IMPROVED PROCESS FOR THE PREPARATION OF (2R,3S)-2-(2,4-DIFLUOROPHENYL)-3-(5-FLUOROPYRIMIDIN-4-YL)-l-(lH-l,2,4-TRIAZOL-l-
YL)BUTAN-2-OL
TECHNICAL FIELD OF THE INVENTION
The present invention is directed to an improved industrially viable, cost effective
process to manufacture substantially pure form of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol (Voricaonazole) with a chiral purity level of greater than 99.9% and impurity level of less than 0.1%.
BACKGROUND OF THE INVENTION
2R,3S-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol commomly known as Voriconazole of Formula-I,

is a triazole antifungal medication used to treat various fungal infections. These include invasive candidiasis, invasive aspergillosis, and emerging fungal infections.
Voriconazole is commercially available as VFEND® in the form of lyophilized powder for solution for intravenous infusion, film-coated tablets for oral administration, and as a powder for oral suspension.
US5,567,817 and US5,278,175 discloses a process for the preparation of voriconazole comprising reacting 4-chloro-6-ethyl-5-fluoropyrimidine of Formula II with l-(2,4-diflouorophenyl)-2-(lH-l,254-triazol-l-yl)ethanone of Formula III in the presence of lithium diisopropylamine to yield 2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazole-l-yl) butan-2-ol which is further purified by column

chromatography to give (2R,3S/2S,3R) enantiomeric pair of 2-(2,4-difluorophenyl)-3-(4-
chloro-5-fluoropyrimidin-6-yl)-l-(lH-l,2,4-triazole-l-yl) butan-2-ol of Formula IV. The
compoimd of Formula IV was dehalogenated with a 10% Pd/C in the presence of sodium
acetate, followed by flash chromatographic separation to yield (2R,3S/2S,3R)-2-(2,4-
difluoropheny l)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazole-1 -y l)butan-2-ol of
Formula V and then resolved to give compoimd of Formula V with R-(-)-10-camphor sulfonic acid in the presence of methanol and subsequent hydrolysis of the camphor sulfonate salt to free base with alkaline medium to yield Voriconazole of Formula I. The process can be represented as in scheme-I given below,

The drawbacks of this process are use of hazardous reagents as lithium diisopropylamine for the condensation, the reaction condition are very low temperature of-78oC which is difficult to maintain all the time at manufacturing scale production. The process describes chromatographic separation of the enantiomeric pair which is not advisable at plant scale production and use of palladium carbon for dehalogination under pressure which is associated with safety problems at plant scale. Moreover the yields are very low.
US6,586,594 and Organic Process Research & Development (2001), 5(1), 28-36, discloses a process for the preparation of voriconazole comprising reacting 6-(l-bromoethyl)-2,4-dichloro-5-fluoropyrimidine of Formula VI with l-(2,4-diflouorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone of Formula III in the presence of Zinc, lead, iodine and tetrahydrofuran to yield the compoimd of Formula IV. It also has been disclosed that the

compound after the condensation yields two different diastereomeric pairs such as (2R, 3S: 2S, 3R and 28, 3S; 2R,3R). The desired pair is separated by forming hydrochloride salt. This hydrochloride salt is further dehalogenated with 10%Pd/C to yield compound of Formula V, which on resolution with R-(-)-camphor-10-sulphonic acid and further basification give voriconazole of Formula I. The process is represented in scheme-II given below

The drawbacks of this process are: the formation of HCl salt which requires further basification and thus increases the number of steps and makes the reaction as time consuming process. Moreover use of palladium carbon for dehalogination is not advisable because of the safety problem.
WO2006065726 disclose a process for the preparation of voriconazole comprising reacting 4-chloro-6-ethyl-5-fluoropyrimidine of Formula II with l-(2,4-diflouorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone of Formula III in the presence of diisopropylamine, n-heptane/THF, n-butyl lithium to yield (2R,3S/2S,3R) 2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyrimidin-6-yl)-l-(lH-l,2,4-triazole-l-yl) butan-2-ol of Formula IV which is further reduced with Raney Nickel in the presence of sodium acetate to yield (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazole-1 -yl)butan-2-0l of Formula V and then resolution of compound of Formula V with R-(-)-10-camphor sulfonic

acid in the presence of methanol to yield camphor sulfonate salt of Formula VII followed by hydrolysis of the camphor sulfonate salt to free base with 20% spdium bicarbonate solution in the presence of dichloromethane gives voriconazole of Formula I. The process is represented in scheme-Ill given below,

The drawbacks of this process are: use of hazardous reagents as lithiimi diisopropylamine for the condensation is not advisable, the reaction condition require low temperature maintainenance i.e. -78°C which is difficult to maintain all the time at manufacturing scale, the reaction requires chromatographic separation of the enantiomeric pair which is not advisable at plant scale production, use of Raney nickel for dehalogination under pressure is not advisable because of the safety problem. Moreover the yields are also very low.
WO2007013096 discloses the process for the preparation of voriconazole comprising reacting 4-chloro-6-ethyl-5-fluoropyrimidine of Formula II with l-(2,4-diflouorophenyl)-2" (lH-l,2,4-triazol-l-yl)ethanone of Formula III in the presence of lithium diisopropylamine, n-heptane, tetrahydrofuran to yield (2R,3S/2S,3R) 2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyrimidin-6-yl)-l-(lH-l,2,4-triazole-l-yl) butan-2-ol of Formula IV which is further reduced with Raney Nickel in the presence of sodium acetate to yield (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-1,2,4-triazole-l-yl)butan-2-ol of Formula V (racemic voriconazole) and then resolution of compound of Formula V with R-(-)-10-

camphor sulfonic acid in the presence of methanol to yield camphor sulfonate salt of Formula VII followed by hydrolysis of the camphor sulfonate salt to free base with sodium hydroxide solution in the presence of dichloromethane and 2-propanol gives voriconazole of Formula I. The process is represented in scheme-IV given below,

The drawbacks of this process are use of hazardous reagents as lithium diisopropylamine for the condensation, the reaction has to be maintain at very low temperature of -78°C which is difficult to maintain all the time at manufacturing scale, the reaction requires chromatographic separation of the enantiomeric pair which cannot be done at plant scale, use of Raney nickel for dehalogination under pressure is not advisable because of the safety problem. Moreover the yields are very low.
CN1814597, CN1488629, CN1488630 discloses the process for the preparation of voriconazole which is as follows:


reacting the compound formula II with compound of formula III in an inert organic solvent in the presence of Zn, I2 and a lewis acid, reducing the coupled compoimds into I followed by basifying with suitable base to give compound of Formula L
The drawbacks of this process are use of palladium carbon or Raney nickel for dehalogination is not advisable because of the safety problem. Moreover the yields are very low.
Voriconazole Antifungal. UK-109496.Drugs of the Future (1996), 21(3), 266-271
« « * •
describes a process a given in scheme below

The drawbacks of this process are use of hazardous reagents as lithium diisopropylamine for the condensation, the reaction condition requires low temperature of -78°C which is difficult to maintain at all times at larger scale production and use of Raney nickel for dehalogination under pressure which is not viable at plant scale production, moreover the yields are very low.
It's apparent from most of the prior art that; the preparation of voriconazole has certain disadvantages such as
• the use of hazardous and costly raw materials like lithium diisopropyl amide, iodine,
Pd/C, Raney Ni and n-butyl lithium
• reaction requires to be maintained at lower temperature which is difficult to maintain all
the time at production scale
• the processes involves chromatographic purification techniques which is viable at
higher manufacturing scale

• more reaction steps and lengthy work-up
• overall higher cost of production
• low yields and purity
Therefore, there is a continuing need for developing a new process for the manufacturing of voriconazole which is cost effective, industrially viable and eco-friendly.
SUMMARY OF THE INVENTION
The present invention describes an industrially viable and an improved process for the manufacturing of (2R,3 S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazol-l-yl)butan-2-ol (commonly known as Voriconazole).
The process can be given in Scheme VII as :
SCHEMEVn

• reaction of 6-( 1 -Bromoethyl)-4-chloro-5-fluoro pyrimidine with 1 -(2,4-diflouorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone in the presence of zinc powder, lead, zinc chloride, THF followed by dehalogination in presence of ammoniimi formate, resolution with suitable resolving agent to give (2R,3S)-2-(2,4-difIuorophenyl)-3-(5-fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazole-1 -yl)butan-2-ol salt all this in the one pot
• formation of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazole-l-yl)butan-2-ol or Voriconazole by basification.
Another aspect of the present invention provides a process for preparation of racemic Voriconazole which process comprises condensation of 6-(l-Bromoethyl)-4-chloro-5-fluoro pyrimidine with l-(2,4-diflouorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone in the presence of zinc powder, lead, zinc chloride, THF followed by dehalogination in suitable metal catalyst and base to give

Further aspect of the present invention provides a process for preparation of (2R,3S)-2-
(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1 -(IH-1,2,4-triazole-1 -yl)butan-2-ol salt
which process comprises reacting racemic (2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazole-l-yl)butan-2-ol with suitable resolving agent in suitable solvent.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of (2R,3S)-2-
4 4*
(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazol-1 -yl)butan-2-ol compound of Formula I, which comprises of following steps:
a) activation of metal
b) condensation of 6-(l-Bromoethyl)-4-chloro-5-fluoro pyrimidine and l-(2,4-diflouorophenyl)-2-( 1H-1,2,4-triazol-1 -yl)ethanone
c) dehalogenation
d) resolution
e) formation of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(IH-1,2,4-triazol-l-yl)butan-2-ol by basification
Another embodiment of the present invention relates to the single pot synthesis of (2R,3S)-2-(2,4-difluorophenyl)-3K5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol salt, which process comprises the following steps of
a) heating a mixture of metal and lewis acid at 100°C and maintaining this temperature for 1-1.5 hrs, cooling to 70°C followed by addition of suitable organic solvent and further refluxing for 3 hrs to complete the activation of the metal, cooling the mixture to 0°C -5°C
b) addition of 6-(l-Bromoethyl)-4-chloro-5-fluoro pyrimidine and l-(2,4-diflouorophenyl)-2-( 1H-1,2,4-triazol-1 -yl)ethanone dissolved in a suitable solvent below 5*°C to the activated metal mixture, maintaining the reaction temperature at 0-5°C for 30 minutes and distillation of excess solvent to get a thick slurry
c) dehalogenation of the compound obtained from the step b by addition of suitable base and zinc metal and an organic solvent, stirring the reaction mixture at room temperature for 12-16 hrs, filtering the reacton mixture and quenching with a mixture of water and acetic acid
d) basification with saturated sodium carbonate solution followed by neutralization with conc, hydrochloride to form a slurry

e) filtration and extraction of the filtrate with ethyl acetate two to three times, combining the ethyl acetate layers, washing with 5% aq. EDTA disodium solution, drying oyer sodium sulphate and distilling off the ethyl acetate layer under reduced pressure at 43-45°C to obtain racemic 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-1,2,4-triazol-1 -yl)butan-2-ol
f) resolving the racemic mixture obtained with suitable resolving agent in presence of organic solvent to get the corresponding salt of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-
* * 4
fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazol-1 -yl)butan-2-ol
Another embodiment provides a process for preparation of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazole-l-yl)butan-2-ol salt which process comprises reacting racemic (2,4-difluorophenyl)-3 -(5 -fluoropyrimidin-4-y 1)-1 -(1H-1,2,4-triazole-1 -yl)butan-2-ol with suitable resolving agent in suitable solvent.
Further embodiment of the present invention give a process for to manufacture (2R,3S)-2-
(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazol-1 -yl)butan-2-ol by
conversion of the sah to (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol using appropriate base.
The metal used in the step a can be selected form a group of organometals such as zinc, magnesium, manganese lead metal or mixture thereof
The lewis acid used n step a can be selected from or zinc iodide most preferably zinc chloride.
The solvent used for activation and condensation of 6-(l-Bromoethyl)-4-chloro-5-fluoro pyrimidine and l-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-yl)ethanone is selected from a group of solvents consisting of tetrahydrofuran diethylether, dimethylether diisopropyl ether, methyl tertiary-butyl ether or 1,4-dioxane; most preferably tetrahydrofuran.
The dehalogenation is carried out in the presence of suitable salt complex formed by the presence of suitable metal like zinc or magnesium most preferably zinc and suitable base such as ammomum formate, sodium formate, ammonium acetate or sodium acetate most preferably ammonium formate in presence of a suitable organic solvent such as methanol, ethanol or isopropanol most preferably methanol.
The resolving agent used in the step f is selected form a group consisting of R-(-)-camphor sulphonic acid, L-(-)-mandelic acid or L-(-)-tartaric acid most preferably R-(-)-camphor sulphonic acid in a suitable solvents selected from a group consisting of ketonic

solvents such as acetone, butanone, propanone, ethylmethylketone; alcoholic solvents such as methanol, ethanol, isopropanol or their mixtures and more preferably mixture of ketone: alcohol as acetone: methanol.
The salt is converted in a free base in the presence of suitable base selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or sodium bicarbonate most preferably sodium hydroxide in a suitable organic solvents selected from a group consisting dichloromethane, chloroform, ethylacetate and more preferably
*
dichloromethane.
The other isomer (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol can be isolated from the mother liquor by the known prior art method.
(2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol commonly known as Voriconazole formed by the process disclosed above is crystalline form B.
The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.
ADVANTAGE OF THE PRESENT INVENTION
• Single pot reaction to form desired enantiomer
• Activation of the metal by heating reduces the overall time for the completion of the reaction.
• Use of Zn ammonium formate complex for dehalogenation is cost effective and not hazardous.
• No consequent process of column purification which reduces the cost at a manufacturing scale.
• Higher yield and greater chiral purity of the desired compound.
EXAMPLES
Example 1: Preparation of (2R, 3S)-2-(2,4-difluorophenyl)~3'(5-fluoropyrimidin-4-yl)-l-(lH' 1,2,4'triazol-l-yl)butan-2-oh R (-)-10-Camphor sulphonate.
Zinc(35gm), lead metal(1.75gm) and zinc chloride(19.8gm) were taken together heated to 100°C and maintained at this same temperature with occasional stirring for 1-1.5 hrs. The mixture was cooled to 70°C and to it was added tetrahydrofuran (315ml), refluxed for three

hours and further cooled to -5°C to 0°C . A solution of 6-(l-Bromoethyl)-4-chloro-5-
fluoropyrimidine (35gm) and 1 -(2,4-diflouorophenyl)-2-( 1H-1,2,4-triazol-1 -
yl)ethanone(26gm) in tetrahydrofuran (175ml) was added to this reaction mixture at -5 to 5°C to and stirred for 30 minutes, the solvent is distilled off under reduced pressure to get a thick slurry. Methanol (175ml), zinc metal (35gm) and ammonium formate (35gm) was added to slurry solution under stirring and maintained for 16 hrs at ambient temperature. The mixture is filtered, washed with methanol and added to an aqueous solution of water and acetic
« • *
acid(350ml:17mL). The pH is adjusted above 10 with saturated solution of sodium carbonate solution (-'350ml) and further to pH about 8 with cone, hydrochloric acid(60ml).The mixture is filtered and washed with ethylacetate( 105ml). The filtrate is extracted with ethylacetate (3X175ml). The ethyl acetate layer is washed with water (350mL), 5% aq. EDTA disodium(525ml) and water(350mL) again, dried over sodium sulphate, filtered and distilled xmder reduced pressiu^e at 40-45**C. The residue is dissolved iu a mixture of methanol (75ml) and acetone (560ml) and to it was added l-(R)-camphor-10-sulphonic acid (16.6gm) under stirring, the reaction mixture is heated and refluxed for an hr., cooled to 25-30°C and stirred at the same temperature for 15 hours, the solid is filtered off washed with acetone and dried at 45-50°C to get the desired compound. (Weight: 11.5g),
Example 2: Preparation of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-'triazol'l-yl)butan-2'Ol.
To a solution of (2R, 3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-1-yl)butan-2-ol, R (-)-10-camphor sulphonate(10g) in dichloromethane(50ml) and water (50ml) was added 40% sodium hydroxide solution(10ml) vmder stirring. The layers were separated and the aqueous layer was washed with dichloromethane (50ml). The dichloromethane layers were combined, washed with water(2X50ml), dried over sodium sulphate(25gm) and filtered. The solvent was distilled off till one volume of the solvent remained and to it was added isopropyl alcohol(50mL). The distillation is continued imder reduced pressure at 40-45°C till 3 volumes of isopropanol remained. At this temperature the compoimd starts isolating. The reaction mixture is cooled to 0°C, stirred for one hour, filtered, washed with cold isopropyl alcohol and dried at 45-50°C. (Dry weight: 5g, Chiral purity: 99.9% HPLC purity: 99.9)

Example 3: Preparation of 2-(2,4-difluorophenyl)-3-(5'fluoropyrimidin-4-yl)-l-(lH-l2A' triazol-l-yl)butan-2-ol.
2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazol-1 -yl)butan-2-ol hydrochloride(2g)(obtained from US6,586,594) was taken in methanol(20ml) and to it was added ammonium formate (4gm) and stirred for 10 minutes followed by the addition of zinc metal (2gm) and the stirring was continued till reaction completion. The mixture is filtered, washed with methanol and added to an aqueous solution of water and acetic acid (20ml: ImL). The pH is adjusted above 10 with saturated solution of sodivim carbonate solution (-20ml) and further to pH about 8 with cone, hydrochloric acid. The mixture is filtered and washed with ethylacetate (5ml). The filtrate is extracted with ethylacetate (3X10ml). The ethyl acetate layer is washed with water (20niL), 5% aq. EDTA disodium (30ml) and water (20mL) again, dried over sodium sulphate, filtered and distilled under reduced pressure at 40-45°C, to the residue is added isopropanol (10mL) and the distillation is continued till the volume is approximately 6mL. The resultant mixture is cooled to 0°C, stirred fro 15-20minutes at 0°C, filtered, washed with chilled isopropanol and dried to get the desired compound (yield: 1.2g)
Example 4: Preparation of 2-(2,4-difluorophenyl)-3'(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol'l-yl)butan-2-ol
2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazol-1 -yl)butan-2-ol hydrochloride(2g)obtained from US6,586,594) was taken in methanol(20ml) and to it was added ammonium formate (2gm) and stirred for 10 minutes followed by the addition of magnesium metal (2gm) and the stirring was continued till reaction completion. The mixture is filtered, washed with methanol and added to an aqueous solution of water and acetic acid (20ml: ImL). The pH is adjusted above 10 with saturated solution of sodium carbonate solution (-201111) and further to pH about 8 with cone, hydrochloric acid. The mixture is filtered and washed with ethylacetate (5ml). The filtrate is extracted with ethylacetate (3X10ml). The ethyl acetate layer is washed with water (20mL), 5% aq. EDTA disodium (20ml) and water (2mL) again, dried over sodium sulphate, filtered and distilled under reduced pressure at 40-45°C, to the residue is added isopropanol (10mL) and the distillation is continued till the volume is approximately 6mL. The resultant mixture is cooled to, stirred for 15-20 minutes at 0°C, filtered, washed with chilled isopropanol and dried to get the desired compound (yield: 1.2g)

WE CLAIM
1. An improved process for manufacturing (2R, 3S)-2-(2,4-difluorophenyl)-3-(5-
fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazol-1 -yl)butan-2-ol comprising:

• activation of metal
• condensation of 6-( 1 -Bromoethyl)-4-chloro-5-fluoro pyrimidine and 1 -(2,4-diflouorophenyl)-2-( 1H-1,2,4-triazol-1 -yl)ethanone
• dehalogenation
• resolution
• formation of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol by basification
2. One pot synthesis of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-
l,2,4-triazol-l-yl)butan-2-ol, R (-)-lO-camphor sulphonate, comprising:
a. heating the metal at 100°C, cooling and adding suitable solvent followed by refluxing
and further cooling below 0°C
b. addition of 6-(l-Bromoethyl)-4-chloro-5-fluoro pyrimidine and l-(2,4-difluorophenyl)-
2-(lH-l,2,4-triazol-l-yl)ethanone dissolved in a suitable solvent to the activated metal
mixture, maintaining the reaction temperature below 5°C for 30 minutes after the
addition is completed, distillation of excess solvent to get a thick slurry
c. addition of suitable solvent, zinc metal and suitable base to the slurry obtained from the
step b above and stirring the reaction mixture at room temperature for 12-16 hrs,
filtering the reaction mixture and quenching with a mixture of water and acetic acid
d. basification with saturated sodium carbonate solution followed by neutralization with
cone, hydrochloride to form a slurry
e. filtration and extraction of the filtrate with ethyl acetate two to three times, combining
the ethyl acetate layers, washing with water, 5% aq. EDTA disodium solution and
water, drying over sodium sulphate and distilling off the ethyl acetate layer under
reduced pressure at 43-45°C to obtain racemic 2-(2,4-difluorophenyl)-3-(5-
fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazol- 1 -yl)butan-2-ol

f. resolving the racemic mixture obtained in presence of suitable resolving agent and suitable solvent to get the corresponding salt of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazol- 1 -yl)butan-2-ol
3. One pot synthesis of racemic (2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-
triazoI-l-yl)butan-2-ol which process comprises activation of metal followed by condensation with 6-(1-Bromoethyl)-4-chloro-5-fluoro pyrimidine and 1 -(2,4-diflouorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone and further dehalogenation to give

racemic (2R,3 S)-2-(2,4-difluoropheny l)-3 -(5-fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazol-1 -yl)butan-2-ol.
4. A process according to claim 1, 2 and 3 wherein the metal catalyst is selected from a group comprising organometal such as zinc, magnesium or manganese most preferably zinc metal powder, lead metal and zinc chloride.
5. A process according to claim 1, 2 and 3 wherein the solvent used in the activation and
condensation as claim 1 and 2 are selected from a group comprising of tetrahydrofuran, diethylether, dimethylether, diisopropyl ether, methyl tertiary-butyl ether and 1,4-dioxane more preferably tetrahydrofuran.
6. A process according to claim 1, 2 and 3 wherein the dehalogention is carried out in the
presence of metal like zinc or magnesium most preferably zinc and suitable base such as ammonium formate, sodium formate, ammonium acetate or sodium acetate most prefembly ammonium formate in presence of a suitable organic solvent such as methanol, ethanol or isopropanol most preferably methanol.
7. A process for the preparation of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-
l-(lH-l,2,4-triazol-l-yl)butan-2-ol according to of claim 1 and 2, wherein resolution of the racemic mixture is carried out in the presence of suitable resolving agent selected from R-(-)-camphor sulphonic acid, L-(-)-mandelic acid or L-(-)-tartaric acid most preferably R-(-)-camphor sulphonic acid, in suitable solvents selected from a group comprising of ketonic solvents such as acetone, butanone, propanone, ethylmethylketone; alcoholic solvents such as methanol, ethanol, isopropanol or their mixtures and more preferably mixture of ketone: alcohol as acetone and methanol.
8. A process for the preparation of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-
l-(lH-l,2,4-triazol-l-yl)butan-2-ol accordmg to claim 1 and 2 wherein the salt is converted in a free base or (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyriniidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol in the presence of suitable organic solvents selected from a group

consisting dichloromethane, chloroform, ethylacetate and more preferably dichloromethane.
9. An improved process for the preparation of substantially pure crystalline form of (2R, 3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol (commonly known as Voriconazole) by basification of (2R,3S)-2-(254-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazol- 1 -yl)butan-2-ol salt
10. Substantially pure crystalline form of (2R, 3S)-2-(2,4-difluorophenyI)-3-(5-
fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol with a chiral purity of greater than 99.9% and impurity level of less than 0.1%.