Field of the Invention
The present invention relates to an improved and commercially viable process for the
preparation of voriconazole. The process further relates to efficient recovery of key
staring materials to make the process environmentally and economically viable by
recycling.
Background of the Invention
Voriconazole, also known as (2R,3S)-2-(2,4-difluoropheny1)-3-(5-fluoropyrimidin-4-y1)-
1 -(1 H- 1,2,4-triazol-1 -yl)-2-butanol is structurally represented as Formula I.
F
Formula I
Voriconazole was generically disclosed in US 5,116,844 and specifically disclosed in US
5,567,8 17 and in Bioorganic & Medical Chemistry Letters, 1996,6,203 1.
US 5,567,817 discloses preparation of voriconazole by the reaction of 1-(2,4-
difluoropheny1)-2-(1H - 1,2,4-triazol- 1- yl)ethanone with 4-chloro-6-ethyl-5-
fluoropyrimidine, in the presence of lithium diisopropylamine (LDA) and
tetrahydrofuran, to yield 3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-
(1 H- 1,2,4-triazol- 1 -yl)butan-2-01 as a residue. Column chromatography of the residue on
silica gives (2R,3S) and (3S,2R) diastereomeric pair of 3-(4-chloro-5-fluoropyrimidin-6-
y1)-2-(2,4-difluoropheny1)- 1 -(1 H- l,2,4-triazol- 1 -yl)butan-2-01 which . is further
dehalogenated with 10% palladium on carbon in ethanol in the presence of sodium
acetate, followed by flash chromatographic separation to yield (2R,3S/2S,3R)-2-(2,4-
difluoropheny1)-3-(5-fluoropyrimidin-4-y1)- 1 -(1 H- 1,2,4-triazol- 1 -yl)butan-2-01 (racemic
voriconazole). The racemic voriconazole on resolution with R-(-)- 10-camphor sulfonic
acid in methanol gives a corresponding carnphorsulfonate salt, which on neutralization
with aqueous sodium bicarbonate solution gives voriconazole. The process disclosed
involves chromatographic separation at more than one place, which makes the process
cumbersome and difficult to handle on commercial scale.
I)
US 6,586,594 discloses a process for the preparation of voriconazole comprising reacting
4-(1 -bromoethyl)-6-chloro-5-fluoropyrimidine with 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-
triazol-1-yl) ethanone in the presence of zinc, lead, iodine and tetrahydrofuran, the
condensation reaction yields two different diastereomeric pairs such as (2R,3S:2S,3R and
2S,3S:2R,3R). The desired pair is separated by forming hydrochloride salt. This
hydrochloride salt is further dehalogenated with 10% palladium on carbon and the
resulting product on resolution with R-(-)-camphor- 1 0-sulfonic acid and further
basification gives voriconazole. The process requires preparation of hydrochloride salt of
diastereomeric pair and its fbrther basification, which increases number of process steps
and makes the process lengthy thereby increasing the batch time that makes the process
unsuitable for industrial application. Also, the lead used during the reaction goes in the
effluent. Lead is known to be hazardous for nervous system and causes headaches,
irritability, memory problems and difficulty in sleeping.
W02006065726 discloses a process for the preparation of voriconazole comprising
reacting 4-chloro-6-ethyl-5-fluoropyrimidine with 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-
triazol- 1 -yl)ethanone in the presence of diisopropylamine, n-heptane/tetrahydrofuran, nbutyl
lithium to yield (2R,3S/2S,3R) 2-(2,4-difluoropheny1)-3-(4-chloro-5-
fluoropyrimidin-6-y1)- 1 -(1 H- l,2,4-triazol- 1 -yl)butan-2-01. The resulting compound is
isolated using n-heptane and is further reduced with hydrogenIRaney Nickel and sodium
acetate to yield (2R,3S/2S,3R) 2-(2,4-difluoropheny1)-3-(5-fluoropyrimidin-4-y1)-1-(1H -
1,2,4-triazol- 1 -yl)-butan-2-01 and then resolution with R-(-)- 1 0-camphor sulfonic acid
using about 18 volume of methanollacetone mixture to yield camphor sulfonate salt of
(2R,3 S/2S,3R) 2-(2,4-difluoropheny1)-3-(5-fluoropyrimidin-4-1)-1 - (1 H- l,2,4-triazol-l -
y1)-butan-2-01 followed by isolation of the desired enantiomer i.e. (2R,3S) 2-(2,4-
difluoropheny1)-3-(5-fluoropyrimidin-4-yl)1 - (1H - 1,2,4-triazol- 1- yl)-butan-2-01 camphor
sulfonate salt. Further, the neutralization of desired camphor sulfonate salt to free base
with 20% sodium carbonate solution in the presence of dichloromethane gives
voriconazole. The process involves the use of Raney Nickel for dehalogenation under
pressure which is not advisable for large scale production due to safety concerns. Further,
the process involves preparation of (2R,3S/2S,3R) 2-(2,4-difluoropheny1)-3-(4-chloro-5-
fluoropyrimidin-6-y1)- 1 -(1 H- l,2,4-triazol- 1 -yl)butan-2-01 in mixture of solvents, which
a makes recovery of solvent difficult and isolation of said intermediate in n-heptane, which
eventually is not economic to be applicable on large scale production. Another
disadvantage lies in the use of high volume of methanollacetone mixture for resolution of
racemic voriconazole, which leads to large volumes of eMuent generation and thus the
process is rendered inappropriate for commercial application and environmentally unsafe.
W02007013096 discloses the process for the preparation of voriconazole comprising
reacting 4-chloro-6-ethyl-5-fluoropyrimidinien the presence of lithium diisopropylamine,
n-heptaneltetrahydrofuran to yield (2R,3S/2S,3R) 2-(2,4-difluoropheny1)-3-(4-chloro-5-
fluoropyrimidin-6-y1)- 1 -(1 H- l,2,4-triazol- 1 -yl)butan-2-01 which is further dehalogenated
with hydrogen with Raney Nickel and sodium acetate to yield (2R,3S/2S,3R)-2-(2,4-
difluoropheny1)-3 -(5-fluoropyrimidin-4-y1)- 1 -(1 H- 1,2,4-triazol- 1 -yl)butan-2-01 (racemic
voriconazole) and then resolution with R-(-)-camphor sulfonic acid in the presence of
methanollacetone to yield camphor sulfonate salt followed by its neutralization to free
base using a base. The process disclosed again suffer from the drawbacks as mentioned
for the process disclosed in W02006065726, which renders the process unsuitable for
plant scale production due to safety reasons and being uneconomic.
W020070132354 discloses a process for the preparation of voriconazole by
dehalogenation of hydrochloride salt of 3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-
difluoropheny1)- 1 -(1 H- l,2,4-triazol- 1 -yl)butan-2-01 to form racemic voriconazole,
followed by resolution with R-(-)-lO-camphor sulfonic acid gives voriconazole camphor
sulfonate salt, which upon neutralization with base gives voriconazole.
Thus, the above mentioned drawbacks of prior arts implicate additional chemical
operations, increased energy input arising from increased number of steps, use of
chromatographic separation leading to difficult operating conditions at commercial scale.
Thus, there remains a need for a simple, convenient, environmental friendly, high
yielding, commercially viable and energy efficient process for synthesis of voriconazole.
The present invention provides a simple, convenient, commercially viable and energy
efficient improved process for synthesis of voriconazole. The process further relates to
efficient recovery of key staring material to make the process environmentally and
economically viable by recycling.
Object and Summary of the Invention
The principal object of the present invention is to provide an improved process for
synthesis of voriconazole, which alleviates the drawbacks of prior art process.
It is another object of the present invention to provide a simple, convenient,
commercially viable process for synthesis of voriconazole.
It is yet another object of the present invention to provide efficient recovery process for
un-reacted starting material i.e. 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone
used during the preparation of voriconazole to make the overall process economical and
environmental friendly.
In an embodiment, the present invention encompasses an improved process for the
preparation of voriconazole comprising,
a) condensing 4-chloro-6-ethyl-5-fluoropyrimidine of Formula I1 and 1-(2,4-
difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone of Formula I11 in presence of
an organo metallic base and solvent to obtain a mixture of desired diastereomeric
pair and undesired diastereomeric pair of 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-
(2,4-difluorophenyl)-l -(l H-l,2,4-triazol- 1 -yl)butan-2-01 of Formula IV;
CH3 F
~N / 3 3 ~ T;Jpcl /
CH3 F F
Formula I1 Formula I11 Formula IV
b) enriching the desired 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-
1 -(1 H- l,2,4-triazol-1 -yl)butan-2-01 diastereomeric pair of Formula IV by treating
the residue from step (a) with an aromatic solvent and filtering off the undesired
diastereomeric pair along with unreacted 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-
triazol- 1 -yl)ethanone;
e c) dechlorination of diastereomeric pair of 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-
(2,4-difluoropheny1)- 1 -(1 H- 1,2,4-triazol- 1 - 1 ) b t a n - 2 - of Formula IV from step
(b) using catalytic hydrogenation to provide 2-(2,4-difluoropheny1)-3-(5-
fluoropyrimidin-4-y1)- 1 -(1 H- 1,2,4-triazol- 1 -yl)butan-2-01 of Formula V (racemic
voriconazole);
F
Formula V
d) reacting 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-y1)-1 - (1H -1,2,4-triazol-
1-y1)butan-2-01 of Formula V using R-(-)-camphor sulfonic acid in a solvent to
provide (2R,3S) 2-(2,4-difluoropheny1)-3-(5-fluoropyrimidin-4-y1)1-- (1H - 1,2,4-
triazol- 1 -yl)butan-2-01 camphor sulfonate salt of Formula VI;
Formula VI
wherein CSA is camphor sulfonic acid
e) neutralizing the salt of step (d) with a base in a solvent to provide voriconazole.
According to another object of the present invention, there is provided an efficient
process for recovery of 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone of
Formula I11 comprising the steps of,
i. treating a mixture of 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone and
undesired diastereomeric pair of 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-
difluoropheny1)- 1 -(1 H- 1,2,4-triazol- 1 - y l ) b t - 2 - with an acid in solvent to
obtain salt of 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone;
. .
11. neutralizing the salt of 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone
using a base to isolate 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone of
Formula 111.
Description of the Invention
The present invention is directed to a process of preparing voriconazole by enriching the
desired diastereomeric pair of 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-
difluoropheny1)- 1 -(1 H- 1,2,4-triazol- 1 -yl)btan-2- avoiding chromatographic separation
in the process as is used in prior arts, making the process environment friendly and
economical for industrial application. The method utilizes a carehl solvent selection for
reducing the undesired diastereomeic pair of 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-
difluoropheny1)- 1 -(1 H- 1,2,4-triazol- 1 - y l ) b t - 2 - formed during the reaction of 4-
chloro-6-ethyl-5-fluoropyrimidine and 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol-l -
y1)ethanone from the reaction mixture with an added advantage of removal and recycle of
unreacted 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone. Furthermore, the
efficient removal of undesired diastereomeric pair results in lesser molar requirements of
R-(-)-camphor sulfonic acid and solvents in further reaction steps, accordingly, another
advantage of the present invention is realized in decrease in costs attributed to a more
efficient use of reagents and solvents. Furthermore, the present invention involves the use
of single solvent for the reaction of 4-chloro-6-ethyl-5-fluoropyrimidine of Formula I1
and 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone of Formula I11 as
compared to prior arts, wherein the reaction was done in mixture of solvents. Thus, the
present invention in utilizing single solvent for reaction makes the process more feasible
in terms of recovery of solvents making the process all the more environment friendly
and economic.
The present invention also overcomes problems associated with prior art involving salt
I formation of intermediates; the present invention avoids the use of salt formation of
e intermediates. This elimination of salt formation requirement has substantial advantage in
reducing the number of process steps, which eventually lowers the cycle time of process,
which is an ideal requirement for an industrial process.
In an embodiment, the present invention encompasses an improved process for the
preparation of voriconazole comprising,
a) condensing 4-chloro-6-ethyl-5-fluoropyrimidine of Formula I1 and 1 -(2,4-
difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone of Formula I11 in presence of
an organo metallic base and solvent to obtain a mixture of desired diastereomeric
pair and undesired diastereomeric pair of 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-
(2,4-difluoropheny1)- 1 -(1 H-1,2,4-triazol- 1 -yl)butan-2-01 of Formula IV;
F
Formula I1 Formula I11 Formula IV
b) enriching the desired 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-
1 -(1 H- l,2,4-triazol- 1 -yl)butan-2-01 diastereomeric pair of Formula IV by treating
the residue from step (a) with an aromatic solvent and filtering off the undesired
diastereomeric pair along with unreacted 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-
triazol- 1 -yl)ethanone;
c) dechlorination of diastereomeric pair of 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-
(2,4-difluoropheny1)- 1 -(1 H- 1,2,4-triazol- 1 -yl)butan-2-01 of Formula IV fiom step
(b) using catalytic hydrogenation to provide 2-(2,4-difluoropheny1)-3-(5-
fluoropyrimidin-4-y1)- 1 -(1 H-l,2,4-triazol- 1 -yl)butan-2-01 of Formula V (racemic
voriconazole);
F
Formula V
d) reacting 2-(2,4-difluoropheny1)-3-(5-fluoropyrimidin-4-1)1-- (1H - l,2,4-triazol-l -
y1)butan-2-01 of Formula V using R-(-)-camphor sulfonic acid in a solvent to
provide (2R,3 S) 2-(2,4-difluoropheny1)-3-(5-fluoropyrimidin-4-y1)-1 - (1H - 1,2,4-
triazol-1-y1)butan-2-01 camphor sulfonate salt of Formula VI;
F
Formula VI
wherein CSA is camphor sulfonic acid
e) neutralizing the salt of step (d) with a base in a solvent to provide voriconazole.
According to the present invention, the condensation of 4-chloro-6-ethyl-5-
fluoropyrimidine and 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone is carried
out in presence of an organo metallic base and solvent to provide a mixture of desired
diastereomer pair and undesired diastereomer pair of 3-(6-chloro-5-fluoropyrimidin-4-
y1)-2-(2,4-difluoropheny1)- 1 -(1 H- l,2,4-triazol- 1 -yl)butan-2-01, wherein the organo
metallic base used is selected from the group comprising of butyl lithium, lithium
diisopropylamide, magnesium diisopropylamide, sodium bis(trimethylsilyl)amide,
potassium bis(trimethylsilyl)amide, zinc diisopropyl amide, magnesium hexamethyl
disilazane and the like. The solvent used is selected from the group comprising of ethers
such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran,
methyl tetrahydrofuran, 1,4-dioxane and the like; aliphatic hydrocarbons such as hexanes,
heptane, cyclohexane, pentane and the like; and mixtures thereof. The condensation
reaction is carried out under inert atmosphere at temperature of about -80°C to about -
20°C. After the completion of the condensation reaction, the reaction mass is quenched
by adding a suitable acid such as acetic acid, hydrochloric acid, ammonium chloride and
the like and then diluting with water. After separation of layers and the residue is
obtained by concentrating the organic layer.
According to the present invention, the residue from step (a) is subjected to enrichment of
desired 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)1-- (1H - 1,2,4-triazol-l -
y1)butan-2-01 diastereomeric pair in step (b), by treating the residue from step (a) with an
aromatic solvent. The aromatic solvent used is selected from the group comprising of
toluene, xylene, chlorobenzene and the like. After treatment of residue with aromatic
solvent, the undissolved solid material containing the undesired diasteromeric pair along
with un-reacted 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone is separated by
usual separation techniques like filtration. The resultant organic layer containing majorly
desired 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl1)-- ( 1H - l,2,4-triazol-l -
y1)butan-2-01 diastereomeric pair is either processed directly or alternatively, the solvent
is removed by methods known in the art, for example evaporation at atmospheric
pressure, evaporation under vacuum and isolate 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-
(2,4-difluoropheny1)- 1 -(1 H- l,2,4-triazol- 1 -yl)butan-2-01. Neither chromatographic
separation nor crystallization is implemented to recover the compound of Formula IV,
thereby providing dual benefit of less manufacturing cycle time and lesser cumbersome
process as compared to prior arts.
According to the present invention, the dechlorination of diastereomeric pair of 3-(6-
chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)1-- (1H - 1,2,4-triazol- 1- yl)butan-2-
01 of Formula IV is carried out using catalytic hydrogenation, wherein a metal catalyst is
used in on organic solvent optionally in presence of a base. The source of hydrogen used
for catalytic hydrogenation is selected from the group comprising of hydrogen,
ammonium formate, formic acid and the like. The metal catalyst used is selected from the
group comprising of palladium on carbon, palladium hydroxide on carbon, platinum and
the like. The base used is selected from the group comprising of sodium acetate,
potassium acetate and the like. The organic solvent used is selected from the group
comprising of alcohols such as methanol, ethanol, propanol, butanol, and the like; esters
such as ethyl acetate, isopropyl acetate, tertiary butyl acetate and the like; water and
mixtures thereof. The dechlorination reaction is carried out at a temperature between
about 20°C to about 80°C and about 3 hours to about 20 hours of time. The metal
catalysts is separated from the reaction mixture by methods known in prior art such as
filtration. The resultant filtrate is concentrated and the product is extracted using organic
solvent selected from the group comprising of esters, halogenated hydrocarbons, aromatic
hydrocarbons and mixtures thereof. The product of Formula V, which is racemic
voriconazole, is used as such in solution for next step or alternatively as residue obtained
by subjecting the extracted layer to concentration to get residue by any known method in
the art, for example distillation, evaporation, rotational drying, freeze-drying, flashdrying
and the like.
According to the present invention, the racemic voriconazole of Formula V is reacted
with R-(-)-camphor sulfonic acid in a solvent to obtain voriconazole-R-(-)-camphor
sulfonate salt, wherein the solvent used is selected from the group comprising of C1-C4
alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutyl alcohol,
tertiary butyl alcohol and the like; ketones such as acetone, methyl ethyl ketone and the
like; water or mixtures thereof. The resolution reaction is carried out at a temperature of
about 20°C to about reflux for about 16-20 hours.
According to the present invention, the neutralization of voriconazole-R-(-)-camphor
sulfonate salt to obtain voriconazole at step (e) is carried out in the presence of a base in
mixture of solvents, such as water and hydrocarbon solvent, wherein the hydrocarbon
solvent used is selected from the group comprising of dichloromethane, dichloroethane,
toluene and the like. The base used is selected from the group comprising of ammonia,
sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate,
sodium carbonate, potassium carbonate and the like. The neutralization reaction is carried
out at temperature of about 20°C to about 30°C. The layers so obtained after
neutralization are separated; the organic layer is washed with water and removed the
solvent by distillation at temperature below about 70°C to obtain voriconazole.
I The voriconazole obtained is optionally crystallized from suitable organic solvent to get
pure voriconazole. The suitable organic solvent for crystallization is selected from the
a group comprising of alcohols, esters, ketones, water or mixtures thereof; particularly
I methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tertiary butanol,
methyl acetate, ethyl acetate, isopropyl acetate, tertiary butyl acetate, acetone, methyl
ethyl ketone, water or mixtures thereof.
In another embodiment, the present invention encompasses an efficient process for
recovery of 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone of Formula I11
comprising the steps of,
i. treating a mixture of 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone
and undesired diastereomeric pair of 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-
(2,4-difluoropheny1)- 1 -(1 H- l,2,4-triazol- 1 -yl)butan-2-01 with an acid in
solvent to obtain salt of 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol-l -
y1)ethanone and
ii. neutralizing the salt of 1 -(2,4-difluorophenyl)-2-(1 H- 1,2,4-triazol- 1 -
y1)ethanone by using a base to isolate 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-
triazol- 1 -yl)ethanone of Formula 111.
According to the present invention, the mixture of 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-
triazol-1-y1)ethanone and undesired diastereomeric pair of 3-(6-chloro-5-fluoropyrimidin-
4-y1)-2-(2,4-difluoropheny1)- 1 -(1 H- l,2,4-triazol- 1 -yl)butan-2-01, obtained from step (a)
for the process for preparation of voriconazole is treated with an acid in solvent. The acid
used is selected from the group comprising of organic acid such as acetic acid, oxalic
acid, benzoic acid and the like; inorganic acid such as hydrochloric acid, hydrobromic
acid, hydroiodic acid and the like. The solvent used is selected from the group comprising
of alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and
the like; ketones such as acetone, methyl ethyl ketone and the like; esters such as methyl
acetate, ethyl acetate and the like; water or mixtures thereof. The reaction is performed at
a temperature of about room temperature to about reflux.
According to the present invention, the isolation of 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-
triazol- 1 -yl)ethanone is carried out by neutralizing the salt of 1 -(2,4-difluoropheny1)-2-
t (1 H- 1,2,4-triazol- 1 -yl)ethanone using a base, wherein the base is selected from the group
comprising of organic such as methylamine, ethylamine, triethylamine, diisopropylethyl
mine and the like; inorganic base such as sodium hydroxide, potassium hydroxide,
sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate,
ammonia and the like. The resulting 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol-ly1)
ethanone is isolated by known methods like, extraction, filtration, etc.
The recovered 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone is optionally
purified by conventional methods like crystallization, leaching, etc. before being used for
the synthesis of voriconazole. The present invention by following an efficient recovery
method for an important starting material for voriconazole provides the edge over prior
art methods for being economical and environmental friendly.
Having described the invention with reference to certain preferred embodiments, other
embodiments will become apparent to one skilled in the art from consideration of the
specification. The invention is further defined by reference to the following examples
describing in detail the preparation of voriconazole. It will be apparent to those skilled in
the art that many modifications, both to materials and methods, may be practiced without
departing from the scope of the invention.
Examples
Preparation of voriconazole
Step 1: Preparation of 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-l-
(1H-1,2,4-triazol-l-y1)butan-2-01:
(a) Preparation of 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-l-
(1H-1,2,4-triazol-l-y1)butan-2-01
To a solution of 120.0 g of diisopropyl mine in 250 ml tetrahydrofuran under nitrogen
atmosphere at a temperature of -5 to 5"C, added 580 ml solution of n-butyl lithium in
hexanes. The reaction mixture is stirred for about 90 minutes and is further cooled to -
80°C. To the cooled reaction mixture, added a solution of 100 g of 4-chloro-6-ethyl-5-
fluoropyrimidine in 100 ml of tetrahydrofuran and stirred for about 90 minutes. Added a
solution of 208 g of 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone in 800 ml
tetrahydrofuran to the reaction mixture over a period of time at -80 to -75 "C under
nitrogen atmosphere, the reaction mixture was maintained at -80 to -75°C for about 3
hours. To the reaction mixture, further added a 200 ml solution of 1:l glacial acetic
acid:water. The temperature of reaction mixture was then raised to 0-5 "C and added 200
ml of water and temperature was further raised to 20-30°C. The layers were separated and
the aqueous layer was extracted with toluene. The two organic layers were combined and
the solvent was evaporated to obtain a residue.
(b) Enrichment of desired diastereomeric pair of 3-(6-chloro-5-fluoropyrimidin-4-
yl)-2-(2,4-difluorophenyl)-l-(1H-l,2,4-triazol-l-yl)butan-2-ol
To the residue obtained in step (a) above, charged 400 ml toluene and raised the
temperature of reaction mixture to 55-60 "C. The reaction mixture was stirred for about
30 minutes and the solvent was distilled under vacuum. The reaction mixture so obtained
was again taken in 400 ml toluene and stirred for about 30 minutes at 55-60 "C. The
reaction mixture was then cooled to 20-30 "C and stirred for 4-6 hrs. The solid material
(residual DTE) in reaction mixture was filtered out and the filtrate was distilled under
vacuum to obtain the title compound as residue that was used as such in next step.
Step 2: Preparation of 2-(2,4-difluoropheny1)-3-(5-fluoropyrimidin-4-y1)-1-(1H-
1,2,4-triazol-1-y1)butan-2-01
To a solution of 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H -1,2,4-
triazol-1-y1)buta.n-2-01 (obtained in step 1) in 200 ml methanol, added 10 g of 10%
palladium on carbon and 50 g of ammonium forrnate at 20-30 "C under nitrogen
atmosphere. The reaction mixture was then refluxed for 2 hrs. The reaction was
monitored by HPLC. After the completion of reaction, the solid catalyst was filtered out
and the solvent from the filtrate was distilled under vacuum. The residue obtained was
diluted with 300 ml of dichloromethane and stirred for about 30 minutes at 20-30 "C. The
layers were settled and separate and aqueous layer was extracted with 150 ml of
il)
dichloromethane. The two organic layers were combined and washed with water and then
distilled at atmospheric pressure. The residue was so obtained was taken up in 50 ml
acetone and stirred for about 20 minutes at 20-30 "C. The organic solvent was the
distilled under vacuum to obtain title compound as residue that was used as such in next
step.
Step 3: Preparation of (2R,3S) 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-y1)-1-
(1H-1,2,4-triazol-1-y1)butan-2-01c amphor sulfonate salt
To a solution of 2-(2,4-difluoropheny1)-3-(5-fluoropyrimidin-4-1)-1 - (1 H- 1,2,4-triazol- 1-
y1)butan-2-01 (obtained as residue in previous step) in 200 ml acetone and 100 ml of
methanol, added a solution of 73 g R-(-)-camphor sulphonic acid in 125 ml acetone and
75 ml methanol at 20-30 "C. The temperature of reaction mixture was raised to 45-50 "C
and stirred for about 30 minutes and then cooled to 20-30 "C. The reaction mixture was
then stirred further for about 10-12 hrs. The solid so obtained was filtered, washed with
acetone and dried to obtain the title compound.
Yield: 42%
HPLC Purity: 99.5%
Chiral purity: 100%
Step 4: Preparation of voriconazole
To a solution of 65 g of 2R,3 S 2-(2,4-difluoropheny1)-3-(5-fluoropyrimidin-4-y1)-1 - (1H -
1,2,4-triazol-1 -yl)butan-2-01 camphor sulfonate salt in 150 ml dichloromethane and 150
ml water, added about 17 ml liquor ammonia to adjust the pH to about 9.0 to 10.0. The
reaction mixture was then stirred for about 30 minutes. The layers were separated and
organic layer was washed with water. The solvent was distilled under vacuum and the
resulting residue was crystallized from isopropyl alcohol to obtain voriconazole.
Yield: 90%
HPLC Purity: 100%
Chiral purity: 100%
Recoverv of un-reacted 1-(2A-difluorophenvl)-2-(1H-l,2,4-triazol-l-vl)ethanone
A solution of residual DTE (solid material obtained in step l(b)) in 300 ml of isopropyl
alcohol was heated to a temperature of 65-7O0C, stirred for about 45 minutes and then
cooled to 35-40°C. To the resulting reaction mixture added 250 ml of isopropyl alcohol
hydrochloride over a period of time and reaction mixture is further cooled to 20-30°C and
stirred for 2-3 hrs. The solid so obtained was filtered; suck dried and was taken up in 100
ml toluene. To the reaction mixture, added 35 ml of aqueous ammonia to adjust pH to
9.0-10.0. The solid obtained is filtered, washed with toluene and dried to recover 86 g of
unreacted 1 -(2,4-difluoropheny1)-2-(1 H-1,2,4-triazol- 1 -yl)ethanone.

Claims:
1. A process for the preparation of voriconazole of Formula I comprising the steps
of,
(a) condensing 4-chloro-6-ethyl-5-fluoropyrimidine of Formula 11 Ad 1 -(2,4-
difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone of Formula I11 in presence of a
base and solvent to obtain a mixture of desired diastereomeric pair and undesired
diastereomeric pair of 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-
difluoropheny1)- 1 -(1 H- 1,2,4-triazol- 1 -yl)butan-2-01 of Formula IV;
Formula I1 Formula I11 Formula IV
(b) enriching the desired 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-
1 -(1 H- l,2,4-triazol- 1 -yl)butan-2-01 diastereomeric pair of Formula IV by treating
the residue from step (a) with an aromatic solvent and filtering off the undesired
diastereomeric pair along with unreacted 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-
triazol-1 -yl)ethanone of Formula 111;
(c) dechlorination of resulting enriched desired diastereomeric pair of 3-(6-chloro-5-
fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-l-(1 H- l,2,4-triazol- 1 -yl)butan-2-01
of Formula IV from step (b) using catalytic hydrogenation to provide 2-(2,4-
difluoropheny1)-3-(5-fluoropyrimidin-4-yl)1 - (1H - 1,2,4-triazol- 1- yl)butan-2-01 of
Formula V (racemic voriconazole);
F
Formula V
(d) reacting 2-(2,4-difluoropheny1)-3-(5-fluoropyrimidin-4-y1)1-- (1 H- 1,2,4-triazol-
1-y1)butan-2-01 of Formula V with R-(-)-camphor sulfonic acid in a solvent to
provide (2R,3S) 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-y1)- 1 -(1 H- 1,2,4-
triazol-1 -yl)butan-2-01 camphor sulfonate salt of Formula VI;
F
Formula VI
wherein CSA is R-(-)-camphor sulfonic acid and
(e) neutralizing the salt of step (d) with a base in a solvent to provide voriconazole.
2. The process according to claim 1, wherein the base used in step (a) is selected
from the group comprising of butyl lithium, lithium diisopropylamide,
magnesium diisopropylamide, sodium bis(trimethylsilyl)amide, potassium
bis(trimethylsilyl)amide, zinc diisopropyl amide,magnesium hexamethyl
disilazane sodium hydride and lithium hydride.
3. The process according to claim 1, wherein the solvent used in step (a) is selected
from the group comprising of diethyl ether, diisopropyl ether, methyl tertiarybutyl
ether, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane, hexanes,
heptane, cyclohexane, pentane and mixtures thereof.
4. The process according to claim 1, wherein the aromatic solvent used in step (b) is
selected from the group comprising of toluene, xylene and chlorobenzene.
5. The process according to claim 1, wherein the catalytic hydrogenation in step (c)
is carried out using hydrogen source selected from the group comprising of
hydrogen, ammonium formate and formic acid in the presence of metal catalyst
selected from the group comprising of palladium on carbon, palladium hydroxide
on carbon and platinum.
6. The process according to claim 1, wherein the solvent used in step (d) is selected
from the group comprising of methanol, ethanol, n-propanol, isopropanol, n0
6 JAN 20\1
-
butanol, isobutanol, tertiary butanol, acetone, methyl ethyl ketone, water and
mixtures thereof.
0
7. The process according to claim 1, wherein the base used in step (e) is selected F
from the group comprising of ammonia, sodium hydroxide, potassium hydroxide, (55r : 4- sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium
carbonate. F
8. The process of enriching the desired diastereomeric pair of 3-(6-chloro-5-
fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H - 1,2,4-triazol- 1- yl)butan-2-01
of Formula IV by treating the mixture of desired diastereomeric pair and
undesired diastereomeric pair of 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-
difluoropheny1)-1 -(1 H-1,2,4-triazol- 1 -yl)btan-2- of Formula IV with an
aromatic solvent and separating enriched desired diastereomeric pair.
9. The process according to claim 8, wherein the aromatic solvent is selected from
the group comprising of toluene, xylene and chlorobenzene.
10. A process for recovery of unreacted 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol-l -
y1)ethanone of Formula I11 comprising the steps of,
F
Formula I11
(i) treating a mixture of 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone and
undesired diastereomeric pair of 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-
difluoropheny1)- 1 -(1 H- 1,2,4-triazol- 1 -yl)btan-2- obtained from step (b) of
claim 1 with an acid in solvent to obtain salt of 1-(2,4-difluoropheny1)-2-(1H-
1,2,4-triazol- 1 -yl)ethanone and
(ii)neutralizing the salt of 1 -(2,4-difluoropheny1)-2-(1 H- 1,2,4-triazol- 1 -yl)ethanone
using a base to isolate 1 -(2,4-difluoropheny1)-2-(1 H-1,2,4-triazol-1 -yl)ethanone of
Formula 111.
11. The process according to claim 10, wherein the acid used in step (i) is selected
from the group comprising of organic and inorganic.
12. The process according to claim 11, wherein the organic acid is selected from the
group comprising of acetic acid, oxalic acid and benzoic acid.
13. The process according to claim 1 1, wherein the inorganic acid is selected from the
group comprising of hydrochloric acid, hydrobromic acid and hydroiodic acid.
14. The process according to claim 10, wherein the solvent used in step (i) is selected
from the group comprising of methanol, ethanol, n-propanol, isopropanol, nbutanol,
isobutanol, acetone, methyl ethyl ketone, methyl acetate, ethyl acetate,
water and mixtures thereof.
15. The process according to claim 10, wherein the base used in step (ii) is selected
from the group comprising of organic and inorganic.
16. The process according to claim 15, wherein the organic base is selected from the
group comprising of methylamine, ethylamine, triethylamine and diisopropylethyl
mine.
17. The process according to claim 15, wherein the inorganic base is selected from
the group comprising of sodium hydroxide, potassium hydroxide, sodium
bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and
ammonia.