FIELD OF THE INVENTION
The present invention provides a process for preparation of a compound of formula I, which is useful synthetic intermediate in pharmaceuticals and agrochemicals.

Formula I
wherein R1 represents C1-C3 alkyl group and R2 represents C1 alkyl group substituted with at least one fluorine atom.

BACKGROUND OF THE INVENTION
Organic compounds containing pyrazole ring are useful intermediates in pharmaceutical and agro industry. These compounds are key intermediates for preparing various fungicides such as penthiopyrad.
U.S. Patent Number 8,884,028 discloses process for preparation of N-methyl-3-substituted-pyrazole carboxylate involving the steps of condensation, enolate formation and cyclisation. The process is carried out in situ and occurs without isolation of the intermediates thus resulting in the formation of impurities and provides final pyrazole carboxylate in low yields.
U.S. Patent Number 7,863,460 discloses a process for preparation of N-substituted-3-fluoroalkyl-pyrazole-4-carboxylate by a reaction of 2-alkoxymethylenefluoroacylacetate and hydrazine in the presence of a base and water. The process require cost of intensive extraction step for isolation of N-substituted-3-fluoroalkyl-pyrazole-4-carboxylate.
Thus, there is an urgent need in the art to develop an economical, yield selective, safe and robust process for preparation of pyrazole derivatives.

OBJECT OF THE INVENTION
The main object of the present invention is to provide a simple, selective and industrially applicable and economical process for the preparation of compound of formula I.

Formula I
wherein R1 represents C1-C3 alkyl group and R2 represents C1 alkyl group substituted with at least one fluorine atom.

SUMMARY OF THE INVENTION
The present invention provides a process for preparation of a compound of formula I,

Formula I
wherein R1 represents C1-C3 alkyl group and R2 represents C1 alkyl group substituted with at least one fluorine atom,
comprising the steps of:
a) providing a reaction mixture 1 containing a compound of formula VI and a base;

Formula VI
b) adding a compound of formula V to the reaction mixture 1 to obtain reaction mixture 2;

Formula V
wherein R2 represents C1 alkyl group substituted with at least one fluorine atom and R3 represents C1-C3 alkyl group.
c) acidifying the reaction mixture 2 and isolating a compound of formula IV;

Formula IV
wherein R2 and R3 are as defined above,
d) providing a mixture of acetic anhydride and a compound of formula III to obtain a reaction mixture 3;

Formula III
e) adding the compound of formula IV to the reaction mixture 3 to isolate a compound of formula II;

Formula II
wherein R2 and R3 are as defined above,
f) providing monoalkylhydrazine in solvent to obtain reaction mixture 4;
g) adding the compound of formula II to reaction mixture 4 to obtain reaction mixture 5;
h) adding aqueous alkali metal hydroxide solution to reaction mixture 5 to obtain alkali metal salt of compound of formula II; and
i) adding an acid to the alkali metal salt of compound of formula II to isolate the compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION:
As used herein, “base” refers to metal alkoxides, metal hydrides, metal hydroxides, metal carbonates, or amines. Metal alkoxides are selected from a group consisting of sodium ethoxide, sodium methoxide, potassium ethoxide, potassium methoxide or the like. Metal hydroxide are selected from sodium hydroxide, potassium hydroxide, lithium hydroxide or the like. Metal hydrides are selected from a group consisting of sodium hydride, potassium hydride or the like. Metal carbonates are selected from a group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or the like. Amine are selected from diethylamine, triethylamine or the like.
As used herein, the term “acidifying” refers to the step of adding acid to attain the pH of about 2 to 2.5.
As used herein, “acid” refers to inorganic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, nitric acid or an organic acid such as formic acid, acetic acid, propionic acid, citric acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid or the like.
As used herein, the term “isolate” refers to a method of chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or crystallization or a combination thereof.
As used herein, the term “monoalkylhydrazine” refers to methyl hydrazine, ethyl hydrazine and aqueous solution thereof. The preferred monosubstituted hydrazine for the present invention is 35% methyl hydrazine aqueous solution. The molar ratio of monosubstituted hydrazine to compound of formula II may be selected in range 1-1.1 and more preferably in range 1.02-1.05.
As used herein, the solvent is selected from a group consisting of water, ethanol, xylene, toluene, ethanol, isopropanol, methanol, tetrahydrofuran, propanol and acetonitrile or mixture thereof.
The compound of formula VI may be selected from a group consisting of ethyl acetate, propyl acetate, methyl acetate, isopropyl acetate or the like.
The compound of formula V may be selected from a group consisting of methylfluoroacetate, methyldifluoroacetate, methyltrifluoroacetate, ethylfluoroacetate, ethyldifluoroacetate, ethyltrifluoroacetate and propylfluoroacetate.
The addition of compound of formula V is performed in reaction mixture of compound of formula VI and base at a temperature in the range of 12-15°C within a period of 3 hours. After addition the reaction mass is heated to 60- 65°C in 1 hour and maintained at this temperature for another 1-2 hour. The molar ratio of compound of formula VI to formula V may be selected in the range 3-10 and preferably between 5-7 and more preferably selected in the 5. The most preferred base is sodium ethoxide in the range 1-1.5 equivalent and preferably selected in the range 1.1-1.2 equivalent. The metal alkoxide are sensitive to moisture present in atmosphere and degradation takes place on long time exposure and thus are added in a single lot to prevent such degradation.
The compound of formula IV may be selected from a group consisting of ethyl-4,4,4-trifluoroacetoacetate, methyl-4,4,4-trifluoroacetoacetate, ethyl-4,4-difluoroacetoacetate, methyl-4,4-difluoroacetoacetate, propyl-4,4-difluoroacetoacetate, ethyl-4-fluoroacetoacetate, methyl-4-fluoroacetoacetate. The compound of formula IV is isolated in 99% purity.
The compound of formula III may be selected from trimethylorthoformate, triethylorthoformate and tripropylorthoformate and triisopropylorthoformate. The reaction of acetic anhydride with a compound of formula III is carried out at 100-105°C. The molar ratio of acetic anhydride to compound of formula IV is selected from a range of 3-4 and preferably 3.3-3.5. The molar ratio of compound of formula III to formula IV is selected in a range 2-2.5 and preferably between 2.3-2.4. The acetic anhydride may be replaced by ethanol and methanol.
The compound of formula II may be selected from a group consisting of ethyl-2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate, ethyl-2-(ethoxymethylidene)-4,4-difluoro-3-oxobutanoate, ethyl-2-(ethoxymethylidene)-4-fluoro-3-oxobutanoate, methyl-2-(methoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate, methyl-2-(methoxymethylidene)-4,4-difluoro-3-oxobutanoate, propyl-2-(propoxymethylidene)-4,4-difluoro-3-oxobutanoate, propyl-2-(propoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate and methyl-2-(methoxymethylidene)-4-trifluoro-3-oxobutanoate. The compound of formula II may be isolated and purified by any method selected from concentration, distillation, solvent extraction, filtration, recrystallization and combination thereof. The preferred method of isolation and purification of compound of formula II are concentration and distillation. The compound of formula II is isolated of purity 94%.
The reaction of compound of formula II and reaction mixture of aqueous monoalkylhydrazine in a solvent is carried out a temperature of 10-15°C.
In preferred embodiment, o-xylene and 35% methyl hydrazine aqueous solution is cooled to 5°C in a reactor. A solution of ethyl-2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate in o-xylene is added to the solution at 5°C in 1-2 hours. After 15-30 minutes, reaction mass layer separated and top o-xylene layer is added to a solution of xylene and water in another flask. The addition of 30% aq. sodium hydroxide solution is performed and heated to 65°C. Reaction mass was refluxed for 4-5 hours at 65°C. After refluxing, the organic and aqueous layer are separated. The aqueous layer is acidified using acid.
In an embodiment of the first aspect of the present invention, the reaction mixture 1 is maintained at a temperature of 0°C to 15°C under inert atmosphere of nitrogen or argon to prevent the decomposition of reactant in presence of base at high temperature.
In another embodiment of the present invention, all the intermediates are isolated before carrying out the next step.
The compound of formula I is isolated by any method given in the art, for example extraction, chemical separation, filtration, recrystallization, decantation, distillation and evaporation or a combination thereof.
The completion of the reaction may be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), gas chromatography (GC), liquid chromatography (LC) and alike.
In a specific embodiment, the present invention provides a process for preparation of 3-(trifluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid, comprising the steps of:
a) providing a reaction mixture 1 containing ethylacetate and metal alkoxide;
b) adding ethyl trifluoroacetate to the reaction mixture 1 to obtain reaction mixture 2;
c) acidifying reaction mixture 2 using anhydrous hydrochloric acid to isolate ethyl 4,4,4-trifluoroacetoacetate;
d) providing a mixture of acetic anhydride and triethylorthoformate to obtain reaction mixture 3;
e) adding ethyl 4,4,4-trifluoroacetoacetate to reaction mixture 3 to isolate ethyl-2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate;
f) providing monomethylhydrazine in o-xylene to obtain reaction mixture 4;
g) adding ethyl-2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate to reaction mixture 4 at 0-20°C to obtain reaction mixture 5;
h) adding aqueous solution of sodium hydroxide to reaction mixture 5 and separating the aqueous layer containing sodium salt of 3-(trifluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid; and
i) adding aqueous hydrochloric acid to the aqueous layer to isolate 3-(trifluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid.
In another embodiment of the present invention, the reaction mixture 1 containing ethylacetate and metal alkoxide is cooled to 0-15°C.
Trifluoroethylacetate used for the preparation of ethytrifluoroacetoacetate may be prepared by any methods given in the art or can be obtained commercially. CN106699568 discloses preparation of trifluoroacetate using trifluoroacetic acid and ethanol in presence of sulphuric acid. Ethyl acetate is obtained commercially for the present invention.
Unless stated to the contrary, any of the words “comprising”, “comprises” and includes mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.

EXAMPLE
Example 1: Preparation of 3-(trifluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid
Preparation and Isolation of Ethyl-4, 4, 4-trifluoroacetoacetate:
Sodium ethoxide (1.15 mol eq.) was added in one lot into ethyl acetate (5.0 mol eq.) and the mixture was cooled to 10°C. Ethyl trifluoroacetate (1.0 mol eq.) was slowly added to the reaction mixture at a temperature of 12° to 15°C over a period of 2 hours. After the addition, the temperature of the mass was heated to 65°C in 1 hour and maintained for 2 hours at this temperature. The progress of reaction was monitored by gas chromatography (GC) analysis. The entire reaction was performed under nitrogen atmosphere. After completion of the reaction, the reaction mass was cooled to 15°C and anhydrous hydrogen chloride (1.2 mol eq.) was purged for a period of 45 minutes while maintaining the temperature between 15°-25°C. The reaction mixture turned acidic (pH ~ 2). Acidified reaction mass was concentrated to remove excess acidity followed by filtration. Filtered solid was washed with ethyl acetate. All combined filtrates were concentrated to obtain crude ethyl-4, 4, 4-trifluoroacetoacetate (95%). The crude product was distilled to obtain pure Ethyl-4, 4, 4-trifluoroacetoacetate of purity 99%.
Yield: 90%
Purity (By GC): 99%

Preparation and Isolation of Ethyl-2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate:
Triethylorthoformate (348g) and acetic anhydride (354g) were charged in a reactor. The reaction mixture was heated 100°C and ethyl-4,4,4-trifluoroacetoacetate (216g) was added dropwise in an hour. Reaction mass was maintained for 3 hours at 105°C under stirring. On completion of the reaction, the temperature was raised to 110°C and concentrated under vacuum at 760mmHg up to 12mmHg to isolate Ethyl-2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate.
Yield: 85%
Purity (By GC): 94%

Preparation and Isolation of 3-(trifluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid:
O-xylene (300g) and methyl hydrazine (118g, 35%, aqueous solution) were charged in the reactor equipped with mechanical stirrer and cooled to 5°C. A solution of Ethyl-2-(ethoxymethylidene)-4,4,4-trifluoro-3-oxobutanoate (224g) in o-xylene (210g) was added dropwise to the reactor for 1.5 hours maintaining temperature below 10°C. The o-xylene layer was separated and charged into water (138g) followed by addition of 30% aqueous sodium hydroxide solution (203g). Reaction mass was heated to 65°C and maintained for 4 hours. After reaction completed, water (500g) was added to the reaction mass and layers were separated. Aqueous layer was neutralized with hydrochloric acid solution (20%) at 80°C in 15 minutes and maintained at same temperature for 15 minutes. The reaction mixture was allowed to cool to room temperature and further cooled to 15°C and filtered. The product was washed with water to reach isomer ratio below 1.0%. The filtered solid was recrystallized using water (2240g) at 103°C, cooled and filtered at 20°C. Filtered solid was dried at 70°C under 2-5mmHg vacuum for about 4-6 hours.
Yield: 57%
Purity (By HPLC): 99%

WE CLAIM:

1. A process for preparation of a compound of formula I,

Formula I
wherein R1 represents C1-C3 alkyl group and R2 represents C1 alkyl group substituted with at least one fluorine atom,
comprising the steps of:
a) providing a reaction mixture 1 containing a compound of formula VI and a base;

Formula VI
b) adding a compound of formula V to the reaction mixture 1 to obtain reaction mixture 2;

Formula V
wherein R2 represents C1 alkyl group substituted with at least one fluorine atom and R3 represents C1-C3 alkyl group.
c) acidifying the reaction mixture 2 using an acid and isolating a compound of formula IV;

Formula IV
wherein R2 and R3 are as defined above,
d) providing a mixture of acetic anhydride and a compound of formula III to obtain a reaction mixture 3;

Formula III
e) adding the compound of formula IV to the reaction mixture 3 to isolate a compound of formula II;

Formula II
wherein R2 and R3 are as defined above,
f) providing monoalkylhydrazine in a solvent to obtain reaction mixture 4;
g) adding the compound of formula II to reaction mixture 4 to obtain reaction mixture 5;
h) adding aqueous alkali metal hydroxide solution to reaction mixture 5 to obtain alkali metal salt of compound of formula II; and
i) adding an acid to the alkali metal salt of compound of formula II to isolate the compound of formula I.
2. The process as claimed in claim 1, wherein the base used in step a) is selected from a group consisting of metal alkoxides, metal hydroxides, metal hydrides, metal carbonates and amines or a mixture thereof.
3. The process as claimed in claim 2, wherein the metal alkoxide is selected from a group consisting of sodium ethoxide, sodium methoxide, potassium ethoxide, potassium methoxide or a mixture thereof; metal hydroxide is selected from a group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide or a mixture thereof; metal hydride is selected from a group consisting of sodium hydride, potassium hydride or a mixture thereof; metal carbonate is selected from a group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or a mixture thereof; and amine is selected from a group consisting of diethylamine, triethylamine or a mixture thereof.
4. The process as claimed in claim 1, wherein the acid used in step c) and step i) is an inorganic acid selected from a group consisting of hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, nitric acid or an organic acid selected from a group consisting of formic acid, acetic acid, propionic acid, citric acid, oxalic acid, methanesulfonic acid and p-toluenesulfonic acid or a mixture thereof.

5. The process as claimed in claim 1, wherein the solvent used in step f) is selected from a group consisting of water, ethanol, xylene, toluene, ethanol, isopropanol, methanol, tetrahydrofuran, propanol and acetonitrile or a mixture thereof.

6. The process as claimed in claim 1, wherein the alkali metal hydroxide used in step h) is selected from a group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide or a mixture thereof.