CROSS-REFERENCE TO REUATED APPUICATIONS

This application claims the benefit of Indian provisional patent applications IN202041017057, filed on April 21, 2020, and IN202041050043, filed on November 17, 2020, the contents of which are expressly incorporated by reference herein.

FIEUD

The present disclosure relates to an improved process for the preparation of Roxadustat by employing novel intermediates.

BACKGROUND

Roxadustat is chemically known as [(4-hydroxy-l-methyl-7-phenoxy-isoquinoline-3- carbonyl)-amino] -acetic acid and is represented by Formula I. Roxadustat is used for the treatment of anemia in patients with chronic kidney disease (CKD). It is in Phase III clinical development in the US.

Formula I

Roxadustat was first disclosed in US patent 7323475B2.

US 9340511 B2; WO 2018072662; EP 3305769 B1 and CN 104892509 disclose processes for the preparation of Roxadustat.

However, there is a need for an improved process. Disclosed herein is an industrially viable process for the preparation of Roxadustat by employing novel intermediates. The process is commercially feasible and economical and does not involve column chromatography. SUMMARY

The present disclosure provides an improved process for the preparation of Roxadustat by employing novel intermediates.

In one aspect, the present disclosure provides a process for the preparation of Roxadustat, the process comprising: a) reacting chloromethyl ester with tosyl morpholine to obtain N-alkyl tosyl morpholine; chloromethyl ester

N-alkyl tosyl morpholine or morpholine ester b) cyclizing N-alkyl tosyl morpholine to obtain cyclic morpholine; N-alkyl tosyl morpholine or morpholine ester c) treating cyclic morpholine with N,N,N’,N’-tetramethyldiamino-methane to obtain diamino methyl morpholine; d) treating the diamino methyl morpholine [with or without isolation] with acetic anhydride to obtain a mixture of diacetyl and monoacetyl morpholine compounds, wherein the diacetyl morpholine compound is treated with morpholine in the presence of dichloromethane to obtain the monoacetyl morpholine; e) converting monoacetyl morpholine to methyl morpholine; f) converting methyl morpholine to methyl acid; g) treating methyl acid with pivaloyl chloride followed by treatment with glycine methyl ester hydrochloride to obtain Roxadustat pivaloyl methyl ester; and h) converting Roxadustat pivaloyl methyl ester to Roxadustat, or a pharmaceutically acceptable salt thereof.

Roxadustat pivaloyl methyl ester or Roxadustat diester

In another aspect, disclosed herein are one or more novel compounds selected from:

In another aspect, disclosed herein is an improved process for the preparation of Roxadustat, the process comprising a) reacting chloromethyl ester compound with tosyl morpholine to obtain morpholine ester; b) cyclizing the morpholine ester to obtain cyclic morpholine; c) treating the cyclic morpholine with N, N, N’, N’-tetramethyl- diaminomethane to obtain dimethyl morpholine; d) converting the dimethyl morpholine to methyl morpholine; e) converting the methyl morpholine to obtain methyl acid; f) treating the methyl acid with pivaloyl chloride followed by treatment with glycine methyl ester hydrochloride to obtain Roxadustat diester; and g) converting Roxadustat diester to Roxadustat, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION

The present disclosure relates to an improved process for the preparation of Roxadustat by employing novel intermediates. In one embodiment, disclosed herein is an improved process for the preparation of Roxadustat, the process comprising: a) reacting chloromethyl ester with tosyl morpholine to obtain N-alkyl tosyl morpholine; b) cyclizing the N-alkyl tosyl morpholine to obtain cyclic morpholine; N-alkyl tosyl morpholine or morpholine ester c) treating the cyclic morpholine with N,N,N’,N’-tetramethyldiamino-methane to obtain diamino methyl morpholine; d) treating the diamino methyl morpholine [with or without isolation] with acetic anhydride to obtain a mixture of diacetyl and monoacetyl morpholine compounds, wherein the diacetyl morpholine compound is treated with morpholine in the presence of dichloromethane to obtain monoacetyl morpholine; e) converting the monoacetyl morpholine to methyl morpholine; f) converting the methyl morpholine to methyl acid; g) treating the methyl acid with pivaloyl chloride followed by treatment with glycine methyl ester hydrochloride to obtain Roxadustat pivaloyl methyl ester; and h) converting Roxadustat pivaloyl methyl ester to Roxadustat, or a pharmaceutically acceptable salt thereof.

According to the present disclosure, reacting chloromethyl ester with tosyl morpholine can be done in the presence of a base selected from the group consisting of potassium carbonate, sodium carbonate, and lithium carbonate, preferably potassium carbonate, a catalyst selected from the group consisting of sodium iodide, potassium iodide, sodium bromide, and potassium bromide, preferably sodium iodide, and/or a solvent selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, dimethylsulfoxide,l,4-dioxane, tetrahydrofuran, dichloromethane and mixtures thereof, preferably N,N-dimethylformamide, to obtain N-alkyl tosyl morpholine.

The N-alkyl tosyl morpholine may be cyclized in the presence of a base selected from the group consisting of sodium methoxide, sodium hydride, sodium tertiary butoxide, and potassium tertiary butoxide, preferably sodium methoxide, and a solvent selected from the group consisting of dimethylsulfoxide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dixoane, and N,N-dimethylacetamide, preferably dimethylsulfoxide, to obtain cyclic morpholine.

The cyclic morpholine may be treated with N,N,N’,N’-tctramcthyldiamino methane in the presence of a polar solvent selected from the group consisting of acetic acid, 1,4- dioxane, propionic acid, dimethylformamide, and dimethylsulfoxide, preferably acetic acid, to obtain diaminomethyl morpholine. The diaminomethyl morpholine, with or without isolation, may be treated with acetic anhydride to obtain a mixture of diacetyl morpholine and monoacetyl morpholine. The diacetyl morpholine compound may be treated with morpholine in the presence of dichloromethane to obtain monoacetyl morpholine.

The monoacetyl morpholine may be hydrogenated using a palladium catalyst in ethyl acetate/tetrahydrofuran to obtain the methyl morpholine which is then treated with a base selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, preferably sodium hydroxide, in the presence of a mixture of solvents selected from methanol/ 1,4-dioxane to obtain methyl acid.

The methyl acid may be treated with pivaloyl chloride in the presence of a base selected from the group consisting of N,N-diisopropylethylamine, triethylamine, n-butylamine, N,N-diisopropylamine, and l,8-diazabicyclo[5.4.0]undec-7-ene, preferably N,N- diisopropylethylamine, and a solvent selected from the group consisting of tetrahydrofuran, ethyl acetate, dichloromethane, 1,4-dioxane, and acetonitrile, preferably tetrahydrofuran, followed by treating with glycine methyl ester hydrochloride in the presence of N,N-diisopropylethylamine to obtain Roxadustat pivaloyl methyl ester. Roxadustat pivaloyl methyl ester may be deprotected in the presence of a solvent selected from the group consisting of tetrahydrofuran, methanol, ethanol, dioxane, water, and mixtures thereof, preferably a tetrahydrofuran/water mixture, and a base selected from the group consisting of lithium hydroxide, sodium hydroxide, sodium carbonate, and potassium carbonate, preferably lithium hydroxide, to form Roxadustat which may optionally be converted to a pharmaceutically acceptable salt thereof.

Yet in another embodiment, disclosed herein is an improved process for the preparation of Roxadustat, the process comprising: a) reacting a chloromethyl ester compound with tosyl morpholine to obtain morpholine ester; b) cyclizing the morpholine ester to obtain cyclic morpholine; c) treating the cyclic morpholine with N, N, N’, N’- tetramethyl diaminomethane to obtain dimethyl morpholine; d) converting the dimethyl morpholine to methyl morpholine; e) converting the methyl morpholine to obtain methyl acid; f) treating the methyl acid with pivaloyl chloride followed by treatment with glycine methyl ester hydrochloride to obtain Roxadustat diester; and g) converting the Roxadustat diester to Roxadustat, or a pharmaceutically acceptable salt thereof.

Roxadustat diester Roxadustat

According to the present disclosure, chloromethyl ester may be reacted with tosyl morpholine in the presence of a base selected from the group consisting of potassium carbonate, sodium carbonate, and lithium carbonate, preferably potassium carbonate, a catalyst selected from the group consisting of sodium iodide, potassium iodide, sodium bromide, and potassium bromide, preferably sodium iodide, a suitable solvent selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, dimethylsulfoxide, 1,4-dioxane, tetrahydrofuran, dichloromethane, and toluene, and/or a phase transfer catalyst like benzyltriethylammonium chloride to obtain the morpholine ester.

The morpholine ester may be cyclized in the presence of a base selected from the group consisting of sodium methoxide, sodium hydride, sodium tertiary butoxide, and potassium tertiary butoxide, preferably sodium methoxide, and a solvent selected from the group consisting of dimethylsulfoxide, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dixoane, and N,N-dimethylacetamide, preferably dimethylsulfoxide, to obtain the cyclic morpholine.

The cyclic morpholine may be treated with N, N, N’, N’-tetramethyldiaminomethane in the presence of a polar solvent selected from the group consisting of acetic acid, 1,4- dioxane, propionic acid, dimethylformamide, and dimethylsulfoxide, preferably acetic acid, to obtain dimethyl morpholine.

The dimethyl morpholine may be treated with zinc in the presence of an acid mixture selected from acetic acid/aqueous hydrochloric acid, propionic acid/aqueous hydrochloric acid, and propionic acid/formic acid, preferably acetic acid/aqueous hydrochloric acid, to obtain the methyl morpholine.

The methyl morpholine may be treated with a base such as sodium hydroxide or potassium hydroxide in dioxane/methanol mixture followed by pH adjustment to obtain methyl acid.

The methyl acid may be treated with pivaloyl chloride in the presence of a base selected from the group consisting of N,N-diisopropylethylamine, triethylamine, tri-n- butylamine, and l,8-diazabicyclo[5.4.0]undec-7-ene, preferably N,N- diisopropylethylamine, and a solvent selected from the group consisting of tetrahydrofuran, ethyl acetate, dichloromethane, 1,4-dioxane, and acetonitrile, preferably tetrahydrofuran, followed by treatment with glycine methyl ester hydrochloride in the presence of N,N-diisopropylethylamine to obtain Roxadustat diester.

Roxadustat diester may be deprotected in the presence of a solvent selected from the group consisting of tetrahydrofuran, methanol, ethanol, dioxane, water and mixtures thereof, preferably a tetrahydrofuran/water mixture, in the presence of a base selected from the group consisting of lithium hydroxide, sodium hydroxide, sodium carbonate, and potassium carbonate, preferably lithium hydroxide, to form Roxadustat, which may optionally be converted to a pharmaceutically acceptable salt.

In yet another embodiment, disclosed herein is a pharmaceutical composition comprising Roxadustat, or a pharmaceutically acceptable salt thereof, prepared according to the methods disclosed herein, and one or more pharmaceutical excipient.

One advantage of the process described in the present disclosure is that all the intermediate compounds can be isolated as solid compounds without using column chromatography, thus making the process industrially feasible and economical with high yields.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the subject matter herein in anyway. EXAMPLES:

Example 1: Process for the preparation of Roxadustat:

Stage-I: Preparation of 5-phenoxyisobenzofuran-l(3H)-one or Phenoxy phthalide Toluene, Reflux 5 -bromophthalide 5-phenoxy phthalide

A suspension of 5-bromoisobenzofuran-l(3H)-one (300.0 g, 1.408 mol), phenol (177.6 g, 1.887 mol), potassium carbonate (261.2 g, 1.889 mol), copper (I) bromide (30.0 g, 0.209 mol) and acetyl acetone (28.0 g, 0.279 mol) in N,N-dimethylformamide (3000 mL) was stirred at 100-105 °C. After completion, the reaction mass was cooled and added to precooled water (3000 mL) at 10-15 °C and stirred for 60 min. The precipitated product was filtered, washed with water, and dissolved in dichloromethane (2000 mL). Water (2000 mL) was added and the pH was adjusted to ~2.0 with cone hydrochloric acid. The organic layer was separated, washed with water and aq. 5% sodium bicarbonate sequentially. The obtained organic layer was concentrated and the obtained residue was stirred with methanol (1000 mL) at room temp. The product was filtered, washed with methanol, and dried to yield 5-phenoxyisobenzofuran-l(3H)-one (130.0 g)·

Stage-II: Preparation of methyl 2-(chloromethyl)-4-phenoxybenzoate or chloromethyl ester

Phenoxy phthalide (25.0 g, 0.110 mol), trimethyl borate (0.22 g, 0.002 mol) and triphenylphosphine dibromide (0.9 g, 0.002 mol) in thionyl chloride (50 mL) were refluxed (72-75 °C). After the reaction was complete, excess thionyl chloride was distilled off and the residue was cooled to 5-10 °C. Methanol (50 ml) was added and stirring continued at 50-55 °C for 1.0 h. The product was subjected to concentration by solvent removal and product purification by column chromatography to yield methyl 2-(chloromethyl)-4-phenoxybenzoate (23.0 g). Stage-III: Preparation of methyl 2-(((4-methyl-N-(2-morpholino-2- oxoethyl)phenyl)sulfonamido)-methyl)-4-phenoxybenzoate or N-alkyl tosyl morpholine

4-Methyl-N-(2-morpholino-2-oxoethyl)benzene sulfonamide (33.0 g, 0.111 mol), potassium carbonate (19.8 g, 0.143 mol), methyl 2-(chloromethyl)-4-phenoxybenzoate

(36.6 g, 0.132 mol) and sodium iodide (1.6 g, 0.011 mol) in N,N-dimethylformamide (165 mL) were stirred at 49-55 °C. After completion, the reaction mass was cooled to

5-10 °C, ethyl acetate (165 mL) and water (330 mL) were sequentially added and stirring continued for 120 min at 5-10 °C. The product was filtered, washed with water and precooled ethyl acetate (3x 33 ml, 5-10 °C), and dried to yield methyl 2-(((4- methyl-N-(2-morpholino-2-oxoethyl)phenyl)sulfonamido)methyl) -4-phenoxy- benzoate (40.0 g) as a white solid.

Stage-IV: Preparation of (4-hydroxy-7-phenoxyisoquinolin-3-yl)(morpholino) methanone or cyclic morpholine N-alkyl tosyl morpholine or morpholine ester

30% Sodium methoxide in methanol (37.1 g, 0.206 mol) was added to a solution of methyl 2-(((4-methyl-N-(2-morpholino-2-oxoethyl)phenyl)sulfonamido) methyl)-4- phenoxy benzoate (37.0 g, 0.069 mol) in dimethylsulfoxide (185 mL) at 20-25 °C and stirred. After ~1 hr., the reaction mass was cooled to 5-10 °C and the pH was adjusted to ~2.0 with cone hydrochloric acid. Water (250 mL) was added and stirring continued at 5-10 °C. The precipitated product was filtered, washed with water, and dried to get (4-hydroxy-7-phenoxyisoquinolin-3-yl)(morpholino)methanone (23.0 g) as a light yellow solid.

Stage- V: Preparation of (4-hydroxy-3-(morpholine-4-carbonyl)-7- phenoxyisoquin-olin-l-yl)methyl acetate or Monoacetyl Morpholine

After adding N,N,N’,N’-tctramcthyldiamino methane (1.9 g, 0.019 mol) to a solution of (4-hydroxy-7-phenoxyisoquinolin-3-yl)(morpholino)methanone (5.0 g, 0.014 mol) in acetic acid (8.5 g) at room temp, the reaction mass was heated and stirred at 57-60 °C. After completion, acetic anhydride (7.2 g, 0.071 mol) was added at room temp, and the reaction mass was again stirred at 95-100 °C for 2 h. After adding water, the reaction mass was stirred at room temp, the precipitated product was filtered and dried to get (4- hydroxy-3-(morpholine-4-carbonyl)-7-phenoxyisoquinolin-l-yl) methyl acetate (2.0 g).

The filtrate containing the diacetylated product i.e. (4-acetoxy-3-(morpholine-4- carbonyl)-7-phenoxyisoquinolin-l-yl)methyl acetate was extracted with ethyl acetate, washed with water/brine and concentrated. The obtained residue was dissolved in dichloromethane (25 mL) and cooled to 0-5 °C. Morpholine (0.5g, 0.006 mol) was added, and the reaction mass was stirred at the same temp. After completion, 10% citric acid (15 mL) was added, and the separated organic layer was washed with water. The obtained organic layer was concentrated under vacuum to afford (4-hydroxy-3- (morpholine-4-carbonyl)-7 -phenoxyisoquinolin- 1 -yl)methylacetate (2.0g) .

Stage-VI: Preparation of (4-hydroxy-l-methyl-7-phenoxyisoquinolin-3- yl)(morpholino)methanone or methyl morpholine

A solution of (4-hydroxy-3-(morpholine-4-carbonyl)-7-phenoxyisoquinolin-l- yl)methyl acetate (4.0 g, 0.009 mol) in an ethyl acetate/tetrahydrofuran mixture (4:1, 150 mL)) was hydrogenated with 10 % Pd/C (1.0 g) at 57-60 °C and at 4.5 kg/cm ² ). After completion, the Pd/C was removed under a nitrogen atmosphere, and the obtained filtrate was washed with water/brine and concentrated. The obtained residue was crystalized with isopropyl alcohol (30 mL) to afford (4-hydroxy- 1 -methyl-7 - phenoxyisoquinolin-3-yl)(morpholino) methanone (2.1 g).

Stage-VII: Preparation of 4-hydroxy-l-methyl-7-phenoxyisoquinoline-3- carboxylic acid or methyl acid

To a solution of (4-hydroxy-l-methyl-7-phenoxyisoquinolin-3-yl)(morpholino) methanone (2.0 g, 0.005 mol) in a methanol/ 1,4-dioxane mixture (1:9, 50 mL), sodium hydroxide powder (6.6 g, 0.165 mol) was added and the reaction mass was stirred at reflux (97-102 °C). After completion of the reaction, the solvents were distilled off and water (50 mL) was added at room temp. The pH of the contents was adjusted to ~3.0 with cone hydrochloric acid and stirring was continued for 120 min. The obtained product was filtered, washed with water and dried to afford 4-hydroxy- 1 -methyl-7 - phenoxyiso-quinoline-3-carboxylic acid (1.6 g) as an off-white solid. Stage-VIII: Preparation of 3-((2-methoxy-2-oxoethyl)carbamoyl)-l-methyl-7- phenoxyisoquinolin-4-yl pivalate or Roxadustat pivaloyl methyl ester

After adding pivaloyl chloride (1.22 g, 0.010 mol) to a precooled solution of 4-hydroxy- l-methyl-7-phenoxyisoquinoline-3-carboxylic acid (1.3 g, 0.004 mol) and N,N- diisopropylethylamine (1.7g, 0.013 mol) in tetrahydrofuran (30 mL) at 0-5 °C, the reaction mass was stirred at the same temp for 60 min and then at room temp for 60 min. The reaction mass was cooled to 0-5 °C and glycine methyl ester hydrochloride (1.65g, 0.013 mol) and N,N-diisopropylethylamine (2.0 g, 0.015 mol) were added sequentially. After stirring the reaction mass at room temperature for 18 hrs., water (30 mL) and ethyl acetate (100 mL) were added. The organic layer was separated and washed with water (3 x 50 mL) followed by 5% sodium bicarbonate solution (50 mL) sequentially. The organic layer was subjected to carbon treatment, and the obtained filtrate was concentrated. The obtained solids were stirred with 30% methyl tertiary butyl ether in hexane at 50-55 °C, cooled to room temperature, filtered, washed with 30% methyl tertiary butyl ether in hexane, and dried to afford 3-((2-methoxy-2- oxoethyl)carbamoyl)-l-methyl-7-phenoxy-isoquinolin-4-yl pivalate (1.3 g).

Stage-IX: Preparation of (4-hydroxy-l-methyl-7-phenoxyisoquinoline-3- carbonyl)glycine or Roxadustat

Roxadustat pivaloyl methyl ester or Roxadustat diester

To 3-((2-methoxy-2-oxoethyl)carbamoyl)-l-methyl-7-phenoxy-isoqu inolin-4-yl pivalate (1.0 g, 0.002 mol) in tetrahydrofuran (12 mL), water (6 mL) and lithium hydroxide monohydrate (0.4 g, 0.009 mol) were added sequentially at room temp and stirred at 48-52 °C . After completion of the reaction, the reaction mass was cooled to room temperature, and 10% citric acid (10 mL) was added. Stirring continued at room temp, and the product was filtered, washed with water followed by hexane, and dried to afford (4-hydroxy- l-methyl-7-phenoxyisoquinoline-3-carbonyl)glycine or Roxadustat (0.67 g) as an off-white solid.

Stage-X: Preparation of tosyl glycine

To an aqueous sodium hydroxide solution (133.2 g in 2000 mL water), glycine (100 g, 1.332 mol) was added and stirred at 20-35 °C. Subsequently, p-toluenesulfonyl chloride (304.2 g, 1.596 mol) was added and stirring continued for 180 min. The pH of the reaction mass was adjusted to ~2.0 with hydrochloric acid and stirring continued at the same temp for 120 min. The product was filtered, washed with water and with hexane (200 mL) and dried to yield tosyl glycine (95.0 g).

Stage-XI: Preparation of 4-methyl-N-(2-morpholino-2- oxoethyl)benzenesulfonamide or tosyl morpholine tosyl glycine tosyl morpholine

After refluxing (72-75 °C) tosyl glycine (35.0 g, 0.153 mol) in thionyl chloride (72.2 g, 0.607 mol) for 120 min, excess thionyl chloride was distilled off and finally co-distilled with toluene. Thereafter, toluene (175 mL) was added, and the solution was cooled to 25-30 °C. Morpholine (29.0 g, 0.333 mol) was added at 25-30 °C and stirring continued. After completion of the reaction, water was added at 25-30 °C and stirred. The obtained product was filtered, washed with water and dried at 60-65 °C to afford 4-methyl-N- (2-morpholino-2-oxoethyl)benzene sulfonamide (33.2 g). Example 2: Process for the preparation of Roxadustat:

Stage-I: Preparation of 5-phenoxyisobenzofuran-l(3H)-one or 5-Phenoxy- phthalide Toluene, Reflux 5 -bromophthalide 5-phenoxy phthalide

Potassium carbonate (110.2g, 0.798 mol), phenol (66.3 g, 0.704 mol) and copper (I) bromide (16.83g, 0.117 mol) were refluxed in toluene (1500 mL) under azeotropic condition for 4 hrs. After cooling to room temperature, 5-bromophthalide (100.0 g, 0.469 mol) and acetyl acetone (7.0 g, 0.070 mol)) were added sequentially and the contents were refluxed under azeotropic condition for 35 hrs. After completion of the reaction, the reaction mass was cooled, hydrochloric acid (200 mL cone HC1 and 400 mL water) was added at 15-25 °C and stirred for 2 hrs. The reaction mass was filtered through a hyflo bed which was washed with toluene and water sequentially. The toluene layer was separated and washed with water and ~5% w/w sodium bicarbonate sequentially. It was then concentrated under vacuum. The obtained residue was crystalized with methanol to afford 5-phenoxyisobenzofuran-l(3H)-one (80.0 g) as a light brown solid.

Stage-II: Preparation of methyl 2-(chloromethyl)-4-phenoxybenzoate or chloromethyl ester

5 -phenoxyphthalide chloromethyl ester

To a suspension of 5-phenoxyphthalide (100.0 g, 0.442 mol) and triphenylphosphine oxide (TPPO) (147.6 g, 0.530 mol) in toluene (300 mL), thionyl chloride (400 mL) was added slowly at room temperature and then cooled to 15-20 °C. Thereafter, trimethyl borate (55.1 g, 0.530 mol) was added slowly at 15-20 °C and the reaction mass was stirred at 70-75 °C for 90 hrs. After completion of the reaction, the reaction mass was concentrated under vacuum, and dichloromethane (300 mL) was added at room temperature and cooled to 0-5°C. Methanol (300 mL) was slowly added at 0-5 °C and the contents were stirred for 2 hrs. After concentration under vacuum, 30% MTBE was added in cyclohexane (700 mL) and water (700 mL). The contents were stirred for 2.0 hrs, cooled to 0-5°C and stirred for 2.0 hrs. The precipitated TPPO by removed by filtration and washed with water followed by precooled 30% MTBE in cyclohexane (150 mL). The organic layer was separated, washed with water and concentrated under vacuum to yield methyl 2-(chloromethyl)-4-phenoxybenzoate (120 g) as a light yellow semi- solid.

Stage-Ill: Preparation of methyl 2-(((4-methyl-N-(2-morpholino-2- oxoethyl)phenyl)sulfonamido)methyl)-4-phenoxybenzoate or morpholine ester 4-Methyl-N-(2-morpholino-2-oxoethyl)benzene sulfonamide (100.0 g, 0.335 mol), potassium carbonate (19.8 g, 0.143 mol), methyl 2-(chloromethyl)-4-phenoxybenzoate (60.2 g, 0.436 mol) and sodium iodide (5.0 g, 0.0335 mol) in dimethylsulfoxide (400 mL) were stirred for 4 hrs at 50-55 °C. Acetic acid (50 mL) was slowly added followed by ethyl acetate (200 mL) and isopropyl ether (400 mL) at room temperature. Water (2000 mL) was added slowly and stirred for 120 min. The precipitated product was filtered, washed with water, a mixture of ethyl acetate and isopropyl ether (400 mL) (1:2, 150 mL) sequentially and dried to give methyl 2-(((4-methyl-N-(2-morpholino-2- oxoethyl)phenyl)sulfon-amido)methyl)-4-phenoxy-benzoate (154.0 g) as an off-white solid. Stage-IV: Preparation of (4-hydroxy-7-phenoxyisoquinolin-3- yl)(morpholino)methanone or cyclic morpholine

To a solution of methyl 2-(((4-methyl-N-(2-morpholino-2-oxoethyl)phenyl)sulfon- amido)methyl)-4-phenoxybenzoate (140 g, 0.260 mol) in dimethylsulfoxide (700 mL), sodium methoxide in methanol (30%, 140.4 g, 0.780 mol) was added slowly at 10- 15°C. After stirring for ~2hrs, the pH was adjusted to ~2.0 with cone hydrochloric acid at 10-20°C. Water (1120 mL) was added slowly and stirring continued at ambient temperature for 3 hrs. The precipitated product was filtered, washed with water and isopropyl alcohol sequentially and dried to get (4-hydroxy-7-phenoxyisoquinolin-3- yl)(morpholino)-methanone (72.5 g) as a light yellow solid.

Stage- V: Preparation of [l-{(dimethylamino)methyl}-4-hydroxy-7- phenoxyisoquinolin-3-yl](morpholino)methanone or dimethyl morpholine dimethyl morpholine

After adding N,N,N,N-tetramethyldiaminomethane (1.9 g, 0.019 mol) to a solution of (4-hydroxy-7-phenoxyisoquinolin-3-yl)(morpholino)methanone (5.0 g, 0.014 mol) in acetic acid (8.5 g), the reaction mass was heated and stirred at 57-60 °C. After reaction completion, the reaction mass was neutralized with aqueous sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water, saturated brine and concentrated under vacuum to get [l-{(dimethylamino)methyl}-4-hydroxy- 7-phenoxyisoquinolin-3-yl](morpholino)methanone (5.2g) as a light pinkish-brown solid.

Stage-VI: Preparation of (4-hydroxy-l-methyl-7-phenoxyisoquinolin-3-yl)

(morpholino) methanone or methyl morpholine cyclic morpholine

To a suspension of [l-{(dimethylamino)methyl}-4-hydroxy-7-phenoxyisoquinolin-3- yl] (morpholino)methanone (500 mg) and zinc dust (400 mg) in N-methyl pyrrolidone (5 mL), a mixture of acetic acid (1 mL) and 5% hydrochloric acid (0.5 mL) was added at 50-55 °C and stirred for 4 hrs. More zinc dust (400 mg) in a mixture of acetic acid (1 mL) and 5% hydrochloric acid (0.5 mL) at 50-55 °C were added and stirred for 15 hrs. After adding ethyl acetate and water, the organic layer was separated, washed with 5% NaHCCL and concentrated under vacuum. The product was crystalized with isopropyl alcohol to afford (4-hydroxy- l-methyl-7-phenoxyisoquinolin-3- yl)(morpholino)methanone (110 mg) as an off-white solid.

Stage- VII: Preparation of 4-Hydroxy-l-methyl-7-phenoxyisoquinoline-3- carboxylic acid or methyl acid

To a solution of (4-hydroxy-l-methyl-7-phenoxyisoquinolin-3- yl)(morpholino)methanone (2.0 g, 0.005 mol) in a methanol/ 1, 4 -dioxane mixture (1:9, 45 mL), sodium hydroxide powder (6.6 g, 0.165 mol) was added and the reaction mass was stirred at reflux (97-102 °C). After completion of the reaction, it was concentrated, and water (25 mL) was added at room temp. The pH was adjusted to ~3.0 with cone hydrochloric acid, and it was stirred for 120 min. The obtained product was filtered, washed with water and dried to afford 4-hydroxy- 1 -methyl-7 -phenoxyisoquinoline-3- carboxylic acid (1.5 g) as an off-white solid.

Stage-VIII: Preparation of 3-((2-methoxy-2-oxoethyl)carbamoyl)-l-methyl-7- phenoxyisoquinolin -4-yl pivalate or Roxadustat diester

After adding pivaloyl chloride (1.22 g, 0.010 mol) under nitrogen atmosphere to a solution of 4-hydroxy- l-methyl-7-phenoxyisoquinoline-3-carboxylic acid (1.3 g, 0.004 mol) and N,N-diisopropylethylamine (1.7g, 0.013 mol) in tetrahydrofuran (30 mL) at 0-5 °C, the reaction mass was stirred at the same temp for 60 min and then for 60 min at room temp. Thereafter, the reaction mass was again cooled to 0-5 °C and glycine methyl ester hydrochloride (1.65g, 0.013 mol) and N,N-diisopropylethylamine (2.0 g, 0.015 mol) were added sequentially. After stirring the reaction mass at room temperature for 18 hrs, water (30 mL) and ethyl acetate (100 mL) were added. The organic layer was separated and washed with water (3 x 50 mL) followed by 5% sodium bicarbonate solution (50 mL). The obtained organic layer was subjected to carbon treatment, and the obtained filtrate was concentrated. The obtained solids were stirred with 30% methyl tertiary butyl ether in hexane at 50-55 °C, cooled to room temperature, filtered, washed with 30% methyl tertiary butyl ether in hexane and dried to afford 3- ((2-methoxy-2-oxoethyl)carbamoyl)-l-methyl-7-phenoxy-isoquin olin-4-yl pivalate

(1.3 g).

Stage-IX: Preparation of (4-hydroxy-l-methyl-7-phenoxyisoquinoline-3- carbonyl) glycine or Roxadustat

To 3-((2-methoxy-2-oxoethyl)carbamoyl)-l-methyl-7-phenoxy-isoqu inolin-4-yl pivalate (1.0 g, 0.002 mol) in tetrahydrofuran (12 mL), water (6 mL) and lithium hydroxide monohydrate (0.4 g, 0.009 mol) were added sequentially at room temp and stirred at 48-52 °C. After reaction completion, the reaction mass was cooled to room temperature and 10% citric acid (10 mL) was added. Stirring continued at room temp, and the product was filtered, washed with water/hexane and dried to afford (4-hydroxy- l-methyl-7-phenoxyisoquinoline-3-carbonyl)glycine or Roxadustat (0.67 g) as an off- white solid.

Stage-X: Preparation of tosyl glycine glycine tosyl glycine

To the aqueous sodium hydroxide solution (133.2 g in 2000 mL water), glycine (100 g, 1.332 mol) was added and stirred at 20-35 °C. After adding toluene (1500 mL), p- toluenesulfonyl chloride (304.2 g, 1.596 mol) was added lot wise at 25-35 °C and stirring was continued for 180 min. The organic layer was then removed. To the aqueous layer, water (400 mL) was added and adjusted pH to ~2.0 with hydrochloric acid and stirring continued at the same temp for 90 min. The precipitated product was filtered, washed with water and dried to yield tosyl glycine (270 g). Stage-XI: Preparation of 4-methyl-N-(2-morpholino-2-oxoethyl) benzenesulfonamide or tosyl morpholine

After refluxing (72-75 °C) tosyl glycine (200 g, 0.872 mol) in thionyl chloride (400 mL) for 120 min, excess thionyl chloride was distilled off and co-distilled with toluene. Dichloromethane (400 mL) was added, and the solution was cooled to 0-5 °C. Morpholine (174.7 g, 2.01 mol) was added at 25-30 °C and stirring continued. After completion of the reaction, water was added at 0-5 °C and stirred for 440 min. More water (200 ml) was added and stirred for 30 min. The dichloromethane was removed . The obtained product was filtered, washed with water and dried at 60-65 °C to afford 4-methyl-N-(2-morpholino-2-oxoethyl)benzene sulfonamide (227 g) as a light brown solid.