AN IMPROVED PROCESS FOR THE PREPARATION OF VORICONAZOLE
AND INTERMEDIATES THEREOF
Field of the Invention
The present invention relates to an improved stereoselective process for the
preparation of (2R,3S/2S,3R)-3-(42-(lH-l ,2,4-triazol- l-yl)ethanone at from -70°C to -50°C.
EP 0871625B1 describes a stereoselective process for preparation of
(2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2 4-difluorophenyl)-l-(lH-l,2,4-
triazol-l-yl)butan-2-ol or an acid addition salt thereof comprising reacting l-(2,4-
difluorophenyl)-2-(lH-l,2,4-triazol -l -yl)ethanone with 6-(l-bromoethyl)-4-chloro-5-
fluoropyrimidine in the presence of zinc, iodine and/or a Lewis acid at about 0°C -5°C. It
is known that the use of iodine in Reformatsky reactions works as a catalyst and decreases
the rate of enolization, but is also known to cause dehydration of the product J. Am.
Chem. Soc, (1915) 37 (7). pp. 1748-1763 andJ. Am. Chem. Soc, 194 1 63 ( ) pp. Hi¬
l l 2).
The present inventors have developed an alternate stereoselective process for the
preparation of (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-
l-(lH-l,2,4-triazol-l-yl)butan-2-ol or an acid addition salt thereof, which involves simple,
cost effective and uniform reaction conditions to provide the product with reproducible
batch-to-batch results (e.g., in yield, purity, etc.) and is thus industrially viable.
Summary of the Invention
The present invention provides a stereoselective process for the preparation of
(2R,3S/2S 3R)-3 4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-l-(lH-l,2,4-
triazol-l-yl)butan-2-ol or an acid addition salt thereof comprising a step of reacting 6-(lbromoethyl)-
4-chloro-5-fluoropyrimidine with 1-(2,4-difluorophenyl)-2-(lH-l ,2,4-triazol-
1-yl)ethanone in the presence of zinc, bromine, and/or an aprotic organic solvent.
The present inventors have surprisingly found that the use of bromine is
advantageous over the use of iodine in the aforementioned reaction step as bromine is not
only cost effective but also provides consistent results in terms of yield and purity of the
product.
The present invention also provides a process for the preparation of voriconazole
using (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-l -(1Hl,
2,4-triazol-l-yl)butan-2-ol or an acid addition salt thereof which is obtained comprising
a step of reacting 6-(l-bromoethyl)^l-chloro-5-fluoropyrimidine with l-(2,4-
difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone in the presence of zinc, bromine, and/or
an aprotic organic solvent.
Detailed Description of the Invention
T e term "about" as used herein, in reference to parameters defined herein, such as
temperature, volume, etc., refers to a variation of ± 10%. In reference to purity, the term
"about", as used herein, refers to a ±5% variation.
The term "trans-enantiomeric pair" as used herein, in reference to certain
compounds refers to (2R,3S/2S,3R) enantiomeric pair of the compound.
The term "cis-enantiomeric pair" as used herein, in reference to certain compounds
refers to (2R,3R/2S,3S) enantiomeric pai of the compound.
A first aspect of the present invention provides a stereoselective process for the
preparation of (2R,3S/2S 3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-
l-(lH-l,2,4-triazol-l-yl)butan-2-ol intermediate compound of Formula II or an acid
addition salt thereof
(2R,3S/2S,3R)
Formula P
comprising a step of reacting l-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone
compound of Formula III
Formula III
with 6-(l-bromoethyl)-4-chloro-5-fluoropyrimidine compound of Formula IV
Formula IV
in the presence of zinc, bromine and an aprotic organic solvent.
In an embodiment of this aspect, the (2R,3S/2S,3R)-3-(4-chloro-5-
fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)- 1-(1H-1,2,4-triazol- 1-yl)butan-2-ol
intermediate compound of Formula II prepared has HPLC purity of greater than about
80%.
In another embodiment of this aspect, (2 3S 2S 3R)-3-(4-chloro-5-
fluoropyrimidin-6-yl)-2-(2 4-difluorophenyl)-l -(1H-1,2,4-triazol- 1-yl)butan-2-ol
intermediate compound of Formula II is prepared as hydrochloride salt thereof.
In another embodiment of this aspect, lead is also used during the reaction of the
compound of Formula III with the compound of Formula IV, along with zinc.
In another embodiment of this aspect, (2R 3S/2S,3R)-3-(4-chloro-5-
fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)- 1-(1H-1,2,4-triazol- 1-yl)butan-2-ol
intermediate compound of Formula II or an acid addition salt thereof is further converted
to voriconazole.
Zinc used in the above reaction may be in the form of zinc metal, dust or powder
obtained from a commercial source. Optionally, lead can also be present in the reaction as
metallic lead and can be added separately or be inherently present in zinc. However, it is
generally preferable to add lead powder to the reaction mixture containing zinc. The
mixture of zinc and lead powder, when lead is added externally, in an aprotic organic
solvent is heated to a temperature from about 45°C to about 50°C followed by cooling to
about 25°C -35°C. This reaction is carried out under a dry, inert atmosphere such as dry
nitrogen gas.
Bromine can be used as such as commercially available or in the form of its
mixture with the aprotic organic solvent and can be introduced before, after or during the
addition of compound of Formula III to the reaction vessel containing zinc and/or lead in
an aprotic organic solvent, wherein the temperature of the reaction mixture is maintained
at about 40°C-50°C during the addition of bromine.
The aprotic organic solvent can be selected from the group consisting of ethers
such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane; hydrocarbons such as toluene and
halohydrocarbons such as dichloromethane. The preferred solvent is tetrahydrofuran. It is
preferable to dry the solvent before use to substantially remove all traces of water. Drying
can be done by using any drying technique known in the art.
A solution of compound of Formula III in aprotic organic solvent can be added to
the reaction mixture containing zinc, bromine and/or lead at 45°C to 50°C. The reaction
mixture can then be cooled to 30°C to 40°C, followed by the addition of the compound of
Formula IV. The compound of Formula IV can be added to the mixture as such, without
isolation, prepared by following general procedure as exemplified in Step II of the
Example 1 or in the form of isolated solid as exemplified in Example 3 of the present
invention. The reaction mixture can then be cooled to about 15°C-20°C, followed by
quenching with acetic acid. The resultant reaction mixture is worked up conventionally
and can include filtration and washing over hyflo-bed. The solvent is then recovered under
reduced pressure at a temperature of about 40-50°C to provide an oily residue. This
residue is mixed with an aprotic organic solvent and then cooled from about 1 °C to about
20°C followed by extraction with water and pH adjustment with inorganic acid.
The inorganic acid can be selected from hydrochloric acid, sulphuric acid, or nitric
acid. Concentrated hydrochloric acid is preferably used for adjusting the pH of the
mixture.
The organic layer so obtained is washed with 2%-3% ethylenediaminetetraacetic
ac d (EDTA) solution to remove metal impurities, if any, followed by pH adjustment using
a base. The base can be selected from sodium hydroxide, potassium hydroxide, potassium
carbonate, sodium carbonate, and the like. Sodium hydroxide is preferably used. An oily
residue is obtained after recovery of solvent. The oily residue is treated with an organic
solvent, optionally repeating the treatment, to provide the compound of Formula II, which
can also be isolated as its acid addition salt. The organic solvent can be selected from the
group comprising ketones, esters, and alcohols, Ketones can be selected from the group
consisting of acetone, 2-butanone, 2-pentanone, 3-pentanone, methyl isobutyl ketone, and
mixtures thereof. Acetone is the preferred ketone. Esters can be selected from the group
consisting of ethyl acetate, n-propyl acetate and a mixture thereof. Alcohols can be
selected from the group consisting of ethanol, propanol, isopropanol, butanol, pentanol,
and mixtures thereof. An isopropanol solution of hydrogen chloride is preferably used to
obtain the hydrochloride salt of the 'trans-enantiomeric pair' of compound of Formula II
with desired purity.
The compound of Formula II as obtained by the present aspect has transenantiomeric
(2R,3S/2S,3R) purity greater than 85%, more preferably greater than 90%
and most preferably greater than 94%. The content of cis-enantiomeric pair (2R,3R/2S,3S)
in compound of Formula II can vary from about 1% to 5% depending upon the batch size
and scale-up conditions.
The compound of Formula Pcan be converted to voriconazole by following any
method(s) known in prior art. For example, the method described in EP 0871625B1 can be
used.
A second aspect of the present invention provides a process for the preparation of
voriconazole comprising the step of reacting l-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-lyl)
ethanone compound of Formula III
Formula PI
with 6-(l-bromoethyl)-4-chloro-5-fluoropyrimidine compound of Formula IV
Formula IV
in the presence of zinc, bromine and an aprotic organic solvent and converting the product
obtained thereby to voriconazole.
In an embodiment of this aspect, the product obtained by reacting the compound of
Formula III with the compound of Formula IV is (2R,3S/2S,3R)-3-(4-chloro-5-
f luoropyrimidin-6-yl)-2-(2,4-difluorophenyl)- 1-(1 H-l,2,4-triazol-l -yl)butan-2-ol
represented by Formula Por an acid addition salt thereof .
(2R,3S/2S,3R)
Formula P
In another embodiment of this aspect, (2R,3S/2S,3R)-3-(4-chloro-5-
fluoropyrimidin-6-y])-2-(2,4-difluorophenyl)- 1-(1H-1,2,4-triazol- 1-yl)butan-2-ol
intermediate compound of Formula II obtained has HPLC purity of about 80%.
In another embodiment of this aspect, the compound of Formula P can be isolated
as the hydrochloride salt thereof.
In another embodiment of this aspect, lead can also optionally be present during
reaction of the compound of Formula III with the compound of Formula IV.
The reaction conditions, reagents, methodology, etc. of the reaction between the
compound of Formula III and the compound of Formula IV to obtain the compound of
Formula II or an acid addition salt thereof is described in detail in the first aspect of
present invention. The description provided for in the first aspect of present invention for
the preparation of a compound of Formula II or an acid addition salt thereof is also
applicable here in this aspect for preparing the compound of Formula II which is then
converted to voriconazole.
The compound of Formula II obtained as per the present aspect can be converted to
voriconazole following Example 4 of the present invention or by following any prior art
method. For example, the method described in EP 0871 625B 1 can be used.
In another embodiment of this aspect, voriconazole having HPLC purity greater
than 99.8% is obtained.
The l-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone compound of
Formula III can be prepared by a process known in prior art, for example, EP 0440 72B1
o EP 0871625Bl.
In the following section, aspects and embodiments thereof are described by way of
examples to illustrate the process. However, these are not intended in any way to limit the
scope of the invention. Several variants of these examples would be evident to persons
ordinarily skilled in the art.
EXAMPLES
Example 1: Preparation of Hydrochloride Salt of (2R.3S/2S.3RV3-r4-chloro-5-
f iuoropyrimidin-6-yl)-2-(2.4-diflTOrophenylV1-( H-1.2.4-triazol-l -yl lbutan-2-ol
Step I: Procedure for preparation of zinc dust
Zinc dust (500 gm) was stirred in de-ionized water (4 L) at 20°C-25°C followed by
the addition of concentrated hydrochloric acid (250 mL) at the same temperature while
maintaining the pH at about 1. The mixture was stirred for about 2 hours at 20°C -25°C
and filtered. This was washed with de-ionized water (1500 mL + 2 x 500 mL). The
resultant mixture was further washed with acetone (5 x 500 mL) and dried in a tray dryer
at 1 0°C- 20°C for about 12 hours.
Dry weight: 452 gm
Step II: Preparation of 6-(l-Bromoethyl )-4-chloro-5-fluoropyrimidine (Formula IV)
4-Chloro-6-ethyl-5-fluoropyrimidine (187 gm) was added to dichloromethane (900
mL) and the mixture was stirred at ambient temperature under anhydrous conditions with
nitrogen blanketing. To the reaction mixture azobisisobutyronitrile ( 0 gm) and NBromosuccinimide
(271.2 gm) were added and stirred under reflux for hours. The
reaction mixture was cooled to lS^C-^C. It was added to de-ionized water (800 mL)
and sodium metabisulphite (38 gm). The reaction mixture was further stirred for about 30
minutes. The mixture was allowed to settle and layers were separated. The aqueous layer
was extracted with dichloromethane (200 mL). The organic layers so obtained were
combined and washed with de-ionized water (2x600 mL). The solvent was recovered
under reduced pressure (50-75 torr) at 40°C-50°C and oily residue was obtained. The oily
residue was used as such in step PI for preparation of hydrochloride salt of
(2R,3S/2S,3R)-3-(4-ch]oro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-l-(lH-l,2 4-
triazol-l-yl)butan-2-ol.
Step III: Preparation of hydrochloride salt of (2R,3S/2S,3R)-3-(4-chloro-5-
fluoropyrimidin-6-yl)-2-(2 ,4-difluoropheny[)-l-(lH-l,2 ,4-triazol-l-yl)butan-2-ol
A mixture of zinc dust (300 gm; from step I above) and lead powder (15.2 gm) in
tetrahydrofuran (1000 mL) at ambient temperature was stirred under anhydrous condition
with nitrogen blanketing. The stirred mixture was heated to 45 C-50°C and then cooled to
30°C-35°C followed by the addition of bromine ( 1 0 gm) at 45°C-50°C. The reaction
mixture was stirred for 30 minutes. A solution of l-(2,4-difluorophenyl)-2-(lH-l,2,4-
triazol-l-yl)ethanone (200 gm; Formula III) in dichloromethane (1800 mL) was added to
the reaction mixture at 45°C-50°C followed by cooling to 30°C-40°C. To the reaction
mixture, a solution of 6-(l-bromoethyl)-4-chloro-5-fluoropyrimidine (entire quantity from
Step II) in dichloromethane (200 mL) was added at 30°C-40°C. This was stirred for 30
minutes to 2 hours and then cooled to 15°C-20°C. Acetic acid (300 gm) was added to it.
The mixture obtained was filtered and washed with dichloromethane (2x400 mL). The
solvents were recovered under reduced pressure at 45°C-50°C to provide an oily residue.
To the oily residue, dichloromethane (1000 mL) was added. This mixture was stirred and
cooled to 15°C-20°C followed by the addition of de-ionized water (1000 mL) and
concentrated hydrochloric acid (200 mL). This was allowed to settle and the layers were
separated. The organic layer was washed with 2% w/v aqueous ethylenediaminetetraacetic
acid solution (EDTA solution; 1000 mL) at 15°C-20°C. De-ionized water (1000 mL) was
added to the organic layer and pH was adjusted with about 40% w/v aqueous sodium
hydroxide solution (98 mL) at 15°C-20°C. This was allowed to settle and the layers were
separated. The solvent was recovered from the organic layer under reduced pressure (50-
500 torr) at 35°C-45°C and oily residue was obtained. Acetone (400 mL) was added to the
residue, stirred and then solvent was recovered under reduced pressure (50-500 torr) at
35°C-45°C. To the so obtained oily residue, acetone (1000 mL) was further added, the
mixture was stirred and then cooled to 20°C-25°C. To the resultant mixture, isopropanol
hydrochloride ( 180 gm) was added and it was stirred for about 2 hours at 20°C-25°C. The
slurry so obtained was cooled to 0°C-5°C and stirred for 60 minutes at 0°C-5°C. The
solid obtained was filtered and washed with acetone (600 mL) at the same temperature.
The solid was dried at 40°C-50°C.
% Yield: 47.8 w.r.t compound of Formula III
% HPLC purity: 95.91%
Example 2: Preparation of Hydrochloride Salt of f2R.3S/2S,3RV3-(4-chloro-5-
fluorop yrimidin-6-ylV2-(2.4-difluorophenylV 1-f1H-1,2,4-triazol- 1-yl>butan-2-ol
A mixture of zinc dust (150 gm) and lead powder (7.6 gm) was stirred in
tetrahydrofuran (500 mL) at ambient temperature under anhydrous conditions with
nitrogen blanketing. The mixture was heated to 45°C-50°C and then cooled to 30°C-35°C
followed by the addition of bromine (90 gm) at 45°C-50°C. The reaction mixture was
stirred for 30 minutes. A solution of l-(2,4-difluorophenyl)-2-(lH-l,2,4-f iazol-1-
yl)ethanone (100 gm) in dichloromethane (900 mL) was added to the reaction mixture at
45°C-50°C. The reaction mixture was cooled to about 30°C-35 C. To the reaction
mixture, solution of 6-(l-bromoemyl)-4-chloro-5-fluoropyrimidine (entire quantity from
Step II of Example 1) in dichloromethane (100 mL) was added at 30°C-40°C. This was
then cooled to 15°C-20°C. Acetic acid (150 gm) was added to it. The mixture obtained
was filtered and washed with dichloromethane (2 x 200 mL). The solvents were recovered
under reduced pressure. The oily residue so obtained was cooled to 20 C-25°C and
dichloromethane (500 mL) was added to it. The mixture was stirred and cooled to 15°C-
20°C followed by addition of de-ionized water (500 mL) and concentrated hydrochloric
acid (100 mL). This was allowed to settle and layers were separated. The organic layer
was washed with 2% w/v aqueous ethylenediaminetetraacetic acid solution (EDTA
solution; 500 mL) at 15°C-20 C. De-ionized water (500 mL) was added to the organic
layer and the pH was adjusted with about 40% w/v aqueous sodium hydroxide solution
(36 mL) at 15°C-20°C. This was allowed to settle and layers were separated. The solvent
was recovered from the organic layer under reduced pressure at 40°C-45°C. To the
resultant oily residue, ethyl acetate (200 mL) was added, stirred and then the solvent was
recovered under reduced pressure. The residue so obtained was cooled to 20°C-25°C and
isopropanol hydrochloride (90 gm) was added to it. Seeds of hydrochloride salt of
(2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difJuorophenyl)-l-(lH-l 2,4-
triazol-l-yl)butan-2-ol ( 1 gm) were added to the mixture and the resultant slurry was
stirred at 20°C -25°C for 4 hours. The mixture was cooled to 15°C-20°C, the solid
obtained was washed with ethyl acetate (3 x 200 mL). The wet material so obtained was
dried at 35°C-40°C.
%yield : 48.5% w.r.t compound of Formula III
%HPLC purity: 94.37%
Example 3: Preparation of Hydrochloride Salt of r2R.3S/2S.3Rt-3-f4-chloro-5-
fluoropwimidin-6-yl)-2-(2.4-dtfluorophenyl)- 1- H- 1.2.4-triazol- -yl)butan-2-ol
A mixture of zinc dust (30 gm) and ead powder (1.52 gm) was stirred in
tetrahydrofuran (100 mL) at ambient temperature under anhydrous condition with nitrogen
blanketing. The stirred mixture was heated to 45°C-50°C and then cooled to 30°C-35°C
followed by addition of bromine (90 gm) at 45°C-50°C. The reaction mixture was stirred
for 10 minutes. A solution of l-(2,4-difluorophenyl)-2-(lH-l 2,4-triazol-l-yl)ethanone (20
gm; Formula III) in dichloromethane (180 mL) was added to the reaction mixture at 45°C-
50°C followed by cooling to 30°C-35°C. The solution of 6-(l-bromoethyl)-4-chloro-5-
fluoropyrimidine (27.8 gm) in dichloromethane (20 mL) was added to the reaction mixture
at 30°C-35°C. This was stirred for 30 minutes to 2 hours and then cooled to 15°C-20°C.
Acetic acid was added (30 gm) to it. The mixture obtained was filtered and washed with
dichloromethane (2x40 mL). The solvents were recovered under reduced pressure at 40°C-
45°C to provide an oily residue. This residue was cooled to 20°C-25°C. To the oily
residue, dichloromethane (100 mL) was added. This mixture was stirred and cooled to
15°C-20°C followed by addition of de-ionized water (100 mL) and concentrated
hydrochloric acid (20 mL). This was allowed to settle and layers were separated. The
organic layer was washed with 2% w/v aqueous ethylenediaminetetraacetic acid solution
(EDTA solution; 100 mL) at 15°C-20°C. De-ionized water (100 mL) was added to the
organic layer and the pH was adjusted with about 40% w/v aqueous sodium hydroxide
solution (8.2 mL) at 15°C-20°C. This was allowed to settle and layers were separated. The
solvent was recovered from the organic layer and oily residue was obtained. Ethyl acetate
(40 mL) was added to the residue, stirred and then the solvent was recovered under
reduced pressure at 40°C-45°C. To the so obtained oily residue, ethyl acetate (140 mL)
was further added; the mixture was stirred and then cooled to 20°C-25°C. To the resultant
mixture, isopropanol hydrochloride (18 gm) was added at 20 C-25°C. Seeds of
hydrochloride salt of (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-
difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol (0.2 gm) were added to the resultant
mixture and the resultant slurry was stirred for about 66 hours at 20°C-25°C. The slurry so
obtained was washed with ethyl acetate (4 x 40 mL) and the solid obtained was dried at
40°C-45°C.
% yield : 43.8% w.r.t. compound of Formula III
% HPLC purity: 79.07%
Example 4: Preparation of ,2R.3S)-3 - 5-ftuoropyrimidin-6-yl)-2-(2.4-difluoropbcnyl>-l-
(lH-l,2,4-triazol-l -yPbutan-2-ol ("Voriconazole)
Step 4A: Preparation of voriconazole camphorsulfonate (wet) from hydrochloride
salt of (2R^S/2S,3R)-3 -(4-chloro-5-fluoropyrimidin-6-yl)-2-(2 ,4-difluorophcnyl)-l-
(lH-l,2 ,4-triazol-l-yl)butan-2-ol
Hydrochloride salt of (2R 3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-
difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol ( 180 gm) obtained from Step III of
Example 1 or Example 2 or Example 3 was added to methanol (720 mL) at 20°C-25°C
followed by pH adjustment (8.0-9.0) with 40% w/v aqueous sodium hydroxide solution
(50 mL) under nitrogen blanketing. To this reaction mixture, ammonium formate (108.2
gm) was added followed by addition of wet palladium/carbon [Pd/C (2.5 % w/w dry, 18
gm)] treated with de-ionized water. The reaction mixture was further heated and stirred at
55°C-60°C followed by cooling of the mixture to 30°C-35°C. The reaction mixture was
filtered through hyflobed and washed with methanol (360 mL) first and then with a
mixture of de-ionized water (1800 mL) and dichloromethane (900 mL) at 15 C-20°C
followed by stirring. To the organic layer, de-ionized water (360 mL) was added followed
by pH adjustment with 2N hydrochloric acid solution (6 mL) at the same temperature. The
solvent was recovered under reduced pressure at 40°C-45°C to give residual solid. To the
residue acetone (2700 mL) was added followed by addition of the methanolic solution of
(lR)-(-)-10-camphorsulfonic acid (99.5 gm in 900 mL methanol) at 40°C-45°C. Seed of
voriconazole camphorsulfonate (0.18 gm) was added to the reaction mixture and the
mixture stirred at 40°C-45°C for 60 minutes. The slurry so obtained was cooled to 30°C-
35°C followed by further cooling to 20°C-25°C. The mixture was stirred for 10-12 hours
at 20°C-25°C followed by filtration and washing with acetone (180 mL) to give wet
voriconazole camphorsulfonate.
Wet wt: 9 1 gm
Step 4B: Preparation of voriconazole from voriconazole camphorsulfonate (wet)
Voriconazole camphorsulfonate (wet) (entire quantity from Step 4A of Example 4)
was added to a stirred mixture of de-ionized water (360 mL) and dichloromethane (360
mL) at 5°C-25°C followed by pH adjustment of the mixture to pH 10-1 1 with 40% w/v
aqueous sodium hydroxide solution (16.2 mL). The organic layer was washed with deionized
water (360 mL) followed by filtration of organic layer through 0.45 micron filter.
The filtered layer was further washed with dichloromethane (90 mL) and solvent was
recovered under reduced pressure (50-500 torr) at 35°C-45°C to give a residual solid.
Isopropyl alcohol (450 mL) was added to the residue followed by heating and stining of
the mixture at 60°C-70°C until the mixture was dissolved, followed by recovery of
isopropyl alcohol under reduced pressure (50-500 torr) at 50°C-60°C to obtain a residual
volume of 270 mL. The concentrated solution so obtained was heated to 60°C-70°C
followed by cooling of the solution to 45°C-50°C. The solution was further cooled to 5°C-
10°C followed by stirring for 60 minutes at the same temperature. The solid obtained was
filtered and washed with isopropyl alcohol (135 mL) followed by drying of the solid under
re ced pressure at 50°C-55°C until constant weight.
% Yield: 42.8%
% HPLC purity: 99.9%

Claims:
1. A stereoselective process for the preparation of (2R,3S/2S,3R)-3-(4-chloro-5-
fluoropyrimidin-6-yl)-2-(2,4-difluoropheny ])- -(1H-1,2,4-triazol- -yl)butan-2-ol
intermediate compound of Formula II or an acid addition salt thereof
(2R,3S/2S,3R)
Formula P
comprising the step of reacting l-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-lyl)
ethanone compound of Formula PI
Formula III
with 6-(l-bromoethyl)-4-chloro-5-fluoropyrimidine compound of Formula IV
in the presence of zinc, bromine and an aprotic organic solvent.
The process of claim 1, wherein compound of Formula II is isolated
hydrochloride salt.
The process of claim 1, wherein lead is used during the reaction.
4 . A process for the preparation of voriconazole comprising the step of reacting l-(2,4-
difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone compound of Formula III
Formula III
with 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine compound of Formula IV
in the presence of zinc, bromine and an aprotic organic solvent to obtain a compound
of Formula II or an acid addition salt thereof.
(2R,3S/2S,3R)
Formula P
5. The process of claim 4, wherein an acid addition salt of compound of Formula II is the
hydrochloride salt.
6. The process of claim 4, wherein lead is used during the reaction.
7. The process of claim 4, wherein the voriconazole so prepared has an HPLC purity of
greater than 99.8%.