An improved process for the preparation of daprodustat and its pharmaceutically acceptable salts

Abstract

The present invention discloses an improved process for preparation of Daprodustat. Further the present invention provides the preparation of Daprodustat or its pharmaceutically acceptable salts thereof. The present invention also provides a process for preparation of intermediates used in the preparation of Daprodustat.

Description

[0001] AN IMPROVED PROCESS FOR THE PREPARATION OF DAPRODUSTAT AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS RELATED PATENT APPLICATION: This application claims the priority to and benefit of Indian Patent Application No. 202441041838 filed on May 29, 2024; the disclosures of which are incorporated herein by reference; FIELD OF THE INVENTION: The present invention relates to Daprodustat. The present invention particularly relates to an improved process for the preparation of Daprodustat and its pharmaceutically acceptable salts. The present invention also relates to the process for preparation of intermediates used in the synthesis of Daprodustat. BACKGROUND OF THE INVENTION: Daprodustat is also known as N-[(1,3-Dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5- yl)carbonyl]glycine and has a structural formula as: Daprodustat (GSK1278863) was developed by GlaxoSmithKline (GSK) for treating anaemia in haemodialysis patients as well as non-haemodialysis-dependent patients with chronic kidney disease (CKD). It is a small molecule Hypoxia Inducible Factor-Prolyl Hydroxylase Inhibitor marketed in the name of “Duvroq” for oral administration as a tablet. Example 18 of US 8,324,208 describes the methods for preparing GSK1278863, but both methods utilizes hazardous reagents, which requires high precaution and control during the manufacturing process. The patent application WO2024022998, discloses Daprodustat and a process for preparing the same using specific solvents such as dichloromethane. However, the process is costly and not environmentally friendly. Therefore, there is a need to develop a process for the preparation of Daprodustat which is cost effective, environmentally friendly, and includes fewer steps. OBJECTS OF THE INVENTION: The primary object of the present invention is to provide an improved process for preparation of Daprodustat. Another object of the present invention is to provide an improved process for preparation of Daprodustat and its pharmaceutically acceptable salts. Yet another process of the present invention is to provide a process for preparation of intermediates used in the preparation process of Daprodustat. Another object of the present invention is to provide Daprodustat for the treatment of anaemia. SUMMARY OF THE INVENTION: Accordingly, the present invention provides a process for preparing Daprodustat and its pharmaceutically acceptable salts, comprising the steps of: (i) treating 2-aminoacetic acid with solvent and a dehydrating agent to obtain a compound of methyl 2-aminoacetate; (ii) treating methyl 2-aminoacetate obtained in above step with a solvent, a base and triphosgene to obtain Methyl 2-isocyanatoacetate; (iii) condensing 1,3-dicyclohexylurea in presence of an acid and solvents to obtain 1,3-dicyclohexylpyrimidine- 2,4,6(1H,3H,5H)-trione;

[0002] (iv) treating 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione with methyl 2- isocynatoacetate in the presence of a solvent and a base to obtain methyl2-(1,3- dicylcohexyl-2,4,6-trioxohexahydropyrimidine-5-carboxamido)acetate; and (v) hydrolysing methyl 2-(1,3-dicylcohexyl-2,4,6-trioxohexahydropyrimidine-5- carboxamido)acetate obtained in above step in presence of a base to obtain Daprodustat. The solvent in step (i) is selected from organic solvent or inorganic solvent, wherein the organic solvent is selected from groups comprising alcohols such as ethanol, methanol or isopropanol; ketone such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon such as toluene or benzene; aliphatic hydrocarbon such as hexane or heptane or its mixtures thereof; the inorganic solvent is selected from water, ammonia, sulfuric acid, fluoride, sulfuryl chloride or mixtures thereof, wherein the organic solvent is methanol. The dehydrating agent in step (i) is selected from thionyl chloride, oxalyl chloride, cyanuric chloride, orthoformic acid, phosphorus pentoxide, or phosphoryl chloride, wherein the dehydrating agent is thionyl chloride. The solvent in step (ii) is selected from organic solvent or inorganic solvent, the organic solvent is selected from groups comprising alcohols such as ethanol, methanol or isopropanol; ketone such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon such as toluene or benzene; aliphatic hydrocarbon such as hexane or heptane; chlorinated hydrocarbons such as dichloromethane (DCM) and chloroform; or its mixtures thereof; the inorganic solvent selected from water, ammonia, sulfuric acid, fluoride, sulfuryl chloride or mixtures thereof, wherein the organic solvent is dichloromethane (DCM). The base in step (ii) is selected from organic base or inorganic base, the organic base is selected from the groups comprising heterocyclic compounds such as pyridine and diazabicycloundec-7-ene (DBU); amines such as diisopropylethylamine (DIPEA), N,N- dimethyl-4-amino-pyridine (DMAP), 1,8-, dicyclohexylamine (DCHA), triethylamine; organometallic agents such as butyllithium; organosilicon compounds such as Lithium bis(trimethylsilyl)amide or sodium hexamethyldisilazide or mixtures thereof; the inorganic base is selected from groups comprising alkali or alkaline earth carbonates such as potassium carbonate, sodium carbonate, caesium carbonate, sodium bicarbonate and potassium bicarbonate; alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali or alkaline earth metal hydride sodium hydride, potassium hydride; or its mixtures thereof, wherein the organic base is pyridine. The solvents in step (iii) are selected from organic solvents or inorganic solvents, the organic solvents are selected from groups comprising alcohols such as ethanol, methanol or isopropanol; ketones such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; ethers such as dioxane and tetrahydrofuran; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbons such as toluene or benzene; aliphatic hydrocarbons such as hexane or heptane; chlorinated hydrocarbons such as dichloromethane and chloroform; aprotic solvents such as acetic anhydride or DMSO or its mixtures thereof, wherein the inorganic solvents are selected from water, ammonia, sulfuric acid, fluoride, sulfuryl chloride or mixtures thereof, wherein the organic solvents are acetic anhydride and toluene. The acid in step (iii) is selected from groups comprising malonic acid, acetic acid, formic acid, benzoic acid, salicylic acid, carboxylic acid or oxalic acid, wherein the acid is malonic acid. The solvent in step (iv) is selected from organic solvent or inorganic solvent, the organic solvent is selected from groups comprising alcohols such as ethanol, methanol or isopropanol; ketones such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; ethers such as dioxane and tetrahydrofuran; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbons such as toluene or benzene; aliphatic hydrocarbons such as hexane or heptane; chlorinated hydrocarbons such as dichloromethane and chloroform; aprotic solvents such as acetic anhydride or DMSO or its mixtures thereof; the inorganic solvent is selected from water, ammonia, sulfuric acid, fluoride, sulfuryl chloride or mixtures thereof, wherein the inorganic solvent is water. The base in step (iv) is selected from organic base or inorganic base, the organic base is selected from the group comprising heterocyclic compounds such as pyridine and diazabicycloundec-7-ene (DBU); amines such as diisopropylethylamine (DIPEA), N,N- dimethyl-4-amino-pyridine (DMAP), 1,8-, dicyclohexylamine (DCHA), triethylamine; organometallic agents such as butyllithium; organosilicon compounds such as lithium bis(trimethylsilyl)amide and sodium hexamethyldisilazide or mixtures thereof; the inorganic base is selected from group comprising alkali or alkaline earth carbonates such as potassium carbonate, sodium carbonate, caesium carbonate, sodium bicarbonate and potassium bicarbonate; alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride; or its mixtures thereof, wherein the organic base is DIPEA. The base in step (v) is selected from the organic base or inorganic base, the organic base is selected from groups comprising heterocyclic compounds such as pyridine and diazabicycloundec-7-ene (DBU); amines such as diisopropylethylamine (DIPEA), N,N- dimethyl-4-amino-pyridine (DMAP), 1,8-, dicyclohexylamine (DCHA), triethylamine; organometallic agents such as butyllithium; organosilicon compounds such as Lithium bis(trimethylsilyl)amide and sodium hexamethyldisilazide or mixtures thereof; inorganic base is selected from groups comprising alkali or alkaline earth carbonates such as sodium hydroxide, sodium tertiary butoxide, sodium hydride, lithium hydride, ammonium hydroxide, potassium hydride, rubidium hydride, caesium hydride, lithium aluminium hydride; alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride; or its mixtures thereof, wherein the inorganic base is sodium hydroxide. The present invention a process for preparation of Daprodustat, wherein the steps (i), (ii), (iii), (iv) or (v) is carried out in the range from ambient temperature to reflux temperature of solvent or its mixture used during the reaction. The present invention also provides the process of preparing methyl 2-isocyanatoacetate, an intermediate used in the process of preparation of Daprodustat, comprising the steps of: (i) treating 2-aminoacetic acid with solvent and a dehydrating agent to obtain a compound of methyl 2-aminoacetate; (ii) treating methyl 2-aminoacetate obtained in above step with a solvent, a base and triphosgene to obtain methyl 2-isocyanatoacetate. The solvent in step (i) is selected from organic solvent or inorganic solvent, wherein the organic solvent is selected from groups comprising alcohols such as ethanol, methanol or isopropanol; ketone such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon such as toluene or benzene; aliphatic hydrocarbon such as hexane or heptane or its mixtures thereof; the inorganic solvent is selected from water, ammonia, sulfuric acid, fluoride, sulfuryl chloride or mixtures thereof, wherein the organic solvent is methanol. The dehydrating agent in step (i) is selected from thionyl chloride, oxalyl chloride, cyanuric chloride, orthoformic acid, phosphorus pentoxide, or phosphoryl chloride, wherein the dehydrating agent is thionyl chloride. The solvent in step (ii) is selected from organic solvent or inorganic solvent, the organic solvent is selected from groups comprising alcohols such as ethanol, methanol or isopropanol; ketone such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon such as toluene or benzene; aliphatic hydrocarbon such as hexane or heptane; chlorinated hydrocarbons such as dichloromethane (DCM) and chloroform; or its mixtures thereof; the inorganic solvent selected from water, ammonia, sulfuric acid, fluoride, sulfuryl chloride or mixtures thereof, wherein the organic solvent is dichloromethane (DCM). The base in step (ii) is selected from organic base or inorganic base, the organic base is selected from the groups comprising heterocyclic compounds such as pyridine and diazabicycloundec-7-ene (DBU); amines such as diisopropylethylamine (DIPEA), N,N- dimethyl-4-amino-pyridine (DMAP), 1,8-, dicyclohexylamine (DCHA), triethylamine; organometallic agents such as butyllithium; organosilicon compounds such as Lithium bis(trimethylsilyl)amide or sodium hexamethyldisilazide or mixtures thereof; the inorganic base is selected from groups comprising alkali or alkaline earth carbonates such as potassium carbonate, sodium carbonate, caesium carbonate, sodium bicarbonate and potassium bicarbonate; alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali or alkaline earth metal hydride sodium hydride, potassium hydride; or its mixtures thereof, wherein the organic base is pyridine. Use of Daprodustat prepared by the process of the present invention for the treatment of anaemia. A pharmaceutical composition comprising Daprodustat or its pharmaceutically acceptable salts by the above process. DETAILED DESCRIPTION OF THE INVENTION: Accordingly, in one aspect the present invention discloses and describes an improved process for the preparation of Daprodustat and its pharmaceutically acceptable salts thereof. In one embodiment, the present invention provides a process for preparing Daprodustat, comprising the steps of: Step i): treating 2-aminoacetic acid, with solvent and a dehydrating agent to obtain a compound of methyl 2-aminoacetate as mentioned below, Step (i) of the present invention, is carried out in presence of suitable solvents selected from but not limited to the group comprising organic solvents selected from alcohols such as ethanol, methanol or isopropanol; ketone such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon such as toluene or benzene; aliphatic hydrocarbon such as hexane or heptane or its mixtures thereof, preferable solvent is methanol; or inorganic solvents selected from water, ammonia, sulfuric acid, fluoride, sulfuryl chloride or mixtures thereof. The preferred solvent is methanol. The dehydrating agent in step (i) is selected from the group comprising thionyl chloride, oxalyl chloride, cyanuric chloride, orthoformic acid, phosphorus pentoxide, or phosphoryl chloride, wherein the dehydrating agent is thionyl chloride. Step ii): treating methyl 2-aminoacetate obtained in step (i) with solvent, a base and triphosgene to obtain Methyl 2-isocyanatoacetate, The step (ii) of the present invention, is carried out in presence of suitable solvents selected from but not limited to the group comprising organic solvents selected from alcohols such as ethanol, methanol or isopropanol; ketone such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon such as toluene or benzene; aliphatic hydrocarbon such as hexane or heptane; chlorinated hydrocarbons such as dichloromethane (DCM) and chloroform; or its mixtures thereof; inorganic solvents such as water, ammonia, sulfuric acid, fluoride, sulfuryl chloride or mixtures thereof. The preferred solvent is dichloromethane (DCM). The step (ii) of the present invention comprises the use of base selected from the group comprising organic base or inorganic base. The organic base is selected from but not limited to the group comprising heterocyclic compounds such as pyridine and diazabicycloundec-7-ene (DBU); amines such as diisopropylethylamine (DIPEA), N,N- dimethyl-4-amino-pyridine (DMAP), 1,8-, dicyclohexylamine (DCHA), triethylamine; organometallic agents such as butyllithium; organosilicon compounds such as Lithium bis(trimethylsilyl)amide and sodium hexamethyldisilazide or mixtures thereof. The inorganic base is selected from the group comprising but not limited to alkali or alkaline earth carbonates such as potassium carbonate, sodium carbonate, caesium carbonate, sodium bicarbonate and potassium bicarbonate; alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali or alkaline earth metal hydride sodium hydride, potassium hydride; or its mixtures thereof. The preferred base is pyridine. Step (iii): condensing 1,3-dicyclohexylurea with acid and solvents to obtain 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione The step (iii) of the present invention, is carried out in presence of suitable solvents selected from but not limited to group comprising organic solvents selected from alcohols such as ethanol, methanol or isopropanol; ketone such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; ethers such as dioxane and tetrahydrofuran; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon such as toluene or benzene; aliphatic hydrocarbon such as hexane or heptane; chlorinated hydrocarbons such as dichloromethane and chloroform; aprotic solvents such as acetic anhydride or DMSO or its mixtures thereof; inorganic solvents selected from the group comprising water, ammonia, sulfuric acid, fluoride, sulfuryl chloride or mixtures thereof. The preferred solvents are acetic anhydride and toluene. The step (iii) of the present invention, may be carried out in the presence of an acid selected from the group comprising malonic acid, acetic acid, formic acid, benzoic acid, salicylic acid, carboxylic acid or oxalic acid. The preferred acid is malonic acid. Step (iv): treating the compound 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione obtained in step (iii) with methyl 2-isocynatoacetate obtained in step (ii) of the process above, in presence of a solvent and a base to obtain methyl 2-(1,3-dicylcohexyl-2,4,6- trioxohexahydropyrimidine-5-carboxamido)acetate

[0003] The step (iv) of the present invention, is carried out in presence of suitable solvents selected from but not limited to organic solvents selected from the group comprising alcohols such as ethanol, methanol or isopropanol; ketone such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; ethers such as dioxane and tetrahydrofuran; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon such as toluene or benzene; aliphatic hydrocarbon such as hexane or heptane; chlorinated hydrocarbons such as dichloromethane and chloroform; aprotic solvents such as acetic anhydride or DMSO or its mixtures thereof; inorganic solvents such as water, ammonia, sulfuric acid, fluoride, sulfuryl chloride or mixtures thereof. The preferred solvent is water. The base according to step (iv) to the process of the present invention is selected from organic base or inorganic base. The organic base is selected from but not limited to heterocyclic compounds such as pyridine and diazabicycloundec-7-ene (DBU); amines such as diisopropylethylamine (DIPEA), N,N-dimethyl-4-amino-pyridine (DMAP), 1,8- dicyclohexylamine (DCHA), triethylamine; organometallic agents such as butyllithium; organosilicon compounds such as Lithium bis(trimethylsilyl)amide and sodium hexamethyldisilazide or mixtures thereof. The inorganic base is selected from but not limited to alkali or alkaline earth carbonates such as potassium carbonate, sodium carbonate, caesium carbonate, sodium bicarbonate and potassium bicarbonate; alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride; or its mixtures thereof. The preferred base is DIPEA. Step (v): hydrolysis of methyl 2-(1,3-dicylcohexyl-2,4,6-trioxohexahydropyrimidine-5- carboxamido)acetate

[0004] with base to obtain daprodustat. The base in step (v) according to the process of the present invention is selected from the group comprising e organic base or inorganic base. The organic base is selected from but not limited to the group comprising heterocyclic compounds such as pyridine and diazabicycloundec-7-ene (DBU); amines such as diisopropylethylamine (DIPEA), N,N- dimethyl-4-amino-pyridine (DMAP), 1,8-, dicyclohexylamine (DCHA), triethylamine; organometallic agents such as butyllithium; organosilicon compounds such as Lithium bis(trimethylsilyl)amide and sodium hexamethyldisilazide or mixtures thereof. The inorganic base is selected from but not limited to the group comprising alkali or alkaline earth carbonates such as sodium hydroxide, sodium tertiary butoxide, sodium hydride, lithium hydride, ammonium hydroxide, potassium hydride, rubidium hydride, caesium hydride, lithium aluminium hydride; alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali or alkaline earth metal hydride sodium hydride, potassium hydride; or its mixtures thereof. The preferredbase is sodium hydroxide. The steps (i), (ii), (iii), (iv) or (v) according to the present invention, may be carried out in the range from ambient temperature to reflux temperature of solvent or its mixture used during the reaction. In another embodiment the present invention also provides daprodustat and its pharmaceutically acceptable salts thereof. The term “pharmaceutically acceptable salt” is taken to mean an active ingredient, which comprises daprodustat obtained using the process as disclosed in the present invention, wherein the daprodustat is in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt form of the daprodustat can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. In another aspect the present invention provides the process for preparation of an intermediate used in the preparation process of Daprodustat comprising the steps of: Step i): treating 2-aminoacetic acid, in presence of a solvent and a dehydrating agent to obtain a compound of methyl 2- aminoacetate; Step (i) of the present invention, is carried out in presence of suitable solvents selected from but not limited to the group comprising organic solvents selected from alcohols such as ethanol, methanol or isopropanol; ketone such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon such as toluene or benzene; aliphatic hydrocarbon such as hexane or heptane or its mixtures thereof, preferable solvent is methanol; or inorganic solvents selected from water, ammonia, sulfuric acid, fluoride, sulfuryl chloride or mixtures thereof. The preferred solvent is methanol. The dehydrating agent in step (i) is selected from the group comprising thionyl chloride, oxalyl chloride, cyanuric chloride, orthoformic acid, phosphorus pentoxide, or phosphoryl chloride, wherein the dehydrating agent is thionyl chloride. Step ii): treating methyl 2-aminoacetate, with a solvent, a base and triphosgene to obtain Methyl 2-isocyanatoacetate The step (ii) of the present invention, is carried out in presence of suitable solvents selected from but not limited to the group comprising organic solvents selected from alcohols such as ethanol, methanol or isopropanol; ketone such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon such as toluene or benzene; aliphatic hydrocarbon such as hexane or heptane; chlorinated hydrocarbons such as dichloromethane (DCM) and chloroform; or its mixtures thereof; inorganic solvents such as water, ammonia, sulfuric acid, fluoride, sulfuryl chloride or mixtures thereof. The preferred solvent is dichloromethane (DCM). The step (ii) of the present invention comprises the use of base selected from the group comprising organic base or inorganic base. The organic base is selected from but not limited to the group comprising heterocyclic compounds such as pyridine and diazabicycloundec-7-ene (DBU); amines such as diisopropylethylamine (DIPEA), N,N- dimethyl-4-amino-pyridine (DMAP), 1,8-, dicyclohexylamine (DCHA), triethylamine; organometallic agents such as butyllithium; organosilicon compounds such as Lithium bis(trimethylsilyl)amide and sodium hexamethyldisilazide or mixtures thereof. The inorganic base is selected from the group comprising but not limited to alkali or alkaline earth carbonates such as potassium carbonate, sodium carbonate, caesium carbonate, sodium bicarbonate and potassium bicarbonate; alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali or alkaline earth metal hydride sodium hydride, potassium hydride; or its mixtures thereof. The preferred base is pyridine. The Daprodustat obtained using the process of present invention can be used in the preparation of a composition comprising Daprodustat and its pharmaceutically acceptable salts therefore for the treatment of anaemia. Surprisingly, the process of the present invention avoids the drawbacks of the process for preparing Daprodustat as disclosed in the prior arts. Technical advantages: ^ The process of the present invention is cost effective since the process avoids expensive reagents such as dichloromethane. ^ The process of the present invention is environmentally friendly and avoids hazardous chemicals such as DCM which can cause severe side effects in humans such as irritation in skin and respiratory disorders. ^ The process of the present invention involves fewer reaction steps due to the absence of steps such as distillation making the process cost effective and quick. Certain specific aspects and embodiments of the present invention will be explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention. EXAMPLES Example-1: Preparation of methyl 2-aminoacetate: To a solution of charged Glycine (100 gm, 1.332 moles, 1.0 mole ratio) in RBF at room temperature methanol (700 ml, 7.0V mole ratio) was added and the mixture was stirred at RT. The reaction mixture was then cooled to 0-5°C. Thionyl chloride (190 ml, 1.2 mole ratio) was added dropwise to the above reaction mixture. The reaction mixture was then heated to 60-65°C for 4-6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was distilled and the product in the reaction mass was extracted with DCM (200 ml, 2.0 V mole ratio) to obtain a residue. Dry weight: 167.0 gm; % Yield: 100%. Example-2: Preparation of methyl 2-isocyanatoacetate: To a solution of charged Methyl 2-aminoacetate (25 gm, 0.280 moles) in RBF at RT, DCM (125 ml, 18V mole ratio) was added, and the mixture was stirred at RT. The reaction mixture was then cooled to 0°C. A solution of pyridine (102 ml, 1.263 moles, 4.5mole ratio) was added to the above reaction mixture and stirred for 30 min. A solution of triphosgene (83.3gm, 0.280 moles) dissolved in 200 ml DCM was added dropwise to the above mixture at 0-5°C. The reaction mixture was maintained at 0-5°C temperature for 1 hour. The reaction mass was allowed to RT and stirred for 1 hour. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was added with 1N NaOH (300 ml) at 0-5°C, stirred for 20 min at 0-5°C.the layer was separated andthen DCM (125 ml) was added to the aqueous layer, stirred for 10 minutes and organic layer was separated. Further the organic layer was combined, and the DCM layer was washed using brine solution. The organic layer was dried using sodium sulphate and was distilled at 30-35°C to obtain an oily liquid mass. Dry weight: 29.0 gm; % Yield: 89.7 %. Example-3: Preparation of 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione: To a charged solution of 1,3-dicyclohexylurea (50 gm, 0.222 moles, 1.0 mole ratio) in RBF at RT toluene (150 ml, 3V mole ratio) was added, and the mixture was stirred at RT. Then malonic acid (23.19 gm, 0.222 moles, 1.0 mole ratio) was added to the above reaction mixture at RT. Then acetic anhydride (100 ml, 2V mole ratio) was added to the reaction mixture at RT and the reaction mixture was heated to 80-85°C for 3-4 hours. After completion of the reaction, the reaction mass was distilled under vacuum at 60°C. A solution of isopropyl alcohol (100 ml, 2V mole ratio) was added to the residue and heated at 70-75°C for 45 min. The reaction mass was allowed to stir at RT for 1 hour. A white solid was filtered and dried under vacuum. Dry weight: 51.3 gm; % Yield: 78.12 %. Example-4: Preparation of methyl 2-(1,3-dicyclohexyl-2,4,6- trioxohexahydropyrimidine-5-carboxamido)acetate: To a charged solution of 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione (20.0 gm, 0.0684 moles, 1.0 V mole ratio) in RBF at RT, water (100 ml, 5V mole ratio) and stirred for 15 minutes. Followed by addition of DIPEA (13.2 gm, 0.1026, 1.5 mole ratio) to the above reaction mixture and stirred for 30 minutes. A solution of methyl 2-isocynatoacetate (9.4 gm, 0.0820 moles, 1.2 mole ratio) was added drop-wise to the above reaction mixture at RT and stirred for 2-3 hours at RT. The progress of the reaction was checked by TLC. After completion of the reaction, the reaction mass was distilled under vacuum to remove DIPEA and water. To the above reaction mass, water (60 ml, 3V mole ratio) was added and stirred for 30 minutes. A solution of 6M HCl (40 ml, 2V mole ratio) was added slowly and stirred for 1 hour at RT until a solid residue was obtained. The obtained residue was filtered and washed with water (40 ml, 2V mole ratio). To the residue, IPA (232 ml, 8V mole ratio) was added and heated to 60-65°C for 1 hour. The reaction mass was allowed to RT. Again, residue was filtered and washed with IPA (87 ml, 3V mole ratio). Then the residue was dried under vacuum at 55-600C. Dry weight: 20.0 gm; % Yield: 69.4 %. HPLC Data: Example-5: Preparation of Daprodustat: To a charged solution of compound of methyl 2-(1,3-dicyclohexyl-2,4,6- trioxohexahydropyrimidine-5-carboxamido)acetate (20 gm, 0.0490 moles, 1.0 mole ratio) in RBF at RT, water (120.0 ml, 6.3 V mole ratio) was added and then the reaction mixture was stirred for 15 minutes. A solution of 6M NaOH (30 ml, 1.5V mole ratio) was added slowly to the above reaction mixture at 25-30°C and stirred for 2 hours at RT. The progress of the reaction mixture was monitored by TLC. After completion of the reaction, the reaction mixture was allowed to cool at 15-20°C, then a solution of 6M HCl (38 ml) was added slowly to the above reaction mass and stirred for 45-60 minutes at RT. The above reaction mixture was filtered to obtain residue and the residue was washed with water (100 ml). The residue was re-slurred with water (100 ml, 10V mole ratio) and stirred for 1-2 hours at 35-40°C. The solid residue was filtered and washed with water (40 ml,2.0V mole ratio). The residue was dissolved in IPA (100 ml, 5.0V mole ratio) and stirred for 1 hour at 65-70°C. The mixture allowed for reaction at RT and stirred for 45-60 minutes. The reaction mixture was filtered to obtain residue and washed with IPA (40 ml, 2.0V mole ratio). The residue dried at 50-550C under vacuum for 6-8 hours. Dry weight: 17.30 gm; % Yield: 75%, Purity: 100% HPLC HPLC Data:

Claims

We claim:

1. A process for preparing daprodustator its pharmaceutically acceptable salts, comprising the steps of: (i) treating 2-aminoacetic acidwith a solvent and a dehydrating agent to obtain methyl 2-aminoacetate; (ii) treating methyl 2-aminoacetate obtained in step (i) with a solvent, base and triphosgene to obtain methyl 2-isocyanatoacetate;(iii) condensing 1,3-dicyclohexylureain presence of an acid and solvents to obtain 1,3-dicyclohexylpyrimidine- 2,4,6(1H,3H,5H)-trione;(iv) treating 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione obtained in step (iii) with methyl 2-isocynatoacetate obtained in step (ii) in the presence of a solvent and a base to obtain methyl 2-(1,3-dicylcohexyl-2,4,6-trioxohexahydropyrimidine- 5-carboxamido) acetate; and(v) hydrolysing methyl 2-(1,3-dicylcohexyl-2,4,6-trioxohexahydropyrimidine-5- carboxamido)acetate obtained in step (iv) with a base to obtain daprodustat.

2. The process as claimed in claim 1, wherein the solvent in step (i) selected from the group comprising organic solvent or inorganic solvent.

3. The process as claimed in claim 2, wherein the organic solvent is selected from the group comprising alcohols such as ethanol, methanol or isopropanol; ketone such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon such as toluene or benzene; aliphatic hydrocarbon such as hexane or heptane or its mixtures thereof.

4. The process as claimed in claim 2, wherein the inorganic solvent is selected from the group comprising water, ammonia, sulfuric acid, fluoride, sulfuryl chloride or mixtures thereof.

5. The process as claimed in claim 3, wherein the organic solvent is methanol.

6. The process as claimed in claim 1, wherein the dehydrating agent in step (i) is selected from the group comprising thionyl chloride, oxalyl chloride, cyanuric chloride, orthoformic acid, phosphorus pentoxide, or phosphoryl chloride.

7. The process as claimed in claim 6, wherein the dehydrating agent is thionyl chloride.

8. The process as claimed in claim 1, wherein the solvent in step (ii) is selected from the group comprising organic solvent or inorganic solvent.

9. The process as claimed in claim 8, wherein the organic solvent is selected from group comprising alcohols such as ethanol, methanol or isopropanol; ketone such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon such as toluene or benzene; aliphatic hydrocarbon such as hexane or heptane; chlorinated hydrocarbons such as dichloromethane (DCM) and chloroform; or its mixtures thereof.

10. The process as claimed in claim 8, wherein the inorganic solvent is selected from the group comprising water, ammonia, sulfuric acid, fluoride, sulfuryl chloride or mixtures thereof.

11. The process as claimed in claim 9, wherein the organic solvent is dichloromethane (DCM).

12. The process as claimed in claim 1, wherein the base in step (ii) is selected from group comprising organic base or inorganic base.

13. The process as claimed in claim 12, wherein the organic base is selected from the group comprising heterocyclic compounds such as pyridine and diazabicycloundec-7-ene (DBU); amines such as diisopropylethylamine (DIPEA),N,N-dimethyl-4-amino-pyridine (DMAP), 1,8-, dicyclohexylamine (DCHA), triethylamine; organometallic agents such as butyllithium; organosilicon compounds such as Lithium bis(trimethylsilyl)amide or sodium hexamethyldisilazide or mixtures thereof.

14. The process as claimed in claim 12, wherein the inorganic base is selected from group comprising alkali or alkaline earth carbonates such as potassium carbonate, sodium carbonate, caesium carbonate, sodium bicarbonate and potassium bicarbonate; alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali or alkaline earth metal hydride sodium hydride, potassium hydride; or its mixtures thereof.

15. The process as claimed in claim 12, wherein the organic base is pyridine.

16. The process as claimed in claim 1, wherein the solvents in step (iii) are selected from organic solvents or inorganic solvents.

17. The process as claimed in claim 16, wherein the organic solvents are selected from groups comprising alcohols such as ethanol, methanol or isopropanol; ketones such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; ethers such as dioxane and tetrahydrofuran; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbons such as toluene or benzene; aliphatic hydrocarbons such as hexane or heptane; chlorinated hydrocarbons such as dichloromethane and chloroform; aprotic solvents such as acetic anhydride or DMSO or its mixtures thereof.

18. The process as claimed in claim 16, wherein the inorganic solvents are selected from water, ammonia, sulfuric acid, fluoride, sulfuryl chloride or mixtures thereof.

19. The process as claimed in claim 17, wherein the organic solvents are acetic anhydride and toluene.

20. The process as claimed in claim 1, wherein the acid in step (iii) is selected from group comprising malonic acid, acetic acid, formic acid, benzoic acid, salicylic acid, carboxylic acid or oxalic acid.

21. The process as claimed in claim 20, wherein the acid is malonic acid.

22. The process as claimed in claim 1, wherein the solvent in step (iv) is selected from the group comprising organic solvent or inorganic solvent.

23. The process as claimed in claim 22, wherein the organic solvent is selected from group comprising alcohols such as ethanol, methanol or isopropanol; ketones such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; ethers such as dioxane and tetrahydrofuran; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbons such as toluene or benzene; aliphatic hydrocarbons such as hexane or heptane; chlorinated hydrocarbons such as dichloromethane and chloroform; aprotic solvents such as acetic anhydride or DMSO or its mixtures thereof.

24. The process as claimed in claim 22, wherein the inorganic solvent is selected from water, ammonia, sulfuric acid, fluoride, sulfuryl chloride or mixtures thereof.

25. The process as claimed in claim 24, wherein the inorganic solvent is water.

26. The process as claimed in claim 1, wherein the base in step (iv) is selected from the group comprising organic base or inorganic base.

27. The process as claimed in claim 26, wherein the organic base is selected from the group comprising heterocyclic compounds such as pyridine and diazabicycloundec-7-ene (DBU); amines such as diisopropylethylamine (DIPEA), N,N-dimethyl-4-amino-pyridine (DMAP), 1,8-, dicyclohexylamine (DCHA), triethylamine; organometallic agents such as butyllithium; organosiliconcompounds such as lithium bis(trimethylsilyl)amide and sodium hexamethyldisilazide or mixtures thereof.

28. The process as claimed in claim 26, wherein the inorganic base is selected from group comprising alkali or alkaline earth carbonates such as potassium carbonate, sodium carbonate, caesium carbonate, sodium bicarbonate and potassium bicarbonate; alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride; or its mixtures thereof.

29. The process as claimed in claim 27, wherein the organic base is DIPEA.

30. The process as claimed in claim 1, wherein the base in step (v) is selected from the group comprising organic base or inorganic base.

31. The process as claimed in claim 30, wherein the organic base is selected from groups comprising heterocyclic compounds such as pyridine and diazabicycloundec-7-ene (DBU); amines such as diisopropylethylamine (DIPEA), N,N-dimethyl-4-amino-pyridine (DMAP), 1,8-, dicyclohexylamine (DCHA), triethylamine; organometallic agents such as butyllithium; organosilicon compounds such as Lithium bis(trimethylsilyl)amide and sodium hexamethyldisilazide or mixtures thereof.

32. The process as claimed in claim 30, wherein inorganic base is selected from groups comprising alkali or alkaline earth carbonates such as sodium hydroxide, sodium tertiary butoxide, sodium hydride, lithium hydride, ammonium hydroxide, potassium hydride, rubidium hydride, caesium hydride, lithium aluminium hydride; alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride; or its mixtures thereof.

33. The process as claimed in claim 32, wherein the inorganic base is sodium hydroxide.

34. A process for preparing methyl 2-isocyanatoacetatecomprising the steps of: (i) treating 2-aminoacetic acidwith a dehydrating agent in presence of a solvent to obtain methyl 2-aminoacetate;(ii) reacting methyl 2-aminoacetate obtained from step (i) with a solvent, base and triphosgene to obtain methyl 2-isocyanatoacetate.

35. The process as claimed in claim 34, wherein the solvent in step (i) is selected from the group comprising organic solvent or inorganic solvent.

36. The process as claimed in claim 35, wherein the organic solvent is selected from the group comprising alcohols such as ethanol, methanol or isopropanol; ketone such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon such as toluene or benzene; aliphatic hydrocarbon such as hexane or heptane or its mixtures thereof.

37. The process as claimed in claim 35, wherein the inorganic solvent is selected from the group comprising water, ammonia, sulfuric acid, fluoride, sulfuryl chloride or mixtures thereof.

38. The process as claimed in claim 36, wherein the organic solvent is methanol.

39. The process as claimed in claim 24, wherein the dehydrating agent in step (i) is selected from the group comprising thionyl chloride, oxalyl chloride, cyanuric chloride, orthoformic acid, phosphorus pentoxide, or phosphoryl chloride.

40. The process as claimed in claim 39, wherein the dehydrating agent is thionyl chloride.

41. Use of daprodustat prepared by the process as claimed in claim 1 in treatment of anaemia.

42. A pharmaceutical composition comprising daprodustat or its pharmaceutically acceptable salts thereof as claimed in anyone of claims 1 to 33.

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