PROCESS FOR THE PREPARATION OF PURE HYDROXY PYRAZOLES
Field of the Invention
The present invention provides a process for the preparation of pure hydroxy pyrazoles of
Formula I.
Background of the invention
The present invention provides a process for the preparation of pure hydroxy pyrazoles of
Formula I which is an important intermediate for production of pharmaceutical and
agrochemical products.
N
N
F
F
OH
H3C
F
Formula I
The Japanese Patent Application No. 2007/031342 describes a process for the preparation of
5-hydroxy-1-methyl-3-trifluoromethyl pyrazole by condensation of 4,4,4-trifluoroethyl
acetoacetate and methyl hydrazine in the presence of acetic acid at 80oC. It has been observed
by the present inventors that if the reaction is carried out at 80oC the reaction completion time
is far long time thus resulting in impurity formation and in turn provides poor yield.
While working on present invention, the present inventors have found that when 4,4,4-
trifluoroethyl acetoacetate and methyl hydrazine in the presence of acid at temperature of
90oC or above leads to faster reaction completion, no impurity formation and increased yield.
Summary of the Invention
The present invention provides a process for the preparation of pure hydroxy pyrazoles of
Formula I, comprising,
a) reacting a compound of Formula II with a compound of Formula III in the presence of
an acid at a temperature of 90oC or above to obtain hydroxy pyrazoles of Formula I,
and
3
F
O CH3
F
F
O O
H2N NH
CH3
Formula II Formula III
b) isolating the hydroxy pyrazoles of Formula I from step a).
N
N
F
F
OH
H3C
F
Formula I
Detailed description of the Invention
In an aspect, the present invention provides a process for the preparation of pure hydroxy
pyrazoles of Formula I, comprising,
a) reacting a compound of Formula II with a compound of Formula III in the presence of
an acid at a temperature of 90oC or above to obtain hydroxy pyrazoles of Formula I,
and
F
O CH3
F
F
O O
H2N NH
CH3
Formula II Formula III
b) isolating the hydroxy pyrazoles of Formula I from step a).
4
N
N
F
F
OH
H3C
F
Formula I
In another aspect, the present invention provides a process for the preparation of pure
hydroxy pyrazoles of Formula I having purity greater than 99%, comprising,
a) reacting a compound of Formula II with a compound of Formula III in the presence of
an acid at a temperature of 90oC or above to obtain a reaction mixture,
F
O CH3
F
F
O O
H2N NH
CH3
Formula II Formula III
b) contacting the reaction mixture with alcohol solvent and activated carbon to obtain
hydroxy pyrazoles of Formula I, and
c) isolating the hydroxy pyrazoles of Formula I having purity greater than 99% from
step b).
N
N
F
F
OH
H3C
F
Formula I
The compounds of Formula II may be prepared by any method known in the art, for
example JP 2007/031342. The compound of Formula III may be obtained from
commercial source.
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The step a) may be carried out for about 10 minutes to about 8 hours, for example, for
about 30 minutes to about 6 hours. The reaction mixture of step a) may be stirred to aid
the reaction.
The alcohol solvent is selected from a group consisting of methanol, ethanol, n-propanol,
n-butanol, tertiary-butanol and n-pentanol or mixture thereof.
In yet another aspect, the present invention provides a process for the preparation of pure
hydroxy pyrazoles of Formula I having purity greater than 99%, comprising,
a) treating hydroxy pyrazoles of Formula I having purity of 91% or less with a mixture
of water and ethanol to obtain hydroxy pyrazoles of Formula I, and,
N
N
F
F
OH
H3C
F
Formula I
b) isolating the pure hydroxy pyrazoles of Formula I having purity greater than 99%
from step a).
The treatment of hydroxy pyrazoles of Formula I having purity of 91% or less with the
mixture of water and ethanol; wherein the mixture of hydroxy pyrazoles: water: ethanol is in
the ratio of 1:35:5
The pure hydroxy pyrazoles of Formula I is isolated by filtration, evaporation, sublimation,
concentration, crystallization and re-crystallization or mixture thereof.
The pure hydroxy pyrazoles of Formula I obtained by present invention has purity greater
than 98%, preferably greater than 99%, more preferably greater than 99.5%.
While the present invention has been described in terms of its specific embodiments, certain
modifications and equivalents will be apparent to those skilled in the art and are intended to
be included within the scope of the present invention.
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Examples
Example 1: Process for the preparation of pure 5-hydroxy-1-methyl-3-trifluoromethyl pyrazole
A 1-lit 4-necked RBF was fitted with a mechanical stirrer, an addition funnel, thermometer sensor and a double walled condenser. The ethyl 4,4,4-trifluoroacetoacetate (278g, 1.43 mol) and formic acid (66g, 1.43 mol) were added into the flask and the temperature of the mass was cooled to 0°C. Monomethyl hydrazine (38%, 190g, 1.57 mol) was slowly added to the mixture with constant stirring.The temperature of the mixture was maintained at 0°-12°C over a period of 1 hour. After the addition of monomethyl hydrazine, the temperature of the mass was raised to 90°C and the temperature was maintained for 3 hours. The completion of the reaction is monitored by gas chromatography. The solvents were removed by boil-off to obtain crude reaction mass.The ice cold water (280 mL) was added to the crude mass and filtered to get title compound.
Purity (%): 91
The title compound with purity 91% was treated with mixture of water:ethanol(1120 mL:560 mL) and heated to dissolve at 65oC. It was then cooled slowly to 10oC and maintained at this temperature for 30 minutes. The crystals were filtered and dried to obtain title compound.
Yield (%): 72
Purity (%): 99.9
Example 2: Process for the preparation of pure 5-hydroxy-1-methyl-3-trifluoromethyl pyrazole
A 1-lit 4-necked round bottom flask was fitted with a mechanical stirrer, an addition funnel, thermometer sensor and a double walled condenser. The ethyl 4,4,4-trifluoroacetoacetate (220 g, 1.09 mol) and formic acid (50 g, 1.03 mol) were added into the flask and the temperature of the mass was cooled to 0°C. The monomethyl hydrazine (38%, 141 g, 1.18mol) was slowly added to the mixture with constant stirring. The temperature of the mixture was maintained at 0°-15°C over a period of 40 minutes. After the addition of monomethyl hydrazine, the temperature of the mass was raised to 90°C and the temperature
7
was maintained for 2 hours to 3 hours. The completion of the reaction by monitored by gas chromatography. After completion, the reaction mixture was diluted with ethanol (350 mL) at 40oC to obtain clear reaction mass. The clear reaction mass was stirred for 10 minutes with activated carbon (10 g) followed by filtration through hyflo bed (20 g) at 35oC - 40oC. The distilled water (700 g) was added to the reaction mass and heated to 60oC to obtain clear solution. The reaction mass was slowly cooled to 10oC and maintained at this temperature for 30 minutes, filtered and dried under vacuum (5-10 mm in Hg) at 55oC-60oC to obtain crystalline title compound.
Yield (%):73.5
Purity (%): 99.85

We claim:
1. A process for the preparation of pure hydroxy pyrazoles of Formula I, comprising,
a) reacting a compound of Formula II with a compound of Formula III in the presence of
an acid at a temperature of 90oC or above to obtain hydroxy pyrazoles of Formula I,
and
F
O CH3
F
F
O O
H2N NH
CH3
Formula II Formula III
b) isolating the hydroxy pyrazoles of Formula I from step a).
N
N
F
F
OH
H3C
F
Formula I
2. A process for the preparation of pure hydroxy pyrazoles of Formula I having purity
greater than 99%, comprising,
a) reacting a compound of Formula II with a compound of Formula III in the presence of
an acid at a temperature of 90oC or above to obtain a reaction mixture,
F
O CH3
F
F
O O
H2N NH
CH3
Formula II Formula III
b) contacting the reaction mixture with alcohol solvent and activated carbon to obtain
hydroxy pyrazoles of Formula I, and
9
c) isolating the hydroxy pyrazoles of Formula I having purity greater than 99% from
step b).
N
N
F
F
OH
H3C
F
Formula I
3. The process as claimed in claims 1 or 2, wherein the step a) is carried out for about 10
minutes to about 8 hours.
4. The process as claimed in claims 1 or 2, wherein the alcohol solvent is selected from a
group consisting of methanol, ethanol, n-propanol, n-butanol, tertiary-butanol and npentanol
or mixture thereof.
5. A process for the preparation of pure hydroxy pyrazoles of Formula I having purity
greater than 99%, comprising,
a) treating hydroxy pyrazoles of Formula I having purity of 91% or less with a mixture
of water and ethanol to obtain hydroxy pyrazoles of Formula I, and,
N
N
F
F
OH
H3C
F
Formula I
b) isolating the pure hydroxy pyrazoles of Formula I having purity greater than 99%
from step a).
6. The process as claimed in claims 5, wherein the treatment of hydroxy pyrazoles of
Formula I having purity of 91% or less with the mixture of water and ethanol has the
mixture of hydroxy pyrazoles: water: ethanol is in the ratio of 1:35:5.
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7. The process as claimed in claims 1, 2 or 5, wherein the pure hydroxy pyrazoles of Formula I is isolated by filtration, evaporation, sublimation, concentration, crystallization and re-crystallization or mixture thereof.
8. The process as claimed in claims 1, 2 or 5, wherein the pure hydroxy pyrazoles of Formula I obtained by present invention has purity greater than 98%.