DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

PROCESS FOR THE PREPARATION OF ROXADUSTAT AND ITS INTERMEDIATES

INTRODUCTION

The present invention provides the process for the preparation of Roxadustat and its intermediates.

BACKGROUND

Roxadustat (I) or 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, in Phase 3 clinical development for treating and preventing disorders associated with HIF, including anemia in chronic kidney disease, or CKD, ischemia, and hypoxia.
(I)
The US patent number 7323475 B2, Example D-81, by referring the examples D-7e,D-78a, D-78b, D78-c and D-78 (d), discloses a process for preparation of roxadustat as given below in scheme-I.

SCHEME-I

The PCT publication WO2014014834, example-3, describes a process for preparation of Roxadustat as given below in scheme-II.

SCHEME-II
The US patent number 9206134 B2, example-1, discloses a process for preparation of Roxadustat as given below in scheme-III.

SCHEME-III
The present invention provides an improved and commercially viable process for the preparation of roxadustat and intermediates thereof.
SUMMARY
An embodiment of the present invention provides an improved process for the preparation of Roxadustat (I) and its intermediates.

DETAILED DESCRIPTION
An embodiment of the present invention provides an improved process for the preparation of Roxadustat (I) comprising;
a) 4-O-alkyl protection of compound of formula (II) to obtain the compound of formula (III)

b) N-oxide formation of compound of formula (III) to obtain the compound of formula (IV)

c) De-esterification of compound of formula (IV) to obtain the compound of formula (V)

d) 1-methylation of compound of formula (V) to obtain the compound of formula (VI)

e) Esterification of compound of formula (VI) to obtain the compound of formula (VII)

f) 4-O-deprotection of compound of formula (VII) to obtain the compound of formula (VIII)

g) Amidation of compound of formula (VIII) to obtain roxadustat (I)

R= Alkyl group which comprises linear, branched or cyclo alkyl group such as methyl, ethyl, butyl, isobutyl, cyclohexane and the like.

In step a), the O-alkyl protection of compound of formula (II) is carried in the presence of triarylphosphine such as triphenyl phosphine and the like and azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate (DIAD) and the like.
In step b), the N-oxide formation of compound of formula (III) is carried out using oxidizing agents in organic solvent. The oxidizing agent comprises per acid such as m-chloro perbenzoic acid (m-CPBA) and the like. The organic solvent comprises hydrocarbon such as hexane, toluene and the like, halogenated hydrocarbon such as dichloromethane, trichloro methane and the like.
In step c), the de-esterification of compound of formula (IV) is carried out using alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal silanolate such as sodium or potassium Trimethylsilanolate in organic solvent. The organic solvent is selected from alcohol such as methanol, ethanol and the like, ether such as diethyl ether, tetrahydro furan and the like.
In step d), introduction of methyl group at 1-position of compound of formula (V) is carried by using alkylating agent in organic solvent. The alkylating agent is selected from Grignard reagent such as CH3MgBr. The organic solvent is selected from ether such as tetrahydro furan.
In step e), esterification of compound of formula (VI) is carried out by converting it into corresponding acid chloride using thionyl chloride followed by reaction with alkyl alcohol.
In step f), the compound of formula (VII) is treated with deprotecting agent to obtain 4-hydroxy compound of formula (VII). The deprotecting agent is selected from boron trihalides such as boron trichloride, boron tribromide and the like. The solvent used for deprotection selected from hydrocarbon such as hexane, toluene and the like; halogenated hydrocarbon such as dichloromethane, trichloromethane and the like; alcohol such as methanol, ethanol, propanol and the like; ether such as diethyl ether, isopropyl ether and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like.
In step g), the preparation of roxadustat involves the coupling of compound of formula (VIII) with glycine can be proceeded via conventional peptide coupling procedure known in the art. The coupling s carried out in the presence of base in solvent. The base is selected from hydroxides such as sodium or potassium hydroxide, alkoxides such as sodium or potassium methoxide. The solvent is selected from alcohol such as methanol, ethanol and the like.
The compound of formula (II) is prepared from the known methods available in the literatures such as US patent 7323475.
In each stage the compounds are isolated from the reaction mixture may involve methods including removal of solvent, cooling, crash cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, fast solvent evaporation, rotational drying, spray drying, thin-film drying, agitated thin film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, rotary vacuum paddle dryer, adding anti-solvent or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
The present invention also covers in-situ preparation of roxadustat from the compound of formula (II).
The present invention also provides a process for preparation of pharmaceutically acceptable salt of roxadustat wherein the said salt are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, malate, oxalate, citrate, fumarate, succinate, tosylate and the like.

Example-1: Preparation of methyl 4-ethoxy-7-phenoxyisoquinoline-3-carboxylate
Methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (12 g) was added to the RBF containing N,-N-dimethyl formamide (60 ml), Triphenyl phosphine (31.97 g) and diazopropyl azo dicarboxylate (24.63 g) at 28°C. Ethanol (24 ml) was added to the reaction mass in the RBF at room temperature and stirred for 60 minutes at 45°C. The reaction mass was poured into water and extracted with ethyl acetate (240 ml). The ethyl acetate layer was washed with water (140 ml) followed by brine solution (120 ml). The ethyl acetate layer dried over sodium sulfate and distilled under vacuum at 45°C to obtain the crude product. The crude product was purified by silica gel column (60/120 mesh) with n-hexane and 5-20% ethyl acetate/n-hexane then distilled off the solvent under vacuum at 45°C to obtain the pure product in the form of syrup. Yield: 10 gm. Purity: 95.48% (by HPLC); Mass [m/z]: 324.2 [M+H]+.

Example-2: Preparation of 4-ethoxy-3-(methoxycarbonyl)-7-phenoxyisoquinoline 2-oxide
m-chloroperbenzoic acid (7.2 g) in dichloromethane (56 ml) was added to a solution of methyl 4-ethoxy-7-phenoxyisoquinoline-3-carboxylate (9 g) in dichloromethane (90 ml) at 28°C. The reaction mass was stirred for 15 hours at 28°C then poured into water (90 ml) and the layers were separated. The organic layer was washed with brine solution (90 ml), dried over sodium sulfate and distilled off under vacuum at 40°C to obtain the crude product. The crude product was purified by silica gel column (60/120 mesh) with dichloromethane and 5-30% ethyl acetate/dichloromethane then distilled off the solvent under vacuum at 28°C to obtain the pure product in the form of syrup. Yield: 6.8 gm. Purity: 98.7% (by HPLC); Mass [m/z]: 340.1 [M+H]+.

Example-3: Preparation of 3-carboxy-4-ethoxy-7-phenoxyisoquinoline 2-oxide
Potassium trimethyl silonate (5.6 g) was added to a solution of 4-ethoxy-3-(methoxycarbonyl)-7-phenoxyisoquinoline 2-oxide (6 g) in tetrahydrofuran (180 ml) at 28°C. The reaction mass was stirred for 15 hours at 28°C then distilled under vacuum at 28°C to obtain the solid. Water (80 ml) was added to the solid followed by washed with ethyl acetate (160 ml) then the layers were separated. The pH of the aqueous layer was adjusted to 3-4 with 6N HCl. The solid was filtered, washed with water (40 ml) and n-hexane (40 ml) and dried to obtain the product. Yield: 4.2 gm. Purity: 95.69% (by HPLC); Mass [m/z]: 326.1 [M+H]+.

Example-4: Preparation of 4-ethoxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid
Methyl magnesium bromide (5.8 g) was added to the solution of 3-carboxy-4-ethoxy-7-phenoxyisoquinoline 2-oxide (4 g) in THF (80 ml) at 0-5°C. The reaction mass was stirred for 40 minutes at 25°C then poured into saturated ammonium chloride solution (60 ml). Ethyl acetate (80 ml) was added to the reaction mass and the layers were separated. The organic layer was washed with water (28 ml) and brine solution (28 ml) then dried over sodium sulfate followed by distilled under vacuum at 25°C to obtain the crude compound. The crude compound was purified by silica gel column (60/120 mesh) with dichloromethane and 2-5% methanol/dichloromethane then distilled off the solvent under vacuum at 25°C to obtain the pure product in the form of syrup. Yield: 1.5 gm. Purity: 82.9% (by HPLC); Mass [m/z]: 324.1 [M+H]+.

Example-5: Preparation of methyl 4-ethoxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate
4-ethoxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid (1.4 g) was added to thionyl chloride (7 ml) at 28°C. The reaction mass was stirred for 2 hours at 75°C.Methanol (14 ml) was added to the reaction mass at 28°C. Saturated sodium bicarbonate solution (28 ml) was added and extracted with ethyl acetate (56 ml). The organic layer was washed with water (28 ml) followed by brine solution (28 ml), dried over sodium sulfate then distilled under vacuum at 28°C to obtain the crude compound. The crude compound was purified by silica gel column (60/120 mesh) with n-hexane and 5-20% ethyl acetate/n-hexane then distilled off the solvent under vacuum at 28°C to obtain the pure product. Yield: 0.87 gm. Purity: 93.86% (by HPLC); Mass [m/z]: 338.1[M+H]+.

Example-6: Preparation of methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate
To the solution of methyl 4-ethoxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (0.7 g) in dichloromethane (7 ml) was added boron tribromide (1 ml) in dichloromethane at 0°C and stirred for 2 hours. The reaction mass was poured into sodium bicarbonate solution (14 ml) then the layers were separated. The organic layer was washed with water (14 ml) followed by brine solution (14 ml), dried over sodium sulfate then distilled under vacuum at 28°C to obtain the crude compound. The crude compound was purified by silica gel column (60/120 mesh) with n-hexane and 5-15% ethyl acetate/n-hexane then distilled off the solvent under vacuum at 28°C to obtain the pure product. Yield: 0.38 gm. Purity: 94.6% (by HPLC); Mass [m/z]: 310.1[M+H]+.

Example-7: Preparation of (4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)glycine (Roxadustat)
Glycine (0.25 g) and sodium methoxide (0.122 g) were added to the solution of methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylate (0.35 g) in methanol (5.25 ml) at 28°C. The reaction mass was stirred for 41 hours at 100-120°C then it was cooled to 28°C and filtered to obtain the solid. The solid was washed with methanol (1.75 ml) followed by dissolved in water (5.25 ml) then washed with ethyl acetate (40 ml). The aqueous layer was separated, cooled to 10°C then pH adjusted to 2-3 with acetic acid (0.21 ml) to obtain the product in the solid form. The product was filtered, washed with water (5.25 ml) and dried at 45-50°C for 6-8 hours. Yield: 0.21 gm. Purity: 97.15% (by HPLC); Mass [m/z]: 353.2[M+H]+.
,CLAIMS:WE CLAIM:

1) An improved process for the preparation of Roxadustat (I) comprising;
a) 4-O-alkyl protection of compound of formula (II) to obtain the compound of formula (III),

b) N-oxide formation of compound of formula (III) to obtain the compound of formula (IV),

c) De-esterification of compound of formula (IV) to obtain the compound of formula (V),

d) 1-methylation of compound of formula (V) to obtain the compound of formula (VI),

e) Esterification of compound of formula (VI) to obtain the compound of formula (VII),

f) 4-O-deprotection of compound of formula (VII) to obtain the compound of formula (VIII),

g) Amidation of compound of formula (VIII) to obtain Roxadustat (I),

R= Alkyl group which comprises linear, branched or cyclo alkyl group such as methyl, ethyl, butyl, isobutyl, cyclohexane.

2) The process as claimed in claim 1, wherein step-a) is carried out in presence of triphenyl phosphine, diethyl azodicarboxylate, diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate (DIAD) or mixtures thereof.
3) The process as claimed in claim 1, wherein step-b) is carried out in presence of oxidizing agent.
4) The process as claimed in claim 3, wherein oxidizing agent is selected from m-chloro perbenzoic acid (m-CPBA).
5) The process as claimed in claim 1, wherein step-f) is treated with deprotecting agent is selected from boron trihalides.
6) The process as claimed in claim 5, wherein boron trihalides is selected from boron trichloride, boron tribromide or mixtures thereof.