DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]

AN IMPROVED ONE-POT PRECESS FOR THE PREPARATION OF 5-METHYL-3-(TRIFLUOROMETHYL)-1H-PYRAZOLE

PIRAMAL PHARMA LIMITED, a company incorporated under the Companies Act, 2013, of Ground Floor, Piramal Ananta, Agastya Corporate Park, Kamani Junction, LBS Marg, Kurla West, Mumbai 400070, State of Maharashtra, India

The following specification particularly describes the nature of this invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to an improved one-pot process for the preparation of 5-methyl-3-(trifluoromethyl)-1H-pyrazole, an oxathiapiprolin intermediate of formula (1).

BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.

Oxathiapiprolin (OXPT) is a new piperidinyl thiazole isoxazoline fungicide discovered and developed by DuPont. Oxathiapiprolin has an extremely high activity against a range of plant pathogenic oomycetes, including Phytophthora nicotianae, Pseudoperonospora cubensis, P. capsici, P. infestans, Peronospora belbahrii, P. cinnamomi, P. parasitica, and P. citrophthora.

Oxathiapiprolin is sold under the trade names Orondis, Zorvec, and Segovis.

The published article European journal of Medicinal Chemistry (2018), 152, 307-317 describes the preparation of 1,1,1-trifluoropentane-2,4-dione (KSM of 5-methyl-3-(trifluoromethyl)-1H-pyrazole) which involves reaction of ethyl 2,2,2-trifluoroacetate with acetone in presence of the base potassium tert-butoxide in Toluene.

The PCT application WO2007071900A1 of Syngenta discloses the preparation of 5-methyl-3-(trifluoromethyl)-1H-pyrazole. The final product viz. 5-methyl-3-(trifluoromethyl)-1H-pyrazole is by isolation by distillation of solvent.

Another PCT application WO2000018851A1 of Isis Innovation Limited discloses the preparation of 5-Methyl-3-(trifluoromethyl)-1H-pyrazole, which is performed in methanol solvent. The solvent is removed by distillation at 200 °C and purification is done by using diethyl ether solvent.

The above synthetic Schemes for the preparation of 5-methyl-3-(trifluoromethyl)-1H-pyrazole have some draw backs, which limits its scope on an industrial scale and some of the drawbacks are listed below:
a) Use of potassium tert-butoxide as a base is not economically feasible at plant level;
b) Use of high volumes of reaction solvent such as methanol is not advisable both in terms of cost and effluent load;
c) Use of diethyl ether for purification is very cumbersome to handle as it is highly volatile and unsafe at production plant;
d) Product isolation by distillation of solvent is not viable at plant.

Hence, there is a continuous need to develop simple, commercially advantageous and industrially viable process for the preparation of 5-methyl-3-(trifluoromethyl)-1H-pyrazole that reduces the number of reaction steps and in turn increases overall yield of the final product.

The present invention offers an improved, efficient, economic, and production friendly one-pot process for preparation of 5-methyl-3-(trifluoromethyl)-1H-pyrazole.
OBJECTS OF THE INVENTION
An object of the invention is to provide one-pot process for the preparation of 5-methyl-3-(trifluoromethyl)-1H-pyrazole, an oxathiapiprolin intermediate of formula (1).
Another object of the invention is to provide an improved process for the preparation of pure 5-methyl-3-(trifluoromethyl)-1H-pyrazole (1) with good yield and quality.
SUMMARY OF THE INVENTION
The problem addressed by the present invention is therefore that of providing a better process for preparing 5-methyl-3-(trifluoromethyl)-1H-pyrazole (1), which permits to avoid above reported with reference to the known prior art.
In one aspect, provided herein is an efficient, industrially advantageous and environmentally friendly one-pot process for the preparation of 5-methyl-3-(trifluoromethyl)-1H-pyrazole of formula 1, in high yield and high purity. The process disclosed herein avoids the tedious procedure of the prior art processes, thereby resolving the problems associated with the processes described in the prior art, which is more convenient to operate on a commercial scale.
DETAILED DESCRIPTION OF THE INVENTION
Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only and is not intended to limit the scope of the present invention.
Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials similar or equivalent to those described herein and can be used in the practice or testing of the present invention. The preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "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. Further the terms disclosed embodiments, which are merely exemplary methods of the invention and which may be embodied in various forms.

In one of the embodiments, the present invention provides an improved one-pot process for the preparation of 5-methyl-3-(trifluoromethyl)-1H-pyrazole (1),

comprising;
(a) reacting ethyl 2,2,2-trifluoro acetate (2) with acetone in a solvent and in presence of a base to give 1,1,1-trifluoropentane-2,4-dione (3), which may or may not be isolated; and

(b) reacting 1,1,1-trifluoropentane-2,4-dione (3) with hydrazine hydrate in a solvent and in presence of acid to give 5-Methyl-3-(trifluoromethyl)-1H-pyrazole (1).

The present invention also relates to the process, wherein step (b) can be carried out without isolating the compound of formula (3).
The solvent used in step (a) and step (b) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected form acetone, propanone, methyl ethyl ketone or methyl isobutyl ketone; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water or a mixture thereof.
The base used in step (a) is an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate; an alkali metal bicarbonate selected from sodium bicarbonate or potassium bicarbonate; an alkali metal alkoxides selected from sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or an organic amines selected from triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

The acid used in step (b) is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, hydrobromic acid in acetic acid, boron trifluride in ether.

The whole synthetic scheme of preparation of 5-methyl-3-(trifluoromethyl)-1H-pyrazole (1) according to the present invention can be represented as below:

According to another specific aspect of the present invention relates to an improved one-pot process for the preparation of 5-methyl-3-(trifluoromethyl)-1H-pyrazole (1),

comprising;
(a) reacting ethyl 2,2,2-trifluoro acetate (2) with acetone in toluene and in presence of sodium methoxide to give 1,1,1-trifluoropentane-2,4-dione (3), which may or may not be isolated; and

(b) reacting 1,1,1-trifluoropentane-2,4-dione (3) with hydrazine hydrate in methanol and in presence of hydrochloric acid to give 5-Methyl-3-(trifluoromethyl)-1H-pyrazole (1).

Thus, the present invention has several advantages over previous methods reported in the literature which include:
(i) the cheaper base is used in the reaction which makes the process economical;
(ii) in-situ process time cycle of isolation/crystallization/distillation/purification of stage-a;
(iii) desired volumes of reaction solvent leads to generation of low volumes of effluent and thereby contributes to greener aspects of the reaction as well as cost reduction;
(iv) final product isolation in water leads to safe environment for handling;
(v) the overall process involves a reduced number of process steps and less expensive reagents, thereby making the process cost effective;
(vi) robustness of the developed process from plant operations perspective.

Thereby, the practicability of the reaction is greatly enhanced both at the laboratory scale and the industrial scale. The present invention results into purity of 95 % by GC, thereby, making the process ef?cient, economic and industrially viable.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. 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.
EXAMPLES
Example 1
Preparation of 1,1,1-trifluoropentane-2,4-dione formula (3)
Toluene (300 ml), sodium methoxide (45.6 g) were charged in a round bottom flask at room temperature under nitrogen atmosphere and reaction mixture was cooled to 0 to -10 °C under nitrogen atmosphere. Ethyl-2,2,2-trifluoro acetate (100 g) was slowly added into the reaction mixture at 0 to -10 °C under nitrogen atmosphere followed by stirring for 10-15 min at 0 to -10 °C. Acetone (49 g) was slowly added into the reaction mixture at 0 to -10 °C, maintained for overnight at 0 to -10 °C. The progress of the reaction was monitored by GC. After completion of the reaction, water (100 ml) was added. Lower aqueous layer was separated, and pH was adjusted to around 4.0 using conc HCl (~60 ml Conc HCl were consumed). The obtained solid was filtered to get organic layer which is used in next step (142 g).

Example 2
Preparation of 5-methyl-3-(trifluoromethyl)-1H-pyrazole (1)
Organic layer of example 1 (142 g), methanol (50 ml) were charged in a round bottom flask at room temperature and reaction mixture was cooled to 0 to -10 °C. 80% strength hydrazine hydrate (32.4 g) was slowly added into the reaction mixture and maintained for 2 hr at 0 to -10 °C. Conc HCl (5 ml) was added and maintained overnight at room temperature. The progress of the reaction was monitored by GC analysis. After the completion of the reaction, the solvent was distilled out under vacuum below 50 °C, (300 ml) water was added, and the obtained suspension basified with potassium carbonate (~5 g potassium carbonate was consumed) till to achieve around pH 8 and stirred for 60 min at room temperature. The solution was filtered and washed with water. Obtained solid was dried under vacuum at 35 °C for 4 -10 hr to obtain 5-methyl-3-(trifluoromethyl)-1H-pyrazole (1).
[Yield = 70 g (65.67%); Purity (GC) = 95%; % of water ~0.67%]

Example 3
Preparation of 1,1,1-trifluoropentane-2,4-dione of formula (3)
Toluene (150 ml), sodium methoxide (22.8 g) were charged in a round bottom flask at room temperature under nitrogen atmosphere and reaction mixture was cooled to 0 to -10 °C under nitrogen atmosphere. Ethyl-2,2,2-trifluoro acetate (50 g) was slowly added into the reaction mixture at 0 to -10 °C under nitrogen atmosphere followed by stirring for 10-15 min at 0 to -10 °C. Acetone (24.8 g) was slowly added into the reaction mixture at 0 to -10 °C, maintained for overnight at 0 to -10 °C. The progress of the reaction was monitored by GC. After completion of the reaction, water (50 ml) was added. Lower aqueous layer was separated which is used in next step (170 g).

Example 4
Preparation of 5-methyl-3-(trifluoromethyl)-1H-pyrazole (1)
Aqueous layer of example 3 (170 g) was charged in a round bottom flask and was cooled to 0 to -10 °C. Hydrazine hydrate (32.4 g) was slowly added into the reaction mixture and maintained for 2 hr at 0 to -10 °C. Conc HCl (32 ml) was added and maintained overnight at room temperature. The progress of the reaction was monitored by GC analysis. After the completion of the reaction, the solvent was distilled out under vacuum below 50 °C. To the obtained residue was added water (150 ml) and the obtained suspension basified with potassium carbonate (~2.5 g potassium carbonate was consumed) till to achieve around pH 8 and stirred for 60 min at room temperature. The solution was filtered and washed with water. Obtained solid was dried under vacuum at 35 °C for 4 - 10 hr to obtain 5-Methyl-3-(trifluoromethyl)-1H-pyrazole (1).
[Yield = 32 g (60.6%); Purity (GC) = 92%]
,CLAIMS:We claim:
1. An improved one-pot process for the preparation of 5-methyl-3-(trifluoromethyl)-1H-pyrazole (1),

comprising;
(c) reacting ethyl 2,2,2-trifluoro acetate (2) with acetone in a solvent and in presence of a base to give 1,1,1-trifluoropentane-2,4-dione (3), which may or may not be isolated; and

(d) reacting 1,1,1-trifluoropentane-2,4-dione (3) with hydrazine hydrate in a solvent and in presence of acid to give 5-methyl-3-(trifluoromethyl)-1H-pyrazole (1).

2. The process as claimed in claim 1, wherein the solvent used in step (a) and step (b) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected form acetone, propanone, methyl ethyl ketone or methyl isobutyl ketone; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water or a mixture thereof.

3. The process as claimed in claim 1, wherein the base used in step (a) is an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate; an alkali metal bicarbonate selected from sodium bicarbonate or potassium bicarbonate; an alkali metal alkoxides selected from sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or an organic amines selected from triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

4. The process as claimed in claim 1, wherein the acid used in step (b) is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, hydrobromic acid in acetic acid, boron trifluride in ether.

5. An improved one-pot process for the preparation of 5-methyl-3-(trifluoromethyl)-1H-pyrazole (1),

comprising;
(c) reacting ethyl 2,2,2-trifluoro acetate (2) with acetone in toluene and in presence of sodium methoxide to give 1,1,1-trifluoropentane-2,4-dione (3), which may or may not be isolated; and

(d) reacting 1,1,1-trifluoropentane-2,4-dione (3) with hydrazine hydrate in methanol and in presence of hydrochloric acid to give 5-Methyl-3-(trifluoromethyl)-1H-pyrazole (1).