Claims:1. A process for the preparation of Pyroxasulfone of Formula (I),

Formula (I)

wherein the process comprising the steps of:
a) reacting compound of formula (II) with sodium 2,2-difluoro-2-chloroacetate in presence of a base and a solvent to obtain a compound of Formula (III)

b) reacting compound of formula (III) with paraformaldehyde in presence of aqueous hydrochloric acid and an acid catalyst to obtain a compound of Formula (IV)

c) reacting compound of Formula (IV) with compound of Formula (V) or its salt in presence of a base to obtain a compound of Formula (VI)

d) reacting compound of Formula (VI) with an oxidizing agent to obtain the compound of Formula (I) or salt thereof.

2. The process as claimed in claim 1, wherein the base used in step a) is selected from alkali metal carbonates, such as sodium carbonate or potassium carbonate, alkali metal hydroxides such as sodium hydroxide or potassium hydroxide.
3. The process as claimed in claim 1, wherein the solvent used in step a) is selected from polar-aprotic solvents such as dimethylformamide (DMF), dimethylacetamide (DMAc) or nitrile solvents such as acetonitrile and propionitrile.
4. The process as claimed in claim 1, wherein the acid catalyst used in step b) is selected from phosphoric acid, sulfuric acid, or perchloric acid.
5. The process as claimed in claim 1, wherein the base used in step c) is selected from N-methyl-2-pyrrolidone (NMP), N-methyl morpholine, hydroxy ethyl morpholine, dimethyl piperazine, and bicyclic tertiary amines such as 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or 1 -methyl imidazole, 1,2,4-triazole, 1 ,4-diazabicyclo[2.2.2] octane (DABCO).
6. The process as claimed in claim 1, wherein the solvent used in step c) is selected from hydrocarbon solvents such as toluene, xylene, or mono chlorobenzene, ether solvents such as dimethoxymethane, 1,2-dimethoxy ethane, tetrahydrofuran, methyl tetrahydrofuran, 1,3-dioxane, or 1,4-dioxane, polar-aprotic solvents such a, dimethylformamide (DMF), dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), and nitrile solvents such as acetonitrile or propionitrile.
7. The process as claimed in claim 1, wherein the oxidizing agent used in step d) is selected from oxone, potassium persulfate or sodium persulfate.
, Description:FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Pyroxasulfone of Formula (I) or salt thereof.

Formula (I)

BACKGROUND OF THE INVENTION

Pyroxasulfone belongs to isoxazoline class of herbicides, which inhibits fatty acid synthesis. It is chemically known as 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ylmethylsulfonyl]-4,5-dihydro-5,5-dimethylisoxazole, compound of Formula (I).

Formula (I)
Pyroxasulfone is available in the market as water dispersible granule and suspension concentrate.
Pyroxasulfone or salts first disclosed in WO2002/062770A1 assigned to Ihara Chemical Industry. The said PCT discloses process for the preparation Pyroxasulfone, which involves oxidation of 3-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethanesulfonyl)-5,5-Dimethyl-2-isooxazoline with m-chloroperbenzoic acid (mCPBA), which is as shown below:

Further, the disclosed process involves use of m-chloroperbenzoic acid (mCPBA) for industrial purposes, which is expensive and has problems with handling and waste. Therefore, the manufacturing method described in WO2002/062770A1 is not practical for manufacturing on an industrial scale.

PCT Publication No. WO2020/240392A1 discloses multi step synthesis of Pyroxasulfone using continuous flow reaction conditions, which is as shown below:

Further in a method for producing Pyroxasulfone, involves oxidation of sulfide (S)-derivative, during this oxidation the reaction may be stopped by sulfoxide derivative (SO)-derivative.

Therefore, the sulfoxide (SO)-derivative remains as a by-product in the final product, which leads to quality deterioration and the possibility of phytotoxicity to crops. Since the physical and chemical properties of sulfoxide (SO)-derivative is very similar to the Pyroxasulfone (I), it leads to difficulty in purifying the final product.

Further, in the method for producing the Pyroxasulfone from the sulfide (S)-derivative, is requires that the oxidation reaction to be proceeds sufficiently, and the sulfoxide (SO)-derivative does not substantially remain in the final product.

Therefore, there is a need to develop an effective process for the preparation of Pyroxasulfone of Formula (I), wherein formation of by-products can be avoided to improvement in the yield, without impacting purity of product.

The purpose of the present invention is to provide a method to produce Pyroxasulfone of Formula (I), which overcomes the disadvantages associated with prior art processes as well as applicable at an industrial scale.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a process for the preparation of Pyroxasulfone compound of Formula (I), which is schematically represented as below:

SUMMARY OF THE INVENTION

The main aspect of the present invention is to provide a process for the preparation of Pyroxasulfone of Formula (I).

Formula (I)

In an aspect of the present invention provides process for the preparation of Pyroxasulfone compound of Formula (I), which comprises:

a) reacting compound of formula (II) with sodium 2,2-difluoro-2-chloroacetate in presence of a base and a solvent to obtain a compound of Formula (III)

b) reacting compound of formula (III) with paraformaldehyde or formaldehyde in presence of an aqueous acid and an acid catalyst to obtain a compound of Formula (IV)

c) reacting compound of Formula (IV) with compound of Formula (V) or its salt in presence of base to obtain a compound of Formula (VI)

d) reacting compound of Formula (VI) with an oxidizing agent to obtain the compound of Formula (I) or salt thereof.

In another aspect of the present invention is to provide a simple, economical, and commercially feasible process for the synthesis of Pyroxasulfone with a high yield.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Pyroxasulfone compound of Formula (I).

Formula (I)

In one embodiment the present invention provides a process for the preparation of Pyroxasulfone compound of Formula (I), which comprises:
a) reacting compound of formula (II) with sodium 2,2-difluoro-2-chloroacetate in presence of a base and a solvent to obtain a compound of Formula (III)

b) reacting compound of formula (III) with paraformaldehyde in presence of aqueous hydrochloric acid and an acid catalyst to obtain a compound of Formula (IV)

c) reacting compound of Formula (IV) with compound of Formula (V) or its salt in presence of base to obtain a compound of Formula (VI)

d) reacting compound of Formula (VI) with an oxidizing agent to obtain the compound of Formula (I) or salt thereof.

According to the present embodiment the step a) is carried out in presence of a base and a solvent.
Within the context of the present invention, the base used in step a) is selected from alkali metal carbonates, such as sodium carbonate, potassium carbonate, lithium carbonate and the like, and alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like. In a particular useful embodiment of the present invention potassium carbonate is used as a base.
Within the context of the present invention, the solvent used in step a) is selected from polar-aprotic solvents such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), and the like, and nitrile solvents such as acetonitrile, propionitrile, butyronitrile and the like. In a particular useful embodiment of the present invention, acetonitrile is used as a solvent.

According to the present embodiment, the step (b) is carried out in the presence of aqueous acid.

Within the context of the present invention, the aqueous acid used in step b) is selected from selected from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid and the like. In a particular useful embodiment of the present invention aqueous hydrochloric acid is used.

Within the context of the present invention, the acid catalyst used in step b) is selected from selected from phosphoric acid, sulfuric acid, perchloric acid, and the like. In a particular useful embodiment of the present invention phosphoric acid is used.

According to the present embodiment the step a) and step b) may be carried out at a temperature of about 80°C to 100°C.

According to the present embodiment the step c) is carried out in presence of a base and a solvent.

Within the context of the present invention, the base used in step c) is selected from N-methyl-2-pyrrolidone (NMP), N-methyl morpholine, hydroxy ethyl morpholine, dimethyl piperazine, and bicyclic tertiary amines such as 1 ,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1 ,5-diazabicyclo (4.3.0) non-5-ene (DBN), 1 -methyl imidazole, 1,2,4-triazole, 1 ,4-diazabicyclo [2.2.2] octane (DABCO) and the like. In a particular useful embodiment of the present invention N-methyl morpholine is used as a base.

Within the context of the present invention, the solvent used in step c) is selected from hydrocarbon solvents such as toluene, xylene, mono chlorobenzene, and the like, ether solvents such as dimethoxymethane, 1,2-dimethoxy ethane, tetrahydrofuran, methyl tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, and the like, polar-aprotic solvents such a, dimethylformamide (DMF), dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), and the like, and nitrile solvents such as acetonitrile, propionitrile, butyronitrile and the like. In a particular useful embodiment of the present invention, toluene is used as a solvent.

According to the present embodiment the step c) may be carried out at a temperature of about 40°C to 100°C.

According to the present embodiment the step d) is carried out in present of an oxidizing agent.

Within the context of the present invention the oxidizing agent used in step d) is selected from oxone, potassium persulfate, sodium persulfate or sodium hypochlorite pentahydrate (NaOCl.5H2O). In a particular useful embodiment of the present invention, oxone is used as an oxidizing agent.

According to the present embodiment the oxidation step d) may be carried out at a temperature of about 25°C to 90°C.

According to the present embodiment, the process for obtaining Pyroxasulfone is more economical, produces less by-products and impurities and further generates considerably less effluents as a result in improved yield.

The further embodiment of the present invention is illustrated by the following examples, which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. 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:

Charge dimethyl formamide (DMF) (20 mL, 2.0 vol), potassium carbonate (12.46 g, 1.5 eq), 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol compound of Formula (II) (10.0 g, 1.0 eq) and sodium 2,2-difluoro-2-chloroacetate (13.77 g, 1.5 eq) into 4-neck RBF equipped with chilled water condenser, overhead stirrer, and thermometer pocket. Heat the reaction mass to 90-95°C and maintain this temperature for 4h. After completion of SM, cool to 25°C and filter. Filtrates distill out DMF under reduced pressure. Reaction mass dissolved in ethyl acetate (60 mL) and washed with water (20 mL). Take ethyl acetate layer, dried over a sodium sulphate; remove the organic layer under reduced pressure to get the 10.40 gm desired product as pink viscous liquid (Yield: 80%).
Example-2:

5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole (CQP) compound of Formula (III) (10.0 gm, 1.0 eq), aqueous hydrochloric acid (25 mL), paraformaldehyde (PFA) (1.94 g, 1.4 eq) and H3PO4 (2 mL) were taken in a four neck RBF. The reaction mixture was heated to 85-90°C and maintained for 5-6 hrs. The reaction was monitored till the SM disappeared, then the reaction mass was cooled to 25-30°C, extracted with dichloromethane (2x50 mL) and concentrated organic phase under reduced pressure and dried to get 10.04 gm of 4-(chloromethyl)-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole (Yield: 82%).

Example-3:

5,5-dimethyl-4,5-dihydroisoxazol-3-yl carbamimidothioate hydrochloride compound of Formula (V) (1.1 eq), N-methyl morpholine (2.0 eq) and water (50 mL) charged in a three neck RBF. Reaction mixture heated at 55oC for 0.5h, then 4-(chloromethyl)-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole compound of Formula (IV) (34 gm, 1.0 eq) in toluene (50 mL) was added dropwise and reaction continued until consume the pyrazole compound (4 h). Reaction mass was cooled to 25-30°C, diluted with water and toluene layer separated. Aq. Phase extracted with Toluene (2x20 mL), combined organic phase concentrated under reduced pressure to obtain 42.0 gm of desired product (Yield: 91%).

Example-4A:

Compound of Formula (VI) (1.0 gm, 1.0 eq), acetonitrile (10 mL) and Oxone (3.0 eq) charged in a three neck RBF. Reaction mixture heated at reflux temperature for 12h, after the starting material consumption, allow the reaction mass to attain room temperature and filter through Buchner funnel, inorganic cake washed with acetonitrile (10 mL). Concentrate the filtrate under reduced pressure and dissolved in Ethyl acetate and washed with water (2x15 mL). Organic phase concentrated under reduced pressure and dried to get 0.86 gm of Pyroxasulfone (Yield: 79%).
Example-4B:

Compound of Formula (VI) (1.0 gm, 1.0 eq), acetonitrile (10 mL), potassium persulfate (3.0 eq) and H2SO4 (2.0 eq) charged in a three neck RBF. Reaction mixture heated at reflux temperature for 12h, after the starting material consumption, allow the reaction mass to attain room temperature and filter through Buchner funnel, inorganic cake washed with acetonitrile (10 mL). Concentrate the filtrate under reduced pressure and dissolved in Ethyl acetate and washed with water (2x15 mL). Organic phase concentrated under reduced pressure and dried to get 1.0 gm of Pyroxasulfone (Yield: 92%).