Field of the invention
The present invention provides a process for the preparation of hydroxy pyrazoles.

Background of the invention
The hydroxy pyrazoles serve as important drug and agrochemical intermediates. Especially, 1-alkyl-5-hydroxy pyrazoles of Formula I are useful as intermediates for various weedicides.

Formula I
wherein R1 is selected from C1-5 alkyl group.

The Japan Patent No. 4,641,667 describes a process for the preparation of 1-methyl-5-hydroxy pyrazole by reacting ethoxymethylene malonic acid diethylester with aqueous ammonia followed by methyl hydrazine. The reaction mixture is stirred at 60oC for 4 hours and thereafter cooled to 20oC. The hydrochloric acid is added to the mixture to yield 1-methyl-5-hydroxy pyrazole-4-carboxylic acid ethyl ester. The 1-methyl-5-hydroxy pyrazole-4-carboxylic acid ethyl ester is treated with 49% aqueous sodium hydroxide at 90oC for 2 hours followed by concentrated hydrochloric acid to yield 1-methyl-5-hydroxy pyrazole.

The present inventors surprisingly observed that the use of alkyl amine results in high purity of 5-Hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester and comparatively less quantity of undesirable isomeric 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester is obtained. Further, the diethyl amine can be easily recovered and recycled back in the reaction, thus minimizing the effluent load on industrial scale.

Summary of the invention
The present invention provides an improved process for the preparation of compound of Formula I:

Formula I
wherein R1 is selected from C1-5 alkyl group.
which comprises:
a) contacting a compound of Formula II with a compound of Formula III to obtain a compound of Formula IV;

Formula II Formula III

Formula IV
b) contacting the compound of Formula IV with a compound of Formula VI to obtain a compound of Formula V;

Formula V Formula VI
c) contacting the compound of Formula V with a base or an acid to obtain the compound of Formula I; and
d) isolating the compound of Formula I obtained from step c).

Detailed description of the invention
The present invention provides an improved process for the preparation of compound of Formula I:

Formula I
wherein R1 is selected from C1-5 alkyl group.
which comprises:
a) contacting a compound of Formula II with a compound of Formula III to obtain a compound of Formula IV;

Formula II Formula III

Formula IV
b) contacting the compound of Formula IV with a compound of Formula VI to obtain a compound of Formula V;

Formula V Formula VI
c) contacting the compound of Formula V with a base or an acid to obtain the compound of Formula I; and
d) isolating the compound of Formula I obtained from step c).

The compound of Formula II may be prepared by any method known in the art.
The step a) may be carried out at temperature in the range of 10oC to about 100oC for about 0.5 hour to about 6 hours. The step b) may be carried out at temperature in the range of - 10oC to about 100oC for about 0.5 hour to about 10 hours. The step b) may be carried out in presence or absence of a solvent. The solvent may be selected from the group consisting of water, alcohol solvent, tetrahydrofuran or dioxane.

The alcohol solvent may be selected from the group consisting of methanol, ethanol, n-propanol, n-butanol, iso-butanol and n-pentanol or mixture thereof.

The step c) may be carried out at temperature in the range of 20oC to 120oC for 0.5 hour to 10 hours. The step c) takes place in the presence of the base or acid. The base may be an inorganic base, for example, alkali metal hydroxides. The alkali metal hydroxides may be selected from group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide and cesium hydroxide or mixture thereof. The acid may be an inorganic acid. The inorganic acid may be selected from group consisting of hydrogen fluoride, hydrogen chloride, hydrogen bromide and sulfuric acid or mixture thereof.

The compound of Formula I is isolated by any method known in the art, for example, acid-base neutralization, distillation, evaporation, crystallization, re-crystallization, column chromatography and filtration or mixture thereof.

Example
Process for the preparation of 1-methyl-5-hydroxy pyrazole
Diethyl ethoxymethylenemalonate (50 g) was taken in the round bottom flask and diethylamine (25 g) was added dropwise. The mixture was stirred and the temperature of the reaction mixture was maintained in the range of 25°C-30°C. The reaction was stirred for 1.0 hour and aqueous solution of monomethyl hydrazine (33.5gm, 35%w/w) was added to the mixture at 25°C-30°C. The progress of reaction was monitored with HPLC. After completion, the reaction mass was acidified using concentrated hydrochloric acid and filtered to obtain 5-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester.
Isomeric 3-hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (% yield): 0.1%

5-Hydroxy-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester was taken in the 250ml round bottom flask and concentrated hydrochloric acid (34 g) was added. The mixture was stirred in the temperature range of 95°C -100°C until completion. The progress of reaction was monitored using HPLC. After completion of reaction, the reaction mass was neutralized using conc. sodium hydroxide solution. The ethanol and water were swiped off with dioxane followed by filtration to obtain the title compound.
Yield: 19.7 g

WE CLAIM:
1) A process for the preparation of compound of Formula I:

Formula I
wherein R1 is selected from C1-5 alkyl group.
which comprises:
a) contacting a compound of Formula II with a compound of Formula III to obtain a compound of Formula IV;

Formula II Formula III

Formula IV
b) contacting the compound of Formula IV with a compound of Formula VI to obtain a compound of Formula V;

Formula V Formula VI
c) contacting the compound of Formula V with a base or an acid to obtain the compound of Formula I; and
d) isolating the compound of Formula I obtained from step c).
2) The process as claimed in claim 1, wherein the step a) is carried out at temperature in the range of 10oC to 100oC for 0.5 hour to 6 hours.
3) The process as claimed in claim 1, wherein the step b) is carried out at temperature in the range of - 10oC to 100oC for 0.5 hour to 10 hours.
4) The process as claimed in claim 1, wherein the step c) is carried out at temperature in the range of 20oC to 120oC for 0.5 hour to 10 hours.
5) The process as claimed in claim 1, wherein the step b) is carried out in presence or absence of a solvent.
6) The process as claimed in claim 5, wherein the solvent is selected from the group consisting of water, alcohol, tetrahydrofuran or dioxane.
7) The process as claimed in claim 6, wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, n-propanol, n-butanol, iso-butanol and n-pentanol or mixture thereof.
8) The process as claimed in claim 1, wherein the step c) is carried out in presence of an acid or a base.
9) The process as claimed in claim 8, wherein the acid is an inorganic acid selected from the group consisting of hydrogen fluoride, hydrogen chloride, hydrogen bromide and sulfuric acid or a mixture thereof.
10) The process as claimed in claim 8, wherein the base is an inorganic base selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide and cesium hydroxide or mixture thereof.