DESC:
FIELD OF INVENTION:
The present invention relates to an improved process for the preparation of Daprodustat. Specifically, the invention provides a simple, cost-effective, commercially viable, and industrially applicable method for synthesizing Daprodustat.

BACKGROUND OF THE INVENTION:
Daprodustat is a small-molecule hypoxia-inducible factor prolyl hydroxylase inhibitor used for the treatment of anemia in patients with chronic kidney disease. The chemical name of Daprodustat is N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl) carbonyl] glycine, having the structural formula as represented by formula I:

Formula I
Daprodustat was approved for medical use in Japan in June 2020 and in the United States in February 2023 under the trade name Duvroq and Jesduvroq.
Daprodustat was first disclosed in US Patent No. 8,324,208 (hereinafter referred to as the “US ‘208 patent”). Example 18 of the US ‘208 patent describes two distinct methods for the preparation of Daprodustat. These processes are schematically illustrated in the following reaction schemes:

Method-1:

Method-2:

WO2023006986 discloses a one-pot or single-vessel process for the preparation of Daprodustat (I). The process involves reacting 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione with ethyl isocyanatoacetate in the presence of a non-nucleophilic organic or inorganic base, without isolating the intermediate Daprodustat ethyl ester. Subsequently, an inorganic base and a protic acid are added to the reaction mixture to yield Daprodustat (I) and the disclosed process is schematically depicted in the following scheme:

The prior art processes employ hazardous reagents such as malonyl dichloride, N,N’-dicyclohexylcarbodiimide, and ethyl isocyanatoacetate, as well as toxic solvents including chloroform and tetrahydrofuran for the preparation of Daprodustat. The use of ethyl isocyanatoacetate results in the formation of a significant amount of impurities, presents critical handling challenges, and involves a reagent that is expensive and chemically unstable. Consequently, these processes are unsafe and unsuitable for large-scale industrial production.

However, there remains a need for an alternative process for the preparation of Daprodustat that utilizes reagents and solvents which are less expensive, safer, and easier to handle. Such a process should also minimize solvent consumption while delivering higher product yield and improved purity. Accordingly, the primary objective of the present invention is to provide a simple, cost-effective, commercially viable, and industrially applicable process for synthesizing Daprodustat of formula I, overcoming the limitations of existing methods.

SUMMARY OF THE INVENTION:
Accordingly, the present invention provides a process for the preparation of Daprodustat of formula I. The process offers advantageous properties, including simplicity, cost-effectiveness, commercial viability, and suitability for industrial-scale application.

In one aspect, the present invention provides a process for the preparation of Daprodustat of formula I, which comprises:
a) reacting 1,3-Dicyclohexylurea of formula II with Malonic acid in the presence of a chlorinating reagent and a suitable solvent to provide 1,3-Dicyclohexylpyrimidine-2,4,6(lH,3H,5H)-trione of formula III;

b) reacting 1,3-Dicyclohexylpyrimidine-2,4,6(lH,3H,5H)-trione of formula III with glycine ester of general formula IV or its salt in the presence of a coupling agent and a base in a suitable solvent to provide N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl) carbonyl] glycine ester of general formula V; and

c) converting N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl) carbonyl] glycine ester of general formula V into Daprodustat of formula I.

In another aspect, the present invention provides a process for the preparation of N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl] glycine ester of general formula V. The process comprises reacting 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione of formula III with a glycine ester of general formula IV or its salt, in the presence of a coupling agent and a base, within a suitable solvent, to yield the N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl] glycine ester of general formula V.

In yet another aspect, the present invention provides a pharmaceutical composition comprising Daprodustat prepared according to the process of the present invention, together with at least one pharmaceutically acceptable excipient.

DETAILED DESCRIPTION:
The following description with accompanying drawings is provided to assist in a comprehensive understanding of exemplary embodiments of the invention. It includes various specific details to assist in that understanding but these are to be regarded as merely exemplary.

Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope of the invention. In addition, descriptions of well-known functions and constructions are omitted for clarity and conciseness.

The terms and words used in the following description and claims are not limited to the bibliographical meanings, but, are merely used by the inventor to enable a clear and consistent understanding of the invention. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present invention are provided for illustration purpose only and not for the purpose of limiting the scope of the invention as defined by the appended claims and their equivalents.

It is to be understood that the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

Features that are described and/or illustrated with respect to one embodiment may be used in the same way or in a similar way in one or more other embodiments and/or in combination with or instead of the features of the other embodiments.

It should be emphasized that the term “comprises/comprising” when used in this specification is taken to specify the presence of stated features, steps or components but does not preclude the presence or addition of one or more other features, steps, components or groups thereof.

The term “base” used herein the present invention until unless specified is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like, ammonia and organic bases such as triethylamine, methylamine, ethylamine, 1,8-diazabicycle[5.4.0]undec7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamine (LDA), n- butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine (DIPA), diisopropylethyl amine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethyl amino pyridine (DMAP), morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methylimidazole, 1,2,4-triazole, 1,4-diazabicyclo [2.2.2]octane (DABCO) or mixtures thereof.

The term “solvent/ suitable solvent” used in the present invention is selected from the group comprising of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated solvents; wherein alcohol is selected from the group consisting of methanol, ethanol, iso-propanol, n-butanol, iso-butanol and the like; ester is selected from the group consisting of ethyl acetate, isopropyl acetate; ketone is selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone; ether is selected from the group consisting of methyl tert-butyl ether, diisopropyl ether, diethyl ether tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether, dioxane and the like; halogenated solvent is selected from the group consisting of dichloromethane, chloroform, chlorobenzene, bromobenzene and the like; hydrocarbons is selected from the group consisting of heptane, hexane, cyclohexane, cycloheptane, toluene, xylene, cyclohexane and the like; nitrile is selected from the group consisting of acetonitrile, propionitrile and the like; amide is selected from the group consisting of N,N-dimethylformamide, N,N-dimethyl acetamide and the like; sulfoxide such as dimethyl sulfoxide; sulfone; or mixtures thereof.

The term “chlorinating reagent” used in the present invention is selected from but not limited to phosphorous oxychloride, thionyl chloride, oxalyl chloride, hydrochloric acid, ammonium chloride, chlorosucinimide, zinc chloride, lithium chloride, sodium chloride, magnesium chloride, sulfuryl chloride, phosphorus pentachloride, cyanuric chloride and the like.

The term “coupling agent” used in the present invention is selected from but not limited to carbonyldiimidazole (CDI), Dimethyl carbonate (DMC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), N, N'-Diisopropyl carbodiimide (DIC) and dicyclohexyl carbodiimide (DCC) and the like.

The invention relates to an environmentally friendly and cost-effective method for the preparation of Daprodustat of formula I. Specifically, the invention provides a process for obtaining Daprodustat from a glycine ester or its salt, offering a safer and more economical alternative to the use of ethyl isocyanatoacetate as disclosed in the prior art.

In one embodiment, the present invention provides a process for the preparation of Daprodustat of formula I, which comprises:
a) reacting 1,3-Dicyclohexylurea of formula II with Malonic acid in the presence of a chlorinating reagent and a suitable solvent to provide 1,3-Dicyclohexylpyrimidine-2,4,6(lH,3H,5H)-trione of formula III;

b) reacting 1,3-Dicyclohexylpyrimidine-2,4,6(lH,3H,5H)-trione of formula III with glycine ester of general formula IV or its salt in the presence of a coupling agent and a base in a suitable solvent to provide N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl) carbonyl] glycine ester of general formula V; and

c) converting N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl) carbonyl] glycine ester of general formula V into Daprodustat of formula I.

The starting compound of formula II is well-known in the art and commercially available; it can be prepared by known methods or obtained from commercial sources.
In accordance with the above process, step (a) involves reacting 1,3-dicyclohexylurea of formula II with malonic acid in the presence of a chlorinating reagent and a suitable solvent under appropriate reaction conditions to yield 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione of formula III.

The chlorinating reagent used in step (a) is selected from phosphorus oxychloride, thionyl chloride, oxalyl chloride, hydrochloric acid, ammonium chloride, chlorosuccinimide, zinc chloride, lithium chloride, sodium chloride, magnesium chloride, sulfuryl chloride, phosphorus pentachloride, cyanuric chloride, and the like; preferably, phosphorus oxychloride.

The suitable solvent used in step a) is as defined above; preferably nitriles such as acetonitrile, propionitrile and the like.

The step a) reaction can be carried out at a suitable temperature of about 20°C to about 70°C for a sufficient period till completion of the reaction; preferably for about 3 to 4 hours at about 40°C to about 60°C.

In the prior art, 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione of formula III is typically produced using malonyl dichloride or N,N’-dicyclohexylcarbodiimide, both of which are hazardous, expensive, and present critical handling challenges. These reagents often lead to the formation of byproducts, resulting in lower yields. Consequently, such processes are unsafe and unsuitable for large-scale production.

However, the inventors of the present invention have surprisingly found that using a catalytic amount of chlorinating agent in the preparation of 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione of formula III results in stable reaction conditions, reduced formation of unwanted impurities, and improved yields. This approach is inexpensive and offers a simple, cost-effective, commercially viable, and industrially applicable process.

In accordance with the above process, step (b) involves reacting 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione of formula III with a glycine ester of general formula IV or its salt, wherein R is an alkyl or aryl group such as methyl, ethyl, propyl, butyl, pentyl, hexyl, benzyl, or the like, preferably ethyl. The reaction is carried out in the presence of a coupling agent and a base in a suitable solvent under appropriate conditions to provide N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl] glycine ester of general formula V.

The coupling agent used in step (b) is selected from carbonyldiimidazole (CDI), dimethyl carbonate (DMC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N'-diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), and the like; preferably carbonyldiimidazole (CDI) or dimethyl carbonate (DMC).

The base used in step (b) is selected from inorganic bases such as alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, ammonia, organic bases, and the like; preferably, an organic base such as diisopropylethylamine.

The suitable solvent used in step b) is as defined above; preferably halogenated solvents such as dichloromethane, chloroform, chlorobenzene, bromobenzene and the like.

The step b) reaction can be carried out at a suitable temperature of about 30°C to about 90°C for a sufficient period till completion of the reaction; preferably for about 3 to 8 hours at about 50°C to about 90°C.

In prior art processes, N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl] glycine ester (e.g., ethyl ester) is prepared from 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione of formula III using ethyl isocyanatoacetate. This reagent is expensive, unstable, and presents critical handling challenges, often resulting in higher impurity levels. Consequently, such processes are unsafe and unsuitable for large-scale production.
However, the inventors of the present invention have surprisingly found that using the adduct prepared from a glycine ester of general formula IV or its salt and a coupling agent in the synthesis of N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl] glycine ester of general formula V results in a process that is simple, cost-effective, commercially viable, and suitable for industrial application.

In accordance with the above process, step (c) involves converting N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl] glycine ester of general formula V, wherein R is an alkyl or aryl group such as methyl, ethyl, propyl, butyl, pentyl, hexyl, benzyl, or the like, preferably ethyl, into Daprodustat of formula I by deprotecting the compound with a base in a suitable solvent.

The base used in step (c) is selected from inorganic bases such as alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, ammonia, organic bases, and the like; preferably, alkali metal hydroxides including lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like.

The suitable solvent used in step c) is as defined above; preferably alcohols such methanol, ethanol, iso-propanol, n-butanol, iso-butanol and the like.

In another embodiment, Daprodustat can be prepared via a one-pot process wherein the intermediate N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl] glycine ester of formula V is not isolated.

In yet another embodiment, the present invention provides a process for the preparation of N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl] glycine ester of general formula V, comprising reacting 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione of formula III with a glycine ester of general formula IV or its salt in the presence of a coupling agent and a base in a suitable solvent to yield the desired glycine ester intermediate:

In accordance with the above process, 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione of formula III is reacted with a glycine ester of general formula IV or its salt, wherein R is an alkyl or aryl group such as methyl, ethyl, propyl, butyl, pentyl, hexyl, benzyl, or the like, preferably ethyl, in the presence of a coupling agent and a base in a suitable solvent under appropriate conditions to provide N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl)carbonyl] glycine ester of general formula V.

The coupling agent used in the above process is selected from carbonyldiimidazole (CDI), dimethyl carbonate (DMC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N'-diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), and the like; preferably carbonyldiimidazole (CDI) or dimethyl carbonate (DMC).

The base used in the above process is selected from inorganic bases such as alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, ammonia, organic bases, and the like; preferably, an organic base such as diisopropylethylamine.

The suitable solvent used in the above process is as defined above; preferably, halogenated solvents such as dichloromethane, chloroform, chlorobenzene, bromobenzene, and the like.

In the above process, the reaction can be carried out at a suitable temperature of about 30°C to about 90°C for a sufficient period till completion of the reaction; preferably for about 3 to 8 hours at about 50°C to about 90°C.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising Daprodustat prepared according to the process of the present invention, together with at least one pharmaceutically acceptable excipient. The composition may include excipients such as diluents, binders, disintegrants, lubricants, and glidants, selected to ensure optimal stability, bioavailability, and manufacturability. Suitable excipients include, but are not limited to, microcrystalline cellulose, mannitol, hypromellose, croscarmellose sodium, magnesium stearate, and colloidal silica.

The pharmaceutical composition can be formulated into immediate release tablets, granules, or other solid dosage forms, providing a stable and effective dosage form for the treatment of anemia associated with chronic kidney disease.

EXAMPLES:
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example-1:
Preparation of 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione (III):
To a stirred solution of 1,3-dicyclohexyl urea (100 g, 0.4457 moles, 1.0 eq) in acetonitrile, malonic acid (55.6 g, 0.5348 moles, 1.2 eq) and phosphorus oxychloride (20.50 mL, 0.1337 moles, 0.3 eq) were added. The reaction mixture was heated to 50 to 60 °C in an oil bath and stirred for 3-4 hours at same temperature. After completion of reaction, the mixture was cooled to room temperature. The solid obtained was filtered and washed with ethyl acetate to get the title compound (98.0 g, 75.38 %).

Example-2:
Preparation of Ethyl N-(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl)-glycinate (IV):
Method-1:
To a stirred solution of 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione (90 g, 0.3078 moles, 1.0 eq) in dichloromethane, 1,1'-Carbonyldiimidazole (49.9 g,0.3078 moles,1.0 eq), ethyl glycinate (32.02g, 0.3078 moles, 1.0 eq) and diisopropylethylamine (107.25 mL, 0.7695 moles, 2.5 eq) were added. The reaction mixture was heated to 50 to 55 °C and stirred for 6-8 hours at same temperature. After completion of reaction, the mixture was concentrated under reduced pressure. The obtained crude product was crystallized in hexane to get the title compound (103 g, 79.38 %)

Method-2:
To a stirred solution of 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione (90 g, 0.3078 moles, 1.0 eq) in dichloromethane, dimethyl carbonate (27.70g, 0.3078 moles, 1.0 eq), ethyl glycinate (32.02g, 0.3078 moles, 1.0 eq) and diisopropylethylamine (107.25 mL,0.7695 moles, 2.5 eq) were added. The reaction mixture was heated to 70 to 85 °C and stirred for 3-4 hours at same temperature. After completion of reaction, the reaction mixture was washed with water (100 mL) and extracted with dichloromethane (2 x 180 mL), resulted organic layer was dried with sodium sulfate and evaporated under reduced pressure, the obtained crude was crystallized in hexane to get the title compound (70 g, 53.95 %).

Example-3:
Preparation of Daprodustat (I):
To a stirred solution of ethyl(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl)-glycinate (90 g, 0.213 moles, 1.0 eq) in ethanol were added to the aqs 6M NaOH solution at 25 to 35 °C and stirred for 2-3 hours at same temperature. After completion of reaction, the reaction mass was acidified with aqs 6M HCl and diluted with water. The crude solid obtained was filtered and washed with water. The crude wet material was slurred in water at 35-40 °C for 30 min and dried under vacuum to get the title compound (78 g, 92.84 %).
,CLAIMS:
1. A process for the preparation of Daprodustat of formula I, which comprises:
a) reacting 1,3-Dicyclohexylurea of formula II with Malonic acid in the presence of a chlorinating reagent and a suitable solvent to provide 1,3-Dicyclohexylpyrimidine-2,4,6(lH,3H,5H)-trione of formula III;

b) reacting 1,3-Dicyclohexylpyrimidine-2,4,6(lH,3H,5H)-trione of formula III with glycine ester of general formula IV or its salt in the presence of a coupling agent and a base in a suitable solvent to provide N-[(1,3-Dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl) carbonyl] glycine ester of general formula V; and

c) converting N-[(1,3-Dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl) carbonyl] glycine ester of general formula V into Daprodustat of formula I.

2. The process as claimed in claim 1, wherein the chlorinating reagent in step a) is selected from phosphorous oxychloride, thionyl chloride, oxalyl chloride, hydrochloric acid, ammonium chloride, chlorosucinimide, zinc chloride, lithium chloride, sodium chloride, magnesium chloride, sulfuryl chloride, phosphorus pentachloride and cyanuric chloride.

3. The process as claimed in claim 1, wherein the coupling agent in step b) is selected from carbonyldiimidazole, dimethyl carbonate, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, N, N'-diisopropyl carbodiimide and dicyclohexyl carbodiimide.

4. The process as claimed in claim 1, wherein R is alkyl or aryl such as methyl, ethyl, propyl, butyl, pentyl, hexyl and benzyl.

5. A process for the preparation of N-[(1,3-Dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl) carbonyl] glycine ester of general formula V, comprising:
reacting 1,3-Dicyclohexylpyrimidine-2,4,6(lH,3H,5H)-trione of formula III with glycine ester of general formula IV or its salt in the presence of a coupling agent and a base in a suitable solvent to provide N-[(1,3-Dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl) carbonyl] glycine ester of general formula V.

6. The process as claimed in claim 5, wherein the coupling agent is selected from carbonyldiimidazole, dimethyl carbonate, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, N, N'-diisopropyl carbodiimide and dicyclohexyl carbodiimide.

7. The process as claimed in claim 5, wherein R is alkyl or aryl such as methyl, ethyl, propyl, butyl, pentyl, hexyl and benzyl.

8. The process as claimed in claim 5, wherein the N-[(1,3-Dicyclohexylhexahydro-2,4,6-trioxopyrimidin-5-yl) carbonyl] glycine ester of general formula V is further converted to Daprodustat of formula I.