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

“PROCESS FOR THE PREPARATION OF PYRAZOLE DERIVATIVES”

SRF LIMITED, AN INDIAN COMPANY,
SECTOR 45, BLOCK-C, UNICREST BUILDING,
GURGAON – 122003,
HARYANA (INDIA)

The following specification particular describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
The present invention provides a process for preparation of a pyrazole derivative represented as a compound of formula I.

Formula I
wherein R represents a hydrogen atom, alkyl or haloalkyl, aryl, heteroaryl ring, R' represents a C1 to C3 haloalkyl group and wherein X represents a halogen, n represents an integer from 1-3.

BACKGROUND OF THE INVENTION
The present invention provides a process for the preparation of pyrazole derivatives which are important intermediates for production of pharmaceutical and agrochemical products.
The Chinese Patent Application No. 109796408 describes a process for the preparation of 1-methyl-5-difluoromethoxy pyrazoles by reacting bromo-1-methylpyrazole in tetrahydrofuran with sodium hydroxide and difluoromethanol at room temperature.
The US Patent No. 7256298 discloses a process for the preparation of pyrazole derivatives like 5-difluoro-methoxy-3-trifluoromethyl-1-methylpyrazole by reaction of 1-tert-butyl-5-hydroxy-3-trifluoromethyl-1H-pyrazole in N,N-dimethylformamide with anhydrous potassium carbonate and chlorodifluoromethane.
The known processes use large quantities of organic solvents and inventors felt the need to circumvent the use of solvent to provide a cost effective and environment friendly process for commercial production of compounds of formula I.

OBJECT OF THE INVENTION
The object of the present invention provides a simple and industrial feasible process for preparation of pyrazole derivatives of formula I in good yield and purity without using any solvent during the reaction step.

SUMMARY OF THE INVENTION
In an aspect, present invention provides a process for the preparation of pyrazole derivatives of formula I,

Formula I
wherein R represents a hydrogen atom, alkyl or haloalkyl, aryl, heteroaryl ring, R' represents a C1 to C3 haloalkyl group and wherein X represents a halogen, n represents an integer from 1-3.
comprising the step of reacting a compound of Formula II with a compound of formula III in presence of base,

Formula II
wherein R, X and n are as represented above.

Formula III
wherein R' represents same as above and Z represents halogen, haloalkyl group.
to obtain the compound of formula I, wherein the reaction is carried out in absence of any organic solvent.

DETAILED DESCRIPTION OF DRAWINGS
Figure 1 describes the flow reactor setup used in the preparation of the present invention.
Figure 1, the feed stock solution ‘S1’, ‘S2’ and ‘S3’ contains 40% aqueous solution of sodium 5-hydroxy-3-(trifluoromethyl)-1-methylpyrazole, 25% aqueous of sodium hydroxide and chlorodifluoromethane were connected to dosing pumps ‘P1’, ‘P2’ and ‘P3’ respectively. All the pumps started simultaneously, and stock solution were fed into flow reactor ‘F1’ followed by flow reactor ‘F2’ and the pressure of flow reactor were maintained by back pressure regulators ‘B1’ and ‘B2’. The biphasic reaction mass was cooled and collected in vessel ‘V1’, and the bottom product layer and top aqueous layer were drained continuously into ‘C1’ and ‘S4’ vessels using level indicator ‘L1’.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, alkyl or haloalkyl may be selected from a group comprising a methyl, an ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl, iso-hexyl, 3,3-dimethylbutyl, fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, trifluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 1-fluoro-1-methylethyl and 1-trifluoromethyl-2,2,2-trifluoroethyl group or the like.
As used herein, aryl and heteroaryl ring includes, benzene, pyridine, pyran, furan, thiophene, pyrrole and imidazole or the like. Aryl and heteroaryl ring may be further substituted with a group selected from C1-C6 alkyl, C1-C6 alkoxy, nitro, fluoro, chloro, bromo, -CX3 (where X = F, Cl), and cyano.
In an embodiment, the process of the present invention is carried out in a batch mode.
In another embodiment, the process of the present invention is carried out in a continuous mode.
In another embodiment, the process of the present invention is carried out in a continuous mode using a flow reactor.
In an embodiment, the residence time in flow reactor is selected in the range of 5-15 minutes.
In an embodiment, the process of the present invention is carried out in the presence of base. The base is selected from alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal bicarbonates such as Sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal hydrides such as potassium hydride and sodium hydride; alkali metal alcoholates such as sodium ethoxide and sodium methoxide, and pyridine or the like.
In an embodiment, the reaction of the present invention is carried out at a temperature of 25°C to 90°C and at a pressure range of 0.5 to 8 bars.
In an embodiment, the reaction of the present invention is carried out at atmospheric pressure under vigorous stirring.
As used herein, “vigorous stirring” refers to a rpm of 500-600. The vigorous stirring helps in achieving high selectivity by removing by-product from the reaction mixture.
In a specific embodiment, the present invention provides a process for preparation of 5-difluoromethoxy-3-(trifluoromethyl)-1-methylpyrazole, comprising the step of reacting 5-hydroxy-3-(trifluoromethyl)-1-methylpyrazole and chlorodifluoromethane using aqueous solution of sodium hydroxide.
In another specific embodiment, the present invention provides a process for preparation of 5-difluoromethoxy-3-(trifluoromethyl)-1-methylpyrazole, comprising the step of reacting 5-hydroxy-3-(trifluoromethyl)-1-methylpyrazole and chlorodifluoromethane using aqueous solution of sodium hydroxide in a flow reactor.
In another specific embodiment, the present invention provides a process for preparation of 5-difluoromethoxy-3-(trifluoromethyl)-1-methylpyrazole, comprising the step of reacting 5-hydroxy-3-(trifluoromethyl)-1-methylpyrazole and chlorodifluoromethane using aqueous solution of sodium hydroxide in a batch reactor.
The present invention for preparation of compound of formula I have following advantages over the known methods:
1. The process provides high yield with high throughput and is carried out without any organic solvent.
2. The process involves use of minimal range of reactant reagents with 100% of conversion, minimizes the impurity and thereby increases the selectivity towards the desired product significantly.
3. The process prevents effluent and improves yield significantly.
4. The process is non-tedious and easy in handling.
5. The process of present invention is safe at commercial scale.
As used herein, the compounds of Formula II may be prepared by any method known in the art. The compound of Formula III may be obtained from commercial source.
In an embodiment, the compound of formula I may be isolated using a solvent selected from dioxane, tetrahydrofuran, and 1,2-dimethoxyethane; halogenated hydrocarbons such as dichloroethane, carbon tetrachloride, chlorobenzene, and dichlorobenzene or the like.
The purity of isolated compound of formula I is greater than 90% and preferably greater than 95% and more preferably greater than 98%.
The yield of compound of formula I is greater than 90% and preferably greater than 94%.
The reagent used in the present invention may be prepared by any method known in the literature or can be obtained commercially.
The compound of Formula I is isolated by any method known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or a mixture 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.
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.
EXAMPLES
Example 1: Preparation of 5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole using batch mode.
Water (100g, 5.5 mol, 4.6 eq.,) and 5-hydroxy-3-(trifluoromethyl)-1-methylpyrazole (200g 1.2 mol, 1 eq.) were charged into autoclave. Aqueous sodium hydroxide (24%, 100g 1.2 mol, 1.0 eq.) was added into the reaction solution at 25-28? with vigorous stirring to form a homogeneous mixture. The reaction mass was heated to 85-90?. Thereafter, chlorodifluoromethane (155g) and aqueous sodium hydroxide (24%, 500g) were simultaneously charged through dip line at 4-8 kg/cm2 pressure for about 3-4 hours. After completion of the reaction, the reaction mass was cooled at 25-30? and followed by layer separation and filtration to obtain titled compound. Yield: 98%; Purity: 99.2%
Example 2: Preparation of 5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole using continuous flow process:
An aqueous solution of sodium 5-hydroxy-3-(trifluoromethyl)-1-methylpyrazole (500g, 40%, 1 mol, 1 eq.), aqueous sodium hydroxide (320g, 25%, 2.0 mol, 2.0 eq.) and chlorodifluoromethane (90g, 1.05 mol) were simultaneously flowed into the flow reactor-1 under 6-8 bar pressure at 55-70°C with the residence time of 10-15 minutes. Maintained the reaction flow under 4-6 bar pressure at 70-110°C with the residence time of 5-10 minutes. The resultant biphasic reaction mixture cooled and collected in vessel at 25-30°C and further followed by layer separation to get the titled compound. Yield: 98.5%; Purity: 99.1%

SRF LIMITED NO. OF SHEETS: 01
APPLICATION NO. IN202311011309 SHEET NO. 01

Figure 1: Continuous process using flow reactor

,CLAIMS:WE CLAIM:
1. A process for the preparation of a pyrazole derivatives of formula I,

Formula I
wherein R represents a hydrogen atom, alkyl or haloalkyl, aryl, heteroaryl ring, R' represents a C1 to C3 haloalkyl group and X represents halogen, and n represents an integer from 1-3.
comprising the step of reacting a compound of Formula II with a compound of formula III in presence of a base,

Formula II
wherein R, X and n are as represented above.

Formula III
wherein R' represents same as above and Z represents halogen, haloalkyl group.
to obtain the compound of formula I, wherein the reaction is carried out in absence of any organic solvent.
2. The process as claimed in claim 1, wherein the reaction is carried out in a batch mode.
3. The process as claimed in claim 1, wherein the reaction is carried out in a continuous mode.
4. The process as claimed in claim 3, wherein the reaction is carried out in a continuous mode using a flow reactor.
5. The process as claimed in claim 1, wherein the process is carried out in presence of a base selected from a group consisting of alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal hydrides, alkali metal alcoholates and pyridines.
6. The process as claimed in claim 5, wherein the base is selected from a group consisting of sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, potassium hydride, sodium hydride, sodium ethoxide, sodium methoxide and pyridine.
7. The process as claimed in claim 1, wherein the reaction is carried out at a temperature of 25°C to 90°C and at a pressure range of 0.5bar to 8 bars.
8. The process as claimed in claim 7, wherein the reaction is carried out at atmospheric pressure under vigorous stirring at a rpm of 500-600.

Dated this 17th day of February 2023.