DESC:Field of the invention:
The present invention relates to a process for the preparation of 3-[[(1S,2S,3R)-2,3-Difluoro-2,3-dihydro-1-hydroxy-7-(methylsulfonyl)-1H-inden-4-yl]oxy]-5-fluorobenzonitrile compound of formula-1 which is represented by the following structural formula:

Formula-1

The present invention also relates to novel intermediate compounds of formula-1 as well as its process for the preparation.

Background of the Invention:
The compound of formula-1 i.e., 3-[[(1S,2S,3R)-2,3-difluoro-2,3-dihydro-1-hydroxy-7-(methylsulfonyl)-1H-inden-4-yl]oxy]-5-fluorobenzonitrile is commonly known as “Belzutifan”.
Belzutifan was approved by U.S. Food and Drug Administration (FDA) in August, 2021 which is a hypoxia-inducible factor inhibitor indicated for treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.
The process for the preparation of Belzutifan was disclosed in US 9908845B2 & Journal of Medicinal Chemistry (2019), 62 (5), 6876-6893.
Still, there remains a need to develop a cost effective and commercially viable process for the preparation of Belzutifan.

Brief description of the Invention:
The first aspect of the present invention is to provide a process for the preparation of Belzutifan compound of Formula-1.
The second aspect of the present invention is to provide novel intermediate compounds of Belzutifan and its process for the preparation.
The third aspect of the present invention is to provide a process for the preparation of crystalline form of Belzutifan compound of Formula-1.

Brief description of the Drawings:
FIG.1: Illustrates the characteristic PXRD pattern of crystalline form of Belzutifan
(Formula-1).
FIG.2: DSC thermogram of crystalline form of Belzutifan.
FIG.3: Thermogravimetric analysis of crystalline form of Belzutifan.

Detailed description of the Invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" selected from aliphatic hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane and the like; and aromatic hydrocarbon solvents such as toluene, xylene and the like; "ether solvents" such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, dioxime and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as N, N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone (NMP) and the like; "chlorinated solvents" such as dichloromethane/ methylene chloride, dichloroethane, chloroform and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, tert.amyl alcohol, t-butanol and the like; "polar solvents" such as water or mixtures thereof.
As used herein the present invention, the term "anti-solvent" refers to a solvent which is used to precipitate the solid from a solution.
As used herein the present invention the term “suitable acid” refers to organic acids or inorganic acids. The “inorganic acid” is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid and the like; and “organic acid” is selected from formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, malonic acid, maleic acid, fumaric acid, malic acid, succinic acid, citric acid, aspartic acid, tartaric acid, mandelic acid, benzoic acid, salicylic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like or mixtures thereof.
As used herein the present invention the term “suitable base” refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; Ammonia; and organic bases like dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), 2,6-lutidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.
As used herein the present invention, the term “suitable brominating agent” is selected from N-bromosuccinamide (NBS), pyridinium bromide, bromine (Br2), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), HBr, benzyl-bromide and the like.
As used herein the present invention, the term “suitable chiral reducing agent” is selected from RuCl(R,R)-Ts-DPEN(p-Cymene), RuCl2[(R)-DM-BINAP][(R)-DAIPEN], [(R)-PhanePhos RuCl2 (S,S)-DACH] and [(R)-HexaPHEMP RuCl2 (R,R)-DPEN] and the like.
As used herein the present invention, the term “suitable fluorinating agent” is selected from (1-chloromethyl-4-fluoro-1,4-Diazoniabicyclo[2.2.2] octane bis(tetrafluoroborate) [Selectfluor], N-Fluorobenzenesulfonimide, (Diethylamino)sulfur Trifluoride (DAST), Perfluoro-1-butanesulfonyl Fluoride (PBSF) and the like.

The first aspect of the present invention is to provide a process for the preparation of Belzutifan compound of Formula-1, comprising of:
a) Reacting the compound of formula-2

Formula-2
with ethylene glycol in presence of trimethyl orthoformate and catalytic amount of acid catalyst in a suitable solvent to provide compound of formula-3,

Formula-3
b) reacting the compound of formula-3 in-situ with the compound of formula-4

Formula-4
in presence of a suitable base and a solvent to provide the compound of formula-5, optionally purifying the compound in a suitable solvent to provide the pure compound of formula-5,

Formula-5
c) reacting the compound of formula-5 with a suitable brominating agent in presence of a suitable activator in a solvent to provide the compound of formula-6,

Formula-6
d) reacting the compound of formula-6 in-situ with a suitable reagent in presence of a suitable base and a solvent to provide the compound of formula-7,

Formula-7
e) reacting the compound of formula-7 with a suitable chiral reducing agent in presence of a suitable acid-base complex in a solvent to provide the compound of formula-8,

Formula-8
f) treating the compound of formula-8 with a suitable acid in a solvent to provide the compound of formula-9, optionally purifying the compound in a suitable solvent to provide the pure compound of formula-9,

Formula-9
g) reacting the compound of formula-9 with an electrophilic fluorinating agent in presence of an acid catalyst in a solvent to provide the compound of formula-10,

Formula-10
h) reacting the compound of formula-10 in-situ with a suitable chiral reducing agent in presence of a suitable acid-base complex in a solvent to provide the compound of formula-11,

Formula-11
i) reacting the compound of formula-11 with a nucleophilic fluorinating agent in presence of a base in a solvent to provide the compound of formula-12, optionally purifying the compound in a suitable solvent to provide the pure compound of formula-12,

Formula-12
j) reacting the compound of formula-12 with a cyanating agent in presence of a metal catalyst in a solvent to provide the compound of formula-1, optionally purifying the compound in a suitable solvent to provide the pure compound of formula-1.
Wherein,
In step (a) of the present invention, wherein the acid used is organic acid or
inorganic acid. The organic acid may be selected from methanesulfonic acid, trifluoroacetic acid, triflic acid, p-toluenesulfonic acid or any other suitable organic acid. The inorganic acid is selected from sulfuric acid, hydrochloric acid, acetic acid or any other suitable inorganic acid
In step (b), (d), (h) & (i) of the present invention, wherein the base used is selected
from organic base or inorganic base. The organic base may be selected from triethylamine, diisopropylethylamine, tertiary butylamine, 1,8-diazabicyclo (5.4.0)undec-7-ene (DBU) or any other equivalent organic base. The inorganic base may be selected from alkali and alkaline metal acetates or carbonates such as sodium acetate, sodium bicarbonate, sodium carbonate, potassium acetate, potassium bicarbonate, potassium carbonate, cesium carbonate, or any other equivalent base.
In step (c) of the present invention, wherein the suitable brominating agent used is
selected from N-bromosuccinamide (NBS), pyridinium bromide, bromine (Br2), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) & HBr in presence of a suitable activator such as azobisisobutyronitrile (AIBN), azobisdimethylvaleronitrile (ABDV), benzildimethyl acetal, benzoyl peroxide (BPO) & meta-chloroperoxybenzoic acid (m-CPBA) or any other suitable activator.
In step (d) of the present invention, wherein the suitable reagent used is 2-picoline
N-oxide or pyridine N-oxide.
In step (e) & (h) of the present invention, wherein the suitable chiral reducing agent
used is selected from RuCl(R,R)-Ts-DPEN(p-Cymene), RuCl2[(R)-DM-BINAP][(R)-DAIPEN], [(R)-PhanePhos RuCl2 (S,S)-DACH] and [(R)-HexaPHEMP RuCl2 (R,R)-DPEN] or any other suitable chiral reducing agent.
In step-(e) & (h) the suitable acid-base complex is formic acid-triethylamine;
In step-(f) the suitable acid is inorganic acid such as hydrochloric acid & sulfuric
acid; or organic acid such as p-toluenesulfonic acid or any suitable organic acid.
In step-(g) the suitable electrophilic fluorinating agent is (1-chloromethyl-4-
fluoro-1,4-Diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) [Selectfluor] or N-Fluorobenzenesulfonimide and the like; and the suitable acid is methanesulfonic acid, p-toluenesulfonic acid or any other suitable acid.
In step-(i) the suitable nucleophilic fluorinating agent is (Diethylamino)sulfur
Trifluoride (DAST) or Perfluoro-1-butanesulfonyl Fluoride (PBSF) and the like; and the suitable base is 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU);
In step-(j) the suitable cyanating agent is selected from zinc cyanide, copper
cyanide and the like; and the suitable catalyst is selected from [1,1'-Bis (diphenylphosphino)ferrocene]dichloropalladium (II) [Pd(dppf)Cl2], copper iodide and Zinc dust.
In step-(a) to (j) the suitable solvent is selected from alcoholic solvents, polar-
aprotic solvents, hydrocarbon solvents, ester solvents, ether solvents, ketone solvents, chloro solvents, nitrile solvents and polar solvents such as water or mixtures thereof.

In a preferred embodiment of the present invention is to provide a process for the preparation of Belzutifan compound of Formula-1, comprising of:
a) Reacting the compound of formula-2 with ethylene glycol in presence of trimethyl orthoformate and catalytic amount of p-toluene sulfonic acid monohydrate (PTSA. H2O) in isopropyl alcohol to provide compound of formula-3,
b) reacting the compound of formula-3 in-situ with the compound of formula-4
in presence of potassium carbonate in dimethylsulfoxide to provide the compound of formula-5, purifying the compound in toluene and n-heptane to provide the pure compound of formula-5,
c) reacting the compound of formula-5 with N-Bromosuccinimide (NBS) in presence of Azobisisobutyronitrile (AIBN) in chloroform to provide the compound of formula-6,
d) reacting the compound of formula-6 in-situ with 2-picoline N-oxide in presence of diisopropylethylamine in acetonitrile to provide the compound of formula-7,
e) reacting the compound of formula-7 with RuCl(R,R)-Ts-DPEN(p-Cymene) in presence of formic acid-triethylamine complex in acetonitrile to provide the compound of formula-8,
f) treating the compound of formula-8 with hydrochloric acid in DM water to provide the compound of formula-9, purifying the compound in ethyl acetate to provide the pure compound of formula-9,
g) reacting the compound of formula-9 with Selectfluor in presence of methanesulfonic acid in methanol to provide the compound of formula-10,
h) reacting the compound of formula-10 in-situ with RuCl(R,R)-Ts-DPEN(p-Cymene) in presence of formic acid-triethylamine complex in ethyl acetate to provide the compound of formula-11,
i) reacting the compound of formula-11 with perfluoro-1-butanesulfonyl fluoride (PBSF) in presence of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) in 1,2-dimethoxyethane (DME) to provide the compound of formula-12, purifying the compound in ethyl acetate and n-Heptane followed by isopropyl alcohol to provide the pure compound of formula-12,
j) reacting the compound of formula-12 with zinc cyanide in presence of Pd(dppf)Cl2 and activated zinc dust in N,N-dimethylacetamide to provide the compound of formula-1, purifying the compound in acetonitrile & water followed by acetonitrile: aqueous isopropyl alcohol [1:1] to provide the pure compound of formula-1.

The second aspect of the present invention is to provide novel intermediate compounds of Belzutifan and its process for the preparation.

In a preferred embodiment of the present invention is to provide a process for the preparation of compound of Formula-5, comprising of:
a) Reacting the compound of formula-2 with ethylene glycol in presence of trimethyl orthoformate and catalytic amount of p-toluene sulfonic acid monohydrate (PTSA. H2O) in isopropyl alcohol to provide compound of formula-3,
b) reacting the compound of formula-3 in-situ with the compound of formula-4
in presence of potassium carbonate in dimethylsulfoxide to provide the compound of formula-5, purifying the compound in toluene and n-heptane to provide the pure compound of formula-5.

In another preferred embodiment of the present invention is to provide a process for the preparation of compound of Formula-7, comprising of:
a) reacting the compound of formula-5 with N-Bromosuccinimide (NBS) in presence of Azobisisobutyronitrile (AIBN) in chloroform to provide the compound of formula-6,
b) reacting the compound of formula-6 in-situ with 2-picoline N-oxide in presence of diisopropylethylamine in acetonitrile to provide the compound of formula-7.
In another preferred embodiment of the present invention is to provide a process for the preparation of compound of Formula-9, comprising of:
a) reacting the compound of formula-7 with RuCl(R,R)-Ts-DPEN(p-Cymene) in presence of formic acid-triethylamine complex in acetonitrile to provide the compound of formula-8,
b) treating the compound of formula-8 with hydrochloric acid in DM water to provide the compound of formula-9, purifying the compound in ethyl acetate to provide the pure compound of formula-9.

In another preferred embodiment of the present invention is to provide a process for the preparation of compound of Formula-11, comprising of:
a) reacting the compound of formula-9 with Selectfluor in presence of methanesulfonic acid in methanol to provide the compound of formula-10,
b) reacting the compound of formula-10 in-situ with RuCl(R,R)-Ts-DPEN(p-Cymene) in presence of formic acid-triethylamine complex in ethyl acetate to provide the compound of formula-11.

In a preferred embodiment of the present invention is to provide a process for the preparation of compound of Formula-12, comprising of reacting the compound of formula-11 with perfluoro-1-butanesulfonyl fluoride (PBSF) in presence of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) in 1,2-dimethoxyethane (DME) to provide the compound of formula-12, purifying the compound in ethyl acetate and n-Heptane followed by isopropyl alcohol to provide the pure compound of formula-12.

In another preferred embodiment of the present invention is to provide a process for the preparation of compound of Formula-1, comprising of reacting the compound of formula-12 with zinc cyanide in presence of Pd(dppf)Cl2 and activated zinc dust in N,N-dimethylacetamide to provide the compound of formula-1, purifying the compound in acetonitrile & water followed by acetonitrile: aqueous isopropyl alcohol [1:1] to provide the pure compound of formula-1.
The third aspect of the present invention is to provide a process for the preparation of crystalline form of Belzutifan of Formula-1, comprising of:
a) Adding a suitable solvent to Belzutifan crude compound of Formula-1,
b) heating and treating the reaction mixture with charcoal,
c) adding a suitable solvent to the reaction mass,
d) cooling and stirring the reaction mixture,
e) filtering, washing and drying the compound to get the crystalline form of Belzutifan compound of formula-1.
Wherein in step-a) & c), the suitable solvent is selected from ether solvents, chloro solvents, ester solvents, alcohol solvents, ketone solvents, polar aprotic solvents, hydrocarbon solvents, nitrile solvents and polar solvents or mixtures thereof.

In a preferred embodiment of the present invention is to provide a process for the preparation of crystalline form of Belzutifan of Formula-1, comprising of:
a) Adding acetonitrile to Belzutifan crude compound of Formula-1,
b) heating and treating the reaction mixture with charcoal,
c) adding a mixture of isopropyl alcohol & water to the reaction mass,
d) cooling and stirring the reaction mixture,
e) filtering, washing the obtained solid with mixture of acetonitrile & aqueous isopropyl alcohol and drying the compound to get the crystalline form of Belzutifan compound of formula-1.

The 4-Fluoro-7-methylsulfonyl-indan-1-one compound of formula-2 and 3-bromo-5-fluorophenol compound of formula-4 are prepared from the processes known in the art.

The advantages of the Invention:

• The process of the present invention is commercially viable & scalable.
• The process for making Belzutifan does not require pyrophoric reaction conditions or special reaction conditions
• The process does not require high solvent consuming chromatographic purifications techniques.
• The process provides Belzutifan having purity >99.6% by HPLC and having all unknown impurities below 0.1%.

PXRD method of analysis:
PXRD analysis of the crystalline form of Belzutifan was carried out using Panlytical Expert Pro DY3248 X-ray powder diffractometer using Cu-Ka radiation of 10 wavelength 1.5406 A° and at continuous scan speed of 0.03°/min.

The process for the preparation of Belzutifan compound of formula-1 is schematically represented as below:

Scheme-I:

The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

Examples:

Example-1: Preparation of 4'-fluoro-2', 3'-dihydro-7'-(methylsulfonyl)spiro-[1,3-dioxolane-2,1'-[1H]indene (Formula-3)
Ethylene glycol (680 g), the compound of Formula-2 (250.0 g) and Isopropyl alcohol (1750 mL) were added into a reaction flask and stirred for 10 minutes at 25-30°C under nitrogen atmosphere. Trimethyl orthoformate (290.60 g) and P-Toluene sulfonic acid monohydrate (5.20 g) were added into reaction mass and stirred for 10 minutes at 25-30°C. The reaction mass temperature was heated to 75-80°C and partially distilled the isopropyl alcohol at same temperature and then maintained for about 2 hrs. The reaction mass was cooled to ambient temperature and N,N-diisopropylethylamine (8.50 g) was added to the reaction mass and maintained for 1 hour. The reaction mass was further cooled to 0-5°C and stirred for 90 mins. Reaction mass was filtered and washed with isopropyl alcohol and collected the wet product.
The above wet product was further purified in isopropyl alcohol to afford the title compound of formula-3.
Yield: ~ 240.39g; Purity by HPLC: 97.39%
m/z: 273.30 (M+H)+
1H NMR (400 MHz, DMSO-d6): d (ppm) 7.88-7.92 (dd, J = 8.8, 5.2 Hz, 1H), 7.45-7.50 (t, J = 8.4 Hz, 1H), 4.18-4.21 (m, 2H), 4.00-4.04 (m, 2H), 3.27 (s, 3H), 2.89-2.92 (t, J = 6.4 Hz, 2H), 2.21-2.24 (t, J = 6.8 Hz, 2H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 160.11-162.63 (d, J = 252.2 Hz), 143.05-143.11 (d, J = 6.5 Hz), 133.80-133.83 (d, J = 3.1 Hz), 133.23-133.45 (d, J = 21.1 Hz), 131.85-131.94 (d, J = 8.5 Hz), 116.98, 116.40-116.61 (d, J = 21.0 Hz), 64.92, 64.92, 44.49, 37.24, 23.69.
Example-2: Preparation of 4'-(3-bromo-5-fluorophenoxy)-2', 3'-dihydro-7'-(methylsulfonyl)-spiro[1,3-dioxolane-2,1'-[1H]indene (Formula-5) :
The compound of Formula-3 (200 g) and Dimethylsulfoxide (1000 mL) were added into reaction flask and stirred for 5-10 minutes at 25-30°C and then added compound of Formula-4 (140.30 g) followed by potassium carbonate (76.10 g) and stirred for 10 mins. Heated the reaction mass to 100-105°C and maintained for about 35-40 hrs under nitrogen atmosphere. Cooled the reaction mass to 25-30°C and filtered the product and washed with DMSO (100 mL). The reaction mass was quenched into DM water at 25-30°C. Heated the reaction mass to 55-60°C and maintained for 1 hour. Filtered the product and washed with DM water.
The above wet material and toluene (3000 mL) were added into a reaction flask, heated the reaction mass to 70-75°C and stirred for 15-20 minutes. Separated the organic layer and washed with sodium chloride solution (500 mL). The organic layer was partially distilled under vacuum. Heated the reaction mass to 60-65°C and added n-heptane (2800 mL) and stirred for 30 mins. Cooled the reaction mass to 25-30°C and stirred for 1 hour. Reaction mass was further cooled to 0-5°C and stirred for 1 hour. Filtered the product and washed with n-heptane and dried at 45-50°C for 5-6 hrs to get the title compound.
Yield: 224.46 g; Purity by HPLC: 97.57 %
m/z: 443.10 (M+H)+
1H NMR (400 MHz, DMSO-d6): d (ppm) 7.84-7.87 (d, J = 8.8 Hz, 1H), 7.44-7.47 (dt, J = 8.0, 2.0 Hz, 1H), 7.25-7.26 (br, m, 1H), 7.14-7.17 (dt, J = 10.0, 2.4 Hz, 1H), 7.11-7.13 (d, J = 8.4 Hz, 1H), 4.19-4.22 (m, 2H), 4.01-4.04 (m, 2H), 3.27 (s, 3H), 2.81-2.84 (t, J = 6.8 Hz, 2H), 2.20-2.23 (t, J = 6.8 Hz, 2H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 161.61-164.09 (d, J = 248.2 Hz), 156.75-156.87 (d, J = 11.9 Hz), 156.20, 142.11, 136.70, 132.78, 131.53, 122.67-122.79 (d, J = 12.1 Hz), 118.77, 117.81, 117.18, 115.13-115.38 (d, J = 24.6 Hz), 106.74-106.99 (d, J = 24.6 Hz), 64.85, 64.85, 44.57, 37.18, 24.81.
Example-3: Preparation of 3'-bromo-4'-(3-bromo-5-fluorophenoxy)-7'-(methane sulfonyl)-2',3'-dihydrospiro[1,3-dioxolane-2,1'-indene] (Formula-6):
The compound of Formula-5 (200 g) and Chloroform(2000 mL) were added into a reaction flask at 25-30°C and stirred for 5-10 minutes under nitrogen atmosphere. N-Bromo succinimide (96.4 g) and Azobisisobutyronitrile (2.08 g) were added into the reaction mass and stirred for 5-10 minutes. The reaction mass was heated to ~60°C and maintained for about 15 hours. The reaction mass was cooled and then slowly added triethylamine (91.0 g) to the reaction mass and stirred for 30 mins. The reaction mass was added to DM Water (2000 mL) and the biphasic solution stirred for 30 mins. The organic and aqueous layers were separated and the organic layer was transferred into reaction flask and washed with aqueous sodium chloride solution. The organic layer was concentrated under vacuum to afford the title compound.
Wet wt: ~280g; Purity by HPLC: 97.53 %
m/z: 520.80 (M+H)+
1H NMR (400 MHz, CDCl3): d (ppm) 8.08-8.10 (d, J = 8.8 Hz, 1H), 7.13-7.16 (dt, J = 7.6, 2.0 Hz, 1H), 7.08-7.09 (m, 1H), 6.93-6.95 (d, J = 8.4 Hz, 1H), 6.79-6.83 (dt, J = 11.2, 2.0 Hz, 1H), 5.45-5.47 (dd, J = 6.8, 1.6 Hz, 1H), 4.46-4.50 (m, 1H), 4.38-4.43 (m, 1H), 4.08-4.18 (m, 1H), 3.23 (s, 3H), 2.83-2.89 (dd, J = 14.8, 6.8 Hz, 1H), 2.76-2.80 (dd, J = 14.8, 2.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): d (ppm) 161.97-164.49 (d, J = 251.2 Hz), 157.05, 156.22-156.34 (d, J = 11.4 Hz), 142.24, 136.27, 134.54, 132.60, 123.26-123.38 (d, J = 11.7 Hz), 119.29-119-33 (d, J = 3.6 Hz), 117.92, 116.16, 116.04 & 116.29 (d, J = 24.4 Hz), 106.97-107.21 (d, J = 24.3 Hz), 65.83, 65.44, 48.40, 45.03, 40.21.

Example-4: Preparation of 4'-(3-bromo-5-fluorophenoxy)-7'-(methane sulfonyl)spiro[1,3-dioxolane-2,1'-inden]-3'(2H)-one (Formula-7):
The compound of Formula-6 crude (235.6 g) and acetonitrile (2000 mL) were added into a reaction flask and stirred for 5-10 minutes. 2-Picoline N-oxide (74.0 g) and N,N-Diisopropylethylamine (117.0 g) were added into reaction mass and stirred for 5-10mins. The reaction mass was heated to 70-75°C and maintained for 5 hours. The reaction mass was cooled to ~60°C and concentrated under vacuum. Acetonitrile (200 mL) was added into the concentrated reaction mass and heated to 70-75°C and added aqueous Isopropyl alcohol (800 mL) and stirred for 15 mins. Cooled the reaction mass to 25-30°C and stirred for 1 hour and further cooled to 0-5°C and stirred for 4 hours. The obtained product was filtered and washed with Isopropyl alcohol (500mL) and then dried under vacuum at 50°C for about 5-6 hours to get the tile compound.
Yield: 131.79g; Purity by HPLC: 98.37 %
m/z: 454.80 (M-H)-
1H NMR (400 MHz, CDCl3): d (ppm) 8.32-8.34 (d, J = 8.8 Hz, 1H), 7.16-7.19 (m, 1H), 7.07-7.08 (m, 1H), 7.00-7.02 (d, J = 8.8 Hz, 1H), 6.80-6.83 (dt, J = 9.2, 2.0 Hz, 1H), 4.45-4.48 (m, 2H), 4.12-4.15 (m, 2H), 3.26 (s, 3H), 2.96 (s, 2H). 13C NMR (100 MHz, CDCl3): d (ppm) 195.61, 161.95-164.47 (d, J = 251.7 Hz), 157.51, 155.61-155.72 (d, J = 11.5 Hz), 151.06, 139.47, 133.15, 128.64, 123.34-123.45 (d, J = 11.6 Hz), 119.58-119.62 (d, J = 3.2 Hz), 118.44, 116.49-116.73 (d, J = 24.4 Hz), 109.59, 107.32-107.56 (d, J = 11.5 Hz), 65.83, 65.83, 50.11, 44.96.

Example-5: Preparation of (1'R)-7'-(3-bromo-5-fluoro-phenoxy)-4'-methyl sulfonyl-spiro[1,3-dioxolane-2,3'-indane]-1'-ol (Formula-8):
The compound of Formula-7 (100 g), acetonitrile (500 mL) and triethylamine (33.19g) were added into a reaction flask at 25-30°C. Cooled the reaction mass to 10-15°C and slowly added formic acid (20.13 g) in about 20 mins and stirred for 5-10 mins. Added RuCl(R,R)-Ts-DPEN(p-Cymene) (2.08 g) at 10-15°C and stirred for 5-10 min. The reaction mass was heated and stirred for 6.5 hrs at 25-30°C and proceeded to next stage as such without holding.
Purity by HPLC: 97.80 %
m/z: 459.00 (M+H)+;
1H NMR (400 MHz, CDCl3): d (ppm) 8.05-8.07 (d, J = 8.8 Hz, 1H), 7.13-7.16 (dt, J = 7.6, 2.0 Hz, 1H), 7.06-7.07 (m, 1H), 6.93-6.95 (d, J = 8.4 Hz, 1H), 6.78-6.81 (dt, J = 9.2, 2.0 Hz, 1H), 5.38-5.40 (m, 1H), 4.38-4.44 (m, 2H), 4.08-4.15 (m, 2H), 3.26 (s, 3H), 2.62-2.67 (m, 1H), 2.27-2.31 (dd, J = 13.2, 4.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): d (ppm) 161.93-164.44 (d, J = 251.4 Hz), 157.55, 156.36-156.48 (d, J = 11.4 Hz), 142.27, 137.62, 133.80, 132.45, 123.22-123.34 (d, J = 11.7 Hz), 119.12-119.15 (d, J = 3.1 Hz), 117.78, 115.85-116.10 (d, J = 24.4 Hz), 115.27, 106.80-107.05 (d, J = 24.2 Hz), 68.73, 65.64, 65.64, 46.81, 44.82.

Example-6: Preparation of (3R)-4-(3-bromo-5-fluoro-phenoxy)-3-hydroxy-7-methylsulfonyl-indan-1-one (Formula-9):
Aqueous hydrochloride (640 mL) was added into reaction mass obtained from example-5 (Formula-8) and stirred for 10 hours at 25-30°C. After completion of reaction, DM water (2000 mL) was added into reaction mass and stirred for 3 hours. Filtered the product and washed with DM water and dried under vacuum at 55 -60°C for 8 hours. Dry wt.: 86.43g
The compound of Formula-9 crude (80 g) and ethyl acetate (400 mL) were added into a reaction flask and heated to 70-75oC and maintained for 2 hours. The reaction mass was cooled to 25-30°C and maintained for 1 hr. Further the reaction mass was cooled to 0-5°C and stirred for 1 hour. After completion of maintenance, filtered the product and washed with chilled ethyl acetate (120 mL). The wet compound was dried under vacuum at 55-60°C to get the title compound.
Yield: 69.4g; Purity by HPLC: 97.04 %
m/z: 414.90 (M+H)+
1H NMR (400 MHz, CDCl3): d (ppm) 8.16-8.18 (d, J = 8.4 Hz, 1H), 7.20-7.23 (m, 1H), 7.12-7.14 (m, 2H), 6.84-6.87 (dt, J = 8.8, 2.4 Hz, 1H), 5.65-5.68 (m, 1H), 3.42 (s, 3H), 3.20-3.26 (dd, J = 18.8, 6.8 Hz, 1H), 2.81-2.87 (dd, J = 19.2, 2.4 Hz, 1H), 2.71-2.72 (d, J = 3.6 Hz, 1H).
13C NMR (100 MHz, CDCl3): d (ppm) 199.33, 162.14-164.66 (d, J = 252.5 Hz), 158.92, 155.62-155.73 (d, J = 11.4 Hz), 146.56, 136.13, 133.06, 132.40, 123.74-123.85 (d, J = 11.2 Hz), 120.59, 119.52, 116.83-117.07 (d, J = 24.2 Hz), 107.23-107.48 (d, J = 24.4 Hz), 65.67, 45.97, 43.26.

Example-7: Preparation of (3S)-4-(3-bromo-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-one (Formula-10):
Methanol (5000 mL) and the compound of Formula-9 (200 g) were added into a reaction flask and stirred for 10 min. Methane sulfonic acid (9.25g) and Selectfluor (256.0 g) were added into reaction mass. Heated the mass to 60-65°C and maintained for 28 hrs. Cooled the reaction mass to 55-60°C and partially concentrated the methanol under vacuum at below 60°C and then cooled to 10-15oC. Filtered the reaction mass under vacuum. To the filtrate, DM water (88.0 mL) was added and heated to 60-65°C and then stirred for 12 hours. Distilled the reaction mass under vacuum and ethyl acetate (400 mL) was added to resulting syrupy residue and distilled off ethyl acetate under vacuum at below 60°C. Ethyl acetate and DM water were added and stirred for 15-20 mins. Ethyl acetate layer (lot-1) and aqueous layer were separated, then the aqueous layer was washed with ethyl acetate (400 mL) and combined the ethyl acetate layers and washed with aqueous sodium chloride solution. Collected the resulting organic layers and partially distilled off under vacuum. To the resulting oily product ethyl acetate (400 mL) was added and again distilled off under vacuum. The concentrated oily product was dissolved in ethyl acetate (2000 mL) and proceeded to next stage without further isolation. Purity by HPLC: 93.82 %
m/z: 433.10 (M+H)+
1H NMR (400 MHz, DMSO-d6): d (ppm) 8.07-8.10 (8.07-8.10) (d, J = 2.8 Hz, 1H), 7.55-7.57 (7.49-7.53) (d, J = 8.4 Hz, 1H), 7.42-7.45 (7.49-7.53) (dt, J = 8.0, 2.0 Hz, 1H), 7.22-7.26 (7.330-7.336) (m, 1H), 7.12-7.15 (7.22-7.26) (dt, J = 10.0, 2.4 Hz, 1H), 6.46-6.48 (6.20-6.21) (d, J = 7.2 Hz, 1H), 5.40-5.41 & 5.53-5.54 (5.65-5.67) (m, 1H), 5.30-5.38 (5.43-5.46) (ddd, J = 17.2, 7.2, 3.6 Hz, 1H), 3.43 (3.45) (s, 3H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 192.68-192.85 (196.60-196.77) (d, J = 16.5 Hz), 161.55 & 164.03 (161.61 & 164.09) (d, J = 247.9 Hz), 157.86 (157.94), 157.36-157.48 (156.74-156.86) (d, J = 12.1 Hz), 142.51-142.62 (142.92) (d, J = 11.2 Hz), 132.14-132.99 (m), 132.14-132.99 (m), 132.14-132.99 (m), 125.49 (123.54), 122.55-122.67 (122.77-122.89) (d, J = 12.1 Hz), 118.34 (119.24), 114.81-115.06 (115.68-115.93) (d, J = 24.6 Hz), 106.32-106.57 (107.27-107.52) (d, J = 24.8 Hz), 97.43-99.38 (90.08-92.08) (d, J = 195.6 Hz), 69.64-69.87 (63.21-63.37) (d, J = 22.7 Hz), 43.25 (43.34).

Example-8: Preparation of (1S,2R,3S)-4-(3-bromo-5-fluoro-phenoxy)-2-fluoro-7-methyl-sulfonyl-indane-1,3-diol (Formula-11):
Transferred the concentrated reaction mass obtained from example-7 (Formula-10) into reaction flask and cooled to 15-20°C. Triethyl amine (146.2 g) followed by formic acid (33.3 g) and RuCl (R, R)-Ts-DPEN(p-Cymene) catalyst (1.53 g) were added into reaction mass and stirred for 10-15 mins. Raised the reaction mass temperature to 25-30°C and stirred for 6 hours at same temperature. Reaction mass was quenched with dil. HCl solution (800 mL) at 25-30°C. The organic layer was washed with aq. sodium chloride solution at 25-30°C and treated with activated carbon (10 g) and heated to 50-55°C. Filtered the reaction mass through Hyflo bed and washed the bed with hot ethyl acetate (200 mL). Transferred the filtrate into reaction flask and distilled off under vacuum at below 60°C and charged methanol (200 mL) into the reaction flask at same temperature and then stirred for 15 mins and distilled off completely. Methanol (500 mL) was added to the resulting residue and heated to 60-65°C and stirred for 30 mins. The reaction mass temperature cooled to 25-30°C and stirred for 12-14 hours at same temperature. Reaction mass temperature was further cooled to 0-5°C and stirred for 3 hours. Filtered the product and washed with chilled methanol and dried the product under vacuum at 40-45°C for 6-8 hours to get the title compound.
Yield: 162g; Purity by HPLC: 98.36 %
m/z: 435.10 (M+H)+
1H NMR (400 MHz, DMSO-d6): d (ppm) 7.87-7.89 (d, J = 8.8 Hz, 1H), 7.39-7.43 (dt, J = 8.0, 2.0 Hz, 1H), 7.16-7.18 (d, J = 8.8 Hz, 1H), 7.143-7.149 (m, 1H), 7.02-7.06 (dt, J = 10.0, 2.4 Hz, 1H), 5.92-5.94 (d, J = 6.8 Hz, 1H), 5.83-5.85 (d, J = 6.8 Hz, 1H), 5.56-5.61 (m, 1H), 5.23-5.30 (m, 1H), 4.82-4.98 (dt, J = 51.2, 4.8 Hz, 1H), 3.33 (s, 3H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 161.60-164.08 (d, J = 247.8 Hz), 157.63-157.75 (d, J = 12.1 Hz), 156.90, 142.84, 133.94-134.03 (d, J = 8.6 Hz), 133.44, 131.97, 122.50-122.62 (d, J = 12.3 Hz), 119.74, 118.27-118.29 (d, J = 2.2 Hz), 114.56-114.81 (d, J = 24.8 Hz), 106.22-106.47 (d, J = 24.6 Hz), 97.07-98.98(d, J = 191.3 Hz), 73.42-73.67 (d, J = 25.3 Hz), 69.38-69.56 (d, J = 17.6 Hz), 45.06.

Example-9: Preparation of (1S,2S,3R)-4-(3-bromo-5-fluoro-phenoxy)-2,3-difluoro-7-methylsulfonyl-indan-1-ol (Formula-12):
The compound of Formula-11 (200 g) and 1,2-Dimethoxyethane (2000 mL) were added into reaction flask and heated to ~80°C and partially distilled of 1,2-Dimethoxyethane. Cooled the reaction mass to -10 to -5°C and Perfluoro-1-butanesulfonyl fluoride (PBSF) (166.57 g) was slowly added at -10 to -5°C followed by a solution of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (83.95 g) in 1,2-Dimethoxyethane (400 mL). Maintained the reaction mass at -10 to -5°C for 1 hour and raised to 10°C and DM water (4400 ml) was added and stirred for 12-14h. The resulting slurry mass was cooled to 0-5°C and stirred for 4 hours at same temperature. Filtered the product and washed with DM water. Transferred the wet material into reaction flask and DM water (800 mL) was added and stirred for 1 hour at 25-30°C. Filtered the product and washed with DM water (200 mL) and then dried under vacuum at 45-50°C for 8-10hrs to get the title compound.
a) Purification of compound of Formula-12 crude in Ethyl acetate and n-Heptane mixture:
The above dried compound of Formula-12 (175 g) followed by ethyl acetate (350 mL) were added into reaction flask and heated the suspension to 55-60?. To this, n-Heptane (1400 mL) was added at 55-60? and stirred for 30 mins at same temperature. Cooled the product slurry to 25-30? and stirred for 4 hrs and then filtered and washed with n-Heptane (175 mL).
b) Purification of Formula-12 crude in Isopropyl alcohol:
Transferred the above wet compound of Formula-12 (168 g) into reaction flask, added isopropyl alcohol (1680 mL) and heated to dissolve the suspension to 70-75?. The solution was treated with activated carbon (8.5 g) at 70-75? and filtered the reaction mass then washed with hot isopropyl alcohol. The filtrate was partially distilled off under vacuum at below 60? and maintained the reaction mass at 60-65? for 30 mins. The reaction mass was cooled to 25-30? and stirred for 3 hrs at same temperature and further cooled to 0-5?. Filtered the product and washed with chilled isopropyl alcohol under vacuum and dried the wet product under vacuum at 45-50°C for 5-6hrs.
Yield: 140 g; Purity by HPLC: 98.79 %
m/z: 454.0 [M+NH4]+
1H NMR (400 MHz, DMSO-d6): d (ppm) 8.00-8.03 (dd, J = 8.4, 1.6 Hz, 1H), 7.50-7.53 (dt, J = 8.4, 2.0 Hz, 1H), 7.30 (br, s, 1H), 7.19-7.24 (m, 2H), 6.17-6.18 (d, J = 5.6 Hz, 1H), 5.90-6.06 (dd, J = 56.0, 4.4 Hz, 1H), 5.57-5.61 (m, 1H), 5.09-5.28 (ddt, J = 47.6, 17.2, 4.8 Hz, 1H), 3.35 (s, 3H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 161.59-164.08 (d, J = 248.6 Hz), 157.86, 156.41-156.53 (d, J = 11.9 Hz), 144.17, 134.38, 132.94, 128.38-128.54 (d, J = 16.7 Hz), 122.74-122.86 (d, J = 12.2 Hz), 119.32, 118.14, 115.74-115.98 (d, J = 24.8 Hz), 107.37-107.61 (d, J = 24.5 Hz), 87.57-89.71 (dd, J = 198.0, 15.7 Hz), 85.37-87.40 (dd, J = 185.9, 16.4 Hz), 69.12-69.31 (d, J = 18.6 Hz), 44.96.

Example-10: Preparation of 3-[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methyl sulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile(Formula-1 Tech):
The compound of Formula-12 (200 g) and N,N-dimethylacetamide (2000 mL) were added into a reaction flask and stirred for 5-10 min at 25-30°C. Zinc cyanide (32.25 g) followed by activated Zinc dust (6.0 g) were added at 25-30? and degassed the reaction mass with N2 purging. [1,1'-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (20.0 g) was added and again degassed under N2 atmosphere. Heated the reaction mass to 105-110? and maintained for 1 hour at 105-110?. Cooled the reaction mass to 25-30?. Filtered the reaction mass washed with N,N-dimethylacetamide.
DM water (8800 mL) and aq. ammonia (~20% solution; 2200 mL) were added into another reaction flask and cooled to 10-15?. To the cooled ammonia, the above filtrate was added slowly at 10-15? and then stirred for 4 hrs at 10-15?. Filtered the product and washed with DM water. EDTA disodium salt (9.2 g) in DM water (1000 mL) were added into a reaction flask and stirred for 10-15 mins. The obtained wet product (~340 g) was added at 25-30? and stirred for 1 hour and filtered and dried the wet product under vacuum at 55-60°C for 12-14hrs.
The above dried product (~185 g) was dissolved in acetonitrile (1850 mL), treated with activated charcoal (20 g) and filtered. The filtrate was partially distilled off under vacuum and heated to 70-75? and DM water (1330 mL) was added to it. Cooled the reaction mass to 25-30? and stirred for 12-14hrs. The reaction mass was further cooled to 10-15? and stirred for 2 hrs at same temperature. Filtered the product and washed with 50% aqueous acetonitrile and dried the wet product under vacuum at 45-50°C for 5-6 hrs to get the title compound.
Yield: 155 g
a) Purification of 3-[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile-Tech (Formula-1):
The compound of Formula-1 Tech (200 g) and acetonitrile (2000 mL) were added into a RB flask. Heated to ~75? and stirred to dissolve completely. The solution was treated with activated charcoal (20.0 g) and filtered through 0.45µ micro filter paper. The filtrate was partially distilled off under vacuum at below 60? and the reaction mass was heated to 70-75?. To the reaction mass, 50% aqueous isopropyl alcohol were added at 70-75? and stirred for 30 min. Cooled the reaction mass to 25-30? and stirred for 4 hrs and further cooled to 5-10? and stirred for 2 hrs. Filtered the product and washed with acetonitrile: aqueous isopropyl alcohol [1:1] and dried to get the title compound.
Yield: 177 g; Purity by HPLC: 99.64 %
m/z: 401.2 (M+H)+
1H NMR (400 MHz, DMSO-d6): d (ppm) 8.01-8.03 (dd, J = 8.4, 1.6 Hz, 1H), 7.80-7.82 (d, J = 8.4 Hz, 1H), 7.62 (br, s, 1H), 7.57-7.60 (dt, J = 9.6, 2.0 Hz, 1H), 7.23-7.25 (d, J = 8.8 Hz, 1H), 6.19-6.20 (d, J = 5.6 Hz, 1H), 5.90-6.05 (dd, J = 56.0, 4.4 Hz, 1H), 5.59 (br, s, 1H), 5.10-5.29 (ddt, J = 47.6, 16.8, 4.8 Hz, 1H), 3.36 (s, 3H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 161.32-163.79 (d, J = 246.9 Hz), 157.49, 156.38-156.50 (d, J = 11.7 Hz), 144.22-144.31 (t, J = 5.2 Hz), 134.40, 133.29, 128.53-128.73 (t, J = 16.5, 3.9 Hz), 120.04, 118.52, 116.93-116.96 (d, J = 3.5 Hz), 116.19-116.44 (d, J = 25.3 Hz), 113.93-114.06 (d, J = 12.1 Hz), 113.25-113.49 (d, J = 24.7 Hz), 87.64-89.77 (dd, J = 198.0, 15.7 Hz), 85.39-87.42 (dd, J = 186.4, 16.5 Hz), 69.15-69.34 (d, J = 18.4 Hz), 44.96.
The PXRD of Belzutifan compound of formula-1 is illustrated in figure-1 and DSC thermogram in figure-2 & TGA analysis in figure-3.
,CLAIMS:We Claim:

1. A process for the preparation of Belzutifan compound of Formula-1, comprising of:

Formula-1

a) Reacting the compound of formula-2

Formula-2

with ethylene glycol in presence of trimethyl orthoformate and catalytic amount of acid catalyst in a suitable solvent to provide compound of formula-3,

Formula-3

b) reacting the compound of formula-3 in-situ with the compound of formula-4

Formula-4
in presence of a suitable base and a solvent to provide the compound of formula-5, optionally purifying the compound in a suitable solvent to provide the pure compound of formula-5,

Formula-5
c) reacting the compound of formula-5 with a suitable brominating agent in presence of a suitable activator in a solvent to provide the compound of formula-6,

Formula-6

d) reacting the compound of formula-6 in-situ with a suitable reagent in presence of a suitable base and a solvent to provide the compound of formula-7,

Formula-7

e) reacting the compound of formula-7 with a suitable chiral reducing agent in presence of a suitable acid-base complex in a solvent to provide the compound of formula-8,

Formula-8

f) treating the compound of formula-8 with a suitable acid in a solvent to provide the compound of formula-9, optionally purifying the compound in a suitable solvent to provide the pure compound of formula-9,

Formula-9

g) reacting the compound of formula-9 with an electrophilic fluorinating agent in presence of an acid catalyst in a solvent to provide the compound of formula-10,

Formula-10

h) reacting the compound of formula-10 in-situ with a suitable chiral reducing agent in presence of a suitable acid-base complex in a solvent to provide the compound of formula-11,

Formula-11

i) reacting the compound of formula-11 with a nucleophilic fluorinating agent in presence of a base in a solvent to provide the compound of formula-12, optionally purifying the compound in a suitable solvent to provide the pure compound of formula-12,

Formula-12
j) reacting the compound of formula-12 with a cyanating agent in presence of a metal catalyst in a solvent to provide the compound of formula-1, optionally purifying the compound in a suitable solvent to provide the pure compound of formula-1.

2. The process as claimed in claim-1, wherein,
In step (a) of the present invention, the acid used is organic acid or inorganic
acid. The organic acid may be selected from methanesulfonic acid, trifluoroacetic acid, triflic acid, p-toluenesulfonic acid or any other suitable organic acid. The inorganic acid is selected from sulfuric acid, hydrochloric acid, acetic acid or any other suitable inorganic acid.
In step (b), (d), (h) & (i) of the present invention, the base used is selected
from organic base or inorganic base. The organic base may be selected from triethylamine, diisopropylethylamine, tertiary butylamine, 1,8-diazabicyclo (5.4.0)undec-7-ene (DBU) or any other equivalent organic base. The inorganic base may be selected from alkali and alkaline metal acetates or carbonates such as sodium acetate, sodium bicarbonate, sodium carbonate, potassium acetate, potassium bicarbonate, potassium carbonate, cesium carbonate, or any other equivalent base.
In step (c) of the present invention, the suitable brominating agent used is
selected from N-bromosuccinamide (NBS), pyridinium bromide, bromine (Br2), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), HBr, benzyl-bromide or combinations in presence of a suitable activator such as azobisisobutyronitrile (AIBN), azobisdimethylvaleronitrile (ABDV), benzildimethyl acetal, benzoyl peroxide (BPO) & meta-chloroperoxybenzoic acid (m-CPBA) or any other suitable activator.
In step (d) of the present invention, the suitable reagent used is 2-picoline N-
oxide or pyridine N-oxide and the like.
In step (e) & (h) of the present invention, the suitable chiral reducing agent used
is selected from RuCl(R,R)-Ts-DPEN(p-Cymene), RuCl2[(R)-DM-BINAP][(R)-DAIPEN], [(R)-PhanePhos RuCl2 (S,S)-DACH] and [(R)-HexaPHEMP RuCl2 (R,R)-DPEN] or any other suitable chiral reducing agent.
In step-(e) & (h) the suitable acid-base complex used is formic acid-triethylamine;
In step-(f) the suitable acid used is inorganic acid such as hydrochloric acid &
sulfuric acid; or organic acid such as p-toluenesulfonic acid or any other suitable organic acid.
In step-(g) the suitable electrophilic fluorinating agent used is selected from (1-
chloromethyl-4-fluoro-1,4-Diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) [Selectfluor] or N-Fluorobenzenesulfonimide and the like; and the suitable acid is methanesulfonic acid, p-toluenesulfonic acid or any other suitable acid.
In step-(i) the suitable nucleophilic fluorinating agent used is (Diethylamino)sulfur
Trifluoride (DAST) or Perfluoro-1-butanesulfonyl Fluoride (PBSF) and the like; and the suitable base is 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU);

In step-(j) the suitable cyanating agent used is selected from zinc cyanide, copper
cyanide and the like; and the suitable catalyst is selected from [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)[Pd(dppf)Cl2], copper iodide and Zinc dust.
In step-(a) to (j) the suitable solvent used is selected from alcoholic solvents, polar-
aprotic solvents, hydrocarbon solvents, ester solvents, ether solvents, ketone solvents, chloro solvents, nitrile solvents and polar solvents such as water or mixtures thereof.

3. The process as claimed in claim-1, comprising of:
a) Reacting the compound of formula-2 with ethylene glycol in presence of trimethyl orthoformate and catalytic amount of p-toluene sulfonic acid monohydrate (PTSA. H2O) in isopropyl alcohol to provide compound of formula-3,
b) reacting the compound of formula-3 in-situ with the compound of formula-4
in presence of potassium carbonate in dimethyl sulfoxide to provide the compound of formula-5, purifying the compound in toluene and n-heptane to provide the pure compound of formula-5,
c) reacting the compound of formula-5 with N-Bromosuccinimide (NBS) in presence of Azobisisobutyronitrile (AIBN) in chloroform to provide the compound of formula-6,
d) reacting the compound of formula-6 in-situ with 2-picoline N-oxide in presence of diisopropylethylamine in acetonitrile to provide the compound of formula-7,
e) reacting the compound of formula-7 with RuCl(R,R)-Ts-DPEN(p-Cymene) in presence of formic acid-triethylamine complex in acetonitrile to provide the compound of formula-8,
f) treating the compound of formula-8 with hydrochloric acid in DM water to provide the compound of formula-9, purifying the compound in ethyl acetate to provide the pure compound of formula-9,
g) reacting the compound of formula-9 with Selectfluor in presence of methanesulfonic acid in methanol to provide the compound of formula-10,
h) reacting the compound of formula-10 in-situ with RuCl(R,R)-Ts-DPEN(p-Cymene) in presence of formic acid-triethylamine complex in ethyl acetate to provide the compound of formula-11,
i) reacting the compound of formula-11 with perfluoro-1-butanesulfonyl fluoride (PBSF) in presence of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) in 1,2-dimethoxyethane (DME) to provide the compound of formula-12, purifying the compound in ethyl acetate and n-Heptane followed by isopropyl alcohol to provide the pure compound of formula-12,
j) reacting the compound of formula-12 with zinc cyanide in presence of Pd(dppf)Cl2 and activated zinc dust in N,N-dimethylacetamide to provide the compound of formula-1, purifying the compound in aqueous acetonitrile followed by acetonitrile: aqueous isopropyl alcohol mixture to provide the pure compound of formula-1.

4. The process as claimed in claim-1, wherein the preparation of compound of formula-5, comprising of:
a) Reacting the compound of formula-2 with ethylene glycol in presence of trimethyl orthoformate and catalytic amount of acid catalyst in a solvent to provide compound of formula-3,
b) reacting the compound of formula-3 in-situ with the compound of formula-4 in presence of a suitable base and a solvent to provide the compound of formula-5, optionally purifying the compound in a suitable solvent to provide the pure compound of formula-5.

5. The process as claimed in claim-1, wherein the preparation of compound of formula-7, comprising of:
a) reacting the compound of formula-5 with a suitable brominating agent in presence of a suitable activator in a solvent to provide the compound of formula-6,
b) reacting the compound of formula-6 in-situ with a suitable reagent in presence of a suitable base and a solvent to provide the compound of formula-7.

6. The process as claimed in claim-1, wherein the preparation of compound of formula-9, comprising of:
a) reacting the compound of formula-7 with a suitable chiral reducing agent in presence of a suitable acid-base complex in a solvent to provide the compound of formula-8,
b) treating the compound of formula-8 with a suitable acid in a solvent to provide the compound of formula-9, optionally purifying the compound in a suitable solvent to provide the pure compound of formula-9.

7. The process as claimed in claim-1, wherein the preparation of compound of formula-11, comprising of:
a) reacting the compound of formula-9 with an electrophilic fluorinating agent in presence of an acid catalyst in a solvent to provide the compound of formula-10,
b) reacting the compound of formula-10 in-situ with a suitable chiral reducing agent in presence of a suitable acid-base complex in a solvent to provide the compound of formula-11.

8. The process as claimed in claim-1, wherein the preparation of compound of formula-12 comprising of reacting the compound of formula-11 with a nucleophilic fluorinating agent in presence of a base in a solvent to provide the compound of formula-12, optionally purifying the compound in a suitable solvent to provide the pure compound of formula-12.

9. The process as claimed in claim-1, wherein the preparation of compound of formula-1 comprising of reacting the compound of formula-12 with a cyanating agent in presence of a metal catalyst in a solvent to provide the compound of formula-1, optionally purifying the compound in a suitable solvent to provide the pure compound of formula-1.

10. A process for the preparation of crystalline form of Belzutifan of Formula-1, comprising of:
a) Adding a suitable solvent to Belzutifan crude compound of Formula-1,
b) heating and treating the reaction mixture with charcoal,
c) adding a suitable solvent to the reaction mass,
d) cooling and stirring the reaction mixture,
e) filtering, washing and drying the compound to get the crystalline form of Belzutifan compound of formula-1.

11. The process as claimed in claim-10, wherein in step-a) & c), the suitable solvent is selected from ether solvents, chloro solvents, ester solvents, alcohol solvents, ketone solvents, polar aprotic solvents, hydrocarbon solvents, nitrile solvents and polar solvents or mixtures thereof.

12. The process as claimed in claim-10, comprising of:
a) Adding acetonitrile to Belzutifan crude compound of Formula-1,
b) heating and treating the reaction mixture with charcoal,
c) adding a mixture of isopropyl alcohol & water to the reaction mass,
d) cooling and stirring the reaction mixture,
e) filtering, washing the obtained solid with a mixture of acetonitrile & aqueous isopropyl alcohol and drying the compound to get the crystalline form of Belzutifan compound of formula-1.

13. The novel intermediate compounds of Belzutifan having the following structural formulae: