or organosilicon bases. Preferably N,N-diisopropylethylamine.

Suitable coupling reagents used in the reaction is selected from the group consisting of N,N'-Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide (DIC), 1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloric acid (EDC HCl), (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) (DEPBT), ((1H-Benzo[d][1,2,3]triazol-1-yl)oxy)tris(dimethylamino)phosphonium hexafluorophosphate(V) (BOP), (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), Bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), [Ethyl cyano(hydroxyimino)acetato-O2]tri-1-Pyrrolidinyl phosphonium hexafluorophosphate (PyOxim), Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (DMTMM), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 3-[Bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexafluorophosphate (HBTU), O-(1H-6-Chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), 1-Hydroxy-7-azabenzotriazole (HOAt), Hydroxybenzotriazole (HOBt), 2-(3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), 1,1'-Thiocarbonyldiimidazole (TCDI), 1,1'-Carbonyldiimidazole (CDI), Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH), O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), N,N,N',N'-Tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)uronium tetrafluoroborate (TDBTU), N,N,N',N'-Tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate, O-[N-Succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), 2-(5-Norborene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU), O-(2-Oxo-1(2H)pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU), Diethyl 4-oxo-1,2,3-benzotriazin-3(4H)-yl phosphate (DEPBT). Preferably PyBOP.

The reaction temperature may range from 20 °C to 40 °C and preferably at a temperature in the range from 25 °C to 35 °C, more preferably 25 °C to 30 °C. The duration of the reaction may range from 2 to 4 hours, preferably for a period of 3 hours.

In stage-VI), deprotection of benzyl derivative compound of formula Ia in the presence of reducing agent and solvent to give Roxadustat compound of formula I.

Solvent used in the reaction is selected from the group consisting of hydrocarbon solvents; nitrile solvents; ether solvents; ester solvents; polar-aprotic solvents; chloro solvents; ketone solvents; nitrile solvents; alcohol solvents or polar solvents. Preferably Methanol and Ethyl acetate.

The reaction temperature may range from 20 °C to 40 °C and preferably at a temperature in the range from 25°C to 30 °C. The duration of the reaction may range from 1 to 3 hours, preferably for a period of 2 hours.

Reducing agents used in the reaction is selected from the group consisting of Ra/Ni, H2/Ni, Pd/C. Preferably Pd/C.

Advantages:
1. Enhanced the reaction conversion using acetonitrile and DMF solvent system at stage 1 and adopted purification process to eliminate the excess bromine.
2. At stage 2, acid-base purification process was adopted to enrich the purity of desired intermediate.
3. To avoid the formation of highly viscous material at stage 3, adopted coupling reaction of acid intermediate with glycine benzyl ester instead of glycine methyl ester.
4. Roxadustat obtained via a simple de-benzylation protocol with enhanced purity and yield, by avoiding the tedious work-up process or column purification.

Example 1: Process for the preparation of Roxadustat

Stage-I: Process for the preparation of Methyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate

To a four-necked round-bottom flask (10 Litre) equipped with a mechanical stirrer and a thermometer, was charged Acetonitrile (3.0 Liter, 10 volume), Dimethyl formamide (600 mL, 2 Volume), Isoquinoline methyl ester (300 grams, 1.0 eq) and Dibromo hydantoin (17.4 grams, 0.6 eq). The resulted reaction mixture was stirred at 25-30 °C for 3 hours. The reaction progress was monitored by using TLC, after completion of reaction, purified water (10 volume) was added in to the reaction mixture over a period of 30 minutes and the resulted reaction mixture was stirred for 1 hour at 25-30 °C to obtain the solid compound. The solid was filtered and washed with purified water (0.5 volume) and suck dried for 30 minutes, and then the solid compound dried under vacuum for 4-5 hours at 50-55 °C until the constant weight obtained. The obtained solid compound was purified by dissolving in dichloromethane (10 volumes) followed by aqueous 10% sodium thiosulfate (Na2S2O3) (10 volumes) & water (5 volumes) washes. Dry weight: 329 grams & Yield: 86%.

Stage-II: Purification of Methyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate

To a four-necked round-bottom flask (5 Litre) equipped with a mechanical stirrer and a thermometer, was charged Methyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (329 grams, 1.0 volume, obtained from stage-I), dichloromethane (1.97 Litre, 6.0 volume), sodium thiosulphate solution (1.97 Litre, 6.0 volume) and stirred for 30 minutes. Separate the dichloromethane layer and filtered through celite bed. The obtained solid filtered and washed with 100 ml of dichloromethane. Distilled off the solvent under vacuum at below 40 °C. Weight: 263.0 grams.

Stage-III: Process for the preparation of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid

Under N2 atmosphere, to a four-necked round-bottom flask (5 Litre) equipped with a mechanical stirrer and a thermometer, was charged 2-methoxy ethanol (1.8 Litre, 18 volume) methyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (100 grams, 1.0 eq, obtained from stage-II), methyl boric acid (80.2 grams, 5.0 eq), potassium tri phosphate (325grams of 5.7 eq), purified water (400 mL, 4 volume) and triphosphene tetrakis palladium (0.04 eq). The resulted reaction mixture was stirred at 95-100 °C for 12-14 hours. The progress of the reaction was monitored by TLC and after completion of reaction the reaction temperature brought to 25-30 °C. Then 10 grams of activated carbon added into the above RBF and stirred for 30 minutes, and then the reaction mixture was filtered through celite bed and was washed with combined solution of purified water (200 mL, 2 volume) and 2-methoxy ethanol (200 mL, 2 volume). Then transferred the filtered ML`s into another cleaned 5.0 Litre round bottom flask and charged purified water (900 mL) at 25-30 °C. Then the reaction mixture pH adjusted to 2-3 using concentrate HCl solution and allowed to stir for 15 minutes. Then 1.4 Litre of purified water added through addition funnel over a period of 30 minutes. After completion of water addition, the resulted reaction mixture was stirred for 1 hour at 25-30 °C to obtain solid compound. The solid filtered and washed with 500 mL of purified water and suck dried for 30 minutes, and then the solid compound dried under vacuum at 50-55 °C for 8 hours until the constant weight obtained. Dry weight: 68 grams. Yield: 91%.

Stage-IIIa: Process for the Preparation of Methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate

Under N2 atmosphere, to a four-necked round-bottom flask equipped with a mechanical stirrer and a thermometer, was charged Methyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (2 grams, 1.0 eq, obtained from stage-II), n-methyl pyrrolidine (24 mL, 12 volume) were charged at 25-30 °C. Tris(acetylacetonato)iron(III) (Fe(acac)3) 1.26 grams (0.67 eq), THF (8 mL) (4 volume) were charged to the reaction mass at 25-30 °C and stirred for 15 minutes. The reaction mass was cooled to 5-10 °C, slowly added Methyl magnesium chloride (2.07 grams) (5.2 eq) to reaction mass at 5-10 °C for 2 hours. Stirred the reaction mass for 8 hours at 5-10 °C. After reaction complies cooled the reaction mass to -2 °C and slowly added 4 mL of purified water at -2 °C. Then slowly charged 20% aqueous HCl to the reaction mass at -2 °C followed by reaction mass temperature raised to 25-30 °C. Then 20 mL of toluene was added to the reaction mass and stirred for 15 minutes. Separated the organic layer from aqueous layer. Aqueous layer extracted with 2x10 mL of toluene. Combined organic layer washed with 10 mL of 20% aqueous HCl followed by 20 mL of purified water. Concentrated the organic layer under vacuum at 55 °C. To the obtained crude 4 mL of Toluene was added and heated to 60 °C for 10-15 min. Cooled the reaction mass to 25 - 30 °C and charged 4 mL of acetone, followed by adjusted the reaction mass pH to 2-3 using IPA. HCl. Cooled the reaction mass to 0-5 °C. Stirred for 1 hours. Filtered the solid and washed the solid with 4 mL of acetone. Dried the compound at 50-55 °C for 4 hours to give the title compound.

Stage-IV: Purification of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid

To a four-necked round-bottom flask (2 Litre) equipped with a mechanical stirrer and a thermometer, was charged DMSO (81.6 mL), 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid (68 grams) obtained from stage-III. Then the reaction mass pH adjusted to 10-11 with 10% sodium hydroxide solution at 25-30 °C to obtain clear solution. Then 6.8 grams of activated carbon added to the above reaction mixture and stirred for 30 minutes. The above obtained reaction mixture was passed through celite bed to remove the unwanted salts. The celite bed was washed with 140 mL of purified water. Then the ML`s charged into a clean RBF and adjusted pH 2-3 with concentrate HCl at 25-30 °C to obtain solid compound. Then 1.6 Litre of purified water added and stirred the reaction mixture for 1 hour at 25-30 °C. The obtained solid filtered and washed with 200 mL of purified water. Dried the compound under vacuum for 12-15 hours at 50 -55 °C until constant weight obtained. Dry weight: 49 grams, Yield%: 72.

Stage-V: Process for the preparation of Benzyl (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl) glycinate

To a four-necked round-bottom flask equipped with a mechanical stirrer and a thermometer, was charged Dichloromethane (50 mL, 5 volume), 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid (5 grams, 1.0 eq) obtained from stage-IV) at 25-30 °C. Then the reaction mixture was cooled to 0-5 °C. Then under N2 atmosphere, Glycine benzyl ester hydrochloride (4.54 grams, 1.0 eq) and PyBOP (10.58 grams, 1.2 eq) was charged into above RBF at 0-5 °C. Then 8.8 mL of DIPEA added into above RBF through addition funnel over a period of 30 minutes and resulted into a clear solution. After completion of DIPEA addition the temperature was raised to 25-30 °C and stirred for 3 hours. The progress of the reaction was monitored by TLC and after completion of reaction 25 mL of purified water was added into the reaction mixture at 25-30 °C and stirred for 15 minutes. The resulted organic layer separated and washed with 25 mL of 2N HCl solution followed by 5% sodium bicarbonate solution and finally washed with 25mL of brine solution. The organic layer was concentrated under reduced pressure at below 40 °C followed by co-distilled the residue with 5 mL of methanol. To the obtained crude compound 15 mL of methanol was added to obtain solid compound. The resulted slurry stirred for 30 minutes at 25-30 °C. Then the solid was filtered and washed with 5 mL of methanol and suck dried. The obtained solid was dried under hot air oven for 5-6 hours at 50-55 °C until the constant weight obtained. Dry weight:4.3 grams. Yield%: 57.9.

Stage-VI: Process for the preparation of Roxadustat

To a four-necked round-bottom flask equipped with a mechanical stirrer and a thermometer, was charged methanol (10 mL, 5 volume), ethyl acetate (20mL, 10 volume), benzyl (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)glycinate (2.0 grams) obtained from stage-V)and 0.4 grams of 10% Pd-C at 25-30 °C. Then the resulted reaction mixture stirred for 2 hours under hydrogen pressure at 25-30 °C. Progress of the reaction monitored by TLC and after completion of reaction, 30mL of ethyl acetate added to the reaction mass. Then the reaction mixture was filtered over celite bed and washed the bed with 10 mL ethyl acetate. The obtained ML’s concentrated under reduced pressure at below 45 °C followed by co-distilled with 4 mL of methanol. The obtained crude compound cooled 25-30 °C followed by 10 mL of methanol was charged. The obtained reaction mixture was stirred for 30 minutes to obtain solid compound. The solid filtered and washed the wet cake with 5vmL of methanol and suck dried. The solid compound was dried under vacuum at 50-55 °C for 2 hours until constant weight obtained. Dry wt.1.5 grams, Yield%: 94.3. 1H NMR (400 MHz, DMSO-d6): 13.32 (s, 1H), 12.81 (s, 1H), 9.13 (t, J = 6.0 Hz, 1H), 8.32 (d, J = 9.0 Hz, 1H), 7.63 (s, 1H), 7.62-7.46 (m, 3H), 7.28-7.17 (m, 3H), 4.06 (t, J = 6, 2 H), 2.71 (s, 3H). m/z (ESI)- 353.20 [M+H]
,CLAIMS:We Claims:

1. A process for the preparation of Roxadustat having the structural Formula I,

which comprises:
i) reacting isoquinoline compound of Formula II

with 1,3-dibromohydantoin in the presence of suitable solvent to give crude compound Formula III;

ii) purification of crude compound of Formula III in the presence suitable solvent and persulfate salt to give pure compound of Formula III;
iii) reacting pure compound of Formula III with methyl boric acid and palladium catalyst in the presence of suitable base and solvent to give crude compound of Formula IV;

iv) purification of crude compound of Formula IV in the presence of suitable solvent and metal hydroxide solution to give pure compound of Formula IV;
v) coupling of pure compounds of Formula IV with compound of formula V;

in the presence of coupling reagent and suitable base and solvent to give benzyl derivative compound of Formula Ia;

vi) deprotection of benzyl derivative compound of Formula Ia with deprotecting agent in suitable solvent to give compound of Formula I.

2. A process for the preparation of Roxadustat having the structural formula I,

which comprises:
i) reacting isoquinoline compound of Formula II;

with 1,3-dibromohydantoin in the presence of suitable solvent to give crude compound Formula III;

ii) purification of crude compound of Formula III in the presence suitable solvent and persulfate salt to give pure compound of Formula III;
iii) reacting pure compound of Formula III with grignard reagent and ferrous catalyst in the presence of suitable base and solvent to give crude compound of Formula IV;

iv) purification of crude compound of Formula IV in the presence of suitable solvent and metal hydroxide solution to give pure compound of Formula IV;
v) coupling of pure compounds of Formula IV with compound of Formula V;

in the presence of coupling reagent and suitable base and solvent to give benzyl derivative compound of Formula Ia;

vi) deprotection of benzyl derivative compound of Formula Ia with deprotecting agent in suitable solvent to give compound of Formula I.

3. A process for the purification of compound of Formula III,

which comprises:
dissolving crude compound of Formula III in suitable solvent and persulfate salt to give pure compound of Formula III.

4. A process for the preparation of Roxadustat intermediate having the structural Formula IV,

which comprises:
reacting pure compounds of Formula III;

with methyl boric acid and palladium catalyst in the presence suitable base and solvent to give crude compound of Formula IV.

5. A process for the preparation of Roxadustat intermediate having the structural Formula IV,

which comprises:
reacting pure compounds of Formula III;

with grignard reagent and ferrous catalyst in the presence suitable base and solvent to give crude compound of Formula IV.

6. A process for the purification of compound of Formula IV,

which comprises:
dissolving crude compound of Formula IV in suitable solvent and metal hydroxide solution to give pure compound of Formula IV.

7. A process for the preparation of Roxadustat intermediate having the structural Formula Ia,

which comprises:
coupling the compounds of Formula IV;

with compound of Formula V;

in the presence of coupling reagent and suitable base and solvent to give benzyl derivate compound of Formula Ia.

8. A compound of Formula Ia.