DESC:RELATED APPLICATION
This application claims the benefit of priority of Indian patent application number IN 202121026301 filed on Jun. 14, 2021, which is incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to an improved process of preparation of Darolutamide of Formula (I) and its intermediates.
BACKGROUND OF THE INVENTION
Darolutamide, has a chemical name N-((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide. Darolutamide is represented by the following chemical structure according to Formula (I).

I
Darolutamide is an androgen receptor (AR) inhibitor. Darolutamide competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. In addition, darolutamide functioned as a progesterone receptor (PR) antagonist in vitro (approximately 1% activity compared to AR). Darolutamide decreased prostate cancer cell proliferation in vitro and tumor volume in mouse xenograft models of prostate cancer.
U.S. Patent No. 8,975,254 discloses the preparation of Darolutamide by the process as depicted in Scheme I:

Scheme 1
Considering the importance of Darolutamide in the pharmaceutical field, there is a need to develop an alternative process for the synthesis of Darolutamide which is simple and cost effective, and avoids use of palladium catalyst.
SUMMARY OF THE INVENTION
An aspect is to provide an improved process of preparation of Darolutamide, comprising the steps of:

(I)
a) converting compound of Formula (III) in to compound of Formula (V);

(III) (V)
b) converting the compound of Formula (V) into compound of Formula (VII);

(VII)
c) reacting the compound of Formula (VII) with compound of formula (VIII) to obtain compound of Formula (IX);

(IX) (VIII)
wherein PG is amine protecting group selected from BOC, CBz, Bn, trityl, silyl; and
d) condensing the compound of Formula (IX) with the compound of Formula (X) to obtain the compound of Formula (XI); and

(X) (XI)
e) reducing the compound of Formula (XI) into compound of Formula (I) using suitable reducing agent.
Another aspect is to provide a process comprising converting compound of formula (II), (III) and (IV) to Darolutamide compound of formula (I).

II III IV
DETAILED DESCRIPTION OF THE INVENTION
An embodiment is to provide an improved process of preparation of Darolutamide, comprising the steps of:
a) chlorination of compound of Formula (II) to compound of Formula (III) using a chlorinating agent;

II III
b) converting the compound of Formula (III) into compound of Formula (V);

V
c) converting the compound of Formula (V) into compound of Formula (VII) ;

VII
d) reacting the compound of Formula (VII) with compound of Formula (VIII) to obtain the compound of Formula (IX);

VIII IX
wherein PG is amine protecting group such as BOC, CBz, Bn, trityl, silyl and like.
e) reacting the compound of Formula (IX) with Formula (X) to obtain the compound of Formula (XI);

X XI
f) converting the compound of Formula (XI) into compound of Formula (I) in presence of suitable reducing agent.
In one embodiment of the present invention, in step (a) chlorinating agent used is selected from iodobenzne dichloride, N-chloro succinmide (NCS), N-chlorophthalimide, 1,3-dichloro5, 5-dimethylhydantoin, trichloroisocyanuric Acid, N-chlorosaccharin and the like. Optionally, the reaction may be carried out in presence of base such as pyridine, picoline, lutidine, 4-dimethylaminopyridine (DMAP), triethylamiine, diisopropylethylamine and the like. The reaction may be carried out in the presence of an inert organic solvent including but not limited to solvent such as toluene, tetrahydrofuran (THF), dichloromethane (DCM), acetonitrile (ACN), 1,4-Dioxane, acetic acid, isopropyl alcohol (IPA) and mixtures thereof. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used. Specifically, the reaction step (a) may be carried out at a temperature of about 0°C to 5°C.
In one embodiment, compound of Formula (III) may be isolated and purified if required from the reaction mixture by any known technique in the art OR the compound can be subjected to next reaction without isolation and/or purification.
In another embodiment of present invention compound of Formula (III) is converted into compound of Formula (V) by adopting, but not limited to, one of the following three techniques.
In first approach, in step (b), compound of Formula (III) is converted to compound of Formula (IV)

IV
via diazotization using sodium nitrite in presence of acid such a sulfuric acid or hydrochloric acid followed by helogenation using KI/CuI, potassium iodide (KI), sodium iodide (NaI) to obtain compound of formula (IV). The reaction may be carried out in the presence or absence of solvent. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used. Specifically, the reaction step (b) may be carried out at a temperature of about 0°C to ambient temperature.
The Formula (IV) may be isolated and purified if required from the reaction mixture by any known technique in the art OR the compound can be subjected to next reaction without isolation and/or purification.
The compound of formula (IV) is further converted to compound of formula (V) using cyanating agent such as copper cyanide (CuCN), sodium cyanide (NaCN), potassium cyanide, zinc cyanide. The reaction may be carried out in the presence of an inert organic solvent including but not limited to solvent such as N-methyl pyrollidine (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methylmorpholine (NMM) and mixtures thereof. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used. Specifically, the reaction step (b) may be carried out at a temperature of about 100 to 120°C.
In another approach, compound of formula (IV) is converted to compound of formula (V) using grignard regent such as isopropyl magnesium chloride (iPrMgCl), isopropyl magnesium chloride-lithium chloride (iPrMgCl.LiCl); followed by quenching with N-methoxy-N-methylacetamide and N-acetylmorpholine to obtain compound of formula (V). The reaction may be carried out in the presence of an inert organic solvent including but not limited to solvent such as tetrahydrofuran, 2-methyl tetrahtdrofuran, and toluene. The reaction may be carried out at a temperature of about -78 °C to about boiling point of the solvent used. Specifically, the reaction step (b) may be carried out at a temperature of about -78°C to ambient temperature.
In yet another approach, in step (b), compound of Formula (III) is first diazotized using (a) sodium nitrite in presence of acid such a sulfuric acid or hydrochloric acid followed by cyanation such as copper cyanide (CuCN), sodium cyanide (NaCN), potassium cyanide, zinc cyanide or (b) non aqueous condition using tert-butyl nitrite followed by cyanation such as copper cyanide (CuCN), sodium cyanide (NaCN), potassium cyanide, zinc cyanide to obtain compound of formula (V). The reaction may be carried out in the presence or absence of solvent selected from such as acetic acid, water, toluene, acetonitrile. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used. Specifically, the reaction step (b) may be carried out at a temperature of about 0 to ambient temperature.
In one embodiment, compound of Formula (V) may be isolated and purified if required from the reaction mixture by any known technique in the art OR the compound can be subjected to next reaction without isolation and/or purification.
In another embodiment of present invention compound of Formula (V) is converted to compound of Formula (VII) by adopting any one of the following approaches.
In one approach, in step (c), compound of Formula (V) is first converted to compound of Formula (VI);

VI
using reagent such as N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide diisopropyl acetal, gold's reagent, N'-[(dimethylamino)methoxymethyl]-N,N-dimethylmethanimidamide, dimethl acetamide and p-toluenesulfonic acid; ethyl orthoformate, ethyl formate or methyl formate, nitrometane in combination with dimethylamine. The reaction may be carried out in the presence of an inert organic solvent including but not limited to solvent such as toluene, xylene, benzene, N,N-dimethylformamide (DMF), chlorobenzene, anisole, 1,4-dioxane, methanol, ethanol, isopropyl alcohol and mixtures thereof. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used. Specifically, the reaction step (c) may be carried out at a temperature 60-110°C.
The Formula (VI) may be isolated and purified if required from the reaction mixture by any known technique in the art OR the compound can be subjected to next reaction without isolation and/or purification.
The compound of Formula (VI) is converted to compound of Formula (VII) by treating with hydrazine hydrate. The reaction may be carried out in the presence of an inert organic solvent including but not limited to solvent such as ethanol, methanol, isopropyl alcohol, n-propyl alcohol, butanol, THF, 1,4-dioxane, 2-methyl tetrahydrofuran and mixtures thereof. The reaction may optionally be carried out in presence of acid such as p-toluenesulfonic acid, sulfuric acid, hydrochloric acid. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used. Specifically, the reaction step (c) may be carried out at a temperature at 60-70°C.
In another approach, in step (c), compound of Formula (V) is first converted to compound of Formula (VI-a)

VI-a
using 4-methylbenzenesulfonic acid (2E)-2-(1-phenylethylidene)hydrazide. Further, compound of Formula (VI-a) is converted to compound of Formula (VII) using 2-(dimethylamino)malononitrile in presence of catalyst such as selected from Cu(OTf)2, Zn(OTf)2, Yb(OTf)3, Y(OTf)3, TsOH, TFA, AlCl3 followed by tosyl de-protection using suitable base such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate. The reaction may be carried out in the presence of an inert organic solvent including but not limited to solvent such as methanol, ethanol, isopropyl alcohol, propanol, butanol; dichloromethane, dichloroethane, chlorobenzene, and mixtures thereof. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used. Specifically, the reaction step (c) may be carried out at a temperature 100-110°C.
In one embodiment, compound of Formula (VII) may be isolated and purified if required from the reaction mixture by any known technique in the art OR the compound can be subjected to next reaction without isolation and/or purification.
In another embodiment of the present invention, in step (d) can be carried out in presence of the ligand such as from triphenylphosphine (PPh3), tributyl phosphine (TBP), tricyclohexyl- phosphine (PCy3) the oxidant such as from diisopropylazodicarboxylate (DIAD) 1,1'-(azodicarbonyl)dipiperidine (ADDP), 4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-dione (DHTD), and N,N,N',N'-tetramethylazodicarboxamide (TMAD) in presence of an inert organic solvent including but not limited to solvent such as ethyl acetate, ethanol, methanol, THF and mixtures thereof and then; followed by de-protection by treatment with acid such as p-toluenesulfonic acid, hydrobromic acid, sulfuric acid, hydrochloric acid to provide respective acid addition salt.
Obtained acid addition salt can be used directly in next reaction or neutralized with the base such as NaOH, cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, triethylamine, diisopropylethylamine , 2,6-lutidine, DBU or dimethylaniline to obtain compound of Formula (IX).
Further, compound of Formula (IX) can be further converted in the form of acid addition salt such as hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, sulfuric acid.
In one embodiment, compound of Formula (IX) may be isolated and purified if required from the reaction mixture by any known technique in the art OR the compound can be subjected to next reaction without isolation and/or purification.
In another embodiment of the present invention, in step (e) the coupling agent can be selected from BOP, PyBOP, HBTU, HOBt. Optionally the reaction may be carried out in the presence of base which may be organic or inorganic base. The organic base can be selected from di-isopropylethylamine (DIPEA), 1 - propanephosphonic acid cyclic anhydride.
The reaction may be carried out in the presence of an inert organic solvent including but not limited to solvent such as tetrahydrofuran (THF), dioxane, 2-methyl THF ethyl acetate, ethylene dichloride (EDCl), dichloromethane, carbon tetrachloride (CCl4). The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used. Specifically, the reaction step (e) may be carried out at a temperature of about 25°C to 30°C.
In one embodiment, compound of Formula (XI) may be isolated and purified if required from the reaction mixture by any known technique in the art OR the compound can be subjected to next reaction without isolation and/or purification. In another embodiment, compound of Formula (XI) may be crystallized in a suitable solvent selected from acetone or acetonitrile to provide pure compound.
In another embodiment of the present invention, in step (f) the reducing agent can be selected from sodium borohydride (NaBH4). The organic base can be selected from di-isopropylethylamine (DIPEA). The reaction may be carried out in the presence of an inert organic solvent including but not limited to solvent such as ethanol. The reaction may be carried out at a temperature of about 0 °C to about boiling point of the solvent used. Specifically, the reaction step (f) may be carried out at a temperature of about 25°C to 30°C.
In one embodiment, the present invention provides a process for the preparation of compound of Formula (I) as represented schematically in scheme 2 as shown below.

Scheme 2
Wherever applicable in the example of the present invention, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material like N-acetyl-L-cysteine, SilaMetS thiol to remove metallic impurity, color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
The isolated compound according to the present invention may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100° C., less than about 80° C., less than about 60° C., less than about 50° C., less than about 30° C., or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the compound is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
Examples
Example 1: Preparation of 4-Amino-3-chloro acetophenone (Formula III)
To isopropyl alcohol (51.8 ml) 4-amino acetophenone (4.0 gm) was added followed by N-chlorosuccinimide (4.15 gm) was added at 60°C and stirred at 80°C till completion of reaction. After completion of the reaction, obtained reaction mixture was cooled to ambient temperature and diluted with water. The product was extracted with ethyl acetate and the organic layer was concentrated to obtain of crude compound (3.6 gm). The obtained crude compound was purified via column chromatography (yield - 29.5%).

Example 2: Preparation of 4-amino-3-chloro acetophenone (Formula III)
To a solution of 4-amino acetophenone (2.0 gm) in acetic acid (20 ml), N-chlorosuccinimide (3.55 gm) was added and stirred at 25 to 30°C. After completion of the reaction, obtained reaction mixture was diluted with water. The obtained reaction mixture was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate solution and concentrated to obtain of crude product (2.6 gm). The obtained crude compound was dissolved in isopropyl alcohol and treated with HCl in isopropyl alcohol. The precipitated solid was filtered, washed with isopropyl alcohol and dried to obtain pure 4-amino-3-chloro acetophenone as a hydrochloride salt (yield- 52.4%).
Example 3: Preparation of 4-amino-3-chloro acetophenone (Formula III)
To a mixture of 4-amino acetophenone (35.0 gm) and pyridine (20.8 ml) in tetrahydrofuran (350 ml), iodobenzene dichloride (78.22 gm) was added and stirred at 0 to 10°C. After completion of the reaction, reaction mixture was filtered at ambient temperature. The obtained solid was washed with tetrahydrofuran and the combined filtrate was washed sequentially with brine solution, aqueous sodium bisulfite solution and then brine solution. The organic layer was concentrated to obtain crude product (100 gm). The obtained crude compound was dissolved in 1,4-dioxane (100 ml) and treated with HCl in 1,4-dioxane (150 ml) at 10 to 15°C. The precipitated solid was filtered, washed with 1,4-dioxane and dried to obtain pure 4-amino-3-chloro acetophenone as a hydrochloride salt; which was further slurried in aqueous sodium bicarbonate solution, filtered, washed with water and dried to obtain pure 4-amino-3-chloro acetophenone (yield - 73.6%).
Example 4: Preparation of 4-Amino-3-chloro acetophenone (Formula III)
To a mixture of N-chlorosuccinimide (3.55 gm) in toluene (20 ml), 4-amino acetophenone (2.0 gm) and pyridine (1 ml) was added and stirred at 80-95°C till completion of reaction. After completion of the reaction, obtained reaction mixture was cooled to ambient temperature and diluted with water. The organic layer was separated and concentrated. To the obtained residue IPA.HCl was added, filtered. The obtained solid was washed with methanol and solid was slurried in 10% NaOH to obtain 4-Amino-3-chloro acetophenone. (yield - 80%).
Example-5: Preparation of 1-(3-chloro-4-iodophenyl)ethanone (Formula IV)
To a mixture of 4-amino-3-chloro acetophenone (2.0 gm) in conc. sulfuric acid, a solution of (0.92 gm) of sodium nitrite in water was added and stirred at 2 to 5°C till completion of reaction. The obtained reaction mixture was added to an aqueous mixture of cuprous iodide (0.225 gm) and potassium iodide (5.87 gm) and stirred till completion of reaction. The reaction mixture was extracted in ethyl acetate and both layers were separated. The obtained organic layer was concentrated under vacuum to provide 1-(3-chloro-4-iodophenyl)ethanone.
Example-6: Preparation of 1-(3-chloro-4-iodophenyl)ethanone (Formula IV)
To a mixture of of 4-amino-3-chloro acetophenone (25 gm) in conc. sulfuric acid, a solution of (11.46 gm) of sodium nitrite in water was added and stirred at 2 to 7°C till completion of reaction. The obtained reaction mixture was added to an aqueous mixture of cuprous iodide (2.8 gm) and potassium iodide (73.21 gm) and stirred till completion of reaction. The reaction mixture was extracted in toluene and both layers were separated. The obtained organic layer was concentrated under vacuum to provide 1-(3-chloro-4-iodophenyl)ethanone (yield -90.7%)
Example-7: Preparation of 1-(3-chloro-4-iodophenyl)ethanone (Formula IV)
To a mixture of 4-amino-3-chloro acetophenone (25 gm) in water and PTSA, a solution of (11.46 gm) of sodium nitrite and potassium iodide was added at 0-10 °C and stirred at room temperature till completion of reaction. To the reaction mixture, sodium bisulphite solution was added followed by filtration. The obtained solid was washed with 10% sodium bicarbonate solution and then with water, dried. (yield- 95%)
Example-8: Preparation of 4-acetyl-2-chlorobenzonitrile (Formula V)
The solution of 1-(3-chloro-4-iodophenyl)ethanone (3 gm) and of cuprous cyanide (1.15 gm) in N-methyl-2-pyrrolidone (NMP) (12 ml) was stirred at 100 to 120°C till completion of reaction. To the obtained reaction mixture water and toluene was added and both layers were separated. The organic layer was concentrated to provide 4-acetyl-2-chlorobenzonitrile (yield- 76%).
Example-9: Preparation of 4-acetyl-2-chlorobenzonitrile (Formula V)
The solution of 1-(3-chloro-4-iodophenyl)ethanone (37.5 gm) and cuprous cyanide (14.37 gm) in N-methyl-2-pyrrolidone (NMP) (150 ml) was stirred at 110 to 120°C till completion of reaction. The obtained reaction mixture was cooled, diluted with toluene and filtered. The obtained filtrate was washed with aqueous ammonia solution and extracted with ethyl acetate. The organic layer was separated and washed with aqueous ammonia solution, treated with activated carbon and filtered through hyflo. The obtained organic layer was concentrated and triturated with hexane. The resulting solid was filtered and dried to provide 4-acetyl-2-chlorobenzonitrile (yield - 90.2%).
Example-10: Preparation of 4-acetyl-2-chlorobenzonitrile (Formula V)
The solution of 1-(3-chloro-4-iodophenyl)ethanone (37.5 gm) and cuprous cyanide (14.37 gm) in N-methyl-2-pyrrolidone (NMP) (150 ml) was stirred at 110 to 120°C till completion of reaction. The obtained reaction mixture was cooled, diluted with toluene and filtered. The obtained filtrate was washed with aqueous ammonia solution. The organic layer was separated and concentrated followed by addition of cyclohexane. The obtained solid was filtered and dried to provide 4-acetyl-2-chlorobenzonitrile (yield - 95%).
Example-11: Preparation of 2-chloro-4-[(2E)-3-(dimethylamino)prop-2-enoyl] benzonitrile (Formula VI)
To a solution of 4-acetyl-2-chlorobenzonitrile (1.46 gm) in toluene (25 ml), N-dimethylformamide dimethyl acetal (2.9 gm) was added and the mixture was stirred at 100°C to 105°C and stirred. After completion of reaction, volatiles were removed under vacuum to provide 2-chloro-4-[(2E)-3-(dimethylamino)prop-2-enoyl]benzonitrile (yield - 89.5%).
Example-12: Preparation of 2-chloro-4-[(2E)-3-(dimethylamino)prop-2-enoyl] benzonitrile (Formula VI)
To a solution of 4-acetyl-2-chlorobenzonitrile (21.6 gm) in toluene (108 ml), N-dimethylformamide dimethyl acetal (48.06 gm) was added and the mixture was stirred at 100 to 105°C. After completion of reaction, reaction mixture was concentrated under vacuum to provide 2-chloro-4-[(2E)-3-(dimethylamino)prop-2-enoyl]benzonitrile.
Example-13: Preparation of 2-chloro-4-[(2E)-3-(dimethylamino)prop-2-enoyl] benzonitrile (Formula VI)
To a solution of 4-acetyl-2-chlorobenzonitrile (1.0 gm) in toluene (10 ml), N-dimethylformamide diethyl acetal (2.46 gm) was added and the mixture was stirred at 100 to 105°C. After completion of reaction, reaction mixture was concentrated under vacuum to provide 2-chloro-4-[(2E)-3-(dimethylamino)prop-2-enoyl]benzonitrile.
Example-14: Preparation of 2-chloro-4-[(2E)-3-(dimethylamino)prop-2-enoyl] benzonitrile (Formula VI)
To a solution of 4-acetyl-2-chlorobenzonitrile (1.0 gm) in toluene (10 ml), N-dimethylformamide diisopropyl acetal (2.92 gm) was added and the mixture was heated at 100 to 105°C and stirred. After completion of reaction, reaction mixture was concentrated under vacuum to provide 2-chloro-4-[(2E)-3-(dimethylamino)prop-2-enoyl]benzonitrile.

Example-15: Preparation of 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile (Formula VII)
To a solution of 2-chloro-4-[(2E)-3-(dimethylamino)prop-2-enoyl]benzonitrile (28.2 gm) in methanol (141 ml), hydrazine hydrate (8.81 ml) was added and stirred at 65 to 70°C. After the completion of reaction, the reaction mass was cooled and diluted with water and hexane and stirred. The obtained precipitate was filtered, washed with water and hexane and dried to yield 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile (yield - 86.6% yield).
Example-16: Preparation of 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile (Formula VII)
To a solution of 2-chloro-4-[(2E)-3-(dimethylamino)prop-2-enoyl]benzonitrile (1.30 gm) obtained from example 10 in methanol (13 ml), hydrazine hydrate (0.406 ml) was added and stirred at 65 to 70°C. After completion of reaction, the reaction mass was cooled and diluted with water and stirred. The obtained reaction mixture was cooled at 0-5°C and stirred. The obtained precipitate was filtered, washed with pre-cooled methanol:water mixture and dried to yield 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile. (yield - 69.1%).
Example-17: Preparation of 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile (Formula VII)
To a solution of 2-chloro-4-[(2E)-3-(dimethylamino)prop-2-enoyl]benzonitrile (1.30 gm) obtained from example 11 in methanol (13 ml), hydrazine hydrate (0.406 ml) was added and stirred at 65 to 70°C till completion of the reaction. After completion, the reaction mass was cooled and diluted with water and stirred. The obtained reaction mixture was cooled at 0-5°C and stirred. The obtained solid was filtered, washed with pre-cooled methanol:water mixture and dried to yield 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile. (yield - 72.7%).
Example-18: Preparation of 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile (Formula VII)
To a solution of 4-acetyl-2-chlorobenzonitrile (100 gm) in 1,4-dioxane (450 ml), N-dimethylformamide diisopropyl acetal (106.14 gm) was added and the mixture was heated at 87±5°C. After completion of reaction, reaction mixture was cooled at room temperature and hydrazine hydrate (69.68 gm) was added to reaction mixture and stirred at 65±5°C. After completion of reaction, the reaction mass was cooled and diluted with water and filtered. To the obtained wet cake 1,4 dioxane was added and stirred at 25±5°C followed by addition of water and stirred at 60±15°C. The obtained reaction mass was cooled at 25±5°C, stirred and filtered. The obtained wet cake was slurred in water at 45±5°C, cooled, filtered and dried. (yield – 92.92%).
Example-19: Preparation of (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro benzonitrile (Formula IX)
To THF (400 mL) 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile (100 gm) was added, followed by addition of (S)-tert-butyl-1-hydroxypropan-2-yl carbamate (103.3 gm) and triphenyl phosphine (13.2 gm) at 30±5 °C. To the obtained reaction mixture, a solution of diisopropylazodicarboxylate (198.6 gm in 200 ml THF) was added at 5±5 °C. The reaction mixture was stirred at 25±3°C till completion of reaction. To the obtained reaction mixture concentrated HCl was added at 32±10°C and stirred at 42±3°C. After completion of reaction, reaction mixture was concentrated atmospherically followed by addition of toluene, stirred. The obtained reaction mixture was concentrated atmospherically and water was removed azeotropically. Acetonitrile was added to obtained residue and stirred at 27±3°C, filtered and obtained solid was dried at 30±5°C under vacuum (yield – 62.5%).
Example-20: Preparation of (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro benzonitrile (Formula IX)
To THF (400 mL), 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile (100 gm) was added, followed by addition of (S)-tert-butyl-1-hydroxypropan-2-yl carbamate (103.3 gm) and triphenyl phosphine (193.2 gm) at 30±5 °C. To the obtained reaction mixture, a solution of diisopropylazodicarboxylate (198.6 gm in 200 ml THF) was added at 5±5 °C and stirred. The reaction mixture was stirred at 25±3°C till completion of reaction. To the obtained reaction mixture concentrated HCl was added at 32±10°C and stirred at 42±3°C. After completion of reaction, reaction mixture was concentrated atmospherically followed by addition of toluene, stirred. The obtained reaction mixture was concentrated atmospherically and water was removed azeotropically. Acetonitrile was added to obtained residue and stirred at 27±3°C, filtered. The obtain residue was slurred in ethyl acetate at 27±3°C; filtered and washed with ethyl acetate and obtained solid was dried at 60±3°C under vacuum (yield – 68.49%).
Example-21: Preparation of (S)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (Formula XI)
To a solution of 5-acetyl-1H-pyrazole-3-carboxylic acid (57.1 gm) in dichloromethane (900 ml), DIPEA (95.7 g), HOBt (9.1 g), EDC.HCl (71.0 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (Formula IX) (100 gm) were added at 23±3°C and stirred till completion of reaction. After completion of reaction, dichloromethane was distilled completely and to residue isopropyl alcohol was added and concentrated. Isopropyl alcohol (850 ml) was added to obtained residue, followed by addition of water at 75-85°C. The obtained reaction mixture was cooled to 27±3°C and solid was filtered and washed with acetone.
To the obtained wet solid, acetone (3500 ml) was added and heated to reflux to obtain the clear reaction mass. The reaction mixture was cooled to 47±3°C and activated carbon was added. The obtained reaction mixture was filtered, and heated to refluxed and distilled out acetone (3200 ml) atmospherically. The reaction mixture was cooled to 27±3°, stirred, filtered and obtained solid was dried at 30±5°C under vacuum (yield – 60%; purity-99.5%).
Example-22: Preparation of (S)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (Formula XI)
To a solution of 5-acetyl-1H-pyrazole-3-carboxylic acid (57.1 gm) in THF (1100 ml), DIPEA (95.7 g), HOBt (9.1 g), EDC.HCl (71.0 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (Formula IX) (100 gm) were added and stirred at 27±3°C till completion of reaction. After completion of reaction, THF was distilled till mass remain 150 ml followed by addition of isopropyl alcohol and water at 75-85°C. The obtained reaction mixture was cooled to 27±3°C and solid was filtered and dried.
To the obtained dried solid, acetone was added and heated to reflux temperature. treated with activated carbon. The obtained reaction mixture was filtered, and cooed to room temperature. The reaction mass was stirred, filtered and dried (yield – 60%; purity -99.9%).
Example-23: Preparation of Darolutamide (Formula I)
To a mixture of (S)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (Formula XI) (100 g) in tetrahydrofurn (500 ml), a solution of NaBH4 (6.7 g in 50 ml water) was slowly added at 27±3°C and stirred till completion of reaction. To the obtained reaction mixture ethanolic HCl was added to adjust the pH about 0.5-1.5 and stirred. To the obtained reaction mixture was distilled out completely under vacuum and the residue is striped of with isopropyl alcohol. To the residue of isopropyl alcohol (500 ml) and water (100 ml) was charged and heated to 70±3°C to obtain clear solution. The reaction mixture was cooled 27±3°C and stirred for overnight. The obtained solid was filtered, washed with mixture of isopropyl alcohol /water and dried under vacuum at 50°C. (yield – 79%).

Example-24: Preparation of Darolutamide (Formula I)
To a solution of sodium borohydride (0.930 g) in EtOH (105 ml), (S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (Formula XI) (15 g) was added in portion wise at a temperature below 25° C and stirred. After 3-4 h sodium borohydride (0.07 g) was added and the mixture was stirred till completion of the reaction. After completion of reaction the reaction mass quenched withaddition of 16 ml of ˜10% HCl in EtOH to set pH to 3.5 and stirred overnight at RT. To the obtained reaction mixture water (30 ml) was added and the stirred for 3 h. The obtained precipitate was filtered, washed with 2×10 ml of cold water:EtOH (1:1) and dried under vacuum. (yield – 80%)
Example-25: Preparation of Darolutamide (Formula I)
To a mixture of (S)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (Formula XI) (100 g) in tetrahydrofuran (500 ml), a solution of NaBH4 (5.71 g in 50 ml water) was slowly added at 27±3°C and stirred till completion of reaction. To the obtained reaction mixture concentrated HCl was added to adjust the pH < 2 and stirred. To the obtained reaction mixture was distilled out till reaction mass remain approximately 150 ml. To the obtained reaction mass isopropyl alcohol (500 ml) and water (100 ml) was charged and heated to 70±3°C to obtain clear solution. The reaction mixture was filtered at 65±3°C. The obtain filtrate was cooled to 27±3°C and stirred. The obtained solid was filtered, washed with mixture of isopropyl alcohol and dried under vacuum at 50°C and milled. The obtained milled material was slurred in water; filtered and dried (yield – 79%).
Example-26: Preparation of Darolutamide (Formula I)
To 2-methyl tetrahydrofurn (7000 ml) Darolutamide (100 g) in was added and heated to 80±3°C to obtain clear solution. To the obtained solution n-heptane (20000 ml) was slowly added at 50±10°C. The obtained reaction mixture was cooled to 27±3°C and stirred for 2 hr. The obtained crystalline solid was filtered and dried under vacuum at 30±5°C. (yield – 70%).
,CLAIMS:We claim;
1. A process of preparation of Darolutamide of Formula (I) comprising the steps of :

(I)
a) converting compound of Formula (III) in to compound of Formula (V);

(III) (V)
b) converting the compound of Formula (V) into compound of Formula (VII);

(VII)
c) reacting the compound of Formula (VII) with compound of formula (VIII) to obtain compound of Formula (IX);

(IX) (VIII)
wherein PG is amine protecting group selected from BOC, CBz, Bn, trityl, silyl;
d) condensing the compound of Formula (IX) with the compound of Formula (X) to obtain the compound of Formula (XI); and

(X) (XI)
e) reducing the compound of Formula (XI) into compound of Formula (I) using suitable reducing agent.
2. The process as claimed in claim 1, wherein step (a), comprising steps of:
i. converting compound of formula (III) into compound formula (IV) using diazotizing agent and an halogenating agent

(III) (IV) (V)
wherein X is halogen; and
ii. reacting compound of formula (IV) with metal cyanide to obtain compound formula (V).
3. The process as claimed in claim 2, step i.), characterized in that said diazotizing agent is nitrous acid or sodium nitrite in dilute aqueous hydrochloric acid or sulfuric acid.
4. The process as claimed in claim 2, step i.), wherein halogenating agent is selected from group of copper iodide (CuI), potassium iodide (KI), sodium bromide (NaBr), copper bromide (CuBr), potassium bromide (KBr) or sodium bromide (NaBr).
5. The process as claimed in claim 2, step ii.), wherein metal cyanide is selected from group of copper cyanide (CuCN), sodium cyanide (NaCN), potassium cyanide(KCN) or zinc cyanide(Zn(CN)2).
6. The process as claimed in claim 1, wherein step (b) comprising:
a. converting compound of Formula (V) to compound of Formula (VI) using reagent such as N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, N,N-dimethylformamide diisopropyl acetal, gold's reagent, N'-[(dimethylamino)methoxymethyl]-N,N-dimethylmethanimidamide, dimethl acetamide and p-toluenesulfonic acid; ethyl orthoformate, ethyl formate or methyl formate, nitrometane in combination with dimethylamine; and

(VI)
b. converting compound of Formula (VI) to compound of Formula (VII) using hydrazine hydrate.
7. The process as claimed in claim 1, wherein step (c) comprising:
a. reacting the compound of Formula (VII) with compound of formula (VIII) in presence of the ligand selected from triphenylphosphine (PPh3), tributyl phosphine (TBP), tricyclohexyl- phosphine (PCy3), the oxidant selected from diisopropylazodicarboxylate (DIAD) 1,1'-(azodicarbonyl)dipiperidine (ADDP), 4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-dione (DHTD), and N,N,N',N'-tetramethylazodicarboxamide (TMAD) in presence of an inert organic solvent selected from ethyl acetate, ethanol, methanol, THF and mixtures thereof; and
b. de-protecting with acid selected from p-toluenesulfonic acid, hydrobromic acid, sulfuric acid, hydrochloric acid.
8. The process as claimed in claim 1, wherein step (d) comprising condensing the compound of Formula (IX) with the compound of Formula (X) using the coupling agent selected from BOP, PyBOP, HBTU, HOBt; the organic base selected from di-isopropylethylamine (DIPEA), 1 - propanephosphonic acid cyclic anhydride (T3P) in presence of the solvent selected from dichloromethane, ethyl acetate and tetrahydrofuran.
9. The process as claimed in claim 1, wherein step (d) further comprises purification of compound of formula (XI) by crystallization in suitable solvent such as acetone, acetonitrile or mixture thereof.
10. The process as claimed in claim 1, wherein reducing agent in step (e) is sodium borohydride (NaBH4).