DESC:
Field of invention
The present invention relates to a process for preparation of 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol. The present invention also relates to a process of preparing Pyroxasulfone using the intermediate.

Background of the invention:
Pyroxasulfone, chemically known as, 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylsulfonyl]-4,5-dihydro-5,5-dimethyl-1,2-oxazole is represented by the structure of Formula (I) and used as pre-emergence herbicide for control of annual grasses and some broad-leaved weeds in maize, soya beans, wheat and other crops.

The compound, 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol, is a key intermediate used in the preparation of Pyroxasulfone and is represented by Formula (II).


This intermediate compound of Formula (II) is disclosed in WO2002062770 (table 3), however the method of preparing the same is not disclosed in this patent.
WO2005095352 discloses method of preparing compound of Formula (II). The process comprises condensation of 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol with 5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl carbamimidothioate to get the intermediate compound. However, the process suffers from disadvantages such as impurity formation, lower yield and thus, not suitable for industrial scale.

Therefore, there exists a need for the process which overcomes the aforesaid drawbacks of the prior art process.

The inventors of the present invention have developed a simple, industrially suitable process which eliminates the formation of undesired impurities formed during the reaction, thereby improving the yield of the process.

Object of the invention:
Accordingly, an object of the present invention is to provide a process for the preparation of 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol Formula (II), with improved yield.

Another object of the present invention is to provide 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol Formula (II) which is substantially free of impurities.

Yet another object of the present invention is to provide a process of preparing Pyroxasulfone which is substantially free of impurities.

Summary of the invention:
In an aspect the present invention provides a process for preparation of 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol Formula (II)

In another aspect the present invention provides a process for preparing compound of formula (II), comprising:

reacting 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol Formula (III)

with formylating agent and 5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl carbamimidothioate Formula (IV) or salt thereof,

at temperature below 20°C.

Another aspect of the present invention is to provide 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol Formula (II), substantially free of impurities.

Another aspect of the present invention is to provide 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol Formula (II), substantially free of impurity wherein said impurity comprise 4,4’-methanediylbis[1-(methyl-3-(trifloromethyl)-1H-pyrazol-5-ol] of Formula (V) or tautomers thereof.

In another aspect, the present invention provides a composition comprising 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol Formula (II) comprising less than 3% of 4,4’-methanediylbis[1-(methyl-3-(trifloromethyl)-1H-pyrazol-5-ol] of Formula (V) or tautomers thereof.

Another aspect of the present invention is to provide the process for preparation of Pyroxasulfone Formula (I),

said process comprising:
reacting 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (III),

with formylating agent and 5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl carbamimidothioate of Formula (IV) or salt thereof, at temperature below 20°C

to get 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol Formula (II),

and,
converting 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol Formula (II) into Pyroxasulfone.

Another aspect of the present invention is to provide Pyroxasulfone substantially free of impurities.

Another aspect of the present invention is to provide Pyroxasulfone substantially free of impurities wherein said impurities comprises a compound of Formula (V), tautomers or derivatives thereof; wherein the derivatives comprises intramolecular cyclized compounds such as compound of Formula (V’), compound of Formula (VI), compound of Formula (VII) or mixture of one or more known and unknown impurities.

In another aspect, the present invention provides an agrochemical composition comprising Pyroxasulfone of Formula (I) produced by the process of present invention as described herein.

In another aspect the present invention provides an agrochemical composition comprising Pyroxasulfone Formula (I) having less than 1% of impurity, 4,4’-methanediylbis[1-(methyl-3-(trifloromethyl)-1H-pyrazol-5-ol] Formula (V) or tautomers or derivatives thereof; wherein said derivatives comprises intramolecular cyclized compounds such as compound of Formula (V’), compound of Formula (VI), compound of Formula (VII) or mixture of one or more known or unknown impurities.

Detailed description of the invention:
In order to provide a clear and consistent understanding of the terms used in the present specification, a number of definitions are provided below. Moreover, unless defined otherwise, all technical and scientific terms as used herein have the same meaning as commonly understood by the person of ordinary skill in the art to which this invention pertains.

The terms used herein are defined as follows.

The term "purity" means purity as determined by HPLC ("High Pressure Liquid Chromatography").

As used herein, the terms “compound of formula (II)” refers to 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol, and the terms are used interchangeably.

As used herein, the terms “compound of formula (IV) or salts thereof” refers to 5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl carbamimidothioate or salts thereof and the terms are used interchangeably.

As used herein, the terms “compound of formula (I)’ refers to 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylsulfonyl]-4,5-dihydro-5,5-dimethyl-1,2-oxazole.

The term "about" shall be interpreted to mean "approximately" or "reasonably close to" and any statistically insignificant variations therefrom. As used herein, the term "about" refers to a measurable value such as a parameter, an amount, a temporal duration, and the like and is meant to include variations of +/-15% or less, specifically variations of +/-10% or less, more specifically variations of +/-5% or less, even more specifically variations of +/-1% or less, and still more specifically variations of +/-0.1% or less of and from the particularly recited value, in so far as such variations are appropriate to perform in the disclosure described herein. Furthermore, it is also to be understood that the value to which the modifier "about" refers is itself specifically disclosed herein.

As used herein, the terms “comprising” “including,” “having,” “containing,” “involving,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to.

The terms “preferred” and “preferably” refer to embodiments of the invention that may afford certain benefits, under certain circumstances. In an embodiment, the aspects and embodiments described herein shall also be interpreted to replace the clause “comprising” with either “consisting of” or with “consisting essentially of” or with “consisting substantially of”.

The term “room temperature” unless stated otherwise, refers to the temperature in the range of about 25°C to about 35°C.

The term ‘impurities’ or ‘impurity’ refers to unreacted synthetic intermediates, reagents, solvents, organic and/or inorganic products of side reactions, organic and/or inorganic salts and/or other undesired materials.

The term “substantially free of impurities” refers to 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (II); Pyroxasulfone of Formula (I) or 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfanyl]-5,5-dimethyl-4H-1,2-oxazole of Formula (VIII) comprising a particular impurity or a mixture of impurities in an amount of less than about 3.0 % of 4,4’-methanediylbis[1-(methyl-3-(trifloromethyl)-1H-pyrazol-5-ol] of Formula (V), tautomers or derivatives thereof; wherein said derivatives comprises intramolecular cyclized compounds such as compound of Formula (V’), compound of Formula (VI), compound of Formula (VII) or mixture of one or more such impurities and other derived impurities.

Accordingly, the present invention is now described with the following embodiments.

In an embodiment, the present invention provides a novel process of preparation 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3 (trifluoromethyl)-1H-pyrazol-5-ol Formula (II),

said process comprising:
reacting compound of Formula (III),

with formylating agent and 5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl carbamimidothioate of Formula (IV) or salt thereof,

at a temperature below 20°C.

In accordance with above embodiment, the process is carried out at a temperature in the range from about -10°C to about 19.9°C.

In an embodiment, the process is carried out at a temperature in the range from about -10°C to about 19°C.

In an embodiment, the process is carried out at a temperature in the range from about -10°C to about 18°C.

In an embodiment, the process is carried out at a temperature in the range from about -5°C to about 15°C. Preferably, the process is carried out at a temperature in the range from about 0°C to about 5°C.

In an embodiment the reaction is carried out in presence of a base.

The base is selected from the group comprising of an alkali metal hydroxide; alkali metal alkoxide, alkali metal carbonate or alkaline earth metal salts.

In an embodiment, the base is selected from the group comprising an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide; and a metal alkoxide such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and tert-butoxy potassium; alkali metal carbonate such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; alkaline earth metal salts selected from magnesium carbonate, calcium carbonate, barium carbonate, magnesium bicarbonate, calcium bicarbonate and the likes.
In an embodiment, the base is an alkali metal hydroxide.

In an embodiment, the base is sodium hydroxide.

In an embodiment, the base used is about 1.0 to about 3.0 equivalent with respect to the compound of Formula (III).

In an embodiment, the base used is about 1.0 to about 2.0 equivalent with respect to the compound of Formula (III).

In an embodiment, the formylating agent is selected from formaldehyde or paraformaldehyde.

In an embodiment, the formylating agent is formaldehyde.

In an embodiment, the formylating agent is paraformaldehyde.

In an embodiment formaldehyde may be used as an aqueous solution of formaldehyde having a concentration in the range of about 30 % to about 70 % (w/w), preferably formaldehyde used is about 35 % (w/w) aqueous formalin solution.

In an embodiment, formaldehyde is used in amount of about 1.0 to about 4.0 equivalent with respect to compound of Formula (III), preferably about 1.5 to about 2.5 equivalents.

In another embodiment, the reaction is carried out in a solvent.

In an embodiment, the reaction is carried out in a solvent selected from the group comprising of water; alcohol; aromatic hydrocarbon; ether; amide; halogenated hydrocarbon; aliphatic hydrocarbon or mixture thereof.

In an embodiment, the solvent used is selected from the group comprising water, alcohol such as methanol, ethanol; aromatic hydrocarbons such as toluene, xylene and chlorobenzene; ethers such as tetrahydrofuran diethyl ether, dioxane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide; halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; aliphatic hydrocarbons such as pentane, n-hexane and n-Heptane or combinations thereof.

In an embodiment, the solvent used is water or alcohol. In an embodiment, the solvent used is water. In an embodiment, the solvent used is alcohol.

In another embodiment, 5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl carbamimidothioate Formula (IV) salt is selected from hydrochloride, hydrobromide, hydroiodide, sulfate or phosphate salt.

In an embodiment, the compound of Formula (IV) salt is 5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl carbamimidothioate hydrochloride.

In yet another embodiment, the compound of Formula (IV) used is about 1.0 to about 1.5 equivalents with respect to compound of Formula (III), preferably about 1.0 to about 1.1 equivalents is used.

In another embodiment, the present invention provides 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (II) prepared according to the present invention is substantially free of impurities.

In an embodiment, the present invention provides 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol, of Formula (II), substantially free of impurities wherein said impurities comprise a compound of Formula (V) or tautomers thereof.

In an embodiment, the impurity namely, the compound of formula (V) is present in an amount of less than 3%.

In an embodiment, 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (II) comprises less than 3% of compound of Formula (V) or tautomers thereof.

In another embodiment, the present invention provides a composition comprising 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (II) having less than 3% of 4,4’-methanediylbis[1-(methyl-3-(trifloromethyl)-1H-pyrazol-5-ol] of Formula (V) or tautomers thereof.

In an embodiment, the present invention provides a process of preparation 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol Formula (II),

comprising:
reacting 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (III),

with formaldehyde and 5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl carbamimidothioate hydrochloride of Formula (IV) at temperature ranging from about 0°C to about 10°C.

wherein said reaction is carried out in presence of sodium hydroxide and water.

In another embodiment, the present invention provides a process of preparation 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol Formula (II),

comprising:
reacting 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (III),

with formaldehyde and 5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl carbamimidothioate hydrochloride of Formula (IV) at temperature ranging from about 15°C to about 19°C

wherein said reaction is carried out in presence of sodium hydroxide and water.

In another embodiment, the present invention provides a process of preparation of Pyroxasulfone of Formula (I):

via the intermediate compound of Formula (II):

;

wherein the compound of Formula (II) is prepared via a reaction carried out at temperature below 20oC.

In another embodiment, the present invention provides the process of preparation of Pyroxasulfone of Formula (I), comprising,
a. reacting 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (III),
b.

with formylating agent and 5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl carbamimidothioate of Formula (IV) or salt thereof, at a temperature below 20°C

to get 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (II),

and
c. converting said compound of Formula (II) into Pyroxasulfone of Formula (I).
d.

In accordance with the above embodiment, the process of step b) proceeds through the formation of 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfanyl]-5,5-dimethyl-4H-1,2-oxazole of Formula (VIII).

In an embodiment, 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfanyl]-5,5-dimethyl-4H-1,2-oxazole of Formula (VIII) is substantially free of impurities wherein said impurities comprise a compound of Formula (V), tautomers or derivatives thereof; wherein the derivatives comprising intramolecular cyclized compounds such as compound of Formula (V’), compound of Formula (VI), compound of Formula (VII) or mixture of one or more such impurities and other derived impurities.

In an embodiment, the step b) of the process comprises fluoromethylating 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (II) to get a compound of Formula (VIII);

and
oxidizing 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfanyl]-5,5-dimethyl-4H-1,2-oxazole of Formula (VIII) to get Pyroxasulfone of Formula (I),

In an embodiment, fluoromethylating agent used is difluorochloromethane (freon gas).
In another embodiment, the amount of difluorochloromethane used is in the range of about 2 to about 10 moles with respect to 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (II), preferably in the range of about 2 to about 5 moles.

In another embodiment, fluoromethylation is carried out in presence of an alkaline reagent and an organic solvent.

The alkaline reagent used is selected from inorganic base or organic base; the inorganic base is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium hydroxide and sodium hydroxide. The organic base is selected from triethylamine, pyridine, triethylene diamine and N, N-dimethyl pyridine. Preferably the based used is an inorganic base, such as sodium hydroxide.

The amount of alkaline reagent used is in the range of about 1.5 to about 7 moles with respect to compound of Formula (II), preferably about 1.5 to about 5 moles.

The organic solvent used is selected from acetonitrile, N, N- dimethylformamide, tetrahydrofuran, methanol, ethanol, isopropanol or mixture thereof; preferably acetonitrile is used.

In an embodiment 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfanyl]-5,5-dimethyl-4H-1,2-oxazole of Formula (VIII) is prepared by fluoromethylating 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (II), using freon gas at about 0°C to about 10°C.

In yet another embodiment, oxidation of 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfanyl]-5,5-dimethyl-4H-1,2-oxazole of formula (VIII) to get Pyroxasulfone of formula (I) is carried out in presence of an oxidizing agent.

The oxidizing agent used is selected from organic peroxides such as m- chloroperbenzoic acid, performic acid, peracetic acid and the like; inorganic peroxides such as hydrogen peroxide, potassium permanganate, sodium periodate (Potassium peroxymonosulfate), preferably hydrogen peroxide is used.

In an embodiment, oxidation of 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfanyl]-5,5-dimethyl-4H-1,2-oxazole of formula (VIII) to get Pyroxasulfone of formula (I) is carried out in the absence of a metal catalyst.

In an embodiment, oxidation of 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfanyl]-5,5-dimethyl-4H-1,2-oxazole of formula (VIII) to get Pyroxasulfone of formula (I) is carried out in presence of a metal catalyst or an acid catalyst.

In an embodiment, oxidation of 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfanyl]-5,5-dimethyl-4H-1,2-oxazole of formula (VIII) to get Pyroxasulfone of formula (I) is carried out in presence of a metal catalyst.

In an embodiment, oxidation of 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfanyl]-5,5-dimethyl-4H-1,2-oxazole of formula (VIII) to get Pyroxasulfone of formula (I) is carried out in presence of an acid catalyst.

In another embodiment, oxidation of 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfanyl]-5,5-dimethyl-4H-1,2-oxazole of formula (VIII) to get Pyroxasulfone of formula (I) is carried out in presence of a metal catalyst selected from tungsten catalyst, molybdenum catalyst, titanium catalyst, zirconium catalyst or mixture thereof. Preferably the tungsten catalyst is used.

The tungsten catalyst used is selected from tungsten, tungstic acid, tungstic acid salt, metallic tungsten, tungsten oxide, tungsten carbide or mixtures thereof.

The tungsten catalyst such as tungsten chloride, tungsten bromide, tungsten sulfide, phosphor-tungstic acid or a salt thereof, tungstic acid or a salt thereof, sodium tungstate or its dihydrate, potassium tungstate, calcium tungstate, lithium tungstate, tungsten tungstate, coordination complex of tungsten or mixture thereof, is used.

Preferably, the tungsten catalyst used is sodium tungstate dihydrate for the oxidation reaction.

In an embodiment, oxidation of 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfanyl]-5,5-dimethyl-4H-1,2-oxazole of formula (VIII) to get Pyroxasulfone of formula (I) is carried out in presence of an acid catalyst such as inorganic acid. The inorganic acid may be selected from, but not limited to, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid and the likes.

In an embodiment, the oxidation is carried out in an organic solvent. The organic solvent used is selected from, but not limited to, formic acid, acetic acid, difluoroacetic acid, trifluoroacetic acid, dichloroacetic acid, trichloroacetic acid and the likes.

In a subsequent embodiment, the organic solvent is acetic acid.

In another embodiment the amount of the organic solvent used is in the range of about 5 moles to about 100 moles with respect to compound of formula (VIII).

In another embodiment, the oxidation of compound of Formula (VIII) is carried out at a temperature in the range from about 0°C to about 120°C.

In another embodiment, oxidation of compound of Formula (VIII) is carried out at temperature ranging from about 0oC to about 120oC and in an organic solvent comprising acetic acid.

In another embodiment, the oxidation is carried out at a temperature in the range from about 0°C to about 70°C.

In another embodiment, the oxidation is carried out at a temperature in the range from about 10°C to about 32 °C.

In another embodiment, oxidation of compound of Formula (VIII) is carried out at temperature ranging from about 10°C to about 32°C in an organic solvent comprising acetic acid and a catalyst.

In another embodiment, the oxidation of compound of Formula (VIII) is carried out at a temperature in the range from about 80°C to about 120°C.

In yet another embodiment, the oxidation of 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfanyl]-5,5-dimethyl-4H-1,2-oxazole of
Formula (VIII) to get Pyroxasulfone of Formula (I) is carried out in a continuous flow reactor.

In a subsequent embodiment, the continuous reaction for the preparation of Pyroxasulfone of Formula (I) is carried out in continuous flow reactor selected from the group comprising of Plug Flow Reactor (PFR), Continuous Stirred Tank Reactor (CSTR), Loop reactor, Packed Bed Reactor (PBR), static coil reactor or combinations thereof.

In another embodiment, the oxidation of 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfanyl]-5,5-dimethyl-4H-1,2-oxazole Formula (VIII) to Pyroxasulfone of Formula (I) is carried out at temperature in the range from about 80 oC to about 120 oC in an organic solvent comprising acetic acid and a catalyst wherein the reaction is performed in a continuous flow reactor.

In another embodiment, Pyroxasulfone of Formula (I) is substantially free of impurities wherein said impurities comprise a compound of Formula (V), tautomers or derivatives thereof; wherein said derivatives comprises intramolecular cyclized compounds such as compound of Formula (V’), compound of Formula (VI), compound of Formula (VII) or mixture of one or more such impurities and other derived impurities.

In another embodiment, the present invention provides a composition comprising Pyroxasulfone having less than 1% of 4,4’-methanediylbis[1-(methyl-3-(trifloromethyl)-1H-pyrazol-5-ol] of Formula (V), tautomers or derivatives thereof; wherein said derivatives comprises intramolecular cyclized compounds such as compound of Formula (V’), compound of Formula (VI), compound of Formula (VII) or mixture of one or more such impurities and other derived impurities.

Analytical methods:
Samples were analyzed on high performance liquid chromatograph (HPLC) with UV detector using Zorbax SB C8 (250 x 4.6 mm, 5 micron).

EXAMPLES
The embodiments of the present invention are illustrated by below given examples. However, the scope of the present invention is not to be construed to be limited by the examples.

Example 1
Preparation of 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (II)
Sodium hydroxide solution (48.16 g in 312 ml of water; 1.204 moles) was charged in the reactor and 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (III) (50 g; 0.301 moles) was added slowly to the solution at 25°C to 30°C. Formalin solution (35% aq. 51.65.01 g; 0.602 moles) was added to above solution in 1 hour and stirred for 1 hour. The reaction mixture was then cooled to 0°C to 5°C and an aq. solution of 5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl carbamimidothioate hydrochloride of Formula (IV) (63.08 g in 238 ml of water; 0.301 moles) was added dropwise to the cooled reaction mixture 1 hour and stirred for 2 hours. After completion of the reaction, 37 % conc. HCl (148.5 g 1.505 moles) was added dropwise in 30 minutes. The reaction mass was further stirred for 1 hour. The solids thus obtained were filtered and washed with water to get the compound of Formula (II) as white solids. The isolated product was dried under vacuum at 45°C to 50°C.(dry weight= 83 g; yield= 89. 15 %); Impurity of compound of Formula (V): 0.28 %.

Example 2
Preparation of 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (II):
Sodium hydroxide solution (48.16 g in 312 ml of water; 1.204 moles) was charged in the reactor and 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (III) (50 g; 0.301 moles) was added slowly to the solution at 25°C to 30°C. Formalin solution (35% aq. 51.65 g; 0.602 moles) was added to above solution in 1 hour. The reaction mixture was then cooled to 15°C to 18°C and an aq. solution of 5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl carbamimidothioate hydrochloride of Formula (IV) (63.08 g in 238 ml of water; 0.301 moles) was added to the cooled reaction mixture in 1 hour and stirred for 2 hours. After completion of the reaction, 37% conc. HCl (148.5 g; 1.505 moles) was added dropwise in 30 minutes and stirred for another 1 hour. The solids thus obtained was filtered and washed with water to obtain the compound of Formula (II) as white solids. The isolated product was dried under vacuum at 45°C to 50°C (dry weight= 79.40 g; yield= 85.28 %); Impurity of compound of Formula (V): 2.37 %.

Example 3
Comparative example as per WO2005095352 (Example 3) for the preparation of 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (II):
Sodium hydroxide solution (48.16 g in 312 ml of water; 1.204 moles) was charged in the reactor. To this solution, 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of Formula (III) (50 g; 0.301 moles) was added slowly at 25°C to 30°C. Added 35% aq. Formalin solution (51.65 g; 0.602 moles) to above solution in 1 hour and stirred for another 1 hour. An aq. solution of 5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl carbamimidothioate hydrochloride of Formula (IV) (63.08 g in 238 ml of water; 0.301 moles) was added dropwise to the reaction mixture at 25°C to 30°C in 30 minutes and stirred for 2 hours. After completion of the reaction, 35 % conc. HCl (156.95 g 1.505 moles) was added dropwise in 30 minutes and stirred for 1 hour. The solids thus obtained was filtered and washed with water to get the compound of Formula (II) as off-white solids. The isolated product was dried under vacuum at 50°C for 2 hours (dry weight= 74.5 g; yield= 80.02 %); Impurity of compound of Formula (V): 10.10%.
Following table summarizes the results of above examples:
Example # Yield (%) Impurity of Compound of Formula (V)
1 89.15 % 0.28 %
2 85.28 % 2.37 %
3 80.10% 10.10 %

From the above summarized table, it is evident that the process of the present invention as exemplified in examples 1 and 2 provide the compound of Formula (II) with the improved yield and having an impurity of compound of Formula (V) in very less amount as compared to example 3 of the comparative process.

Example 4
Preparation of Pyroxasulfone of Formula (I)
The process for preparation of pyroxasulfone comprises two steps as follows.
a. Preparation of 3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfanyl]-5,5-dimethyl-4H-1,2-oxazole of Formula (VIII):
Charged acetonitrile (157.2 g) and 4-[[(4,5-Dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol of formula (II) (40.0 g; 0.116 moles) as obtained in example 1, in the reactor. The reaction mixture was cooled to 15°C to 20°C and NaOH pellets (12.57 g; 0.314 moles) were added to it. The reaction mass was stirred at this temperature for 1.5 hours and cooled the reaction mass to 0°C to 5°C and purged freon gas (30.16 g; 0.349 moles) for 45 minutes. The reaction mixture was maintained for 1 hour at temperature upto 25°C and. After completion of the reaction, acetonitrile was distilled out under vacuum. To the concentrated mass, added toluene (144 g) and water (140 g), followed by addition of 30 % HCl, (19.54 g, 0.16 moles). The reaction mass was stirred for 15 to 20 minutes and separated the organic and aqueous layers. The aqueous layer was extracted with toluene (144 g) and the combined organic layers were washed with 10 % brine solution. The solvent toluene was distilled out under vacuum at 50°C to 55°C to obtain the compound of Formula (VIII) (40 g).

b. Preparation of Pyroxasulfone of Formula (I):
Example b(i):
3-[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfanyl]-5,5-dimethyl-4H-1,2-oxazole of Formula (VIII) (36.936 g: 0.1027 moles) as obtained above in step-a was charged to the reactor, acetic acid (110 g; 1.84 moles) and sodium tungstate dihydrate (1.05 g; 0.0031 moles) were added the mixture. 30 % hydrogen peroxide (29.09 g; 0.256 moles) was then added dropwise in 1 hour, at 23°C to 34°C and stirred the mixture at room temperature for 16 hours. After completion of the reaction, cooled reaction mass upto 30°C and added water (52.7 g) under stirring. Rection mass was further cooled to 10°C and stirred for 1 hour at this temperature. The reaction mass was filtered and washed with water (263 g), followed by petroleum ether wash (168 g). The solids obtained are dried at 45°C to 50°C under vacuum to get the Pyroxasulfone of Formula (I) (13. 18 g).

Example b(ii):
To 31.76g of 3-({[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfanyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole of Formula (VIII) prepared as per process of step-a was added 166g of acetic acid, 1.28g of sodium tungstate dihydrate and 22.24g of 50% hydrogen peroxide. The mixture was stirred at 25-35°C. Then the temperature was increased to 50-55°C and maintained for another 7 hours. The reaction was monitored by HPLC. After completion of reaction, the mixture was cooled to 25-30°C and diluted with 48g of water. The reaction mixture was then cooled to 0°C and maintained for 1 hour. The product was filtered out washed with water and petroleum ether and dried to yield 30.3g of Pyroxasulfone (Yield: 87.62%; Purity: 99.46%).

Example b(iii):
To 14.32g of 3-({[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfanyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole of Formula (VIII) prepared as per process of step-a was added 234.6g of acetic acid, 1.15g of sodium tungstate dihydrate and 10.03g of 50% hydrogen peroxide. The mixture was stirred at 25-34°C for 16 to 18 hours. After completion of reaction, 61.88g of water was added to reaction mixture to precipitate product. The product was filtered out washed with water and petroleum ether and dried to yield 14.67g of Pyroxasulfone (Yield: 94%; Purity: 99.77%).

Example b(iv):
A plug flow reactor was used to perform continuous reaction, to the said reactor was fed 40% solution in acetic acid of 3-({[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfanyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole of Formula (VIII) prepared as per process of step-a by first dosing line at the rate of 8ml/min, 50% aqueous solution of hydrogen peroxide by second dosing line at the rate of 2 ml/min and 20% aqueous solution of sodium tungstate by third dosing line at the rate of 0.7ml/min. The residence time of the reactor based on the total feed rate was 7 minutes and operating temperature was maintained between 95°C to 100°C. At the outlet of the reactor, a set point was maintained at 50-60°C and the reaction mixture was collected. The reaction mixture was diluted with water and then cooled to about 8°C to 10°C. The product was filtered out washed with water and petroleum ether and dried to yield Pyroxasulfone (Yield: 83.37%; Purity: 98.7%).
,CLAIMS:
1. A process for preparing a compound of Formula (II)

comprising: reacting a compound Formula (III) with a formylating agent and a compound of Formula (IV) or salt thereof,

at a temperature below 20°C.

2. The process as claimed in claim 1, wherein the reaction is carried out at temperature ranging from about -10°C to about 19°C.

3. The process as claimed in claim 1, wherein the reaction is carried out in presence of a base.

4. The process as claimed in claim 3, wherein the base is selected from the group comprising of an alkali metal hydroxide, alkali metal alkoxide, alkali metal carbonate or alkaline earth metal salts.

5. The process as claimed in claim 1, wherein the reaction is carried out in a solvent selected from the group comprising of water, alcohol, aromatic hydrocarbon, ether, amide, halogenated hydrocarbon aliphatic hydrocarbon or mixture thereof.

6. A compound of Formula (II) substantially free of 4,4’-methanediylbis[1-(methyl-3-(trifloromethyl)-1H-pyrazol-5-ol] of Formula (V) or tautomers thereof.

7. The compound as claimed in claim 6, wherein said compound of Formula (II) comprises less than 3% of compound of Formula (V) or tautomers thereof.

8. A process of preparation of Pyroxasulfone of Formula (I),

said process comprising:
a. reacting a compound Formula (III) with a formylating agent and a compound of Formula (IV) or salt thereof,

at a temperature below 20°C to get a compound of Formula (II); and

b. converting said compound of Formula (II) into Pyroxasulfone of Formula (I).

9. The process as claimed in claim 8, wherein the step b) comprises fluoromethylating compound of Formula (II) to get a compound of Formula (VIII);

and oxidizing said compound of Formula (VIII) to Pyroxasulfone of Formula (I).

10. The process as claimed in claim 9, wherein said oxidation of compound of Formula (VIII) is carried out at temperature ranging from about 0oC to about 120oC and in an organic solvent comprising acetic acid.

11. The process as claimed in claim 9, wherein said oxidation of compound of Formula (VIII) is carried out at temperature ranging from about 10oC to about 32oC in an organic solvent comprising acetic acid and a catalyst.

12. The process as claimed in claim 9, wherein said oxidation of compound Formula (VIII) is carried out at temperature ranging from about 80oC to about 120oC in an organic solvent comprising acetic acid and a catalyst wherein said reaction is performed in a continuous flow reactor.

13. The process as claimed in claim 11 or 12, wherein said catalyst is a metal catalyst.

14. The process as claimed in claim 13, wherein said metal catalyst is selected from group comprising of tungsten catalyst, molybdenum catalyst, titanium catalyst or zirconium catalyst.