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

Abstract

This invention provides a process for directly preparing precursors for the preparation of pyroxasulfone and phenoxasulfone. [Solution] The process for directly preparing the precursor includes a benzyl bromination reaction without light irradiation (step a), a subsequent vulcanization reaction (substitution of bromine atoms) (step b), and, after the protecting group has been removed, a reaction of the exposed thiol or thiolate with a substituted isoxazoline supporting a leaving group at the 3-position (step c). TIFF2026090651000048.tif54170 Here, Y is a protecting group.

Description

Technical Field

[0001] The present invention relates to a process for producing direct precursors for preparing various sulfone analogs of pyroxasulfone, fenoxasulfone, and 5,5-dimethyl-4H-1,2-oxazole.

Background Art

[0002] 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):

Chem.

[0003] Pyroxasulfone belongs to the class of 3-([(hetero)aryl]methanesulfonyl)-4,5-dihydro-1,2-oxazoles and is used as a herbicide, particularly for pre-emergence control of annual grasses and several broadleaf weeds in corn, soybeans, wheat, and other crops. The mechanism of action of pyroxasulfone is involved in the development of apical meristems and coleoptiles and inhibits the biosynthesis of very long-chain fatty acids in plants with excellent herbicidal activity against grass weeds and broadleaf weeds at low application rates compared to other commercially available herbicides. In the field of genetically modified crops, weeds controlled by pyroxasulfone were resistant to non-selective herbicides. Pyroxasulfone has been classified into group K3 of the Herbicide Resistance Action Committee.

[0004] Pyroxasulfone was first disclosed by Kumiai Chemical Industry Co., Ltd. and Ihara Chemical Industry Co., Ltd. in International Publication No. WO 2002 / 062770 pamphlet. It is commercially available in the market as a water-dispersible granule.

[0005] Phenoxasulfone (chemical name: 3-[(2,5-dichloro-4-ethoxyphenyl)methylsulfonyl]-5,5-dimethyl-4H-1,2-oxazole) has the following structural formula (2): [ka]

[0006] Both phenoxasulfone and pyroxasulfone contain the same residue, namely 5,5-dimethyl-4H-1,2-oxazole, linked to arylmethylsulfone via the 3-position, and are used as herbicides, particularly for pre-emergence control of grass weeds and broadleaf weeds. Research has suggested that phenoxasulfone is a powerful inhibitor of plant VLCFAE (very-long-chain fatty acid elongase) and should be classified as a K3 group herbicide by the Herbicide Resistance Countermeasures Committee. The VLCFAE activity of recombinant fatty acid elongation 1 (FAE1) in Arabidopsis thaliana was inhibited by phenoxasulfone in a time-dependent manner, which is consistent with VLCFAE inhibition by other well-known VLCFAE-inhibiting herbicides. On the other hand, VLCFAE activity in the microsomal fraction of yellowed barnyard grass seedlings was inhibited by phenoxasulfone in a time-independent manner. This time-independent inhibition, similar to that of pyroxasulfone which is classified in the same chemical category as phenoxasulfone, established a novel inhibition mechanism of VLCFAEs by phenoxasulfone, which is also shown in Journal of Pesticide Science, 2011, Vol.36, Issue 3, pp.357-362.

[0007] Phenoxasulfone is a novel rice herbicide discovered and developed by Kumiai Chemical Industry Co., Ltd. It exhibits excellent herbicidal activity and long residual effect against Echinochloa species and other annual weeds at 150-200 g ai / ha, and possesses favorable toxicological, ecotoxicological, and environmental profiles. The mechanism of action of phenoxasulfone has been investigated, and it has been found to inhibit the biosynthesis of very long-chain fatty acids in plants. Phenoxasulfone was approved in Japan in 2014, and various products containing phenoxasulfone have become available. As shown in J. Pestic Sci., 2019, July 25;44(4):282-289, its high potency and long residual effect suggest that phenoxasulfone will contribute to efficient food production in the future.

[0008] Further herbicides containing 5,5-dimethyl-4H-1,2-oxazole residues, such as (but not limited to) those shown in the following formulas, were reported in International Publication No. 2010 / 145992 and International Publication No. 2011 / 018486: [ka]

[0009] Methods for preparing pyroxasulfone have been described in several patent applications, for example, in International Publication No. 2006 / 068092 (Applicant: Ihara), International Publication No. 2004 / 013106 (Applicants: Kumiai and Ihara), and International Publication No. 2005 / 095352 (Applicant: Ihara). [Overview of the project] [Problems that the invention aims to solve]

[0010] The synthesis pathway for pyroxasulfone described in International Publication No. 2004 / 013106 and International Publication No. 2016 / 042435 involves the bromination reaction. However, this was carried out using light irradiation. There are no reports of conversion from formula (III) to formula (II) by means other than photochemical reaction. Bromination of formula (II) at the benzylic position without requiring light irradiation, as described in the present invention, has advantages and benefits in industrial processes compared to light-dependent reactions.

[0011] The present invention discloses a process for synthesizing direct precursors for producing various sulfone analogs of pyroxasulfone, phenoxasulfone, and 5,5-dimethyl-4H-1,2-oxazole. [Means for solving the problem]

[0012] The present invention provides a process for preparing compounds of formula (I) or (I'), [ka] This includes the following steps: a) Brominate a starting material selected from the following compounds: [ka] Steps to obtain the following compounds: [ka] b) The compound obtained in step a is vulcanized with a vulcanizing agent to obtain the following compounds: [ka] (In the formula, Y is a protecting group.) c) A step in which a thiol or thiolate obtained from the compound of formula (II) or (II') in step b is substituted with a 2-isoxazoline residue to obtain the compound of formula (I).

[0013] The present invention also provides a process for preparing compounds of formula (III) or (III'). [Chemical formula] It involves brominating each of the compounds of formula (IV) or (IV') using a brominating agent without light irradiation. [Chemical formula]

[0014] The present invention further provides a process for preparing direct precursors of pyroxasulfone or phenoxysulfone of formula (I) or (I'), and various sulfone analogs of 5,5-dimethyl-4H-1,2-oxazole, which includes the following steps: d) Reacting an isoxazole of formula (V) with a vulcanizing agent to create an S-substituted thioisoxazole of formula (VI); [Chemical formula] (where X is a leaving group and Y is a protecting group); e) Substituting the thiol or thiolate compound obtained from formula (VI) in step d with an arylmethyl-bromide compound of formula (VII) to obtain a compound of formula (VIII). [Chemical formula] **Embodiments for Carrying out the Invention**

[0015] The present invention provides a method for producing direct precursors to pyroxasulfone, phenoxasulfone, and further, direct precursors to various sulfone analogs of 5,5-dimethyl-4H-1,2-oxazole, using a series of reactions including bromination, reaction with a vulcanizing agent to form a protected arylmethanethiol, then deprotection and subsequent formation of a carbon-sulfur bond, thereby attaching an isoxazoline residue. The substance thus obtained can form various sulfone analogs of the known herbicides pyroxasulfone, phenoxasulfone, and 5,5-dimethyl-4H-1,2-oxazole, requiring only oxidation of the sulfurous portion.

[0016] The present invention is shown in Figure 1. [ka]

[0017] The three-step synthesis process is characterized by the following path: a. The bromination reaction is carried out under radical reaction conditions. b. A vulcanizing agent (a sulfur nucleophile with a protecting group) is introduced, which substitutes for the bromine atom. c. Remove the protecting group and react the exposed thiol or thiolate with a substituted isoxazoline that has a leaving group supported at the 3-position.

[0018] In the present invention, a series of bromination reagents, including inexpensive and readily available hydrobromic acid, can be used in the presence of an oxidizing agent or elemental bromine. Furthermore, the present invention can be carried out using a radical reaction initiator.

[0019] Furthermore, an efficient method for synthesizing phenoxasulfone has yet to be published. Therefore, there is an increasing need for an inexpensive, high-yielding, and highly efficient synthetic route to obtain phenoxasulfone.

[0020] Although the reaction between arylmethyl bromide compounds and vulcanizing agents is known, these processes have drawbacks and are therefore in need of improvement: long reaction times (International Publication No. 2016 / 042435A1), catalysts (International Publication No. 2009 / 129954A2, International Publication No. 2016 / 042435A1), long heating times (German Patent Application Publication No. 10 200 506 306.6A1, International Publication No. 2009 / 068170A2), or the formation of difficult-to-remove or non-volatile by-reaction products such as urea (International Publication No. 2007 / 071900A1). In the present invention, if the vulcanizing agent is wisely selected, it is possible to generate volatile, organic-insoluble, or highly water-soluble by-reaction products after deprotection, depending on their chemical properties and the desired means for isolating the reaction products.

[0021] In this invention, the operator can select a vulcanizing agent according to their needs to obtain volatile or insoluble by-reaction products, or to hydrolyze the product slowly, quickly, or in the presence of a specific reagent.

[0022] In this invention, it is possible to replace the bromide with the vulcanizing agent very rapidly, thus other The present invention can also be applied to arylmethyl bromide, which is prone to hydrolysis or side reactions.

[0023] By using a series of vulcanizing agents in step b shown in Figure 1, the isolation process of the reaction product can be simplified and improved. For example, using a thioacetate as the vulcanizing agent allows for the base-mediated deacylation of the formed S-arylmethyl thioacetate in step c, yielding a volatile ester by-reaction product. Furthermore, step b can also be carried out using a nucleophilic catalyst, such as a tertiary amine.

[0024] By using a vulcanizing agent that produces volatile or organic solvent-insoluble by-reaction products, steps b and c can be shortened to create an integrated process for preparing direct precursors to pyroxasulfone or phenoxasulfone that are not contaminated in organic solvents with substances that may interfere with the oxidation of the herbicide-giving substance or interfere with the isolation procedure of the reaction product.

[0025] Step c is carried out under basic conditions, and suitable bases for creating an alkaline environment in the reaction mixture include: alkali metal hydroxides, alkali metal bicarbonates, alkali metal alkoxides, alkali metal hydrides, organic bases, and, if applicable, corresponding alkaline earth bases. The amount of the base is in the range of (2:1) to (10:1) relative to the starting material arylmethanethiol. Furthermore, step c may also be carried out using rongalit, tris-(2-carboxyethyl)phosphine, or other inhibitors of oxidative disulfide formation, and / or nucleophilic catalysts such as tertiary amines.

[0026] Pyroxasulfone and phenoxasulfone can also be synthesized by reacting a vulcanizing agent with a suitable arylmethyl halide. Suitable vulcanizing agents for such processes include: nucleophilic, sulfur-containing reagents, such as xanthogenic salts, thiocarbonyl compounds (excluding thiourea), thiosulfates, sulfinates, substituted thioureas, and thioamides.

[0027] The vulcanizing agent reacts with the arylmethyl compound of formula (II) to produce an intermediate having the form YS-CH2Ar, as shown in Figure 2. [ka]

[0028] The vulcanizing agent reacts with the arylmethyl compound of formula (VII) to produce an intermediate having the form YS-CH2Ar, as shown in Figure 2. [ka] (In the formula, X is a halide and Y is a protecting group.)

[0029] Figure 2. Intermediates containing various "Y" components. These are listed in the following table.

[0030] [Table 1]

[0031] Figures 3 and 4 show the structure represented by the general formulas in the table. [ka]

[0032] Sodium is shown as a representative counterion for sulfonyl salts. [ka]

[0033] Sodium is shown as a representative counterion for sulfonyl salts.

[0034] Figure 5 shows the basic scheme illustrating the chemical reaction included in step c. YS-CH2 The reactant in the form of Ar is first treated with a base to expose the nucleophilic sulfide, which then reacts with 2-isoxazoline having a leaving group at the 3-position (particularly acid-derived residues, such as phosphoryl, sulfanyl, halo, cyano, or carboxyl groups). [ka]

[0035] Substituted isoxazolines with a leaving group at the 3rd position have been previously published, and the process is well known (International Publication No. 2011 / 063843A1 and International Publication No. 2006 / 038657A1).

[0036] Step a of the present invention can also be carried out without an initiator. Furthermore, the reaction may generate radicals thermally without the addition of an initiator.

[0037] Furthermore, in step a of the present invention, chlorination can be used instead of bromination.

[0038] Furthermore, according to the present invention, steps b and c can also be combined as follows: an intermediate YS-CH2Ar is generated from BrCH2Ar and a vulcanizing agent, and treated with a base in an insitz to obtain a thiolate. The thiolate is then reacted with a substituted isoxazoline having a leaving group supported at the 3-position to form a reaction product.

[0039] One aspect of the present invention is formula (I) or (I') [ka] A process for preparing the compound, comprising the following steps: a) Brominate a starting material selected from the following compounds: [ka] Steps to obtain the following compounds: [ka] b) The compound obtained in step a is vulcanized with a vulcanizing agent to obtain the following compounds: [ka] c) A step in which a thiol or thiolate obtained from the compound of formula (II) or (II') in step b is substituted with a 2-isoxazoline residue to obtain the compound of formula (I).

[0040] Yet another aspect of the present invention is a process carried out in an organic solvent selected from the following list: 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 mixtures thereof with water, or water itself.

[0041] Yet another aspect of the present invention is a process that is carried out at a temperature of 0°C to 100°C.

[0042] Yet another aspect of the present invention is that the process is carried out at a temperature of 20°C to 50°C. It is a process.

[0043] One aspect of the present invention is formula (III) or (III') [ka] A process for preparing a compound of formula (IV) or (IV') [ka] This process involves brominating each of the compounds using a bromination reagent without light irradiation.

[0044] Yet another aspect of the present invention is a process in which the bromination reagent is selected from the following list: Br2, HBr / H2O2 system, N-bromosuccinimide, and 1,3-dibromo-5,5-dimethylhydantoin.

[0045] Yet another aspect of the present invention is a process carried out in an organic solvent selected from the following list: chlorinating solvents such as CH2Cl2, 1,2-dichloroethane, CHCl3, CCl4, ethylene carbonate or propylene carbonate, MeCN, water, or mixtures thereof.

[0046] Yet another aspect of the present invention is a process that is carried out at a temperature of 0°C to 100°C.

[0047] Yet another aspect of the present invention is a process that is carried out at a temperature of 20°C to 50°C.

[0048] Yet another aspect of the present invention is a process in which the compound of formula I is of the following formula: [ka]

[0049] Another aspect of the present invention is a process for preparing a direct precursor of pyroxasulfone or phenoxasulfone, wherein the direct precursor of pyroxasulfone or phenoxasulfone is first synthesized from arylmethyl bromide by replacing the leaving group at the 3-position with a suitable vulcanizing agent, thereby forming a carbon-sulfur bond at the 3-position of 2-isoxazoline: [ka] (In the formula, Y is a protecting group and X is a leaving group.)

[0050] Yet another aspect of the present invention is a process in which the direct precursor of pyroxasulfone or phenoxasulfone is an S-protected 3-thio-2-isoxazoline, and the protecting group is removed using a base to expose the thiol or thiolate group: [ka] (In the formula, Y is a protecting group and X is a leaving group.)

[0051] Yet another aspect of the present invention is a process of reacting a direct precursor of pyroxasulfone or phenoxasulfone having a thiol or thioate group with arylmethyl bromide to form a direct precursor of pyroxasulfone or phenoxasulfone: [ka] (In the formula, Ar is an aryl group, Y is a protecting group, and X is a leaving group.)

[0052] Yet another aspect of the present invention is the oxidation step, and thereby pyroxasulfone Or a process further comprising obtaining phenoxasulfone: [ka]

[0053] Finally, the thioethers of the formula (I) analogs are oxidized to yield compounds with herbicidal activity, namely pyroxasulfone, phenoxasulfone, etc. This oxidation reaction is achieved by methods known in the art using oxidizing agents such as organic and inorganic peroxides. Usable oxidizing agents include: hydrogen peroxide, m-chloroperoxybenzoic acid, peroxyacetic acid, perbenzoic acid, magnesium monoperoxyphthalate, potassium peroxymonosulfate, potassium permanganate, and sodium periodate. Instead of directly converting the sulfide functional value to sulfone-SO2-, an equivalent is used. Another possible method involves an oxidation reaction via a sulfoxide (-S(O)-), i.e., isolating the sulfoxide and then oxidizing it to a sulfone. This oxidation can be carried out in water, organic solvents, and / or various combinations thereof. Suitable organic solvents include: halogenated hydrocarbons (halogenated aliphatic hydrocarbons, e.g., dichloromethane and chloroform, or halogenated aromatic hydrocarbons, e.g., both chlorobenzene); ethers, e.g., dioxane, tetrahydrofuran (THF), and diethyl ether; C1-C4 alkanols; ketones; and amides. The oxidation temperature can be varied between 0°C and 80°C, but is usually preferred between 20°C and 40°C. An example of the procedure can be found in International Publication No. 2004 / 013106 (≡European Patent No. 1541561).

[0054] In each step, the reactants and reagents can be converted sequentially into the reaction vessel, or two or more reactants can be fed simultaneously. There are no requirements regarding the order of addition.

[0055] definition Unless otherwise specified, the technical and academic terms used herein have the meanings that are generally understood by those skilled in the art relating to the subject matter.

[0056] As used herein, the term "alkyl" refers to a branched, unbranched, or cyclic carbon chain, including methyl, ethyl, propyl, isopropyl, cyclopropyl, and the like.

[0057] As used herein, the term "2-isoxazoline" refers to 5,5-dimethyl-4H-isoxazole.

[0058] As used herein, the term "S-substituted thioisoxazole" refers to 5,5-dimethyl-4H-isoxazole, which supports a sulfur atom substituted at the 3-position.

[0059] As used herein, the term "vulcanizing agent" refers to a reactant capable of forming novel sulfur-carbon bonds.

[0060] As used herein, the term “leaving group” refers to a molecular fragment resulting from heterolytic bond cleavage, which removes an electron pair from a bond broken during fragmentation.

[0061] Specifically, the leaving group may be, but is not limited to, fluoroalkylsulfinates, alkylsulfinates, arylsulfinates, chlorides, and bromides.

[0062] Specifically, the "protecting group" may be any of the fragments disclosed as substituent Y in Figure 2, but is not limited to these.

[0063] As used herein, the term “stable,” when used in relation to a composition, means that the composition is physically and chemically stable. As used herein, the term “chemically stable” means that no significant degradation of the active ingredient was observed after storage in sealed packaging at a temperature of 54°C for at least two weeks. As used herein, the term “physically stable” means that no significant precipitation was observed after storage in sealed packaging at a temperature of 54°C for at least two weeks.

[0064] The indefinite articles "a" or "an," as used herein, mean singular and plural, respectively, unless otherwise specified. Therefore, the terms "a," "an," or "at least one" are interchangeable in this application.

[0065] Throughout this application, the descriptions of various embodiments have been written using the term "comprising." However, as those skilled in the art will readily understand, in some specific examples, a particular embodiment could instead be described using the phrase "consisting essentially of" or "consisting of."

[0066] In this specification, the term "about" specifically includes a range of ±10% of the given numerical value. Furthermore, in this specification, the endpoints of all ranges for the same component or property include those endpoints and can be combined independently, and all intermediate points and intermediate ranges are included.

[0067] It will be understood that, given a parameter range, all integers and “some tenths thereof” within that range are also given by the present invention as if those integers and “some tenths thereof” were explicitly stated herein. For example, “0.1% to 70%” includes 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, and so on, up to 70%.

[0068] All publications, patents, and patent applications described herein are incorporated herein by reference as if each individual publication, patent, and patent application were incorporated specifically and individually by reference.

[0069] The following embodiments illustrate the implementation of the subject matter of the present invention in several forms, but this should not be considered to limit the scope of the subject matter of the present invention. Other embodiments that fall within the spirit and scope of the appended claims and are apparent to those skilled in the art upon consideration of this specification and the examples contained herein are also part of the present invention. This specification, including the examples, is intended to be illustrative only and does not limit the scope and spirit of the present invention.

[0070] Each embodiment disclosed herein is considered applicable to each of the other disclosed embodiments. Therefore, all combinations of the various elements described herein are encompassed within the scope of the present invention. In addition, elements referenced in the process embodiments can be used in combination with the compound embodiments described herein, and vice versa.

[0071] The present invention can be better understood by referring to the following examples, but those skilled in the art will readily recognize that the specific experiments detailed are merely for the purpose of illustrating the invention as fully described in the subsequent claims.

[0072] The present invention will be described by the following examples, but this does not limit the present invention. [Examples]

[0073] Bromination without initiator (step a) Example 1: 4-(bromomethyl)-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole [ka] Dichloromethane (150 g) was added to a three-necked round-bottom flask equipped with a condenser and connected to a nitrogen stream. 5-(difluoromethoxy)-1,4-dimethyl-3-(trifluoromethyl)-1H-pyrazole (10 g), a 48% solution of HBr (8.06), and a 28% solution of hydrogen peroxide (5.81) were added to the flask, and the reaction mixture was heated under N2 for 10 minutes. The reaction mixture was then heated to 60°C and refluxed overnight. 1.61 g of 48% HBr solution and 1.16 g of 28% hydrogen peroxide solution were added, and reflux was continued for 7 hours. 1.61 g of 48% HBr solution and 1.16 g of 28% hydrogen peroxide solution were added, and reflux 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 mixed twice with 10% Na2S2O3 aqueous solution (2 × 20 m³). L) Wash, combine the extracts, dry them on MgSO4, and remove the solvent under vacuum. A yellow oily substance was obtained, which was then distilled to yield 4-(bromomethyl)-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole (10.2g, 88% purity, 76%).

[0074] Example 2: 4-(bromomethyl)-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole [ka] 30 mL of carbon tetrachloride was added to a three-necked round-bottom flask equipped with a condenser and connected to a nitrogen stream. 2.16 g, 9.39 mmol of 5-(difluoromethoxy)-1,4-dimethyl-3-(trifluoromethyl)-1H-pyrazole and 2.69 g, 9.41 mmol of 1,3-dibromo-5,5-dimethylhydantoin were added to the flask, and the reaction mixture was purged under N2 for 10 minutes. The mixture was then heated and refluxed for 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 (2 × 20 mL) with a 10% Na2SO3 aqueous solution. The extracts were then combined, dried on MgSO4, and the solvent was removed under vacuum to obtain 4-(bromomethyl )-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole was obtained as a yellow liquid (2.38 g, 82%).

[0075] Example 3: 4-(bromomethyl)-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole [ka] Take 2,4-dimethyl-5-trifluoromethyl-2H-pyrazole-3-ol (920 mg, 4.0 mmol, 1.0 equivalent) and place it in CCl4 (20 mL), and so on. The mixture obtained was sparged with nitrogen for 10 minutes while stirring vigorously. While continuing to sparge and stir, 1,3-dibromo-5,5-dimethylhydantoin (572 mg, 2.0 mmol, 0.5 equivalents) was added, followed by AIBN (100 mg, 0.41 mmol, 0.10 equivalents). The mixture was heated under reflux (3 hours), then poured onto ice (100 g), and 100 mL of 5% sodium sulfite aqueous solution was added. The mixture was extracted with CH2Cl2 (3 × 20 mL), and the organic extracts were combined, washed with water (100 mL) and saline solution (50 mL), passed through a silica plug, washed with CH2Cl2 (50 mL), and concentrated to obtain 4-(bromomethyl)-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole as a slightly yellow oily substance (891 mg, 84%).

[0076] Reaction of arylmethyl bromide with vulcanizing agent (step b) Example 4: S-((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl)methyl)ethanethioate [ka] 4-(bromomethyl)-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole (0.50 g) was added to MeOH (10 mL), and a solution of KSAc (0.28 g) in water (5 mL) was added. After stirring for 0.5 hours, the MeOH (5 mL) was removed under vacuum, and the resulting mixture was extracted with ethyl acetate (2 × 10 mL). The extracts were combined and dried on MgSO4 under vacuum. Upon removal of the solvent, S-((5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl)methyl)ethanethioate was obtained (0.47 g, 94.1% purity, 90%).

[0077] Simultaneous implementation of steps b and c Example 5: 3-(5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl)methylsulfanyl-4H-5,5-dimethylisoxazole [ka] 4-(bromomethyl)-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole (0.50 g) was added to MeOH (10 mL), and KSAc (0.28 g) was added. After stirring for 0.5 hours, the mixture was filtered, and the filtrate was added to a mixture of potassium carbonate (0.55 g) and 3-bromo-5,5-dimethyl-4H-isoxazole (0.35 g) under reflux conditions over a period of 1 hour or more. Reflux was continued for a further 3 hours, and then the methanol solvent was removed under vacuum at 40°C. The mixture was vigorously stirred at ambient temperature (0.5 hours) to partition it between water (10 mL) and methyl tert-butyl ether (10 mL). When the methyl tert-butyl ether fraction was concentrated, an orange oily substance, 3-(5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl)methylsulfanyl-4H-5,5-dimethylisoxazole, was obtained (1.67 g, 15.3% purity, 44%).

[0078] Arylmethyl bromide and S-protected 3-thio-2-isoxazoline Example 6: 3-(5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl)methylsulfanyl-4H-5,5-dimethylisoxazole [ka] Acetonitrile (20 mL) was sparged with nitrogen (10 minutes) while stirring. Dimethylthioformamide (0.706 g) was added, followed by trifluoroacetic acid (30 μL), and then 3-bromo-5,5-dimethyl-4H-isoxazole (1.41 g) was added over 5 minutes at ambient temperature. This mixture was stirred under a nitrogen atmosphere (16 hours).

[0079] Separately, potassium carbonate (2.7 g) was placed in methanol (20 mL), and the mixture was heated to 50°C while stirring. 4-(bromomethyl)-5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole (2.0 g) was added, followed by the addition of a pre-prepared solution of dimethylthioformamide / 3-bromo-5,5-dimethyl-4H-isoxazole adduct in acetonitrile, which was added over 0.5 hours at 50°C. After stirring at 50°C for 2 hours, the reaction mixture was concentrated under vacuum until its weight was approximately 10 g, and water (50 mL) was added. The mixture thus obtained was extracted with ethyl acetate (2 × 20 mL), and the ethyl acetate extract was combined with the mixture. The solvent was then removed under vacuum to obtain 3-(5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl)methylsulfanyl-4H-5,5-dimethylisoxazole as an orange oily substance (2.3 g, 79% purity, 78%).

Claims

1. A process for preparing a compound of formula (I) or (I'), 【Chemistry 1】 a) Brominate a starting material selected from the following compounds: 【Chemistry 2】 Steps to obtain the following compounds: 【Transformation 3】 b) The compound obtained in step a is vulcanized using a vulcanizing agent to obtain the following compounds, respectively: 【Chemistry 4】 (In the formula, Y is a protecting group); c) Substituting the thiol or thiolate obtained from the compound of formula (II) or (II') in step b with a 2-isoxazoline residue to obtain the compound of formula (I); A process that includes this.

2. The process according to claim 1, wherein the vulcanizing agent is selected from the group consisting of dimethylthioformamide, thiosulfate, dithiooxamide, alkyl xanthogenic acid, thiobenzamide, N-substituted thiourea, and thioacetate.

3. The process according to claim 1, wherein the process is carried out in an organic solvent selected from the group consisting of aliphatic alcohols such as MeOH, EtOH, iProOH, MeCN, DMF, NMP, DMSO, ethylene carbonate or propylene carbonate, DMA, cyclic ethers such as 1,4-dioxane or THF, and a mixture thereof with water, or water itself.

4. The process according to claim 1, wherein the process is carried out at a temperature of 0°C to 100°C.

5. The process according to claim 4, wherein the process is carried out at a temperature of 20°C to 50°C.

6. The process according to any one of claims 1 to 5, further comprising the step of oxidation and thereby obtaining pyroxasulfone or phenoxasulfone: 【Transformation 5】

7. Formula (III) or (III') 【Transformation 6】 A process for preparing a compound of formula (IV) or (IV'): 【Transformation 7】 A process comprising brominating each of the compounds using a bromination reagent without light irradiation.

8. The brominated reagent is Br 2 HBr / H 2 O 2 , N-bromosuccinimide, and 1, The process according to claim 7, selected from the group consisting of 3-dibromo-5,5-dimethylhydantoin.

9. The process involves using a chlorinating solvent, for example, CH 2 Cl 2 , 1,2-dichloroethane, CHCl 3 , CCl 4 The process according to claim 7, carried out in an organic solvent selected from the group consisting of ethylene carbonate or propylene carbonate, MeCN, water, or a mixture thereof.

10. The process according to claim 6, wherein the process is carried out at a temperature of 0°C to 100°C.

11. The process according to claim 6, wherein the process is carried out at a temperature of 20°C to 50°C.

12. A process for preparing direct precursors of pyroxasulfone or phenoxasulfone of formula (I) or (I'), and various sulfone analogs of 5,5-dimethyl-4H-1,2-oxazole, d) A step of reacting the isoxazole of formula (V) with a vulcanizing agent to produce the S-substituted thioisoxazole of formula (VI); 【Transformation 8】 (In the formula, X is a leaving group and Y is a protecting group); e) Substituting the thiol or thioate compound obtained from formula (VI) in step d with the arylmethyl-bromide compound of formula (VII) to obtain the compound of formula (VIII); 【Chemistry 9】 A process that includes this.

13. The process according to claim 12, wherein the direct precursor of pyroxasulfone or phenoxasulfone is S-protected 3-thio-2-isoxazoline, which is treated with a base to remove the protecting group and expose the thiol or thiolate group. 【Chemistry 10】 (In the formula, Y is a protecting group and X is a leaving group.)

14. The direct precursor of pyroxasulfone or phenoxasulfone having a thiol or thioate group is then reacted with arylmethyl bromide to form the direct precursor of pyroxasulfone or phenoxasulfone. 【Chemistry 11】 (In the formula, Ar is an aryl group, Y is a protecting group, and X is a leaving group.) The process according to claim 13.

15. The process according to any one of claims 1 to 14, further comprising the step of oxidation and thereby obtaining pyroxasulfone or phenoxasulfone. 【Chemistry 12】

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