DESC:FIELD OF INVENTION

The present invention relates to a process for preparation of Doravirine and its intermediates.

BACK GROUND OF THE INVENTION

Doravirine is chemically known as 3-chloro-5-[[1-[(4,5-dihydro-4-methyl-5-oxo-1H-1,2,4-triazol-3-yl)methyl]-1,2-dihydro-2-oxo-4-(trifluoromethyl)-3-pyridinyl]oxy]benzonitrile, which has been approved as a tablet having dosage strength 100MG under the trade name PIFELTRO®, which is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adult patients. Doravirine is structurally represented as Formula I, and is as follows:

Doravirine as well as its pharmaceutically acceptable salts were disclosed in US 8,486,975 B2 (US ’975) of Merck Canada Inc. Further, discloses the synthesis of Doravirine and is as shown below:

3-chloro-5-{[2-hydroxy-4-(trifluoromethyl)pyridin-3-yl]oxy}benzonitrile of Formula II(a) and 5-(Chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one of Formula III(a) are the key-intermediates in the synthesis of Doravirine of Formula I.

Further, alternatively, US’975 also discloses the synthesis for Doravirine intermediate analogous compounds, which is as shown below:

US 8,404,856 B2 (US ‘856), discloses the synthesis of 3-Chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile of Formula II(a), which is as shown below:

Bioorganic & Medicinal Chemistry Letters 2014, 24, 3, Pages 917 to 922, discloses the synthesis of Doravirine intermediates as well as analogous compounds, which is similar to the process disclosed in prior-art references, US ’975 & US ‘856, and as shown below:

Wherein, discloses the synthesis of Doravirine intermediate, 3-chloro-5-{[2-hydroxy-4-
(trifluoromethyl)pyridin-3-yl]oxy}benzonitrile comprises the condensation of 3-Chloro-5-bromophenol with 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine in presence of K2CO3 in NMP at 120°C yields 3-(3-chloro-5-bromophenoxy)-2-chloro-4-(trifluoromethyl)pyridine (Yield: 79%), further hydrolysis yields pyridinol compound (Yield: 71%) and followed by cyanation reaction yields benzonitrile compound.

Further, discloses the synthesis of analogous compound, 3-(3-chloro-5-iodophenoxy)-2-chloro-5-nitropyridine-1-oxide (Yield: 80%) involves the condensation reaction of commercially available 5-iodo-3-chlorophenol with nitropyridine-N-oxide compound in presence of K2CO3 in DMF at 55°C. Further, brominaiton yields 3-(3-chloro-5-iodophenoxy)-2,4-bromopyridine (Yield: 87%) and followed by cyanation yields 3-chloro-5-[(4-bromo-2-hydroxypyridin-3-yl)oxy]benzonitrile (Yield: 72%).

Journal of Organic Process Research & Development 2016, 20, Pages 1476 to 1481, discloses the synthesis of Doravirine and its intermediates are as shown below:

Wherein, 3-chloro-5-iodophenol was coupled with pyridine 2-chloro-3-fluoro-4-trifluoromethylpyridine in K2CO3 and NMP yields 3-(3-chloro-5-iodophenoxy)-2-chloro-4-(trifluoromethyl)pyridine (assay: 91%), followed by hydrolysis gives pyridinol compound and is further recrystallized / purified using EtOAc / n-Heptane solvents. However, this process may cause the formation of nitrosamine impurities and economically not viable process, as costly solvents (such as Heptane) have been used for purification.

US 9,663,490 B2, discloses the preparation of 3-Chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile of Formula II(a), which is as shown below:

US 9,598,397 B2, discloses the preparation of 3-Chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile of Formula II, which is as shown below:

The present inventors have observed that the prior-art process for preparing 2-halo-3-(3,5-dihalophenoxy)-4-(trifluoromethyl)pyridine, comprising condensation of 3,5-dihalophenol with 2-halo-3-fluoro-4-(trifluoromethyl)pyridine at higher temperature (120°C) using K2CO3 and NMP / DMF as solvents, which process leads lower yields (=80%) and nitrosamine impurities, then further purification is required and hence, is not economically viable process.

In view of the above, there is a need for an industrially applicable and cost-effective process for the preparation of intermediate compound of Formula II, which can be used as key starting material in the synthesis of Doravirine.

OBJECTIVES

An objective of the present invention is to provide a process for the preparation of Doravirine using intermediate compound of Formula II(a), which is economically suitable and industrially applicable.

Another objective of the present invention is to provide a process for the preparation of compound of Formula C-1, which can be used in the synthesis of Doravirine intermediate compound of Formula II(a), which is economically suitable and industrially viable process over than the prior-art process.

SUMMARY OF THE INVENTION

A process for the preparation of Doravirine of Formula I:

which comprises:
i) condensing 3-chloro-5-halophenol of Formula A-1

with 2,3-dihalo-4-(trifluoromethyl)pyridine of Formula B

in presence of a phase transfer catalyst to give 2-halo-3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine of Formula C-1;

wherein, phase transfer catalyst is 18-Crown-6 ether
ii) converting the obtained 2-halo-3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine of Formula C-1 in step (i) to 3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine-2-ol of Formula D-1; and

iii) reacting the obtained 3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine-2-ol of Formula D-1 in step (ii) with cyanide source to give 3-Chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile of Formula II(a);

iv) condensing the obtained 3-Chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile of Formula II(a) in step (iii) with the 5-(halomethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one of Formula III

to give 3-chloro-5-({2-oxo-1-[(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile of Formula IV

v) converting the obtained 3-chloro-5-({2-oxo-1-[(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile of Formula IV in step (iv) to Doravirine of Formula I.

A process for the preparation of 2-halo-3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine of Formula C-1:

which comprises:
condensing 3-chloro-5-halophenol of Formula A-1

with 2,3-dihalo-4-(trifluoromethyl)pyridine of Formula B

in presence of a phase transfer catalyst to give 2-halo-3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine of Formula C-1.
wherein, phase transfer catalyst is 18-Crown-6 ether.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Doravirine of Formula I, which comprises condensing 3-chloro-5-halophenol of Formula A-1 with 2,3-dihalo-4-(trifluoromethyl)pyridine of Formula B in a solvent selected from the group comprising of halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles or mixture of solvents thereof; in a base, in presence of a phase transfer catalyst selected from the group comprising of Crown ethers, quaternary ammonium salts, organic phosphonium salts; Crown ethers selected from 18-Crown-6 ether (18C6), Dibenzo-18-crown-6 (DB18C6), 12-crown-4 (12C4), 15-crown-5 (15C5), monobenzo-15crown-5 (B15C5), 21-crown-7 (21C7) and the like; quaternary ammonium salts selected from tetra-n-butylammonium bromide (TBAB), tetra-n-butylammonium fluoride (TBAF), tetra-n-butylammonium chloride (TBAC), Tetrabutylammonium tribromide (TBATB), benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, and methyltrioctylammonium chloride and the like; organic phosphonium salts selected from hexadecyltributylphosphonium bromide and the like; stirred the obtained reaction mixture at room temperature for 10 to 30 minutes; heating the obtained reaction mixture to 30 – 80°C for 10 to 40 hours; cooling the obtained reaction mixture to 0 – 10°C; optionally isolating the 2-halo-3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine of Formula C-1 and optionally purifying the obtained 2-halo-3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine of Formula C-1.
Converting the obtained compound of Formula C-1 by reacting with a base, in a solvent selected from the group comprising of halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles, polar aprotic solvents or mixture of solvents thereof; to give 3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine-2-ol of Formula D-1; treating the obtained compound of Formula D-1 with cyanide source selected from the group comprising of CuCN, Zn(CN)2, KCN, NaCN, Ethyl Cyanoacetate and the like; in a solvent selected from the group comprising of halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles, polar aprotic solvents or mixture of solvents thereof; to give 3-Chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile of Formula II(a).
Condensing the obtained 3-Chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile of Formula II(a) with the 5-(halomethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one of Formula III in a solvent selected from the group halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles, polar aprotic solvents or mixture of solvents thereof; in a base to give 3-chloro-5-({2-oxo-1-[(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile of Formula IV; converting the obtained compound of Formula IV by methylation to Doravirine of Formula I using methylating agent selected from the group comprising of methyl halide, dimethyl sulphate, dimethyl carbonate and the like, in a base; in a solvent selected from the group halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles, polar aprotic solvents or mixture of solvents thereof; isolating Doravirine of Formula I and optionally purifying the obtained Doravirine of Formula I.

The present invention also relates to a process for the preparation of 2-halo-3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine of Formula C-1, which comprises condensing 3-Chloro-5-halophenol of Formula A-1 with 2,3-dihalo-4-(trifluoromethyl)pyridine of Formula B in a solvent selected from the group comprising of halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles or mixture of solvents thereof; in a base, in presence of a phase transfer catalyst selected from the group comprising of Crown ethers, quaternary ammonium salts, organic phosphonium salts; Crown ethers selected from 18-Crown-C6 ether (18C6), Dibenzo-18-crown-6 (DB18C6), 12-crown-4 (12C4), 15-crown-5 (15C5), monobenzo-15crown-5 (B15C5), 21-crown-7 (21C7) and the like; quaternary ammonium salts selected from tetra-n-butylammonium bromide (TBAB), tetra-n-butylammonium fluoride (TBAF), tetra-n-butylammonium chloride (TBAC), Tetrabutylammonium tribromide (TBATB), benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, and methyltrioctylammonium chloride and the like; organic phosphonium salts selected from hexadecyltributylphosphonium bromide and the like; stirred the obtained reaction mixture at room temperature for 10 to 30 minutes; heating the obtained reaction mixture to 30 – 80°C for 10 to 40 hours; cooling the obtained reaction mixture to 0 – 10°C; optionally isolating the 2-halo-3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine of Formula C-1 and optionally purifying the obtained 2-halo-3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine of Formula C-1.

In another embodiment throughout the invention, the halogenated solvents are selected from the group comprising of dichloromethane (MDC), ethylene dichloride (EDC), chloroform and the like; alcohols are selected from the group comprising of methanol, ethanol, butanol, t-BuOH, isopropanol and the like; ketones are selected from the group comprising of acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), N,N-dimethylformamide (DMF) and the like; ethers are selected from the group comprising of tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), diethyl ether, isopropyl ether, methyl isobutylether (MIBE), methyl t-butyl ether (MTBE), dioxane and the like; esters are selected from the group comprising of ethyl acetate, isopropyl acetate and the like; hydrocarbons are selected from the group comprising of toluene, xylene and the like; nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, acrylonitrile, Potassium cyanide and the like; Polar aprotic solvents are selected from the group comprising of DMF, dimethylacetamide (DMA), acetonitrile (CAN), dimethylsulfoxide (DMSO) and the like.

In another embodiment throughout the invention, the mixture of solvents means two or more solvents.

In another embodiment throughout the invention, the base is selected from the group comprising of alkali hydroxides, alkali hydrides, alkali carbonates, organic amines, organic or inorganic metal reagents, metal alkoxides; alkali hydroxides selected from NaOH, KOH, CaOH and the like; alkali hydrides selected from sodium hydride, potassium hydride; alkali carbonates selected from Na2CO3, K2CO3, NaHCO3, KHCO3, and the like; oraganic amines selected from triethylamine, trimethylamine, butylamine, N,N-diisopropylethylamine and the like; organic or inorganic metal reagents selected form the group comprising of n-butyl lithium, sec-butyl lithium, t-butyl lithium and the like; metal alkoxides selected form the group comprising of sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and the like.

In another embodiment, obtained compound of Formula C-1 can be optionally isolated and optionally purified by conventional methods.

In another embodiment, obtained Compound of Formula II(a) can be optionally isolated and optionally purified by conventional methods.

In another embodiment throughout the invention, Isolation of Doravirine and its intermediate compounds can be performed by conventional methods such as cooling, removal of solvents, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, filtration, centrifugation and the like.

In another embodiment, the obtained Doravirine of Formula I can be used in medicaments such as pharmaceutical formulation & solid dispersion or pre-mix.

The present invention provides a process for the preparation of 2-halo-3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine of Formula C-1, comprising condensing 3-Chloro-5-halophenol compound of Formula A-1 with 2,3-dihalo-4-(trifluoromethyl)pyridine compound of Formula B in presence of a phase transfer catalyst, in a solvent other than DMF / NMP (used in prior-art) at lower temperature, leads the better reaction conversion and higher yield (=91%), without formation of nitrosamine impurities, followed by simple isolation techniques and conversion to compound of Formula II(a), also leads higher yield (=84%) and purity, which process is economically friendly and industrially applicable process.

The Abbreviations used throughout the invention are as follows:
AcOH: Acetic acid
CuCN: Copper(I) cyanide
DMF: N,N-Dimethyl formamide
DIPEA: N,N-Diisopropylethylamine
Et2O: Diethyl ether
EA / EtOAc: Ethyl acetate;
HPMCAS: Hypromellose acetate succinate (or) Hydroxypropylmethylcellulose acetate succinate
K2CO3: Potassium carbonate
NMP: N-methylpyrrolidinone;
t-BuOH: tert-butanol;
TEA: Triethylamine
Zn(CN)2: Zinc cyanide

The invention of the present application will be explained in more detail with reference to the following examples, which should not be construed as limiting the scope of the invention in any manner.

Examples
Example 1: Preparation of 2-chloro-3-(3-chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridine
To the 3-Chloro-5-iodophenol (100 gm), added 2-Chloro-3-fluoro-(trifluomethyl)pyridine (75.5 gm), anhydrous K2CO3 (79 gm), 18-Crown-6 ether (10 gm), and Acetonitrile (500 ml) at room temperature. Stirred the reaction mixture at 25-35°C for 10 minutes to 15 minutes and heated to 50-55°C. The obtained reaction mass was maintained at 50-55°C for 20 hours to 22 hours. Cooled to 0 to 5°C, slowly added water (1000 ml) and stirred the reaction mass at 0 to 5°C for 2 to 3 hours. The obtained solid was filtered and washed with water (200 ml), followed by drying at 55-60°C to yield 2-chloro-3-(3-chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridine (155 gm).
Yield: 91%
Purity by HPLC: 98.24%

Example 2: Preparation of 3-(3-Chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridine-2-ol
To the 2-Chloro-3-(3-chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridine (150 gm), added KOH (99 gm) & t-Butanol (300 ml) and stirred for 10 minutes to 15 minutes at 25-35°C, heated the reaction mass at 75-80°C and stirred at 75-80°C for 3 hours to 5 hours. The obtained reaction mass was Cooled to 25-35°C and added water (450 ml) at 25-35°C. pH of the reaction mass was adjusted to 2.5 to 3.5 with 2N dil.HCl at 25-35°C, stirred for 30 minutes to 60 minutes. The obtained solid was filtered and washed with water (150 ml). To the obtained wet solid, added Toluene (675 ml), heated to reflux (about 105-115°C) and maintained for 30 minutes to 60 minutes. The reaction mass was cooled to 25-30°C and stirred for 2 hours to 3 hours. The obtained solid was filtered and washed with Toluene (75 ml), followed by drying at 50-60°C to yield 3-(3-Chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridine-2-ol (115 gm).
Yield: 80%
Purity by HPLC: 99.44%

Example 3: Preparation of 3-Chloro-5-((2-oxo-4-(trifluoromethyl-1,2-dihydropyridin-3-yl)oxy)benzonitrile
To the 3-(3-Chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridine-2-ol (50 gm), added N,N-DMF (250 ml) and stirred the reaction mass under mild nitrogen purging at 25-35°C. The obtained reaction mass was heated to 110-115°C and maintained for 15 minutes to 30 minutes. To the obtained reaction mass, added CuCN (21 gm) at 110-115°C, stirred and maintained for 20 hours to 24 hours at 110-115°C. Cooled the reaction mass to 25-35°C, added ammonia buffer solution (500 ml), THF (500 ml) and distilled off organic layer under vacuum at 40-50°C. Co-distilled the obtained residue with Acetone (100 ml). To the obtained residue, added Acetone (250 ml) and stirred at 25-35°C for 2 hours to 3 hours. The obtained solid was filtered and washed with Acetone (100 ml), followed by drying at 50-60°C to yield 3-Chloro-5-((2-oxo-4-(trifluoromethyl-1,2-dihydropyridin-3-yl)oxy)benzonitrile (32 gm).
Yield: 84%
Purity by HPLC: 99.08%

Example 4: Preparation of 3-Chloro-5-((2-oxo-1-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile
To the 3-Chloro-5-((2-oxo-4-(trifluoromethyl-1,2-dihydropyridin-3-yl)oxy)benzonitrile (100 gm), added DMF (400 ml), anhydrous K2CO3 (24 gm) and stirred at 30-35°C for 15 minutes. To the obtained reaction mass, added 5-(Chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (45 gm) in DMF (200 ml) and stirred at 30-35°C for 2 hours to 3 hours. Added Conc.HCl (34 ml) and Water (66 ml) to the reaction mass at 25-35°C and stirred for 15 minutes to 20 minutes, followed by added water (700 ml) and stirred for 30 minutes to 45 minutes. The obtained solid was filtered and washed with Water (400 ml). Dried the obtained solid at 50-60°C for 15 hours to 16 hours, followed by added Acetonitrile (900 ml), Water (90 ml), heated to reflux (at 75-85°C) and maintained for 60 minutes to 75 minutes. Cooled the reaction mass to 25-30°C and maintained for 2 hours to 3 hours. The obtained solid was filtered and washed with mixture of Acetonitrile (90 ml) and Water (10 ml), followed by dried the obtained solid at 50-60°C to yield 3-Chloro-5-((2-oxo-1-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile (80 gm).
Yield: 61%
Purity by HPLC: 99.2%
Example 5: Preparation of Doravirine Crude
To the 3-Chloro-5-((2-oxo-1-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl)oxy)benzonitrile (60 gm), added acetonitrile (600 ml), dimethyl sulphate (36 ml) at 35-40°C and stirred for 15 minutes to 20 minutes. To the obtained reaction mass, added DIPEA (39 gm) and maintained at 35-40°C for 1 hour to 2 hours. Cooled to 15-25°C and maintained for 1 hour to 2 hours. Filtered the obtained solid and washed with Acetonitrile (120 ml), followed by dried under vacuum. To the obtained wet solid, added acetonitrile (570 ml) and water (30 ml), stirred the reaction mass at 25-35°C for 10 minutes to 15 minutes. Heat the reaction mass to reflux (at 75-85°C) and maintained for 2 hours to 3 hours. Cooled to 20-30°C and maintained for 2 hours to 3 hours. Filtered the obtained solid and washed with mixture of Acetonitrile (114 ml) & Water (6 ml), followed by drying at 50-60°C to yield Doravirine (48 gm).
Yield: 77%
Purity by HPLC: 99.37%

Example 6: Purification of Doravirine
To the Doravirine (40 gm), added DMF (320 ml) and stirred the reaction mass at 30-40°C. To the obtained clear solution, added activated charcoal (2 gm), stirred for 30 minutes to 45 minutes. The reaction mass was filtered and washed with DMF (80 ml), filtered, heated to 90-95°C, added water (400 ml) and maintained at 90-95°C for 2 hours to 3 hours. Cooled to 25-35°C and maintained at 25-35°C for 2 hours to 3 hours. The obtained solid was filtered and washed with Water (80 ml). To the obtained wet solid, added Acetonitrile (400 ml) and heated to reflux (at 75-85°C), followed by maintained for 2 hours to 3 hours. Cooled the reaction mass to 25-30°C and stirred for 2 hours to 3 hours. The obtained solid was filtered and washed with Acetonitrile (80 ml), followed by drying at 50-60°C to yield Doravirine (34 gm).
Yield: 85%
Purity by HPLC: 99.7%

Example 6: Preparation of Doravirine pre-mix with HPMCAS
To Doravirine (50 gm), added Acetone (5000 ml) and water (1250 ml), then heated to 30-40°C and stir for minimum 25 minutes. To the obtained clear solution was added HPMCAS (200 gm) and stirred for minimum 30 minutes at 30-40°C. Spray dried the solution under nitrogen flow at 60-70°C and continued nitrogen flow at 60-70°C for minimum 60 minutes to yield Doravirine – HPMCAS Premix (200 gm).
Yield: 80%

,CLAIMS:
1. A process for the preparation of Doravirine of Formula I:

which comprises:
i) condensing 3-chloro-5-halophenol of Formula A-1

with 2,3-dihalo-4-(trifluoromethyl)pyridine of Formula B

in presence of a phase transfer catalyst to give 2-halo-3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine of Formula C-1;

wherein, phase transfer catalyst is 18-Crown-6 ether
ii) converting the obtained 2-halo-3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine of Formula C-1 in step (i) to 3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine-2-ol of Formula D-1; and

iii) reacting the obtained 3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine-2-ol of Formula D-1 in step (ii) with cyanide source to give 3-Chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile of Formula II(a);

iv) condensing the obtained 3-Chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile of Formula II(a) in step (iii) with the 5-(halomethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one of Formula III

to give 3-chloro-5-({2-oxo-1-[(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile of Formula IV

v) converting the obtained 3-chloro-5-({2-oxo-1-[(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile of Formula IV in step (iv) to Doravirine of Formula I.

2. The process as claimed in claim 1, wherein solvent used in step i) & step ii) is selected from the group comprising of halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles or mixture of solvents thereof; base used in step i) & step ii) is selected from alkali hydroxides, alkali hydrides, alkali carbonates, organic amines, organic or inorganic metal reagents, metal alkoxides.

3. The process as claimed in claim 1, wherein cyanide source used in step iii) is selected from the group comprising of CuCN, Zn(CN)2, KCN, NaCN, Ethyl Cyanoacetate and the like.

4. The process as claimed in claim 1, wherein solvent used in step iv) is selected from the group comprising of halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles or mixture of solvents thereof; base used in step iv) is selected from alkali hydroxides, alkali hydrides, alkali carbonates, organic amines, organic or inorganic metal reagents, metal alkoxides.

5. The process as claimed in claim 1, wherein conversion of compound of Formula IV to Doravirine of Formula I in step v) was carried out by methylation using methylating agent, wherein methylating agent is selected from the group comprising of methyl halide, dimethyl sulphate, dimethyl carbonate and the like.

6. A process for the preparation of 2-halo-3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine of Formula C-1:

which comprises:
condensing 3-chloro-5-halophenol of Formula A-1

with 2,3-dihalo-4-(trifluoromethyl)pyridine of Formula B

in presence of a phase transfer catalyst to give 2-halo-3-(3-chloro-5-halophenoxy)-4-(trifluoromethyl)pyridine of Formula C-1.
wherein, phase transfer catalyst is 18-Crown-6 ether.

7. The process as claimed in claim 7, wherein solvent used in step i) is selected from the group comprising of halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles or mixture of solvents thereof; base used in step i) is selected from alkali hydroxides, alkali hydrides, alkali carbonates, organic amines, organic or inorganico metal reagents, metal alkoxides.