Processes and intermediates for preparation of various sulfone analogs of pyroxasulfone, oxaflutole and 5, 5-dimethyl-4H-1, 2-oxazole

Abstract

The present invention relates to a process for the preparation of direct precursors for the preparation of pyroxasulfone and oxaflutole, having formula (I). The invention relates to a process for the preparation of an isoxazoline, comprising a bromination reaction of the benzyl position in the absence of light irradiation (step a) followed by a sulfuration reaction of substituted bromine atoms (step b) and, after removal of the protecting group, a reaction of the exposed thiol or thiol radical with a substituted isoxazoline bearing a leaving group at the 3-position (step c), where Y = protecting group. In another variant of the invention, the pyroxasulfone or oxaflutole besilate direct precursor is synthesized from aryl methyl bromides by first forming a carbon-sulfur bond at the 3-position of 2-isoxazoline by replacing the leaving group at the 3-position, in particular an acid-derived residue, such as phosphoryl, sulfanyl, halo, cyano or carboxyl, with a suitable sulfurizing agent. The resulting adduct, which is an S-protected 3-thio-2-isoxazoline, can be treated with a base to remove the protecting groups to expose a thiol or thiol radical, which can then react with the aryl methyl bromide to form the pyroxasulfone or oxaflutole besilate direct precursor. Ar = aryl, Y = protecting group and X = leaving group.

Description

[0001] This application is a divisional application of the patent application for invention no. 202180047678.3 entitled "Processes and intermediates for the preparation of various sulfone analogs of pyroxasulfone, fenoxasulfone and 5,5-dimethyl-4H-1,2-oxazole". The original application corresponds to international application PCT / IB2021 / 055954, filed on July 2, 2021, with a priority date of July 10, 2020. TECHNICAL FIELD

[0002] The present invention relates to a process for the production of an immediate precursor for the preparation of various sulfone analogs of pyroxasulfone, fenoxasulfone and 5,5-dimethyl-4H-1,2-oxazole. BACKGROUND

[0003] Pyroxasulfone, chemical name 3-(5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl]methanesulfonyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole, has the following structural formula (1): (1).

[0004] Pyroxasulfone belongs to the class of 3-([ (hetero)aryl]methanesulfonyl)-4,5-dihydro-1,2- oxazoles and is used as a herbicide, in particular for the pre-emergence control of annual grasses and some broadleaf weeds in corn, soybean, wheat and other crops. The mode of action of pyroxasulfone affects the apical meristem and coleoptile development and inhibits the biosynthesis of very long chain fatty acids in plants, with superior herbicidal activity on grasses and broadleaf weeds at lower application rates compared to other commercial herbicides. The weeds controlled by pyroxasulfone are resistant to non-selective herbicides in transgenic crop fields. Pyroxasulfone has been classified in the Herbicide Resistance Action Committee Group K3.

[0005] Pyroxasulfone was first disclosed by Kumiai Chemical Industry Co., Ltd. and Ihara Chemical Industry Co., Ltd. in WO 2002 / 062770. It is available on the market as a water dispersible granule.

[0006] The chemical name is 3-[(2,5-dichloro-4-ethoxyphenyl)methylsulfonyl]-5,5-dimethyl-4H-1,2- oxazole, and has the following structural formula (2): .

[0007] Both pyrasulfotole and pyroxasulfone have the following common moieties: 5,5-dimethyl-4H-1,2-oxazole attached to an arylmethylsulfone through the 3-position, and are used as herbicides, particularly for pre-emergence control of grass and broadleaf weeds. Studies have shown that pyrasulfotole is an effective inhibitor of plant VLCFAE (very long chain fatty acid elongase (VLCFAE)) and should be classified in the K3 group of the Herbicide Resistance Action Committee. Pyrasulfotole inhibits VLCFAE activity of Arabidopsis thaliana recombinant fatty acid elongase 1 (FAE1) in a time-dependent manner, which has been shown in inhibition of VLCFAE by other well-known VLCFAE-inhibiting herbicides. On the other hand, pyrasulfotole inhibits VLCFAE activity of microsomal fractions of yellow foxtail seedling in a time-independent manner. This time-independent inhibition suggests a new inhibition mechanism of pyrasulfotole to VLCFAE, possibly like pyroxasulfone, which is classified in the same chemical class as pyrasulfotole, as has been shown in Journal of Pesticide Science, 2011, Vol. 36, No. 3, pp. 357-362.

[0008] Pyrasulfotole is a novel herbicide for rice fields discovered and developed by Kumiai Chemical Industry Co., Ltd. It exhibits excellent herbicidal activity against Echinochloa spp. and other annual weeds at 150-200 g a.i. / ha, has long residual activity, and has favorable toxicological, ecotoxicological, and environmental characteristics. The mode of action of pyrasulfotole was investigated, and has been shown to inhibit the biosynthesis of very long chain fatty acids in plants. Pyrasulfotole was registered in Japan in 2014, and various products containing pyrasulfotole have been launched. With its high efficacy and long residual activity, it is estimated that pyrasulfotole will contribute to efficient food production in the future, as cited from J Pestic Sci, 2019 Jul 25; 44(4): 282-289.

[0009] Additional herbicides containing the 5,5-dimethyl-4H-1,2-oxazole moiety have been reported in WO 2010 / 145992 and WO 2011 / 018486, which include but are not limited to: .

[0010] Preparation methods of pyroxasulfone are described in several patent applications, namely WO 2006 / 068092 in the name of Ihara, WO 2004 / 013106 in the name of Kumiai and Ihara and WO 2005 / 095352 in the name of Ihara.

[0011] In the synthetic pathway of pyroxasulfone described in (WO 2004 / 013106 and WO 2016 / 042435), the bromination reaction is performed with light irradiation. There is no report of a non- photochemical transformation of formula (III) to formula (II). The bromination of formula (II) at the benzyl position without light irradiation described in the present invention has benefits and advantages in the industrial process compared to the light dependent reaction.

[0012] The present invention discloses a process for the synthesis of direct precursors for the production of various sulfonyl analogs of pyroxasulfone, benzenesulfonazole and 5,5-dimethyl-4H-1,2-oxazole. SUMMARY

[0013] The present invention provides a process for preparing a compound of formula (I) or (I') , The process comprises the following steps: a) bromination of a starting material selected from the following compounds: to obtain the following compounds, respectively: ; b) thionation of the resulting compound of step a with a thionation agent to obtain the following compounds, respectively: wherein Y is a protecting group; c) substitution of the resulting thiol or thiolate produced from the compound of formula (II) or (II') of step b with a 2-isoxazoline moiety to produce a compound of formula (I).

[0014] The present invention also provides a process for preparing a compound of formula (III) or (III') , The process comprises bromination of a compound of formula (IV) or (IV') with a bromination reagent, respectively .

[0015] The present invention further provides a method for preparing direct precursors of pyroxasulfone or bensulfuron-methyl having formula (I) or (I') and various sulfone analogs of 5,5-dimethyl-4H-l,2-oxazole, the method comprising the steps of: d) reacting the isoxazole having formula (V) with a sulfurizing reagent to produce an S-substituted thioisoxazole having formula (VI); wherein X is a leaving group and Y is a protecting group; e) substituting the resulting mercaptan or mercaptide produced from the compound of formula (VI) of step d with an arylmethyl bromide compound having formula (VII) to produce a compound having formula (VIII) DETAILED DESCRIPTION

[0016] The present invention is a method for producing direct precursors of pyroxasulfone, bensulfuron-methyl and direct precursors for additional various sulfone analogs of 5,5-dimethyl-4H-l,2-oxazole using a sequence of bromination, reaction with a sulfurizing reagent to form a protected arylmethyl mercaptan, then deprotection and subsequent formation of a new carbon-sulfur bond to install the isoxazoline moiety. What is obtained is a material that only requires oxidation at the sulfur to form the known herbicide pyroxasulfone, bensulfuron-methyl and various sulfone analogs of 5,5-dimethyl-4H-l,2-oxazole.

[0017] The present invention is shown in Scheme 1. The present invention can be utilized with a range of brominating reagents in the presence of an oxidizing agent or elemental bromine, including hydrobromic acid which is inexpensive and readily available. Furthermore, the present invention can be utilized with a free radical initiator.

[0018] Furthermore, an efficient synthesis of bensulfuron-methyl has not been reported. Thus, there is an increasing need for an inexpensive, high-yielding and efficient synthesis route for bensulfuron-methyl.

[0019] The reaction of arylmethyl bromide compounds with sulfurizing reagents is known, however the need for long reaction times (WO 2016 / 042435 Al), catalysts (WO 2009 / 129954 A2, WO 2016 / 042435 Al), prolonged heating (DE 10200 506 306.6 Al, WO 2009 / 068170 A2) or the use of sulfurizing reagents with difficult to remove or non-volatile byproducts such as urea (WO 2007 / 071900 Al) means that these processes have room for improvement. Depending on the chemical nature and the means of desired isolation of the product, the judicious choice of sulfurizing reagents in the present invention allows the production of volatile, organic insoluble or highly water soluble byproducts after deprotection.

[0020] The present invention allows the selection of the production of volatile or insoluble byproducts or the sulfurizing reagent that hydrolyzes slowly, rapidly or in the presence of specific reagents depending on the requirements of the operator.

[0021] The present invention allows the very rapid substitution of the bromide with the sulfurizing reagent, allowing the extension of the present invention to arylmethyl bromides that would otherwise be prone to hydrolysis or side reactions.

[0022] The use of a range of sulfurizing reagents in step b according to scheme 1 allows the simplification and improvement of the product isolation sequence, for example, the use of thioacetate as the sulfurizing reagent produces a volatile ester byproduct in step c after base mediated deacylation of the formed S-arylmethyl thioacetate. In addition, step b can be performed using a nucleophilic catalyst such as a tertiary amine.

[0023] The use of sulfurizing reagents that produce volatile or non-organic soluble byproducts allows the compression of steps b and c into an integrated process that produces the direct precursors of pyroxasulfone or benzenesulfonazole in organic solvents, uncontaminated by materials that would hinder the oxidation of these materials to give these herbicides or would interfere with the product isolation procedure.

[0024] Step c is performed under basic conditions: suitable bases for creating a basic environment in the reaction mixture include alkali metal hydroxides, alkali metal bicarbonates, alkali metal alkoxides, alkali metal hydrides, organic bases and, where applicable, the corresponding alkaline earth metal bases. The amount of base is in the range of 2: 1 to 10: 1 relative to the arylmethylthiol starting material. In addition, step c can be performed using Rongalite, tris-(2-carboxyethyl)phosphine or other oxidized dithioform inhibitors and / or nucleophilic catalysts such as tertiary amines.

[0025] The synthesis of pyroxasulfone and benzenesulfonazole can be achieved by reacting a sulfurizing agent with an appropriate arylmethyl halide. Suitable sulfurizing reagents for such a process are nucleophilic sulfur-containing reagents such as xanthates, thiocarbonyl compounds (except thiourea), thiosulfates, sulfinites, substituted thioureas and thioamides.

[0026] The reaction of a sulfurizing reagent with an arylmethyl compound of formula (II) to yield an intermediate in the form Y-S-CH2Ar is depicted in Scheme 2 The reaction of a sulfurizing reagent with an arylmethyl compound of formula (VII) to yield an intermediate in the form Y-S-CH2Ar is depicted in Scheme 2 and described in the following table. Schemes 3 and 4 show the structures implied by the general formula in the table. Scheme 5 shows the basic scheme showing the chemical reactions involved in step c. The reactant in the form Y-S-CH2Ar is first treated with a base to expose the nucleophilic sulfide which reacts with a 2-isoxazoline having a leaving group in position 3, in particular an acid-derived residue such as a phosphoryl, sulfanyl, halogeno, cyano or carboxyl group. Substituted isoxazolines bearing a leaving group in position 3 have been described previously and the process is well known (WO 2011 / 063843 Al and WO 2006 / 038657 Al).

[0027] Step a of the present invention can be carried out without initiator. Furthermore, the reaction can be thermally generating free radicals without addition of an initiator.

[0028] Furthermore, step a of the present invention can be chlorination instead of bromination.

[0029] Furthermore, the present invention allows to combine steps b and c in the following way: the intermediate Y-S-CH2Ar is generated from BrCH2Ar and a sulfurizing reagent and treated in situ with a base to obtain the thiolate. Then, the thiolate reacts with a substituted isoxazoline bearing a leaving group in position 3 to form the product.

[0030] In one aspect of the present invention is a process for preparing a compound of formula (I) or (I') or The method comprises the following steps: a) brominating a starting material selected from the following compounds: or to obtain the following compounds, respectively: or ; b) sulfidizing the resulting compound of step a with a sulfidizing agent to obtain the following compounds, respectively: or ; c) substituting the resulting mercaptan or mercaptide resulting from the compound of formula (II) or (IT) of step b with a 2-isoxazoline moiety to produce a compound of formula (I).

[0031] In yet another aspect of the application is a method, wherein the method is carried out in an organic solvent selected from the list comprising aliphatic alcohols such as MeOH, EtOH, iPrOH, MeCN, DMF, NMP, DMSO, vinyl or propylene carbonate, DMA, cyclic ethers such as 1,4-dioxane or THF, and aqueous mixtures thereof or water itself.

[0032] In yet another aspect of the application is a method, wherein the method is carried out at a temperature between 0°C and 100°C.

[0033] In yet another aspect of the application is a method, wherein the method is carried out at a temperature between 20°C and 50°C.

[0034] In one aspect of the application is a method for preparing a compound of formula (III) or (III) or .

[0035] The method comprises brominating a compound of formula (IV) or (IV) with a brominating reagent, respectively, in the absence of light irradiation: or .

[0036] In yet another aspect of the application is a method, wherein the brominating reagent is selected from the list comprising Br2, HBr / H2O2 system, N-bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin.

[0037] In yet another aspect of the application is a method, wherein the method is carried out in an organic solvent selected from the list comprising: chlorinated solvents such as CH2Cl2, 1,2-dichloroethane, CHCl3, CCl4, ethylene carbonate or propylene carbonate, MeCN, water or mixtures thereof.

[0038] In yet another aspect of the application is a method, wherein the method is carried out at a temperature between 0 °C and 100 °C.

[0039] In yet another aspect of the application is a method, wherein the method is carried out at a temperature between 20 °C and 50 °C.

[0040] In yet another aspect of the application is a method, wherein the compound of formula I is .

[0041] In another aspect of the application is a method for the preparation of a direct precursor of pyroxasulfone or benzenesulfonazole, wherein the direct precursor of pyroxasulfone or benzenesulfonazole is synthesized from an aryl methyl bromide by first forming a carbon-sulfur bond at the 3-position by substitution of a leaving group at the 3-position of the 2-isoxazoline by a suitable sulfurizing reagent: wherein Y is a protecting group and X is a leaving group.

[0042] In yet another aspect of the application is a method, wherein the direct precursor of pyroxasulfone or benzenesulfonazole is an S-protected 3-thio-2-isoxazoline and treated with a base to remove the protecting group, thereby exposing a thiol or thiolate group: wherein Y is a protecting group and X is a leaving group.

[0043] In still another aspect of the application is a method, wherein the direct precursor of pyroxasulfone or benzenesulfonazole with a thiol or thiolate group is subsequently reacted with an aryl methyl bromide to form a direct precursor of pyroxasulfone or benzenesulfonazole: wherein Ar is an aryl group, Y is a protecting group and X is a leaving group.

[0044] In yet another aspect of the application is a method, which further comprises the step of oxidation, and thereby obtaining pyroxasulfone or benzenesulfonazole: .

[0045] Finally, the thioether analogues of formula (I) are oxidized to obtain herbicidally active compounds, i.e. pyroxasulfone, benzenesulfonazole, etc. The oxidation reaction is achieved by methods known in the art using oxidizing agents such as organic and inorganic peroxides; effective oxidizing agents include hydrogen peroxide, meta-chloroperoxybenzoic acid, peroxyacetic acid, peroxybenzoic acid, magnesium monoperoxyphthalate, potassium peroxymonosulfate, potassium permanganate and sodium periodate. As an alternative to the direct conversion of the sulfide function into a sulfone -SO2-, it is possible to consider the oxidation through the corresponding sulfoxide (-S(O)-), i.e. where the sulfoxide is isolated and subsequently oxidized to the sulfone. The oxidation can be carried out in water, in organic solvents and / or in any combination thereof. Organic solvents such as halogenated hydrocarbons (halogenated aliphatic hydrocarbons such as dichloromethane and chloroform or halogenated aromatic hydrocarbons such as chlorobenzene); ethers such as dioxane, tetrahydrofuran (THF) and diethyl ether; C1-C4 alkanols; ketones; and amides can be used. The temperature during oxidation can vary from 0 °C to 80 °C, with temperatures of 20 °C to 40 °C generally preferred. Illustrative procedures can be found in WO 2004 / 013106 (≡ EP 1541561).

[0046] The reactants and reagents in each step can be added to the reaction vessel consecutively; it is also feasible to feed two or more reactants simultaneously. The order of addition is not critical.

[0047] Definitions Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which the presently subject matter belongs.

[0048] As used herein, the term "alkyl" refers to branched, unbranched or cyclic carbon chains including methyl, ethyl, propyl, isopropyl, cyclopropyl, and the like.

[0049] As used herein, the term "2-isoxazoline" is a 5,5-dimethyl-4H-isoxazole.

[0050] As used herein, the term "S-substituted thioisoxazole" is a 5,5-dimethyl-4H-isoxazole bearing a substituted sulfur atom in the 3-position.

[0051] As used herein, the term "sulfurizing reagent" is a reagent capable of forming a new sulfur-carbon bond.

[0052] As used herein, the term "leaving group" is a molecular fragment that results from the homolytic bond cleavage and that carries a pair of electrons from the bond broken during the cleavage.

[0053] In particular, the leaving group can be, but is not limited to, a fluoroalkylsulfinate, an alkylsulfinate, an arylsulfinate, a chloride and a bromide.

[0054] In particular, "protecting group" can be, but is not limited to, all fragments under substituent Y disclosed in Scheme 2.

[0055] As used herein, the term "stable" when used in connection with a composition means that the composition is physically and chemically stable. As used herein, the term "chemically stable" means that no significant decomposition of the active ingredient is observed after storage in a sealed package at a temperature of 54 °C for at least 2 weeks. As used herein, the term "physically stable" means that no significant sedimentation is observed after storage in a sealed package at a temperature of 54 °C for at least 2 weeks.

[0056] As used herein, the term "a" or "an" includes singular and plural, unless specifically stated otherwise. Accordingly, the singular or plural form of the term "a", "an" or "at least one" are used interchangeably in the present application.

[0057] Throughout this application, the description of different embodiments has used the term "comprising" to describe the embodiments; however, the skilled person will understand that in some specific instances, the language "consisting essentially of" or "consisting of" can be used to describe the embodiments.

[0058] The term "about" herein specifically includes ±10% of the indicated value within a range. In addition, the endpoints of all ranges directed to the same component or property are included within the scope of the range and are independently combinable with each other, as well as the other ranges directed to the same component or property, unless the context clearly dictates otherwise.

[0059] It should be understood that in providing a range of parameters, the present application also provides all integers within the defined range and tenths thereof, as if the integers and tenths thereof were explicitly described herein. For example, "0.1% to 70%" includes 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, etc. up to 70%.

[0060] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference herein.

[0061] The following examples illustrate the practice of the subject application in some of its embodiments, but should not be construed as limiting the scope of the subject application. Other embodiments falling within the spirit and scope of the appended claims are part of the present application as will be apparent to a person skilled in the art in view of the specification and examples herein. The specification, including the examples, is intended to be merely exemplary and not limiting of the scope and spirit of the application.

[0062] Each embodiment disclosed herein is contemplated to apply to each of the other disclosed embodiments. Thus, all combinations of various elements described herein are within the scope of the application. In addition, the elements recited in the method embodiments can be used in combination with the compound embodiments described herein, and vice versa.

[0063] The application will be better understood by reference to the following examples, but one skilled in the art will readily recognize that the specific experiments detailed are only illustrative of the application as described more fully in the claims that follow thereafter.

[0064] The application is illustrated by the following examples without limiting the application thereby.

[0065] Example Bromination without initiator (step a.) Example 1 : 4-(bromomethyl)-5-(difluoromethoxy)-1 -methyl-3-(trifluoromethyl)- 1 H-pyrazole Dichloromethane (150 g) was added to a three necked round bottom flask equipped with a condenser and connected to a nitrogen flow. To the flask was added 5- (difluoromethoxy)-1,4-dimethyl-3-(trifluoromethyl)-1 H-pyrazole (10 g), HBr 48% solution (8.06) and hydrogen peroxide 28% solution (5.81 ) and the reaction mixture was purged under N2for 10 minutes. The reaction was then heated to 60°C and refluxed overnight. Additional 1.61 g of HBr 48% solution and 1.16 g of hydrogen peroxide 28% solution were added and refluxing was continued for 7 hours. Additional 1.61 g of HBr 48% solution and 1.16 g of hydrogen peroxide 28% solution were added and refluxing was continued overnight. The reaction mixture was diluted with 20 mL of water and transferred to a separatory funnel. The organic phase was separated and washed twice with 10% Na2S203aqueous solution (2 x 20 mL), the combined extracts were dried over MgS04and the solvent was removed under vacuum to give a yellow oil which was distilled to give 4-(bromomethyl)-5-(difluoromethoxy)-1 -methyl-3- (trifluoromethyl)-1 H-pyrazole (10.2 g, 88% purity, 76%).

[0066] Example 2: 4-(bromomethyl)-5-(difluoromethoxy)-1 -methyl-3-(trifluoromethyl)- 1 H-pyrazole Carbon tetrachloride (30 mL) was added to a three-necked round bottom flask equipped with a condenser and connected to a stream of nitrogen. To the flask was added 5-(difluoromethoxy)-l,4-dimethyl-3-(trifluoromethyl)-lH-pyrazole (2.16 g, 9.39 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (2.69 g, 9.41 mmol) and the reaction mixture was purged under N2for 10 minutes. The mixture was heated to reflux (16 hours). The reaction mixture was diluted with 20 mL of water and transferred to a separatory funnel. The organic phase was separated and washed twice with 10% aqueous Na2SO3(2 x 20 mL) and then the combined extracts were dried over MgSO4and the solvent was removed in vacuo to give 4-(bromomethyl)-5-(difluoromethoxy)-l-methyl-3-(trifluoromethyl)-lH-pyrazole as a yellow liquid (2.38 g, 82%).

[0067] Example 3: 4-(Bromomethyl)-5-(difluoromethoxy)-l-methyl-3-(trifluoromethyl)-lH- pyrazole Example 3: 4-(Bromomethyl)-5-(difluoromethoxy)-l-methyl-3-(trifluoromethyl)-lH- pyrazole

[0068] Reaction of arylmethyl bromides with sulfurizing agents (step b.) Example 4: S-((5-(Difluoromethoxy)-l-methyl-3-(trifluoromethyl)-lH-pyrazol-4- yl)methyl) ethanethioate S-((5-(difluoromethoxy)-l-methyl-3-(trifluoromethyl)-lH-pyrazol-4-yl)methyl) ethanethioate (0.47 g, 94.1% purity, 90%) was obtained by dissolving 4-(bromomethyl)-5- (difluoromethoxy)-l-methyl-3-(trifluoromethyl)-lH-pyrazole (0.50 g) in MeOH (10 mL) and adding a solution of KSAc (0.28 g) in water (5 mL). After stirring for 0.5 hours, the MeOH (5 mL) was removed in vacuo and the resulting mixture was extracted with ethyl acetate (2 x 10 mL), the combined extracts were dried over MgS04and the solvent removed in vacuo to give S-((5-(difluoromethoxy)-l-methyl-3- (trifluoromethyl)-lH-pyrazol-4-yl)methyl)ethanethioate (0.47 g, 94.1% purity, 90%).

[0069] Steps b and c are carried out together Example 5: 3-(5-(difluoromethoxy)-l-methyl-3-(trifluoromethyl)-lH-pyrazol-4- yl)methylsulfanyl-4H-5,5-dimethylisoxazole S-((5-(difluoromethoxy)-l-methyl-3-(trifluoromethyl)-lH-pyrazol-4-yl)methyl) ethanethioate (0.47 g, 94.1% purity, 90%) was obtained by dissolving 4-(bromomethyl)-5- (difluoromethoxy)-l-methyl-3-(trifluoromethyl)-lH-pyrazole (0.50 g) in MeOH (10 mL) and adding a solution of KSAc (0.28 g) in water (5 mL). After stirring for 0.5 hours, the MeOH (5 mL) was removed in vacuo and the resulting mixture was extracted with ethyl acetate (2 x 10 mL), the combined extracts were dried over MgS04and the solvent removed in vacuo to give S-((5-(difluoromethoxy)-l-methyl-3- (trifluoromethyl)-lH-pyrazol-4-yl)methyl)ethanethioate (0.47 g, 94.1% purity, 90%).

[0070] Arylmethyl bromide with S-protected 3-thio-2-isoxazoline Example 5: 3-(5-(difluoromethoxy)-l-methyl-3-(trifluoromethyl)-lH-pyrazol-4- yl)methylsulfanyl-4H-5,5-dimethylisoxazole Acetonitrile (20 mL) was sparged with nitrogen gas (10 minutes) with stirring. Dimethylthiocarbamide (0.706 g) was added, followed by trifluoroacetic acid (30 μΐ), then 3-bromo-5,5-dimethyl-4H-isoxazole (1.41 g) was added over 5 minutes at ambient temperature. The mixture was stirred under a nitrogen atmosphere (16 hours).

[0071] Separately, potassium carbonate (2.7 g) was dissolved in methanol (20 mL) and the mixture was heated to 50 °C with stirring. 4-(Bromomethyl)-5-(difluoromethoxy)-1-methyl-3- (trifluoromethyl)-1H-pyrazole (2.0 g) was added, followed by the previously prepared dimethylthiocarbamide / 3-bromo-5,5-dimethyl-4H-isoxazole adduct solution in acetonitrile over 0.5 h at 50 °C. Stirring was continued at 50 °C (2 h), then the reaction mixture was concentrated in vacuo to ~10 g weight and water (50 mL) was added. The resulting mixture was extracted with ethyl acetate (2 x 20 mL), and the ethyl acetate extracts were combined and the solvent removed in vacuo to give 3-(5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methylsulfanyl-4H-5,5-dimethylisoxazole as an orange oil (2.3 g, 79% purity, 78%).

Claims

1. A method for preparing compounds having formula (III) or (III'). The method involves brominating compounds having formula (IV) or (IV') with a brominating agent, respectively, in the absence of light irradiation: The brominating reagent is selected from the group consisting of: Br2, HBr / H2O2, N - Bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin.

2. The method according to claim 1, wherein, The method is carried out in an organic solvent selected from the group consisting of: chlorinated solvents selected from CH2Cl2, 1,2-dichloroethane, CHCl3, CCl4, ethylene carbonate or propylene carbonate, MeCN, water or mixtures thereof.

3. The method according to claim 1 or 2, wherein, The method is carried out at temperatures ranging from 0°C to 100°C.

4. The method according to claim 3, wherein, The method is carried out at temperatures ranging from 20°C to 50°C.

5. The method according to any one of the preceding claims, wherein, The method is used to prepare compounds having formula (I) or (I'). The method includes the following steps: a) Brominate a starting material selected from the following compounds in the absence of light irradiation: The following compounds were obtained respectively: b) The compound obtained in step a is vulcanized with a vulcanizing agent selected from the group consisting of: dimethyl thioformamide, thiosulfate, dithiooxanil, alkyl xanthate, thiobenzamide, etc. N -Substituted thiourea and thioacetate salts to obtain the following compounds, respectively: Where Y is a protecting group; c) Replace the resulting thiol or thioglycolate produced by the compound of formula (II) or (II') in step b with 2-isooxazoline to produce the compound having formula (I).

6. The method according to claim 5, wherein, The method is carried out in an organic solvent selected from the group consisting of: aliphatic alcohols such as MeOH, EtOH, iPrOH, MeCN, DMF, NMP, DMSO, ethylene carbonate or propylene carbonate, DMA, cyclic ethers such as 1,4-dioxane or THF, and aqueous mixtures thereof or water itself.

7. The method according to claim 5, wherein, The method is carried out at temperatures ranging from 0°C to 100°C.

8. The method according to claim 7, wherein, The method is carried out at temperatures ranging from 20°C to 50°C.

9. The method according to any one of the preceding claims, further comprising an oxidation step, and thereby obtaining sulfonylpyrazine or benzyloxazine: 。

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