The present invention relates to a method for preparation of a pyrazole compound, particularly, a compound having formula used as an intermediate in the manufacturing of pharmaceutical and agricultural chemicals, such as pyroxasulfone.

BACKGROUND

Pyrazole compound having formula I, (I), commonly known as 1-Methyl-3-(Trifluoromethyl)-1 H- Pyrazol-5-ol, is a useful research chemical and key intermediate for important building blocks in pharmaceuticals and agrochemicals.

Prior art document CN Pat. No. 101824000 teaches a method for synthesis of 1-methyl-3-trifluoromethyl pyrazol by reacting trifluoroacetyl vinyl alkyl ether with methyl hydrazine. Another prior art document WO2017084995 teaches synthesis of 1-Methyl-3-(Trifluoromethyl)-1 H-pyrazol-5-ol from ethyl 4,4,4- trifluoroacetoacetate and methyl hydrazine. Still another prior art document WO201 8154097 teaches a method for synthesis of 1 -methyl-3- (trifluoromethyl)-1 H-pyrazol-5-ol by reacting ethyl 4,4,4-trifluoroacetoacetate with methyl hydrazine in the presence of 1-methyl-3-(trifluoromethyl)-1 H- pyrazol-5-ol. Generally, methyl hydrazine is one of the key raw materials in the synthesis of 1-Methyl-3-(Trifluoromethyl)-1 H-Pyrazol-5-ol.

Methyl hydrazine is a volatile liquid and a potent carcinogen. The chemical has a high acute oral, dermal and inhalation toxicity. Some studies have also reported evidence of DNA damage and reproductive or developmental toxicity from the chemical. Further, handling of methyl hydrazine requires adherence to stringent health and safety legislation and control measures to minimize risk. Owning to the health and safety risks and stringent handling guidelines, methyl hydrazine is costly and has limited accessibility.

Nonetheless, although methyl hydrazine has been classified as a hazardous chemical and carries huge risk, it continues to find wide application in the synthesis of 1-Methyl-3-(Trifluoromethyl)-1 H-Pyrazol-5-ol. Surprisingly, there have been no successful efforts to replace methyl hydrazine with a safer and more stable chemical compound. Some studies have indicated that increased reaction time and tedious processes have deterred replacement of methyl hydrazine with other chemical compounds.

The present invention aims to overcome the drawbacks of the prior art by a novel method for synthesis of 1-Methyl-3-(Trifluoromethyl)-1 H-Pyrazol-5-ol which alleviates the human health and environmental impacts of the previously known methods. OBJECTS

Accordingly, an object of the present invention is to provide a novel process for the preparation of 1-Methyl-3-(Trifluoromethyl)-1H-Pyrazol-5-ol which eliminates the use of methyl hydrazine as a key raw material.

Another object of the present invention is to provide a single-step process for the preparation of 1-Methyl-3-(Trifluoromethyl)-1 H-Pyrazol-5-ol which is simple, safe, economical and environmental-friendly. Other objects, aspects and advantages of the present invention will be more apparent from the following description.

SUMMARY

According to a preferred embodiment of the present invention, there is provided a process for preparation of a pyrazole compound having formula (I) said process comprising the steps of: condensing a compound having formula (II) (II) with a methyl hydrazine salt in an acidic medium, where R is selected from C _{1 -5} alkyl, aryl and C _3-7 cycloalkyl.

Preferably, the pyrazole compound of formula (I) is 1-Methyl-3- (Trifluoromethyl)-1 H-Pyrazol-5-ol. The compound of formula (II) is preferably alkyl 4,4,4-trifluoroacetoacetate, and more preferably, ethyl 4,4,4- trifluoroacetoacetate.

According to the preferred embodiment, the methyl hydrazine salt is selected from methyl hydrazine hydrochloride, methyl hydrazine sulfate, methyl hydrazine oxalate, and the like.

According to the preferred embodiment, the acidic medium consists of an acid in a solvent. The acid is selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, and the like. The solvent is selected from water, ethanol, methanol, diethyl ether, and the like.

According to the preferred embodiment, the process is carried out at a reaction temperature between 25 to 100 °C. Preferably, the reaction is carried out in the presence of a buffering agent selected from sodium acetate, potassium acetate, and the like.

DETAILED DESCRIPTION

The description of the specific embodiments herein will reveal the general nature of the embodiments of the present invention that a person skilled in the art can, by applying current knowledge, readily modify and/or adapt for various applications without departing from the general concept, and, therefore, such adaptations and modifications are to be comprehended within the meaning of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. The present invention relates to a process for synthesis of a pyrazole compound having formula (I), (I). The process includes condensing a compound having formula (II), (II), with a methyl hydrazine salt in an acidic medium. R is selected from C _{1 -5} alkyl, aryl and C _3-7 cycloalkyl. The term “alkyl” as used herein refers to a straight or branched chain aliphatic hydrocarbon chain, having from 1 to 5 carbon atoms. Examples of alkyl include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, t-butyl, and the like. The term “cycloalkyl” as used herein refers to cyclic alkyl groups constituting of 3 to 7 carbon atoms having a single cyclic ring or multiple condensed rings, such cycloalkyl groups include, by way of example, single ring structures, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, or multiple ring structures.

The term “aryl” as used herein refers to a mono- or poly- carbocyclic aromatic group, for example phenyl or naphthyl ring and the like. The pyrazole compound of formula (I) is preferably 1-Methyl-3- (Trifluoromethyl)-1 H-Pyrazol-5-ol.

The compound having formula (II) is an alkyl 4,4,4-trifluoroacetoacetate, preferably, ethyl 4,4,4-trifluoroacetoacetate.

The methyl hydrazine salt is selected from methyl hydrazine hydrochloride, methyl hydrazine sulfate, methyl hydrazine oxalate, and the like. Hydrazine salts are neutralized compounds having better stability as compared to methyl hydrazine. The salts of methyl hydrazine are more economical, safer in terms of oral, dermal and inhalation toxicity, and easy-to-access in terms of handling, storage and availability.

The ratio of the alkyl 4,4,4-trifluoroacetoacetate and methyl hydrazine salt is in the range of 1 :1 to 1 :1.5, preferably 1 :1.

The reaction is carried out at a temperature between 25 to 100 °C in an acidic medium. The acidic medium consists of an acid in a solvent. The acid is selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, and the like. The solvent is selected from water, ethanol, methanol, diethyl ether, and the like. The ratio of the acid and the solvent is in the range of 0 : 3 to 1 : 1 , preferably 0 : 3.

A buffering agent may be selectively added to the alkyl 4,4,4- trifluoroacetoacetate to adjust its pH in the range of 2.5 to 8. Alternatively, the reaction may be carried out without any buffering agent. The buffering agent is selected from sodium acetate, potassium acetate, and the like. The buffering agent is added to the alkyl 4,4,4-trifluoroacetoacetate, and then the alkyl 4,4,4- trifluoroacetoacetate is reacted with the methyl hydrazine salt to obtain 1- Methyl-3-(Trifluoromethyl)-1 H-Pyrazol-5-ol. The ratio of the alkyl 4,4,4- trifluoroacetoacetate and the buffering agent is in the range of 1 : 1 to 1 : 3, preferably 1 : 2. According to a preferred embodiment of the present invention, the compound of Formula I is obtained by condensation of ethyl 4,4,4-trifluoroacetoacetate with methyl hydrazine sulfate in aqueous sulfuric acid at reaction temperature between 25 to 100 °C. The reaction scheme is illustrated here below in

Scheme 1.

Scheme 1 ;

In another preferred embodiment of the present invention, the compound of Formula I is obtained by condensation of ethyl 4,4,4-trifluoroacetoacetate with methyl hydrazine hydrochloride in aqueous acetic acid in the presence of sodium acetate.

In still another preferred embodiment of the present invention, the compound of Formula I is obtained by condensation of ethyl 4,4,4-trifluoroacetoacetate with methyl hydrazine oxalate in a medium of ethanol and trifluoroacetic acid in the presence of potassium acetate. In yet another preferred embodiment of the present invention, the compound of Formula I is obtained by condensation of ethyl 4,4,4-trifluoroacetoacetate with methyl hydrazine sulfate in a medium of methanol and hydrochloric acid.

EXAMPLES:

The present invention will now be described with the help of following specific embodiments which are only intended to exemplify the invention and shall not be construed to limit the scope and ambit of the invention.

NMR referencing:

¹ H-NMR (DMSO-d6), 400 mHz: d 11.68 (s, 1 H), 5.72 (s, 1 H), 3.58 (s, 3H) ¹⁹ F-NMR (DMSO-d6), 400 mHz: d 61.34

HPLC condition:

Column: Inertsil ODS 3V (250 x 4.6mm, 5m)

Mobile phase: A: 0.1%OPA in water with 10%ACN

B: Acetonitrile

Flow Rate: 1.0 ml /min

Column Temperature: 25 °C

Wave length: 230 nM

Program: (Gradient)

T (min): 0.01 , 50.0, 50.1 , 60.0 B (%): 5.666.7 5.6 5.6 Diluent: Water : CAN (1 :1)

Sample preparation: 20.06 mg of sample dissolved in 20 mL of diluent. Retention time: 19.18 min. Example 1: Preparation of 1-Methyl-3-(Trifluoromethyl)-1 H-Pyrazol-5-ol Ethyl-4, 4, 4-trifloroacetoacetate (1 g, 5.4 mmol) was treated with methylhydrazine sulfate (0.782 g, 5.4 mmol) in acetic acid (2.5 ml) and water (3 ml) at 85°C for 24 h. Reaction mixture was extracted with ethyl acetate (2 x 20 ml). Combined organic layers were washed with water (20 ml) and brine solution (20 ml) successively. Volatiles were evaporated to obtain residue that was washed with hexane (10 ml) to obtain 1-Methyl-3-(Trifluoromethyl)-1 H- Pyrazol-5-ol as white solid (340 mg).

Example 2: Preparation of 1-Methyl-3-(Trifluoromethyl)-1 H-Pyrazol-5-ol in the presence of buffering agent

Ethyl-4, 4, 4-trifloroacetoacetate (1 g, 5.4 mmol) was treated with methylhydrazine sulfate (0.782 g, 5.4 mmol) in acetic acid (2.5 ml) and water (3 ml) in presence of sodium acetate (891 mg, 10.8 mmol) at 85°C for 24 h. Reaction mixture was extracted with ethyl acetate (2 x 20 ml). Combined organic layers were washed with water (20 ml) and brine solution (20 ml) successively. Volatiles were evaporated to obtain residue that was washed with hexane (10 ml) to obtain 1-Methyl-3-(Trifluoromethyl)-1 H-Pyrazol-5-ol as white solid (700 mg).

Example 3: Preparation of 1-Methyl-3-(Trifluoromethyl)-1 H-Pyrazol-5-ol in the presence of buffering agent

Ethyl-4, 4, 4-trifloroacetoacetate (20 g, 0.108 mmol) and sodium acetate (17.8 g, 0.217 mmol) were treated with methylhydrazine sulfate (15.7 g, 0.108 mmol) in water (60 ml) at 85°C for 24 h. The reaction mixture was cooled to 0 °C, and the product was precipitated, filtered and dried to obtain white solid of 1- Methyl-3-(Trifluoromethyl)-1 H-Pyrazol-5-ol (13 g, Yield: 72%). Example 4: Preparation of 1-Methyl-3-(Trifluoromethyl)-1 H-Pyrazol-5-ol in the presence of buffering agent

Ethyl-4, 4, 4-trifloroacetoacetate (420 g, 2.28 mol) and sodium acetate (374 g, 4.55 mmol) were treated with methylhydrazine sulfate (328.9 g, 2.28 mol) in water (1.68 L) at 85°C for 24 h. The reaction mixture was cooled to 0 °C, the product precipitated, filtered and dried to obtain white solid of 1-Methyl-3- (Trifluoromethyl)-1 H-Pyrazol-5-ol (295 g). The yield and melting point of the product was determined. The purity of the product was determined by HPLC and ¹ HNMR. Sample results are shown in Table 1 below. Table 1

Embodiment of the present invention is applicable over a wide number of uses and other embodiments may be developed beyond the embodiment discussed heretofore. Only the most preferred embodiments and their uses have been described herein for purpose of example, illustrating the advantages over the prior art obtained through the present invention; the invention is not limited to these specific embodiments or their specified uses. Thus, the forms of the invention described herein are to be taken as illustrative only and other embodiments may be selected without departing from the scope of the present invention. It should also be understood that additional changes and modifications, within the scope of the invention, will be apparent to one skilled in the art and that various modifications to the composition described herein may fall within the scope of the invention.