WO2021245590A1

WO2021245590A1 - An improved process for the preparation of triazole derivatives

Info

Publication number: WO2021245590A1
Application number: PCT/IB2021/054863
Authority: WO
Inventors: Venkateswara Rao Nandepu; Srinivasa Rao SADHANALA
Original assignee: Metrochem Api Private Limited
Priority date: 2020-06-04
Filing date: 2021-06-03
Publication date: 2021-12-09

Abstract

The present invention relates to an improved process for the preparation of triazole derivatives such as ravuconazole and isavuconazole.

Description

“An improved process for the preparation of triazole derivatives”

Related applications:

This application claims the benefit under Indian Provisional Application No(s). 202041023395, filed on Jun 4, 2020 entitled “An improved process for the preparation of ravuconazole”, and 202141000845 filed on Jan 8, 2021 entitled “An improved process for the preparation of isavuconazole”, the content of each of which are incorporated by reference herein.

Field of the Invention:

The present invention relates to an improved process for the preparation of triazole derivatives such as ravuconazole and isavuconazole, represented by the following general formula I, wherein R₁ and R₂ are independently selected from fluorine or hydrogen.

Background of the Invention:

Ravuconazole and isavuconazole are triazole derivatives and known as antifungal compounds for treatment of systemic mycoses. Ravuconazole and isavuconazole was approved in their prodrug forms namely Fosravuconazole and Isavuconazonium sulfate respectively for the treatment of onychomycosis, invasive aspergillosis and mucormycosis in different countries.

Ravuconazole is chemically known as 4-[2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1- methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-thizolyl]benzonitrile and is represented by the following general formula I, when R₁ is fluorine and R₂ is hydrogen; Isavuconazole is chemically known as 4-[2-[(1R,2R)-2-(2,5-difluoro phenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4- triazol-1-yl)propyl]-4-thizolyl]benzonitrile and is represented by the following general formula I, when R₁ is hydrogen and R₂ is fluorine;

Triazole derivatives, specifically ravuconazole and process for its preparation was first disclosed in US5648372 (the US’372 patent) and the disclosed process is schematically depicted in the following scheme:

The process reported in US’372 involves ring opening reaction of the trisubstituted oxirane compound (1) by diethylaluminium cyanide in toluene provides nitrile compound (2), which on reaction with O,O'-Diethyl dithiophosphate in water provides thioamide compound (3), which is further reacted with 4-bromoacetyl benzonitrile (4) in ethanol yields Ravuconazole. The said process involves use of diethylaluminium cyanide for the formation of nitrile compound (2). Diethyl aluminium cyanide is highly toxic and flammable, and the reported process involves dangerous work-up with aqueous hydrochloric acid. Moreover, the disadvantage in ring opening of epoxides is the formation of number of by-products like diols, hydroxyesters, estolides and other dimers. Hence this process is not suitable for large-scale synthesis. Similar process was disclosed for isavuconazole in US 6300353 (the US’353 patent) and the disclosed process is schematically depicted in the following scheme:

The article in “Synthetic Communications, 39, 1611-1625, 2009” journal discloses a process for the preparation of ravuconazole, which comprises the reaction of compound (5) with chloroacetylchloride in presence of aluminium chloride to provide the compound (6), which on reaction with chiral alkyne compound (7) in the presence of palladium catalyst and diethyl zinc in THF/toluene to provide halo phenyl compound (8); which on condensation with triazole in presence of sodium hydroxide to provide compound (9); the compound (9) was oxidized in presence of sodium metaperiodate, ruthenium dioxide and a phase transfer reagent such as trialkyl(Cs/C10)methylammonium chloride (ADOGEN®464) to provide acid compound (10), which on further reaction with carbonyldiimidazole to provide oxetanone compound (11), followed by ring opening with aqueous ammonia to provide amide compound (12); the amide compound is reacted with POCI₃ to provide nitrile compound (2). Thus obtained nitrile compound was further converted into ravuconazole in a similar manner as described in US ’372 patent. The disclosed process in this journal is represented by the following scheme

Though the above process avoids the use of diethylaluminium cyanide and ring opening of epoxide of prior art, the said process involves large number of steps, costly reagents such as ruthenium dioxide, palladium(II)-dichloride-diacetonitrile, ADOGEN®464 and carbonyl diimidazole, which increases overall cost of product. Further involves usage of column chromatography technique in all intermediate stages for purification and hence commercially not viable.

The US 9783508 patent (the US’508 patent) discloses a process for the preparation of diastereomerically and enantiomerically enriched triazole compounds such as isavuconazole and ravuconazole. The disclosed process involves Reformatsky reaction between a ketone compound and 2-halozincpropionate ester to provide an ester compound, which is then subjected to enzymatic resolution with an esterase enzyme to provide desired isomer. Enzyme used in this process is not commercially available.

Hence in the view of above, there is a need in the art for the preparation of triazole derivatives such as ravuconazole and isavuconazole, which is simple, cost effective, industrially feasible and avoids costly reagents and lengthy process of prior art.

Summary of the Invention:

Accordingly, the present invention provides an improved process for the preparation of triazole derivatives of general formula I, which is simple, cost effective and industrially feasible.

In accordance with one embodiment, the present invention provides an improved process for the preparation of triazole derivatives of general formula I, wherein R₁ and R₂ are independently selected from fluorine or hydrogen,

comprising, a) reacting keto compound of formula II, wherein R₁ and R₂ are each of fluorine or hydrogen,

with 2-halopropionate ester compound of formula III, wherein X is halogen; R is C₁-C₁₂ alkyl,

in the presence of a zinc source and a catalyst in a suitable solvent to provide compound of formula IV, wherein R is C₁-C₁₂ alkyl; R₁ and R₂ are each of fluorine or hydrogen;

b) hydrolyzing the compound of formula IV with a suitable base in a suitable solvent to provide compound of formula V, wherein R₁ and R₂ are each of fluorine or hydrogen,

c) resolution of the compound of formula V with a suitable resolution reagent to provide corresponding chiral salt compound of formula VI, wherein R₁ and R₂ are each of fluorine or hydrogen,

which on neutralization with a suitable base to provide compound of formula VII, wherein R₁ and R₂ are each of fluorine or hydrogen,

d) reacting the compound of formula VII with an activating agent, followed by a suitable ammonia source to provide compound of formula VIII, wherein R₁ and R₂ are each of fluorine or hydrogen,

e) converting the compound of formula VIII into triazole derivatives of general formula I.

In accordance with another embodiment, the present invention provides a process for the preparation of triazole derivatives of general formula I, wherein R₁ and R₂ are each of fluorine or hydrogen,

which comprising the step of reacting a compound of formula II, wherein R₁ and R₂ are each of fluorine or hydrogen,

with 2-halopropionate ester compound of formula IP, wherein R is C₁-C₁₂ alkyl,

in the presence of zinc source and a solvent to provide compound of formula IV, wherein R is C₁-C₁₂ alkyl and R₁ and R₂ are each of fluorine or hydrogen, wherein the reaction is carried out in presence of additional catalyst.

which comprising the step of resolving the compound of formula V,

wherein R₁ and R₂ are each of fluorine or hydrogen, with a suitable resolution reagent in a suitable solvent; wherein the suitable resolution agent is selected from (S)-phenyl ethyl amine, (S)-(-)-N-methyl-1-phenylethylamine, (S)-(-)-N,N,α-trimethylbenzylamine, (S)-1-(4-chloro phenyl) thylamine, (S)-(-)-4-bromo-α-methyl benzylamine and n-octyl-D-glucamine.

In accordance with another embodiment, the present invention provides a chiral salt compound of formula VI, wherein R₁ and R₂ are each of fluorine or hydrogen,

wherein the chiral salt is selected from (S)-phenyl ethyl amine, (S)-(-)-N-methyl-1- phenylethylamine, (S)-(-)-N,N,α-trimethylbenzylamine, (S)-1-(4-chlorophenyl) ethylamine, (S)- (-)-4-bromo-α-methylbenzylamine and n-octyl-D-glucamine.

In accordance with another embodiment, the present invention provides a process the preparation of triazole derivatives of general formula I, wherein R₁ and R₂ are each of fluorine or hydrogen, which comprising the step of reacting the compound of formula VII, wherein R₁ and R₂ are each of fluorine or hydrogen,

with an activating agent, followed by ammonia source to provide compound of formula VIII,

wherein R₁ and R₂ are each of fluorine or hydrogen.

In accordance with another embodiment, the present invention provides an improved process for the preparation of triazole derivatives of general formula I, which comprises reacting the compound of formula VIII, wherein R₁ and R₂ are each of fluorine or hydrogen, with phosphorous oxychloride in the presence of additional solvent to provide compound of formula IX, wherein R₁ and R₂ are each of fluorine or hydrogen, and converting the compound of formula IX into triazole derivatives of general formula I.

Detailed description of the Invention:

Accordingly, the present invention provides an improved process for the preparation of triazole derivatives of general formula (I), wherein R₁ and R₂ are independently selected from fluorine or hydrogen.

The term “suitable solvent” used in the present invention until unless specified is selected from, but are not limited to “alcohols” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “esters” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, “ethers” such as tetrahydrofuran, 2- methyl tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane and the like; “hydrocarbons” such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane, petroleum ether and the like; “chloro solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like; “nitriles” such as acetonitrile and the like; “ketones” such as acetone, methyl isobutyl ketone, methyl ethylketone and the like; and water.

In one embodiment, the present invention provides an improved process for the preparation of triazole derivatives of general formula I, wherein R₁ and R₂ are independently selected from fluorine or hydrogen,

in the presence of a zinc source and a catalyst in a suitable solvent to provide compound of formula IV, wherein R is C₁-C₁₂ alkyl; R₁ and R₂ are each of fluorine or hydrogen,

e) converting the compound of formula VIII into triazole derivatives of formula I. The starting compound of formula II and compound of formula III are known in the art and are commercially available. They can be procured from the available commercial sources or can be prepared by the methods known in the art.

In a preferred embodiment, the compound of general formula I represents ravuconazole, when R₁ is fluorine and R₂ is hydrogen; the compound of general formula I represents isavuconazole, when R₁ is hydrogen and R₂ is fluorine.

The step a) of the aforementioned process involves reaction of keto compound of formula II, wherein R₁ and R₂ are each of fluorine or hydrogen; with a compound of formula III, wherein X is halogen selected from Cl, Br, I and F, preferably bromine; and R is selected from C₁-C₁₂ alkyl such as methyl, ethyl, propyl, butyl, isopropyl and the like; preferably ethyl; in the presence of a zinc source and a catalyst in a suitable solvent to provide compound of formula IV; wherein the zinc source is zinc dust/powder or zinc chloride; preferably the zinc source may be activated before the use by the methods known in the art; the catalyst is iodine; and the solvent is selected from the group consisting of ethers, such as tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert- butyl ether, 1,4-dioxane and the like; nitriles, such as acetonitrile or propionitrile; esters, such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; chloro solvents, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; hydrocarbons such as toluene, xylene, benzene and the like; or mixtures thereof; preferably the solvent is ethers, such as tetrahydrofuran or 2-Me-THF. In addition to iodine catalyst, chlorotrimethyl silane, trichlorosilane or methane sulfonic acid added in step a) in catalytic amount.

The step a) reaction may advantageously be carried out at a suitable temperature of 20°C to about reflux temperature of the solvent used. Preferably the reaction is carried out at a temperature of about 35°C to about 70°C; more preferably at about 55°C to about 70°C. The reaction is allowed to stir for a sufficient period of time from about an hour to until completion of the reaction; preferably for 12-16 hrs.

In the reported process the compound of formula IV was obtained in very low yield of 40-50% due to poor insertion of Zinc metal into the carbon-halogen bond of the α-haloester even after zinc dust activated with trimethylsilyl chloride. The present inventor surprisingly found that the use of iodine as an additional catalyst for the reaction of compound of formula II and compound of formula III in the presence of activated zinc and TMSCl leads to the smooth insertion of zinc and reaction get completed within 16 hours with higher yield.

In an embodiment, the present invention provides a process for the preparation of triazole derivatives of general formula I, wherein R₁ and R₂ are each of fluorine or hydrogen, which comprising the step of reacting a compound of formula II, wherein R₁ and R₂ are each of fluorine or hydrogen, with 2-halopropionate ester compound of formula IP, wherein R is C₁-C₁₂ alkyl, in the presence of zinc source and a solvent to provide compound of formula IV, wherein R is C₁-C₁₂ alkyl and R₁ and R₂ are each of fluorine or hydrogen, wherein the reaction is carried out in presence of iodine catalyst.

Optionally, the compound of formula IV obtained in step a) is not isolated as a solid and proceeds to next step without isolation.

The step b) of the aforementioned process involves hydrolysis of compound of formula IV, wherein R is C₁-C₁₂ alkyl such as methyl, ethyl, propyl, butyl, isopropyl and the like; preferably ethyl; R₁ and R₂ are each of fluorine or hydrogen; in the presence of a base in a suitable solvent to provide compound of formula V, wherein R₁ and R₂ are each of hydrogen or fluorine; wherein the suitable base is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; and a suitable solvent selected from the group consisting of alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; ethers, such as tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane and the like; and water or mixtures thereof. Preferably the solvent is alcohols, water or mixtures thereof; and more preferably methanol and water. The step b) reaction is suitably carried out at a temperature of about 25°C to about 50°C, preferably at about 30°C to about 35°C for sufficient period of time to complete the reaction, for example 1-2 hrs.

The step c) of the aforementioned process involves resolution of compound of formula V, wherein R₁ and R₂ are each of fluorine or hydrogen; with a suitable resolution reagent in a solvent to provide the corresponding chiral salt compound of formula VI, which on neutralization with a base to provide the compound of formula VII; wherein the suitable resolution reagent is selected from the group consisting of but not limited to (S)-phenyl ethyl amine, (S)-(-)-N-methyl-1-phenyl ethyl amine, (S)-(-)-N,N,α-trimethylbenzylamine, (S)-1-(4- chlorophenyl) ethylamine, (S)-(-)-4-bromo-α-methylbenzylamine, n-octyl-D-glucamine and the like; preferably (S)-phenyl ethyl amine; and the base used for neutralization is selected from the group consisting of but not limited to alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, potassium methoxide and the like; preferably alkali metal hydroxide such as sodium hydroxide; the suitable solvent is selected from “esters” such as ethyl acetate, methyl acetate, n- butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; “alcohols” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “chloro solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; water or mixtures thereof; preferably the suitable solvent is esters or alcohols; and more preferably ethyl acetate, isopropyl alcohol or mixtures thereof.

The step c) resolution process may advantageously carried out at a temperature of about 25°C to about reflux temperature; preferably at about 65°C to about 75°C for a sufficient period of time until completion of reaction, for example 30-60 mins. Optionally the chiral salt compound of formula VI or compound of formula VII can be further purified by the methods known in the art for example recrystallisation, slurrying and the like; using suitable solvents selected from esters, alcohols or mixtures thereof; preferably the solvent is selected from methanol, ethanol, isopropanol and ethyl acetate.

The reported process discloses enzymatic resolution of corresponding alkyl ester of compound of formula V and not specifically reported for acid compound of formula V. Enzyme utilized in the said process is not commercially available. The present inventor surprisingly found that the resolution of compound of formula V with chiral amines such as (S)-phenyl ethylamine provides required isomer as a crystalline solid with high purity and yields.

In an embodiment, the present invention provides a process for the preparation of triazole derivatives of general formula I, wherein R₁ and R₂ are each of fluorine or hydrogen, which comprising the step of resolving the compound of formula V, where R₁ and R₂ are each of fluorine or hydrogen, with a suitable resolution reagent in a suitable solvent; wherein the suitable resolution agent is selected from (S)-phenyl ethyl amine, (S)-(-)-N-methyl-1-phenyl ethylamine, (S)-(-)-N,N,α-trimethylbenzyl amine, (S)-1-(4-chlorophenyl) ethylamine, (S)-(-)-4-bromo-α- methylbenzylamine and n-octyl-D-glucamine.

In an embodiment, the present invention provides a chiral salt compound of formula VI, wherein R₁ and R₂ are each of fluorine or hydrogen,

wherein the chiral salt is selected from (S)-phenyl ethyl amine, (S)-(-)-N-methyl-1- phenylethylamine, (S)-(-)-N,N,α-trimethylbenzylamine, (S)-1-(4-chlorophenyl) ethyl amine, (S)-(-)-4-bromo-α-methylbenzylamine and n-octyl-D-glucamine.

The step d) of the aforementioned process involves reaction of the compound of formula VII, wherein R₁ and R₂ are each of fluorine or hydrogen, with an activating agent, followed by suitable ammonia source in a suitable solvent to provide compound of formula VIII, wherein the activating agent is selected from thionyl chloride, oxalyl chloride or sulfuryl chloride; preferably thionyl chloride; and the ammonia source is selected from liquor ammonia, alcoholic ammonia or ammonia gas; preferably liquor ammonia; and a suitable solvent is selected from the group consisting of hydrocarbons such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane, petroleum ether and the like; ethers, such as tetrahydrofuran, 1,4-dioxane, 2-methyl tetrahydrofuran, tert-butyl methyl ether, diisopropyl ether, diethyl ether and the like; preferably the solvent is tetrahydrofuran or toluene.

The reported process involves the reaction of (2R,3R)-3-(2,4-difluoro-phenyl)-3-benzoyloxy-2- methyl-4-[1,2,4]-triazol-1-yl-butyric acid with carbonyldiimidazole in THF to get (3R,4R)-4- (2,4-difluoro-phenyl)-3-methyl-4-[1,2,4]-triazol-1-ylmethyl-oxetan-2-one, which on further reaction with aqueous ammonium hydroxide to get (2R,3R)-3-(2,4-difluoro-phenyl)-3-hydroxy- 2-methyl-4-[1,2,4]-triazol-1-yl-butyramide. The said process involves costly carbonyl diimidazole, requires column chromatography purification in each stage and when reproduced results in lower yield. The present inventor surprising found that activation of acid group with suitable thionylchloride followed by treatment with ammonia provides compound of formula VII in higher yields and the same time avoids the formation of unstable oxetanone intermediate and column chromatography of prior art process.

The step d) reaction may advantageously carried out at a temperature of about 25 °C to about reflux temperature; preferably at about 40°C to about 60°C for a sufficient period of time until completion of reaction, for example 1-2 hrs. The compound of formula VII obtained may optionally further purified using suitable hydrocarbon solvents; preferably toluene, xylene, heptanes or hexanes.

The step e) of the aforementioned process involves the conversion of compound of formula VII into triazole derivatives of general formula I. The conversion of compound of formula VII into compound of general formula I comprise of the following steps; i) reacting the compound of formula VIII, wherein R₁ and R₂ are each of hydrogen or fluorine, with phosphorous oxychloride, in the presence or absence of additional solvent to provide compound of formula IX, wherein R₁ and R₂ are each of fluorine or hydrogen,

ii) reacting the compound of formula IX with diethyl dithiophosphoric acid in a suitable solvent to provide compound of formula X, wherein R₁ and R₂ are each of fluorine or hydrogen; and

iii) condensing the compound of formula X with 2-bromo-4-cyanoacetophenone in a suitable solvent to provide triazole derivatives of general formula I. The step i) of the aforementioned process involves the reaction of compound of formula VII, wherein R₁ and R₂ are each of fluorine or hydrogen, with phosphorous oxychloride in the presence of additional solvent to provide compound of formula VIII; the suitable solvent for this step is selected from “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; preferably dimethylformamide.

The step ii) of the aforementioned process involves reaction of compound of formula VIII, wherein R₁ and R₂ are each of fluorine or hydrogen; with diethyl dithiophosphoric acid in a suitable solvent selected from the group consisting of water, esters, alcohols, chloro solvents or mixtures thereof, to provide compound of formula IX.

In an embodiment, the compound of formula IX is not isolated as a solid and proceeds to next step without isolation.

The step iii) of the aforementioned process involves condensing the compound of formula IX with 2-bromo-4-cyanoacetophenone in a suitable alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol or mixtures thereof, to provide compound of general formula I.

The compound of general formula I obtained is isolated by the methods known in the art and is further purified by recrystallisation, slurrying, solvent/anti-solvent techniques using suitable solvent selected from alcohols, hydrocarbons, ethers, esters and mixtures thereof; preferably methanol, ethanol, isopropanol, toluene, xylene, heptanes, hexanes, t-butyl methyl ether, diisopropylether and ethyl acetate.

In an embodiment, the triazole derivatives of general formula I such as ravuconazole (when R₁ is F and R₂ is H) and isavuconazole (when R₁ is H and R₂ is F) prepared according to the present invention can be further converted into their prodrug forms such as Fosravuconazole and isavuconazonium sulfate as per the methods known in the art.

In another embodiment, the present invention provides an improved process for the preparation of triazole derivatives of general formula I according to the following scheme:

Examples:

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

Example-1: Preparation of 3-(2, 4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1, 2, 4- triazol-1-yl) butanoic acid (Formula V, where R₁=F and R₂=H):

To a suspension of activated zinc (102 g) and iodine (2.5 g) in THF (1.5 L), TMSCl (40 ml) was added and stirred under nitrogen atmosphere at ambient temperature. Subsequently l-(2,4- difluorophenyl)-2-(1H-1 ,2,4-triazol-1 -yl)ethanone (100 g) in THF (700 ml) was added and stirred for 30 min at ambient temperature. Ethyl-2 bromo propionate (160 g) was added at 35- 45°C, then heated to 60-70°C and stirred for 36 hrs at reflux. The reaction mass was filtered over celite bed, aqueous HCl followed by ethyl acetate was added to the filtrate and stirred. The organic and aqueous layers were separated, and the aqueous layer was extracted twice with ethyl acetate. Organic layer washed with aqueous sodium carbonate solution, water, followed by brine, dried over sodium sulphate and concentrated under reduced pressure. The obtained residue was suspended in methanol (10 v) and water (10 v), 6N sodium hydroxide was added and stirred. After reaction completion, pH of reaction mass adjusted to 2-3 with 6N HCl. The reaction mass was stirred for an hour and the obtained solid was filtered and dried to get the title compound. Yield: 70 g.

Example-2: Preparation of 3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol- 1-yl) butanoic acid (Formula V, where R₁=F and R₂ =H):

To a suspension of activated zinc (102 g) and iodine (2.5 g) in THF (1.5 L), TMSCl (40 ml) was added and stirred under nitrogen atmosphere at ambient temperature. Subsequently 1-(2,4- difluorophenyl)-2-( 1H- 1 ,2,4-triazol- 1 -yl)ethanone (100 g) in THF (700 ml) and ethyl-2 bromo propionate (160 g) was added at 50-70°C, and stirred for 16 hrs at reflux. The reaction mass was filtered over celite bed and washed with ethyl acetate. Filtrate washed with aqueous sodium carbonate solution until pH >9.0. The organic and aqueous layers were separated, and the aqueous layer was extracted twice with ethyl acetate. Organic layer washed with water, followed by brine, dried over sodium sulphate and concentrated under reduced pressure. The obtained residue was suspended in methanol (10 v) and water (10 v), 6N sodium hydroxide was added and stirred at 25-35°C. After reaction completion, pH of the reaction mass was adjusted to 2-3 with 6N HCl. The reaction mass was stirred for an hour and the obtained solid was filtered and dried to get the title compound. Yield: 80 g.

Example-3: Preparation of 3-(2, 4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol- 1-yl) butanoic acid (Formula V, where R₁=F and R₂ =H):

The title compound was obtained in a similar manner to example 1 except that methane sulfonic acid (30 g) was used in place of TMSCl. Yield: 68.5 g

Example-4: Preparation of 3-(2, 4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol- 1-yl) butanoic acid (Formula V, where R₁=F and R₂ =H):

The title compound was obtained in a similar manner to example 1 except that 2-MeTHF used as solvent in place of THF. Yield: 69.5 g

Example-5: Preparation of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1,2,4- triazol-1-yl) butyric acid S-(-) phenyl ethyl amine (Formula Via, where R₁=F and R₂ =H):

A mixture of 3-(2, 4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl) butanoic acid (100 g), ethyl acetate (500 ml), IPA (100 ml) and S-(-) phenyl ethyl amine (35 g) was heated to reflux temperature (75-80°C) and stirred for 30 mins. The solid obtained was filtered, washed with ethyl acetate and dried. The compound was further recrystallized twice from ethyl acetate to get the title compound. Yield: 65 g.

Example-6: Preparation of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1,2,4- triazol-1-yl) butyric acid S-(-) phenyl ethyl amine (Formula Via, where R₁=F and R₂ =H):

A mixture of 3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl) butanoic acid (100 g), ethyl acetate (500 ml), IPA (100 ml) and S-(-) phenyl ethyl amine (44.8 g) was heated to reflux temperature (75-80°C) and stirred for 30 mins. The solid obtained was filtered, washed with ethyl acetate and dried to get the title compound. Yield: 68 g.

Example-7: Preparation of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1,2,4- triazol-1-yl) butyricacid (S)-(-)-4-bromo-α-methylbenzylamine (Formula VIb, where R₁=F and R₂ =H):

The title compound obtained in a similar manner to example 6 except that (S)-(-)-4-bromo-α- methylbenzylamine (67g) was utilized in place of S-(-) phenyl ethyl amine. Yield: 63 g.

Example-8: Preparation of (2R,3R)-3-(2, 4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H- 1,2,4-triazol-1-yl) butanoic acid (Formula VII, where R₁=F and R₂ =H):

(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1,2,4-triazol-1-yl)butyric acid S-(-) phenyl ethyl amine (65 g) was dissolved in 100 ml of water and pH was adjusted to above 10 with 6N sodium hydroxide solution. The reaction mass was extracted three times with methylene chloride (100 ml each time). The methylenechloride phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 31.5 g of S-(-) phenyl ethyl amine with a recovery rate of 90%; in an ice water bath, the aqueous phase pH was adjusted to 3-4 with 6N hydrochloric acid and stirred for 30 min. The precipitated solid was filtered and dried to get the title compound. Yield: 40 g, Purity: 99.8% e.e.

Example-9: Preparation of (2R, 3R)-3-(2, 4-difluorophenyl)-3-hydroxy-2-methyl -4-(1H- 1,2,4-triazol-1-yl) butanoic acid (Formula VII, where R₁=F and R₂ =H):

The title compound was obtained in a similar manner to example 8 except that (2R,3R)-3-(2,4- difluorophenyl)-3-hydroxy-2-methyl-4-(1,2,4-triazol-1-yl)butyric acid (S)-(-)-4-bromo-α- methylbenzylamine (67 g) used as a starting material instead of corresponding S-(-) phenyl ethyl amine salt of formula Via. Yield: 40 g. Example-10: Preparation of (2R, 3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl -4-(1H-

1,2,4-triazol-1-yl) butanamide (Formula VIII, where R₁=F and R₂ =H):

Mixture of thionyl chloride (300 ml) and (2R,3R)-3-(2, 4-difluorophenyl)-3-hydroxy-2-methyl - 4-(1H-1,2,4-triazol-1-yl) butanoic acid (100 g) was heated to 55-60°C and stirred. After reaction completion, the reaction mass was distilled under reduced pressure at below 40°C. The obtained residue was dissolved in toluene (250 ml) and slowly added to a pre-cooled ammonia solution (1000 ml) taken in another RBF at below 10°C and stirred for 2 hours at 5-10°C. The obtained solid was filtered, washed with water and dried at 80-85°C to get title compound. Yield: 72.5 g.

Example-11: Preparation of (2R, 3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl -4-(1H-

1,2,4-triazol-1-yl) butanamide (Formula VIII, where R₁=F and R₂ =H):

Mixture of thionyl chloride (60 ml) and THF (1000 ml) and (2R,3R)-3-(2, 4-difluorophenyl)-3- hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanoic acid (100 g) was heated to 35-40°C and stirred. After reaction completion, the reaction mass was distilled up to 50% under reduced pressure at below 40°C. Obtained reaction mass was added to a pre-cooled ammonia solution (1000 ml) taken in another RBF at below 10°C and stirred for 2 hours at 5-10°C. The obtained solid was filtered, washed with ethyl acetate, filtrate mis separated and aqueous layer was extracted with ethyl acetate (2 x 250 ml). Ethyl acetate layers were combined and distilled under vacuum below 60°C. Thus obtained solid was isolated in toluene (100 ml) at ambient temperature and dried at 80-85°C to get title compound. Yield: 90 g.

Example-12: Preparation of (2R, 3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl -4-(1H-

1,2,4-triazol-1-yl) butanamide (Formula VIII, where R₁=F and R₂ =H):

The title compound was obtained in a similar manner to example 11 except that oxalyl chloride (43 g) was utilized in place of thionylchloride. Yield: 75 g

Example-13: Preparation of (2S,3R)-3-(2, 4-difluorophenyl)-3-hydroxy-2-methyl -4-(1H-1, 2, 4-triazol-1-yl) butanenitrile (Formula IX, where R₁=F and R₂ =H):

Mixture of phosphorous oxychloride (600 ml) and (2R, 3R)-3-(2,4-difluorophenyl)-3-hydroxy-2- methyl -4-(1H- 1,2, 4-triazol-1-yl) butanamide (100 g) was taken in RBF, heated to 40-45°C and stirred for 3 hours at the same temperature. After reaction completion, the reaction mass was distilled under reduced pressure at below 40°C. The reaction mass was cooled and DM water (200 ml) was added at below 30°C. The pH of the reaction mass was adjusted to 8-8.5 with sodium carbonate and stirred for an hour. The solid obtained was filtered, washed with water and dried at 80-85°C for 12 hours to get the title compound. Yield: 85 g.

Example-14: Preparation of (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,

2.4-triazol-1-yl) butanenitrile (Formula IX, where R₁=F and R₂ =H):

Mixture of phosphorous oxychloride (52 g) and dimethylformamide (190 ml) was cooled to 10-15°C and (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1, 2,4-triazol-1-yl) butanamide (100 g) was added. The reaction mass was heated to 25-35°C and stirred at the same temperature. After reaction completion, the reaction mass was added into DM water (1000 ml) at 10-15°C. The pH of the reaction mass was adjusted to 8-8.5 with sodium carbonate solution and stirred for an hour. The solid obtained was filtered, washed with water and dried at 80-85°C for 12 hours to get the title compound. Yield: 85 g.

Example-15: Preparation of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl -4-(1H-

1.2.4-triazol-1-yl) butanethioamide (Formula X, where R₁=F and R₂ =H):

Isopropyl alcohol (125 ml), DM water (40 ml) and (2S,3R)-3-(2, 4-difluorophenyl)-3-hydroxy-2- methyl -4-(1H-1, 2, 4-triazol-1-yl) butanenitrile (100 g) were charged into RBF at 25-30°C and the mixture was heated to 75-80°C. 0,0-diethyl dithiophosphate (180 g) was added to the reaction mass and stirred at reflux for 16 hours. After reaction completion, the reaction mass was cooled to 25-30°C, ethyl acetate (300 ml) and DM water (500 ml) was added to it. The pH of the reaction mass was adjusted to 8.3 with sodium hydroxide solution at 0-5°C. The organic and aqueous layers were separated at 25-30°C. Organic layer was washed with aqueous sodium chloride solution and distilled under vacuum at below 50°C up to 2 volume remains in the flask. The reaction mass was cooled to 25-30°C, sulphuric acid (35 g) followed by methyl tert-butyl ether (200 ml) was added and stirred for an hour. The solid obtained was fdtered, washed with methyl tert-butyl ether (100 ml) and dried at 50-55°C to get the title compound. Yield: 78 g.

Example-16: Preparation of 4-[2-[(1R, 2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)propyl]-4-thizolyl]benzonitrile (Formula I, where R₁=F and R₂ =H):

To a solution of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl -4-(1H- 1,2, 4-triazol-1-yl) butanethioamide (100 g) in methanol (1000 ml), 2-bromo-4-cyanoaceto phenone (80 g) was added, heated to 60-65°C and stirred for 3 hrs at the same temperature. After reaction completion, the reaction mass was cooled to 25-30°C, DM water (100 ml) followed by ethyl acetate (1000 ml) was added and stirred for 15 mins. Organic and aqueous layers were separated. Organic layer washed with sodium bicarbonate solution followed by sodium chloride solution and distilled off under reduced pressure at below 50°C. Isopropyl alcohol (250 ml) was added to the reaction mass at 25-30°C, then cooled to 0-5°C and stirred for an hour. The solid obtained was filtered, washed with isopropyl alcohol and dried at 50-55°C for 12 hrs under reduced pressure to get the title compound. Yield: 120 g. Purity by HPLC: 99.5%; Chiral purity: 99.9% e.e.

Example-17: Preparation of 4-[2-[(1R, 2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)propyl]-4-thizolyl]benzonitrile (Formula I, where R₁=F and R₂ =H):

Isopropyl alcohol (125 ml), DM water (40 ml) and (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2- methyl -4-(1H-1,2,4-triazol-1-yl) butanethioamide (100 g) were charged into RBF at 25-30°C and the mixture was heated to 75-80°C. 0,0-diethyl dithio phosphate (180 g) was added to the reaction mass and stirred at reflux for 16 hours. After reaction completion, the reaction mass was cooled to 25-30°C, ethyl acetate (300 ml) and DM water (500 ml) was added to it. The pH of the reaction mass was adjusted to 8.3 with sodium hydroxide solution at 0-5°C. The organic and aqueous layers were separated at 25-30°C. Organic layer was washed with aqueous sodium chloride solution and distilled under vacuum at below 50°C. The obtained residue was dissolved in methanol (1000 ml), 2-bromo-4-cyanoacetophenone (80 g) was added, heated to 60-65°C and stirred for 3 hrs at the same temperature. After reaction completion, distilled off solvent under vacuum below 60°C. The reaction mass was cooled to 25-30°C, DM water (100 ml) followed by ethyl acetate (1000 ml) was added and stirred for 15 mins. Organic and aqueous layers were separated. Organic layer washed with sodium bicarbonate solution until neutral pH followed by sodium chloride solution and distilled off under reduced pressure at below 50°C. Toluene (200 ml) was added to the reaction mass at 25-30°C, then cooled to 0-5°C and stirred for an hour. The solid obtained was filtered, washed with toluene and dried at 50-55°C for 12 hrs under reduced pressure to get the title compound. Yield: 120 g.

Example-18: Preparation of 3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol- l-yl)butanoic acid (Formula V, where R₁=H and R₂ =F): Tetrahydrofuran (500 ml), activated zinc dust (100 g) and iodine (5 g) was charged into the 3 liter RB flask under nitrogen atmosphere at 25-30°C. Chlorotrimethyl silane (20 ml) was added to the reaction mass, heated to 50-65°C and stirred for an hour. Ethyl bromo propionate (120 g), 1-(2,5-difluorophenyl)-2-(1H,1,2,4-trizol-1-yl) ethanone (100 g) and tetrahydrofuran (200 ml) was added to the reaction mass at 50-70°C under nitrogen atmosphere and stirred for 16 hours. After reaction completion, the reaction mass was cooled to 25-30°C, filtered through hyflow and washed with ethyl acetate. The filtrate mis washed with aqueous sodium carbonate solution until pH > 9.0 at 25-30°C, aqueous layer separated and extracted with ethyl acetate. Separated organic layer was washed with aqueous hydrochloric acid and distilled off completely under reduced pressure at below 50°C. The obtained residue was dissolved in methanol (50 ml). Water (1000 ml) was added to the reaction mass followed by aqueous sodium hydroxide solution (17.25 g in 400 ml water) at 25-30°C and stirred. After reaction completion, ethyl acetate (200 ml) was added to the reaction mass, stirred and layers were separated. Aqueous layer was acidified with hydrochloric acid and stirred for 6 hrs at 20-25°C. The solid obtained was filtered, washed with water and finally dried at 90-100°C for 12 hrs to get the title compound. Yield: 70 g.

Example-19: Preparation of (2R,3R)-3-(2, 5-difluorophenyl)-3-hydroxy-2-methyl -4-(1H-1, 2, 4-triazol-1-yl) butanoic acid (Formula VIE, where R₁=H and R₂ =F):

A mixture of 3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl) butanoic acid (5 g), methanol (50 ml) and S-(-) phenyl ethyl amine (2.25 g) was taken in a RBF and heated to 60-80°C and stirred. After reaction completion, the reaction mass was cooled to 25-30°C and stirred then cooled to 0-5°C. The solid obtained was filtered and washed with methanol. DM water was added to the obtained solid and reaction mass was basified with sodium hydroxide solution. Methylene chloride (12.5 ml) was added to the reaction mass, stirred and layers were separated. The pH of the separated aqueous layer was acidified with aqueous hydrochloric acid and stirred for an hour. The solid obtained was filtered, washed with water and dried at 80°C for 12 hr to get the title compound. Yield: 1.9 g. chiral purity: 99.5%

Example-20: Preparation of (2R,3R)-3-(2, 5-difluorophenyl)-3-hydroxy- 2-methyl -4-(1H-1, 2, 4-triazol-1-yl) butanamide (Formula VIII, where R₁=H and R₂ =F):

A mixture of thionyl chloride (40 ml) and (2R,3R)-3-(2, 5-difluorophenyl)-3-hydroxy-2-methyl- 4-(1H-1, 2, 4-triazol-1-yl) butanoic acid (20 g) was taken in RBF, heated to 40-60°C and stirred for 2 hours. After reaction completion, the reaction mass was distilled under reduced pressure at below 40°C. The reaction was added to ammonia solution at below 10°C and stirred for 2 hours at 5-10°C. The obtained solid was filtered, washed with water and dried for 16 hours at 80-85°C to get title compound. Yield: 18.5 g.

Example-21: Preparation of (2R, 3R)-3-(2, 5-difluorophenyl)-3-hydroxy-2-methyl -4-(1H-1, 2, 4-triazol-1-yl) butanamide (Formula VIII, where R₁=H and R₂ =F):

Mixture of thionyl chloride (60 ml) and THF (1000 ml) and (2R,3R)-3-(2,5-difluorophenyl)-3- hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanoic acid (100 g) was heated to 35-40°C and stirred. After reaction completion, the reaction mass was distilled up to 50% under reduced pressure at below 40°C. Obtained reaction mass was added to a pre-cooled ammonia solution (1000 ml) taken in another RBF at below 10°C and stirred for 2 hours at 5-10°C. The obtained solid was filtered, washed with ethyl acetate, filtrate mis separated and aqueous layer was extracted with ethyl acetate (2 x 250 mL). Ethyl acetate layers were combined and distilled under vacuum below 60°C. Thus obtained solid was isolated in toluene (100 ml) at ambient temperature and dried at 80-85°C to get title compound. Yield: 90 g.

Example-22: Preparation of (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl -4-(1H- 1,2, 4-triazol-1-yl) butanamide (Formula VIII, where R₁=H and R₂ =F):

The title compound was obtained in a similar manner to example 21 except that oxalyl chloride (43 g) was utilized in place of thionylchloride. Yield: 74 g.

Example-23: Preparation of (2S, 3R)-3-(2, 5-difluorophenyl)-3-hydroxy-2-methyl -4-(1H-1, 2, 4-triazol-1-yl) butanenitrile (Formula IX, where R₁=H and R₂ =F):

Mixture of phosphorous oxychloride (300 ml) and (2R, 3R)-3-(2, 5-difluorophenyl)-3 -hydroxy - 2-methyl-4-(1H- 1,2, 4-triazol-1-yl) butanamide (100 g) was taken in RBF, heated to 40-45°C and stirred for 3 hours at the same temperature. After reaction completion, the reaction mass was distilled under reduced pressure at below 40°C. The reaction mass was cooled and DM water (200 ml) was added at below 30°C. The pH of the reaction mass was adjusted to 0.7 with sodium carbonate and stirred for an hour. The solid obtained was filtered, washed with water and dried at 80-85°C for 12 hours to get the title compound. Yield: 75 g. Example-24: Preparation of (2S,3R)-3-(2, 5-difluorophenyl)-3-hydroxy-2-methyl -4-(1H-1, 2, 4-triazol-1-yl) butanenitrile (Formula IX, where R₁=H and R₂ =F):

Mixture of phosphorous oxychloride (52 g) and dimethylformamide (190 ml) was cooled to 10- 15°C and (2R, 3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl -4-(1H- 1,2, 4-triazol-1-yl) butanamide (100 g) was added. The reaction mass was heated to 25-35°C and stirred at the same temperature. After reaction completion, the reaction mass was added into DM water (1000 ml) was at 10-15°C. The pH of the reaction mass was adjusted to 8-8.5 with sodium carbonate and stirred for an hour. The solid obtained was filtered, washed with water and dried at 80-85°C for 12 hours to get the title compound. Yield: 80 g.

Example-25: Preparation of (2R,3R)-3-(2, 5-difluorophenyl)-3-hydroxy-2-methyl -4-(1H-

1.2.4-triazol-1-yl) butanethioamide (Formula X, where R₁=H and R₂ =F):

Isopropyl alcohol (300 ml), DM water (100 ml) and (2S, 3R)-3-(2, 5 -difluorophenyl)-3 -hydroxy - 2-methyl-4-(1H- 1,2, 4-triazol-1-yl) butanenitrile (100 g) were charged into RBF at 25-30°C and heated to 75-80°C. O, O-diethyldithiophosphate (200 g) was added to the reaction mass and stirred at reflux. After reaction completion, the reaction mass was cooled to 25-30°C, ethyl acetate (400 ml) and DM water (100 ml) was added to it. The reaction mass was pH was adjusted to 8.0-8.5 with sodium hydroxide solution at 0-5°C. The organic and aqueous layers were separated and aqueous layer was extracted with ethyl acetate. Combined organic layer was washed with aqueous sodium chloride solution and distilled off under vacuum at below 55°C. The reaction mass was cooled to 25-30°C and t-butyl methyl ether (200 ml) was added and stirred for 1 hour. The solid obtained was filtered, washed with methyl tert-butyl ether and dried at 50-55°C to get the title compound. Yield: 78 g.

Example-26: Preparation of (2R,3R)-3-(2, 5-difluorophenyl)-3-hydroxy- 2-methyl -4-(1H-1,

2.4-triazol-1-yl) butanethioamide (Formula X, where R₁=H and R₂ =F):

Isopropyl alcohol (300 ml), DM water (100 ml) and (2S, 3R)-3-(2, 5 -difluorophenyl)-3 -hydroxy - 2-methyl-4-(1H- 1,2, 4-triazol-1-yl) butanenitrile (100 g) were charged into RBF at 25-30°C and heated to 75-80°C. O, O-diethyl dithiophosphate (200 g) was added to the reaction mass and stirred at reflux. After reaction completion, the reaction mass was cooled to 25-30°C, DM water (100 ml) was added to it. The reaction mass was pH was adjusted to 8.0-8.5 with sodium hydroxide solution at 0-5°C and stirred for 2 hrs at 0-5°C. The solid obtained was filtered, washed with water (200mL) and dried at 50-55°C to get the title compound. Yield: 90 g.

Example-27: Preparation of 4-[2-[(1R, 2R)-2-(2,5-difluorophenyl)-2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)propyl]-4-thizolyl]benzonitrile (Formula I, where R₁=H and R₂ =F):

To a solution of (2R, 3R)-3-(2, 5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1, 2, 4-triazol-1- yl)butanethioamide (100 g) in ethanol (500 ml), 2-bromo-4-cyanoaceto phenone (72 g) was added, heated to 60-65°C and stirred for 3 hrs at the same temperature. After reaction completion, the reaction mass was cooled to 25-30°C, DM water (100 ml) followed by ethyl acetate (1000 ml) was added and stirred for 15 mins. Organic and aqueous layers were separated. Organic layer washed with sodium bicarbonate solution pH 6-7.0 then separated aqueous layer. Aqueous layer extracted with ethyl acetate (2 x 500 mL) at ambient temperature. Combined organic layer washed with sodium chloride solution and distilled off under reduced pressure at below 50°C. Diisopropylether (250 ml) was added to the reaction mass at 25-30°C, then cooled to 0-5 °C and stirred for an hour. The solid obtained was filtered, washed with diisopropylether and dried at 50-55°C for 12 hrs under reduced pressure to get the title compound. Yield: 120 g. Purity by HPLC: 99.5%; Chiral purity: 99.9% e.e.

Example-28: Preparation of 4-[2-[(1R, 2R)-2-(2,5-difluorophenyl)-2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl)propyl]-4-thizolyl]benzonitrile (Formula I, where R₁=H and R₂ =F):

To a solution of (2R, 3R)-3-(2, 5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1, 2, 4-triazol-1- yl)butanethioamide (100 g) in ethanol (500 ml), 2-bromo-4-cyanoaceto phenone (72 g) was added, heated to 75-80°C and stirred for 3 hrs at the same temperature. After reaction completion, DM water (1000 ml) at 75-80°C and stirred for 15 mins. Cool the contents to 30- 35°C then adjust pH to 6-7 with aqueous sodium bicarbonate solution then cooled to ambient temperature and stirred for an hour. The solid obtained was filtered, washed with aqueous ethanol 100 ml (1:2) and dried at 50-55°C for 12 hrs under reduced pressure to get the title compound. Yield: 118 g.

Claims

We claim:

1. An improved process for the preparation of triazole derivatives of general formula I, wherein R₁ and R₂ are independently selected from fluorine or hydrogen,

d) reacting the compound of formula VII with an activating agent, followed by a suitable ammonia source to provide compound of formula VIII, wherein R₁ and R₂ are each of fluorine or hydrogen, and

e) converting the compound of formula VIII in to triazole derivatives of general formula I.

2. The process as claimed in claim 1) wherein in step a) the zinc source is selected from zinc dust/powder or zinc chloride and the catalyst is iodine.

3. The process as claimed in claim 1) wherein in step c) the suitable resolution agent is selected from (S)-phenyl ethyl amine, (S)-(-)-N-methyl-1-phenyl ethyl amine, (S)-(-)-N,N,α- trimethylbenzylamine, (S)-1-(4-chlorophenyl) ethylamine, (S)-(-)-4-bromo-α-methyl benzyl amine and n-octyl-D-glucamine.

4. The process as claimed in claim 3) wherein the resolution agent is (S)-phenyl ethyl amine or (S)-(-)-4-bromo-α-methyl benzyl amine.

5. The process as claimed in claim 1) wherein in step b) and step c) the suitable base is selected from sodium hydroxide, potassium hydroxide and lithium hydroxide.

6. The process as claimed in claim 1) wherein in step d) the suitable activating agent is selected from thionyl chloride, oxalyl chloride or sulfuryl chloride; and the ammonia source is selected from liquor ammonia, alcoholic ammonia or ammonia gas.

7. The process as claimed in claim 6) wherein the activating agent is thionyl chloride and the ammonia source is liquor ammonia.

8. The process as claimed in claim 1) wherein the step e) the conversion of compound of formula VIII into triazole derivatives of general formula I comprises of the following steps; i. reacting the compound of formula VIII with phosphorous oxychloride in presence of additional solvent to provide compound of formula IX, wherein R₁ and R₂ are each of fluorine or hydrogen,

ii. reacting the compound of formula IX with diethyl dithiophosphoric acid in a suitable solvent to provide compound of formula X, wherein R₁ and R₂ are each of fluorine or hydrogen; and

iii. condensing the compound of formula X with 2-bromo-4-cyanoacetophenone in a suitable solvent to provide triazole derivatives of general formula I.

9. An improved process for the preparation of triazole derivatives of general formula I, wherein R₁ and R₂ are each of fluorine or hydrogen,

with 2-halopropionate ester compound of formula III, where R is C₁-C₁₂ alkyl,

in the presence of zinc source and a solvent to provide compound of formula IV, wherein R is C₁-C₁₂ alkyl and R₁ and R₂ are each of fluorine or hydrogen, wherein the reaction is carried out in the presence of iodine catalyst.

10. An improved process for the preparation of triazole derivatives of general formula I, wherein R₁ and R₂ are each of fluorine or hydrogen,

which comprising the step of resolving the compound of formula V, wherein R₁ and R₂ are each of fluorine or hydrogen,

with a suitable resolution reagent in a suitable solvent; wherein the suitable resolution agent is selected from (S)-phenyl ethyl amine, (S)-(-)-N-methyl-1-phenylethylamine, (S)-(-)- N,N,α-trimethylbenzylamine, (S)-1-(4-chlorophenyl) ethylamine, (S)-(-)-4-bromo-α- methylbenzylamine and n-octyl-D-glucamine.

11. A chiral salt compound of formula VI, wherein R₁ and R₂ are each of fluorine or hydrogen,

wherein the chiral salt is selected from (S)-phenyl ethyl amine, (S)-(-)-N-methyl-1- phenylethylamine, (S)-(-)-N,N,α-trimethylbenzylamine, (S)-1-(4-chlorophenyl) ethylamine, (S)-(-)-4-bromo-α-methylbenzylamine and n-octyl-D-glucamine.

12. An improved process the preparation of triazole derivatives of general formula I, wherein R₁ and R₂ are each of fluorine or hydrogen,

which comprising the steps of reacting the compound of formula VII, wherein R₁ and R₂ are each of fluorine or hydrogen,

with an activating agent, followed by an ammonia source to provide compound of formula VIII,

wherein R₁ and R₂ are each of fluorine or hydrogen.

13. The process according to claim 12) wherein the suitable activating agent is selected from thionyl chloride, oxalyl chloride or sulfuryl chloride; and the ammonia source is selected from liquor ammonia, alcoholic ammonia or ammonia gas.

14. The process as claimed in claim 12) wherein the reaction of compound of formula VII with an activating agent is carried out in the presence of a suitable ether solvents.

15. An improved process for the preparation of triazole derivatives of general formula I, wherein R₁ and R₂ are each of fluorine or hydrogen, which comprises reacting the compound of formula VIII with phosphorous oxychloride in the presence of additional solvent to provide compound of formula IX and converting the compound of formula IX into triazole derivatives of general formula I; wherein the solvent is selected from dimethylformamide, dimethylacetamide, dimethylsulfoxide or mixtures thereof.

16. The process as claimed in any of the preceding claims, wherein R₁ is hydrogen and R₂ is fluorine.

17. The process as claimed in any of the preceding claims, wherein R₁ is fluorine and R₂ is hydrogen.

18. The process as claimed in any of the preceding claims, wherein X is bromine and R is ethyl.