Methods and intermediates for preparing pyroxasulfone

Abstract

The present invention relates to a process for the preparation of a key intermediate of formula (I) in the synthesis of pyroxasulfone. The process comprises reacting an isoxazole of formula (II) with a sulfurizing reagent to produce an S-substituted thioisoxazole of formula (III); and coupling the S-substituted thioisoxazole of formula (III) with a pyrazole of formula (IV) by introduction of a methylene bridge to obtain a compound of formula (I). The present invention also relates to novel S-substituted thioisoxazoles of formula (III) wherein L1 is halogen or an anionic residue derived from an acid; R is an organic residue derived from a suitable sulfurizing reagent selected from dimethylthiocarbamide, thiosulfate, dithiooxamide, alkyl xanthate, thiobenzamide, N-substituted thiourea and thioacetate, and processes for their preparation.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 985,364, filed March 5, 2020, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This invention relates to a method for producing a novel intermediate for the preparation of sulfonylpyrazine. The invention further relates to a new general formula (III). S- Substituted thioisoxazole derivatives. Background Technology

[0004] Pyroxasulfone – chemical name 3-(5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1 H- Pyrazol-4-yl]methanesulfonyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole — has the following structural formula (1):

[0005] (1)

[0006] Sulfonazole belongs to the 3-([(hetero)aryl]methanesulfonyl)-4,5-dihydro-1,2-oxazole class and is used as a herbicide, particularly for pre-emergence control of annual grass weeds and some broadleaf weeds in crops such as corn, soybean, and wheat. Sulfonazole's mechanism of action affects apical meristem and coleoptile development and inhibits the biosynthesis of very long-chain fatty acids in plants. Compared to other commercial herbicides, it exhibits excellent herbicidal activity against grass and broadleaf weeds at lower application rates. In the field of transgenic crops, weeds controlled by sulfonazole are resistant to non-selective herbicides. Sulfonazole has been classified as a herbicide resistance group K3 by the Action Committee.

[0007] Sulfonazole was first disclosed in WO 2002 / 062770 by Kumiai Chemical Industry Co., Ltd. and Ihara Chemical Industry Co., Ltd. It is marketed in the form of water-dispersible granules and suspension concentrates.

[0008] The preparation method of sulfonylpyrazole is described in several patent applications, namely WO2006 / 068092 filed in the name of Ihara, WO 2004 / 013106 filed in the names of Kumiai and Ihara, and WO2005 / 095352 filed in the name of Ihara.

[0009] A typical intermediate used in the synthesis of sulfonylpyrazine is the (4,5-dihydroisoxazo-3-yl)thioformamidine salt compound of formula (2) (e.g., WO 2006 / 068092 published under the name of Ihara):

[0010]

[0011] Among them, R 1 and R 2 Each is independently a hydrogen atom, alkyl group, or cycloalkyl group, R 3 and R 4 Each can be a hydrogen atom or an alkyl group independently, provided that R is a hydrogen atom or an alkyl group. 1 and R 2 Or R 2 and R 3 They can bond to each other to form cycloalkyl groups together with the carbon atoms they bond to, and X 2 It is a halogen or an anionic residue derived from an acid.

[0012] Other typical intermediates used in the synthesis of sulfonylpyrazole are pyrazole derivatives of general formula (3) or salts thereof (e.g., WO 2004 / 013106 disclosed by Kumiai and Ihara):

[0013] (3)

[0014] Where R 1 Represents C1-C6 alkyl groups, R 2 Represents C1-C3 haloalkyl, R 3 Represents a hydrogen atom or a C1-C3 alkyl group, wherein the C1-C3 alkyl group may be substituted by one or more substituents selected from the following substituents: α- or formyl group, R 4 Represents a hydrogen atom or a C1-C3 haloalkyl group, provided that R 3 In the case of hydrogen or formyl, R 4 Represents C1-C3 haloalkyl, and in R 3 In the case of C1-C3 alkyl groups, R 4 It is a hydrogen-based or C1-C3 haloalkyl group, wherein the C1-C3 alkyl group may be substituted by one or more substituents selected from the following substituent α: "substituent α" is a halogen atom, a -SH group, or a -SC(=NH)NH2 group.

[0015] Sulfone pyrazol is obtained by combining the isoxazole salt of general formula (2) with the pyrazole of general formula (3) and then carrying out an oxidation reaction.

[0016] In WO 2004 / 013106 (≡EP 1541561), thiourea is used to introduce a sulfur functional group into the molecule, thiourea and 4-bromomethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1 H The reaction of pyrazole leads to bromine substitution, resulting in 2-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1-yl) H- The hydrobromide form of pyrazol-4-ylmethyl)-isothiourea (Example 10 of EP1541561). Then, in the presence of a base, the salt is combined with 3-chloro-5,5-dimethyl-2-isooxazoline to give a fluorinated sulfide of formula (I) on the pyrazol moiety (Reference Example 1 of EP 1541561).

[0017] As can be seen from the above chemical structure, the sulfide of formula (I) consists of two key segments (thioisoxazole and pyrazole ring), which are connected together by a -CH2- (e.g., methylene) bridge.

[0018] Thiourea is a typical sulfur compound for this reaction, but it has several drawbacks. Thiourea salts are typically prepared in acetonitrile, which is removed under vacuum and the salt is obtained by grinding with different solvents. Finally, the salt is dissolved in water and reacted with formaldehyde and a pyrazole of general formula (3). Direct use of a solution obtained by mixing thiourea and isoxazole derivatives in acetonitrile results in a lower yield, which is related to the use of a separate salt and the inhibition of product crystallization. Thiourea salts require moisture protection during storage.

[0019] This invention discloses a novel intermediate for the production of sulfonylpyrazine. Summary of the Invention

[0020] This invention provides a method for preparing a compound of formula (I).

[0021] (I)

[0022] The method includes the following steps:

[0023] i) React the isoxazole of formula (II) with a sulfiding agent to produce the isoxazole of formula (III). S -Substituted thioisoxazole;

[0024] ii) By introducing a methylene bridge, formula (III) S - A substituted thioisoxazole is combined with a pyrazole of formula (IV) to obtain a compound of formula (I).

[0025]

[0026] in

[0027] L1 is a leaving group; R is an organic residue derived from a suitable sulfiding agent selected from dimethylthioformamide, thiosulfate, dithiooxanil, alkyl xanthate, thiobenzamide, etc. N Substituted thiourea and thioacetate salts.

[0028] The present invention also provides a method for preparing compounds of formula (III), wherein the isoxazole of formula (II) reacts with a sulfiding agent to produce compounds of formula (III):

[0029]

[0030] Equation (III)

[0031] The present invention also provides general formula (III) S- Substituted thioisoxazole derivatives:

[0032]

[0033] Equation (III)

[0034] Where R is acetyl, dithioxanyl, or 1-( N , N 1-(1-phenylmethylimine) salt, sulfonyl salt, alkoxycarbonyl salt, and 1-(1-phenylmethylimine).

[0035] The present invention also provides (5,5-dimethyl-4) H -isoxazol-3-yl)thiobenzoimide ((5,5-dimethyl-4-yl)thiobenzoimide H (-isoxazol-3-yl) benzenecarboximidothioate) or (5,5-dimethyl-4-yl) benzenecarboximidothioate H Salts of 3-isoxazol-3-yl)thiobenzoimide ester:

[0036]

[0037] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

[0038] The present invention also provides (5,5-dimethyl-4) H -isoxazol-3-yl)2-amino-2-thio-thioethyleneimine ester ((5,5-dimethyl-4-yl)2-amino-2-thio-thioethyleneimine ester) H (-isoxazol-3-yl) 2-amino-2-thioxo-ethanimidothioate or (5,5-dimethyl-4-yl) H Salts of -isoxazo-3-yl)2-amino-2-thio-thioethyleneimine ester:

[0039]

[0040] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

[0041] The present invention also provides 5,5-dimethyl-3-sulfothio-4 H -Isoxazole sodium salt:

[0042]

[0043] The present invention also provides 2-(5,5-dimethyl-4- H -isoxazol-3-yl)-1,3-dimethyl-isothiourea or 2-(5,5-dimethyl-4-yl) H -isoxazol-3-yl)-1,3-dimethyl-isothiourea salt:

[0044]

[0045] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

[0046] The present invention also provides 2-(5,5-dimethyl-4- H -isoxazol-3-yl)-1,3-diethyl-isothiourea or 2-(5,5-dimethyl-4-yl) H -Isoxazol-3-yl)-1,3-diethyl-isothiourea salt:

[0047]

[0048] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

[0049] The present invention also provides 3-(4,5-dihydro-1 H- (imidazol-2-ylthio)-5,5-dimethyl-4 H -isoxazole or 3-(4,5-dihydro-1 H- (imidazol-2-ylthio)-5,5-dimethyl-4 H -Isoxazole salts:

[0050]

[0051] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

[0052] The present invention also provides (5,5-dimethyl-4) H ethyl isoxazol-3-yl)thiocarbamate:

[0053]

[0054] The present invention also provides S- (5,5-dimethyl-4) H -isoxazole-3-yl)thioacetate ( S -(5,5-dimethyl-4 H -isoxazol-3-yl) ethanethioate):

[0055]

[0056] The present invention also provides N , N- Dimethyl(5,5-dimethyl-4) H- Isoxazol-3-ylthio)methylimine ( N , N -dimethyl(5,5-dimethyl-4 H -isoxazol-3-ylsulfanyl)methaniminium) or N , N- Dimethyl(5,5-dimethyl-4) H -isoxazole-3-ylthio)methyliminoonium salt:

[0057]

[0058] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate. Detailed Implementation

[0059] We have now discovered new compounds that can be used as alternative intermediates in the synthetic pathway of compounds of formula (I); this new synthetic pathway allows the synthesis of compounds of formula (I) or their analogues without the need to isolate salts derived from the prior art described above. Furthermore, the new intermediates can be isolated, some of which are more stable to hydrolysis. N --substituted thioureas can be used to prepare salts that are insensitive to moisture. Furthermore, non-salt derivatives of isoxazolines of general formula (II) with 3-substituents, such as xanthonyl, thio-, and dithiocarboxyl groups, can be prepared. S -Thiosulfonyl group. These S The difference between the substituted 2-isoxazoline-3-thiol derivatives and their analogues in the synthesis of compounds of formula (I) lies in the ease with which they release the corresponding 2-isoxazoline-3-thiol salt upon alkali treatment. Increased yields of compounds of formula (I) and their analogues can be achieved by slowing the formation of the active thiol nucleophile in the reaction and by increasing the simplicity of the operation in terms of the rate of addition. The method presented represents an environmentally friendly alternative to previously disclosed preparation methods, reducing solvent waste and the generation of harmless byproducts.

[0060] This can be achieved through the new general formula (III). S- The sulfides of formula (I) and substituted thioureas were synthesized by using substituted thioisoxazole derivatives:

[0061]

[0062] Equation (III)

[0063] Where R is acetyl, benzoyl, dithioxanyl, 1-( N , N 1-(1-phenylmethylimine) salt, sulfonyl salt, alkoxycarbonyl, 1-(1-phenylmethylimine).

[0064] Formula (III) is particularly preferred. S- Substituted thioisoxazole derivatives, namely (5,5-dimethyl-4-dioxazole ... H -isoxazol-3-yl)thiobenzoimide or (5,5-dimethyl-4-yl)thiobenzoimide H Salts of 3-isoxazol-3-yl)thiobenzoimide ester:

[0065]

[0066] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

[0067] (5,5-dimethyl-4) H -isoxazol-3-yl)2-amino-2-thio-thioethyleneimine ester or (5,5-dimethyl-4-yl) H Salts of -isoxazo-3-yl)2-amino-2-thio-thioethyleneimine ester:

[0068]

[0069] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

[0070]

[0071] 5,5-Dimethyl-3-sulfothio-4 H- Isoxazole sodium salt:

[0072]

[0073] 2-(5,5-dimethyl-4- H -isoxazol-3-yl)-1,3-dimethyl-isothiourea or 2-(5,5-dimethyl-4-yl) H -isoxazol-3-yl)-1,3-dimethyl-isothiourea salt:

[0074]

[0075] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

[0076] 2-(5,5-dimethyl-4- H -isoxazol-3-yl)-1,3-diethyl-isothiourea or 2-(5,5-dimethyl-4-yl) H -Isoxazol-3-yl)-1,3-diethyl-isothiourea salt:

[0077]

[0078] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

[0079] 3-(4,5-dihydro-1 H -imidazol-2-ylthio)-5,5-dimethyl-4 H -isoxazole or 3-(4,5-dihydro-1 H -imidazol-2-ylthio)-5,5-dimethyl-4 H -Isoxazole salts:

[0080]

[0081] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

[0082] (5,5-dimethyl-4) H ethyl isoxazol-3-yl)thiocarbamate:

[0083]

[0084] S -(5,5-dimethyl-4 H -isoxazole-3-yl)thioacetate:

[0085]

[0086] N , N- Dimethyl(5,5-dimethyl-4) H -isoxazole-3-ylthio)methylimine or N , N- Dimethyl(5,5-dimethyl-4) H -isoxazole-3-ylthio)methyliminoonium salt:

[0087]

[0088] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

[0089] The synthetic pathway for the sulfide of formula (I) is described below:

[0090] Option 1.

[0091]

[0092] in:

[0093] L1 is a leaving group; R is an organic residue derived from a suitable sulfiding agent selected from dimethylthioformamide, thiosulfate, dithiooxanil, alkyl xanthate, thiobenzamide, etc. N Substituted thiourea and thioacetate salts.

[0094] One aspect of the invention is a method comprising reacting an isoxazole of formula (II) with a sulfiding agent to produce an isoxazole of formula (III). S- Methods for replacing thioisoxazoles.

[0095] Another aspect of the present invention is to introduce a methylene bridge to make formula (III) S- A method for combining a substituted thioisoxazole with a pyrazole of formula (IV) to obtain a compound of formula (I).

[0096] S- One method of replacing isoxazole of general formula (II) involves reacting isoxazole of general formula (II) with a sulfiding agent in the presence of a formaldehyde source, preferably in an alkaline environment, said sulfiding agent including but not limited to potassium ethyl xanthate, dithiooxanil, thiobenzamide, potassium thioacetate, thiosulfate, dialkylthiocarbamate and alkyl-substituted thiourea.

[0097] Regarding the pyrazole starting material of formula (IV), it may be commercially available or prepared by methods known in the art, such as the method described in WO 2004 / 013106 (≡EP 1541561), prepared by a ring-closing reaction of methylhydrazine and ethyl 4,4,4-trifluoro-3-oxo-butyrate. Exemplary steps can be found in US 2013 / 015804 and US 7,488,831.

[0098] Formaldehyde sources include aqueous formaldehyde solutions and paraformaldehyde. Paraformaldehyde (molecular formula HOCH2(OCH2)) n- The polymer (of 2OCH2OH) gradually dissolves in an alkaline environment, undergoing depolymerization to generate formaldehyde, which participates in the reaction. For example, paraformaldehyde in particulate or pellet form with a degree of polymerization (n) between 8 < n < 100 can be used in this method. Another compound that can provide paraformaldehyde in situ is 1,3,5-trioxane. A slight molar excess of formaldehyde in the reaction is generally beneficial, i.e., at most 3:1 relative to the pyrazole starting material.

[0099] An alkaline environment, if not mandatory, greatly favors the reaction. Suitable bases for creating an alkaline environment in the reaction mixture include alkali metal hydroxides, alkali metal bicarbonates, alkali metal alkoxides, alkali metal hydrides, and, where applicable, corresponding alkaline earth bases. The alkaline reagent can be added to the reaction vessel in solid form or as a concentrated aqueous solution. Organic bases (i.e., pyridine derivatives and alkylamines) can be used instead of inorganic bases. The ratio of base to starting material is from 2:1 to 10:1.

[0100] Involving the use of pyrazole of formula (IV) with formaldehyde and formula (III) S- The coupling reaction of substituted thioisoxazoles is carried out in water and / or organic solvents, namely protic solvents, polar aprotic solvents (including halogenated hydrocarbons), and aromatic solvents. Aqueous solvents (i.e., water alone and solvent mixtures consisting of water and water-miscible organic solvents) have been found to be useful, particularly polar aprotic solvents such as acetonitrile, dimethylformamide, dimethyl sulfoxide, and propylene carbonate. Other types of organic solvents are also suitable, such as aqueous mixtures of lower alkanols or ethers. Such mixtures (e.g., water / acetonitrile) can also be used to supply the pyrazole of formula (IV) in solution to the reaction vessel to facilitate the feeding of the reactants into the reaction vessel. Thus, a suitable reaction medium consists of water / organic solvent in a weight ratio of 9:1 to 1:9. Generally, a solvent mixture of approximately equal proportions is preferred, or a solvent mixture with a slightly higher water content is also preferred.

[0101] Reactants and reagents can be added to the reaction vessel sequentially; simultaneous feeding of two or more reactants is also feasible. There are no particular requirements regarding the order of addition, except that the pyrazole starting material should be brought into contact with the formaldehyde source in the reaction vessel under alkaline conditions. Typically, the sulfiding agent is added to the reaction mixture derived from the pyrazole and formaldehyde reaction in an alkaline medium.

[0102] A mixture of a sulfiding reagent and isoxazole of general formula (II) or an analogue thereof (e.g., 4,5-dihydroisoxazole with a leaving group such as a sulfonyl leaving group at the 3-position) can be evaporated after a period of time, said time may be from 1 hour to 72 hours, typically 16 hours, and ground together with a solvent (such as an aliphatic or aromatic hydrocarbon, ester or ether solvent) to separate the intermediate reagent of the conjugate base capable of releasing 2-isooxazoline-3-thiol upon alkaline treatment, thus allowing the intermediate reagent to be used in pure or solution form as a substitute for the mixture of the sulfiding reagent and isoxazole of general formula (II) or an analogue thereof.

[0103] Different types of solvents can be used for this reaction, such as ethers (including cyclic ethers such as tetrahydrofuran and dioxane), aliphatic alcohols, halogenated hydrocarbons, and polar aprotic solvents such as dimethylformamide, and optionally aqueous mixtures thereof. Preferably, the reaction is carried out under an inert gas atmosphere, optionally under heating.

[0104] In one aspect of the invention, the method for preparing the compound of formula (I) further includes the step of reacting the compound of formula (I) with the compound of formula F2HC-L1, wherein L1 is a leaving group, optionally followed by an oxidation step to obtain sulfopyrazol.

[0105] The substitution of L1 in F2HC-L1 (preferably chlorine or bromine, e.g., difluoromethane chloride) by the thioester of formula (I) under strongly alkaline conditions can be carried out in various solvents (polar aprotic solvents, such as dimethylformamide, dimethylacetamide, acetonitrile, and dimethyl sulfoxide, generally preferred) in the presence of a base (alkali metal hydroxide, alkali metal carbonate, alkali metal alkoxide, alkali metal hydride, nitrogen-containing organic base, i.e., trialkylamine and pyridine derivatives). The fluorinated methyl halide F2HC-L1 is used in stoichiometric excess. The amount of base added to the reaction vessel is preferably 1-5 equivalents relative to 1 equivalent of the thioester of formula (I).

[0106] Finally, the fluorinated sulfide analogue of formula (I) undergoes oxidation to generate the herbicidal active compound, sulfonylpyrazol. The oxidation reaction is carried out by methods known in the art, using oxidants such as organic and inorganic peroxides; effective oxidants include hydrogen peroxide, m-chloroperoxybenzoic acid, peracetic acid, perbenzoic acid, magnesium monoperoxyphthalate, potassium persulfate, potassium permanganate, and sodium periodate. As an alternative to directly converting the sulfide functional group to sulfone-SO2, oxidation via the corresponding sulfoxide (-SO) can be considered, i.e., separating the sulfoxide and subsequently oxidizing it to sulfone. Oxidation can be carried out in water, in organic solvents, and / or 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 the oxidation process can vary between 0°C and 80°C, but is typically preferred to be between 20°C and 40°C. Exemplary steps can be found in WO2004 / 013106 (≡EP1541561).

[0107] Interestingly, isoxazoles of general formula (II) react in the same manner with different leaving groups attached to the isoxazole. Sulphinate isoxazoles:

[0108]

[0109] The sulfinyl isoxazole reacts in the same manner as the haloisoxazole of general formula (II) in subsequent reactions of the present invention. For example, without limiting the invention, the sulfiding agent in this example is sodium methanethiol (Na₂O₃). + - SMe), and then the product is oxidized, now halogen "X" has been converted to methanesulfinate (MeSO2). - The leaving group is replaced by another thiol to give the product, as shown in Scheme 2:

[0110] Option 2.

[0111]

[0112] The methanesulfinate group, as a leaving group, reduces the compound's sensitivity to moisture, making it easier to handle in reactions. Isoxazoles with the methanesulfinate group can be prepared without using haloisoxaazoles of general formula (II) as starting materials.

[0113] definition

[0114] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this subject pertains.

[0115] As used herein, the term "alkyl" refers to branched, unbranched, or cyclic carbon chains, including methyl, ethyl, propyl, isopropyl, cyclopropyl, etc.

[0116] As used herein, the term "isoxazole" refers to 5,5-dimethyl-4-oxazole. H -Isoxazole.

[0117] As used herein, the term "isoxazole of formula (II)" refers to a 5,5-dimethyl-4-oxazole with a leaving group at the 3-position. H -Isoxazole, or isoxazole with a leaving group at the 3-position, provided that the isoxazole is 5,5-dimethyl-4-oxazole. H - In the case of isoxazol.

[0118] As used in this article, the term " S- "Substituted thioisoxazole" is a 5,5-dimethyl-4H-isoxazole with a substituted sulfur atom at the 3-position.

[0119] As used herein, the term "sulfiding agent" refers to an agent capable of forming new sulfur-carbon bonds.

[0120] As used herein, the term "leaving group" is a molecular fragment produced by the breaking of a heterolytic bond and carrying an electron pair from the bond that breaks during the breaking process.

[0121] In particular, the leaving group can be, but is not limited to, fluoroalkyl sulfinates, alkyl sulfinates, aryl sulfinates, chlorine, and bromine.

[0122] As used herein, the term "stable" when used in conjunction 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 was observed after storage at 54°C in a sealed package for at least 2 weeks. As used herein, the term "physically stable" means that no significant sedimentation was observed after storage at 54°C in a sealed package for at least 2 weeks.

[0123] As used herein, unless otherwise expressly stated, the terms “a” or “an” include both singular and plural forms. Therefore, the terms “a”, “an”, or “at least one” are used interchangeably in this application.

[0124] Throughout this application, the term “comprising” is used to describe various embodiments; however, those skilled in the art will understand that in certain specific cases, the phrases “substantially consisting of” or “consisting of” may be used to describe embodiments.

[0125] The term “about” in this document specifically includes ±10% of the indicated value within a range. Furthermore, the terminology for all ranges of the same component or property includes endpoints, which can be independently combined, and includes all intermediate points and ranges.

[0126] It should be understood that, where a parameter range is provided, all integers and their tenths within that range are also provided by this invention, just as their integer and tenths digits have been explicitly stated herein. For example, "0.1% to 70%" includes 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, etc., up to a maximum of 70%.

[0127] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference in their entirety, to the extent that each individual publication, patent or patent application is specifically and individually indicated to be incorporated herein by reference.

[0128] The following examples illustrate the practice of the subject matter of the invention in some of its embodiments, but should not be construed as limiting the scope of the subject matter. Other embodiments that clearly fall within the spirit and scope of the appended claims will also be part of the invention by consideration of the description and examples herein. The description, including the examples, is intended to be exemplary only and not to limit the scope and spirit of the invention.

[0129] The aspects and embodiments of the invention will now be described.

[0130] This invention provides a method for preparing a compound of formula (I).

[0131] (I)

[0132] The method includes the following steps:

[0133] i) React the isoxazole of formula (II) with a sulfiding agent to produce the isoxazole of formula (III). S- Substituted thioisoxazoles;

[0134] ii) By introducing a methylene bridge, formula (III) S- A substituted thioisoxazole is combined with a pyrazole of formula (IV) to obtain a compound of formula (I).

[0135]

[0136] in

[0137] L1 is a leaving group; R is an organic residue derived from a suitable sulfiding agent selected from dimethylthioformamide, thiosulfate, dithiooxanil, alkyl xanthate, thiobenzamide, etc. N Substituted thiourea and thioacetate salts.

[0138] In some embodiments, according to the method of claim 1, wherein the isoxazole of formula (II) is a sulfinyl isoxazole.

[0139]

[0140] Or halogen-substituted isoxazoles:

[0141]

[0142] Where X is a halogen.

[0143] In some embodiments, the method for preparing the compound of formula (I) includes reacting the isoxazole of formula (II) with a sulfiding agent to produce the compound of formula (III). S- The substituted thioisoxazole, then by introducing a methylene bridge in an alkaline environment, makes formula (III) S- The substituted thioisoxazole is combined with the pyrazole of formula (IV) to obtain the compound of formula (I).

[0144] In some embodiments, the method for preparing the compound of formula (I) includes reacting the isoxazole of formula (II) with a sulfiding agent to produce the compound of formula (III). S- The substituted thioisoxazole, and then the introduction of a methylene bridge using a formaldehyde source, makes formula (III) S-The substituted thioisoxazole is combined with the pyrazole of formula (IV) to obtain the compound of formula (I).

[0145] In some embodiments, the method for preparing the compound of formula (I) includes reacting the isoxazole of formula (II) with a sulfiding agent to produce the compound of formula (III). S- The substituted thioisoxazole, then the introduction of a methylene bridge using an acid, makes formula (III) S- The substituted thioisoxazole is combined with the pyrazole of formula (IV) to obtain the compound of formula (I).

[0146] In some other embodiments, the method for preparing the compound of formula (I) includes reacting the isoxazole of formula (II) with a sulfiding agent under any combination of the synthetic steps described herein to produce the compound of formula (III). S- The substituted thioisoxazole, then by introducing a methylene bridge, makes formula (III) S- The substituted thioisoxazole is combined with the pyrazole of formula (IV) to obtain the compound of formula (I).

[0147] In some embodiments, the method includes reacting the isoxazole of formula (II) with a sulfiding agent to produce the isoxazole of formula (III). S- The substituted thioisoxazole, wherein the sulfiding agent is selected from potassium ethyl xanthate, dithiooxazone, thiobenzamide, potassium thioacetate, thiosulfate, dialkylthiocarbamate, and alkyl-substituted thiourea.

[0148] In some embodiments, the method includes reacting isoxazole of formula (II) with a sulfiding agent in an organic polar aprotic solvent, said solvent being selected from acetonitrile, dimethylformamide, etc. N- Methyl-2-pyrrolidone, dimethyl sulfoxide, ethylene carbonate, propylene carbonate, dimethylacetamide, dichloromethane, dichloroethane, and tetrahydrofuran.

[0149] In some embodiments, the method includes reacting isoxazole of formula (II) with a sulfiding agent at a temperature of -10°C to 60°C.

[0150] In some embodiments, the method includes reacting isoxazole of formula (II) with a sulfiding agent at a temperature of 20°C to 40°C.

[0151] In some implementations, the method includes introducing a methylene bridge in an alkaline environment in the presence of a formaldehyde source to make formula (III) S- The substituted thioisoxazole is bound to the pyrazole of formula (IV).

[0152] In some implementations, the alkaline environment is an aqueous solution of 2.5 M alkali metal hydroxide and water.

[0153] In some implementations, the method includes using a 4.5 M aqueous formaldehyde solution or paraformaldehyde as the formaldehyde source.

[0154] In some embodiments, the method includes loading a reaction vessel while stirring a sulfiding agent and isoxazole of formula (II) in an organic solvent, and then adding the mixture to a mixture of formaldehyde and pyrazole of formula (IV) in an alkaline environment.

[0155] In some embodiments, a method for preparing a compound of formula (III) includes reacting an isoxazole of formula (II) with a sulfiding agent to produce a compound of formula (III):

[0156]

[0157] Equation (III)

[0158] In some embodiments, the method includes reacting isoxazole of formula (II) with a sulfiding agent to produce a compound of the following formula:

[0159]

[0160] R1 is a C1-C3 alkyl group.

[0161] In some embodiments, the method includes reacting isoxazole of formula (II) with a sulfiding agent to produce a compound of the following formula:

[0162]

[0163] Where X is the equilibrium anion.

[0164] In some embodiments, the method includes reacting isoxazole of formula (II) with a sulfiding agent to produce a compound of the following formula:

[0165]

[0166] M is the equilibrium cation.

[0167] In some embodiments, the method includes reacting isoxazole of formula (II) with a sulfiding agent to produce a compound of the following formula:

[0168]

[0169] R2 is H or C1-C3 alkyl.

[0170] In some embodiments, the method includes reacting isoxazole of formula (II) with a sulfiding agent to produce a compound of the following formula:

[0171]

[0172] Where X is the equilibrium anion.

[0173] In some embodiments, the method includes reacting isoxazole of formula (II) with a sulfiding agent to produce a compound of the following formula:

[0174]

[0175] Where X is the equilibrium anion.

[0176] In some embodiments, the method includes reacting isoxazole of formula (II) with a sulfiding agent to produce a compound of the following formula:

[0177]

[0178] Where X is the equilibrium anion; R1 is a C1-C3 alkyl group; and R2, R3 and R4 are H and alkyl groups.

[0179] In some embodiments, the method includes reacting isoxazole of formula (II) with a sulfiding agent to produce a compound of the following formula:

[0180]

[0181] Where X is the equilibrium anion.

[0182] In some embodiments, the method includes reacting isoxazole of formula (II) with a sulfiding agent in an organic solvent.

[0183] In some embodiments, the method includes reacting isoxazole of formula (II) with a sulfiding agent in an inert atmosphere.

[0184] In some implementations, the method includes reacting isoxazole of formula (II) with a sulfiding agent at 0°C.

[0185] In some embodiments, the method includes reacting isoxazole of formula (II) with a sulfiding agent at room temperature.

[0186] In some implementations, the method includes reacting isoxazole of formula (II) with a sulfiding agent in the presence of acid.

[0187] In some embodiments, the method includes reacting isoxazole of formula (II) with a sulfiding agent in an organic solvent, in an inert atmosphere, at 0°C to room temperature, and under conditions of added acid.

[0188] In some other embodiments, the method comprises reacting the isoxazole of formula (II) with a sulfiding agent under any combination of the synthetic steps described herein.

[0189] In some embodiments, the method further includes the step of reacting a compound of formula (I) with a compound of formula F2HC-L1, wherein L1 is a leaving group, optionally followed by an oxidation step, thereby obtaining sulfonylpyrazol:

[0190]

[0191] In another aspect of the invention, general formula (III) S- Substituted thioisoxazoles:

[0192]

[0193] Equation (III)

[0194] Where R is acetyl, dithioxanyl, or 1-( N,N- Dimethylmethyleneimine salt, sulfonyl salt, alkoxycarbonyl and; 1-(1-phenylmethyleneimine).

[0195] In another aspect of the invention, (5,5-dimethyl-4 H- Isoxazol-3-yl)thiobenzyl imide or (5,5-dimethyl-4-yl) H- Salts of isoxazol-3-yl)thiobenzoimide ester:

[0196]

[0197] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

[0198] In another aspect of the invention, (5,5-dimethyl-4 H- Isoxazol-3-yl)2-amino-2-thio-thioethyleneimine ester or (5,5-dimethyl-4-yl) H- Salts of isoxazol-3-yl)2-amino-2-thio-thioethyleneimine ester:

[0199]

[0200] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

[0201] In another aspect of the invention, 5,5-dimethyl-3-sulfothio-4 H- Isoxazole sodium salt:

[0202]

[0203] In another aspect of the invention, 2-(5,5-dimethyl-4 H- Isoxazol-3-yl)-1,3-dimethyl-isothiourea or 2-(5,5-dimethyl-4-yl)-1,3-dimethyl-isothiourea H-Isoxazol-3-yl)-1,3-dimethyl-isothiourea salt:

[0204]

[0205] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

[0206] In another aspect of the invention, 2-(5,5-dimethyl-4 H- Isoxazol-3-yl)-1,3-diethyl-isothiourea or 2-(5,5-dimethyl-4-yl)-1,3-diethyl-isothiourea H- Isoxazol-3-yl)-1,3-diethyl-isothiourea salt:

[0207]

[0208] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

[0209] In another aspect of the invention, 3-(4,5-dihydro-1 H- (imidazol-2-ylthio)-5,5-dimethyl-4 H- Isoxazole or 3-(4,5-dihydro-1 H -imidazol-2-ylthio)-5,5-dimethyl-4 H- Isoxazole salts:

[0210]

[0211] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

[0212] In another aspect of the invention, S- (5,5-dimethyl-4) H- Isoxazol-3-yl)thioacetate:

[0213]

[0214] In another aspect of the invention, (5,5-dimethyl-4 H- Isoxazol-3-yl)thiocarbamate ethyl ester:

[0215]

[0216] In another aspect of the invention, N , N -Dimethyl(5,5-dimethyl-4- H- Isoxazol-3-ylthio)methylimine or N , N- Dimethyl(5,5-dimethyl-4) H -isoxazole-3-ylthio)methyliminoonium salt:

[0217]

[0218] Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

[0219] In some embodiments of the invention, the method for preparing compounds of formula (I) and the novel intermediates of general formula (III) provide increased synthetic yields, slower generation of active thiolate nucleophiles in the reaction, and operational simplicity in terms of improved addition rates.

[0220] Each embodiment disclosed herein is considered applicable to every other disclosed embodiment. Therefore, all combinations of the various elements described herein are within the scope of this invention. Furthermore, the elements listed in the method embodiments can be used in conjunction with the compound embodiments described herein, and vice versa.

[0221] The invention will be better understood by referring to the following embodiments, but those skilled in the art will readily understand that the detailed specific experiments are merely illustrative of the invention, as more fully described in the following claims.

[0222] The present invention is illustrated by the following embodiments, but is not limited thereto.

[0223] Example

[0224] NMR spectra were recorded using a Bruker 400 MHz spectrometer.

[0225] The melting point was determined using a Büchi B-545 melting point apparatus.

[0226] Example 1

[0227] N,N -Dimethyl(5,5-dimethyl-4- H Preparation of 3-isoxazol-3-ylthio)methyliminoonium bromide

[0228]

[0229] As described in Scheme 3: Under a nitrogen atmosphere, dimethyl thioformamide (2.0 g) and 3-bromo-5,5-dimethyl-2-isoxazoline (4.0 g) were dissolved in MeCN (35 mL), and the reaction mixture was cooled to 0 °C. Trifluoroacetic acid (0.13 mL) was added, and the reaction mixture was stirred (for 4 hours) and warmed to room temperature. Methyl tert-butyl ether (100 mL) was added over 5 minutes while stirring, and stirring was continued for 10 minutes. The solid was filtered and washed with methyl tert-butyl ether (50 mL), and then dried under vacuum to give a pale yellow powder (5.5 g, 92%). 1H NMR (400 MHz, CD3CN) 11.13 (1 H, s), 3.84 (3 H, s), 3.42 (3 H, s), 3.51 (2 H, s), 1.46 (6 H, s), 13 C NMR (100 MHz, CD3CN) 179.45 (CH), 147.79 (C), 89.51 (C), 50.28 (CH2), 49.51 (CH3), 44.15(CH3), 27.28 (2 × CH3).

[0230] Option 3.

[0231]

[0232] Example 2

[0233] use N , N- Dimethyl(5,5-dimethyl-4) H- Compound of formula (I) prepared by isoxazol-3-ylthio)methylimine onyx chloride.

[0234]

[0235] As described in Scheme 4: Under a nitrogen atmosphere, dimethylthioformamide (7.06 g) and 3-bromo-5,5-dimethyl-2-isoxazolin (14.1 g) were dissolved in MeCN (100 mL), and the reaction mixture was cooled to 0°C. Trifluoroacetic acid (0.30 mL) was added, and the reaction mixture was stirred (for 4 hours) and warmed to room temperature. 5-hydroxy-1-methyl-3-(trifluoromethyl)pyrazole (13.2 g) was added in portions to a solution of NaOH (19 g) in water (200 mL) while maintaining the temperature below 30°C. The mixture was cooled to 10°C. While stirring, a solution of paraformaldehyde (4.76 g) and NaOH (2.0 g) in water (100 mL) was added over 0.5 hours at 10°C using a syringe pump. The mixture was stirred at 10°C for another 30 minutes, and then a solution of the dimethylthioformamide / bromoisoxazolin adduct was added over 30 minutes at 10°C. The resulting mixture was stirred for another 0.5 hours, the temperature was raised to 15°C, the pH was adjusted to 1 with 4 M HCl, the temperature was maintained at 15°C, and the reaction was stirred for another half hour. The solid product (18.95 g, purity 98.9%, yield 77%) was then collected by filtration. 1H NMR (400 MHz, CDCl3) 10.33 (1 H, s), 3.99 (2 H, s), 3.68 (3 H, s), 2.87 (2 H, s), 1.43 (6 H, s).

[0236] Option 4.

[0237]

[0238] Example 3

[0239] Using the formation at elevated temperatures N , N- Dimethyl(5,5-dimethyl-4) H- Compound of formula (I) prepared by isoxazol-3-ylthio)methylimine onyx chloride.

[0240]

[0241] As described in Scheme 4: Under a nitrogen atmosphere, dimethylthioformamide (12.60 g) and 3-bromo-5,5-dimethyl-2-isoxazolin (24.86 g, 91% purity) were dissolved in MeCN (165 mL), and the reaction mixture was then heated to 40°C. Trifluoroacetic acid (0.50 mL) was added, and the reaction mixture was stirred at 40°C for 1–2 hours. 5-hydroxy-1-methyl-3-(trifluoromethyl)pyrazole (21.21 g) was added to a solution of NaOH (20.44 g) in water (200 mL), and the temperature was maintained at 35°C. Solid paraformaldehyde (6.07 g) was added with stirring, and the temperature was maintained at 35°C. Water (180 mL) was added, and the solution was cooled to 10–15°C. Then, a solution of the dimethylthioformamide / bromoisoxazol adduct was added at 15°C over 20 minutes. The resulting mixture was stirred for another 0.5 hours, the temperature was raised to 15°C, the pH was adjusted to 1 with 30% HCl, the temperature was maintained at 15°C, the reaction was cooled to 10°C and stirred for another half hour, and the solid product was collected by filtration (31.26 g, 98.2% chromatographic purity, 98.0% content, 78% yield).

[0242] Example 4

[0243] 2-(5,5-dimethyl-4- H- Preparation of isoxazol-3-yl)-1,3-dimethyl-isothiourea hydrochloride

[0244]

[0245] Will N , N'-Dimethylthiourea (2.0 g, 19 mmol, 1.0 equivalent) and 3-chloro-5,5-dimethyl-2-isoxazoline (2.6 g, 19 mmol, 1.0 equivalent) were stirred in MeCN (50 mL) for 2 days, then the solvent was removed at 35 °C and the residue was ground with ethyl acetate (10 mL). The mixture was stirred at room temperature (10 min), then filtered and vacuum dried to obtain N , N 'Dimethylaminothioimine ( N , N ′-dimethylcarbamimidothioic acid), colorless crystals of 4,5-dihydro-5,5-dimethyl-3-isooxazolyl ester hydrochloride (3.9 g, 96%).

[0246] Example 5

[0247] Using 2-(5,5-dimethyl-4 H- Isoxazol-3-yl)-1,3-dimethyl-isothiourea hydrochloride was prepared from compounds of formula (I).

[0248]

[0249] As described in Scheme 5: Add 5-hydroxy-1-methyl-3-(trifluoromethyl)pyrazole (0.91 g, 5.5 mmol, 1.0 equivalent) to a solution of NaOH (0.89 g, 22 mmol, 4.0 equivalent) in water (6 mL). Add formaldehyde aqueous solution (37%, stable methanol, 0.80 mL, 11 mmol, 2.0 equivalent) over 30 minutes. Stir again. N , N After one hour of stirring in a solution of dimethylaminothioimine, a solution of 4,5-dihydro-5,5-dimethyl-3-isoxazolyl ester hydrochloride (1.3 g, 5.5 mmol, 1.0 equivalent) in water (5 mL) was added over 5 minutes. After stirring for another hour, the pH was adjusted to 1 by gradually adding 4 M HCl, followed by stirring for 15 minutes and filtration. The solution was then dried under vacuum to obtain 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1 H- Pyrazole-5-ol (1.65 g, 92% purity, 89%).

[0250] Option 5.

[0251]

[0252] Example 6

[0253] Preparation of compounds of formula (I) using compounds of general formula (III) - typical steps

[0254]

[0255] Add 1.0 equivalent of 5-hydroxy-1-methyl-3-(trifluoromethyl)pyrazole to a solution of NaOH (4.0 equivalents) in water (approximately 6 mL). Between 15 minutes and 2 hours, add a formaldehyde source solution (2.0 equivalents). After stirring the solution of the sulfiding agent for 30 minutes to 3 hours, gradually add a compound of general formula (III) (1.0 equivalent) in water (5 mL). After stirring for another 30 minutes to 3 hours, adjust the pH to 1 by gradually adding acid, stir for another 5 minutes to 30 minutes, filter, and then vacuum dry to obtain 4-[[(4,5-dihydro-5,5-dimethyl-3-isoxazolyl)thio]methyl]-1-methyl-3-(trifluoromethyl)-1 H -Pyrazole-5-ol (purity 80% to 99%, yield 70% to 99%).

[0256] Furthermore, any priority documents of this application are incorporated herein by reference in their entirety.

Claims

1. A method for preparing a compound of formula (I), (I) The method includes the following steps: i) React the isoxazole of formula (II) with a sulfiding agent to produce the isoxazole of formula (III). S- Substituted thioisoxazoles; ii) By introducing a methylene bridge, formula (III) S- A substituted thioisoxazole is combined with a pyrazole of formula (IV) to obtain a compound of formula (I). in L1 is a leaving group; R is an organic residue from a suitable sulfiding agent, wherein the suitable sulfiding agent is selected from dialkylthioformamide or alkyl-substituted thiourea.

2. The method according to claim 1, wherein the isoxazole of formula (II) is a sulfinyl isoxazole. Or halogen-substituted isoxazoles: Where X is a halogen.

3. The method according to any one of claims 1-2, wherein the isoxazole of formula (II) reacts with the sulfiding agent in an organic polar aprotic solvent, said organic polar aprotic solvent being selected from acetonitrile, dimethylformamide, etc. N- Methyl-2-pyrrolidone, dimethyl sulfoxide, ethylene carbonate, propylene carbonate, dimethylacetamide, dichloromethane, dichloroethane, and tetrahydrofuran.

4. The method according to any one of claims 1-2, wherein the isoxazole of formula (II) reacts with the sulfiding agent at a temperature of -10°C to 60°C.

5. The method according to any one of claims 1-2, wherein the isoxazole of formula (II) reacts with the sulfiding agent at a temperature of 20°C to 40°C.

6. The method according to any one of claims 1-2, comprising introducing a methylene bridge in the presence of a formaldehyde source and / or in an alkaline environment to make formula (III) S- The substituted thioisoxazole is bound to the pyrazole of formula (IV).

7. The method according to any one of claims 1-2, comprising introducing a methylene bridge using an acid to make formula (III) S- The substituted thioisoxazole is bound to the pyrazole of formula (IV).

8. The method according to claim 6, wherein the alkaline environment is an aqueous solution of 2.5 M alkali metal hydroxide and water.

9. The method according to claim 6, wherein the formaldehyde source is a 4.5 M aqueous formaldehyde solution or paraformaldehyde.

10. The method according to any one of claims 1-2, comprising simultaneously loading the reaction vessel with a sulfiding agent and isoxazole of formula (II) in an organic solvent, and then adding the mixture to a mixture of formaldehyde and pyrazole of formula (IV) in an alkaline environment.

11. A method for preparing a compound of formula (III) according to any one of claims 1-10, wherein the isoxazole of formula (II) reacts with a sulfiding agent to produce a compound of formula (III): Formula (III).

12. The method according to any one of claims 1-2, wherein the isoxazole of formula (II) reacts with a sulfiding agent to produce a compound of the following formula: Where X is the equilibrium anion. Or it may produce compounds of the following formula: Where X is the equilibrium anion; R1 is a C1-C3 alkyl group, and R2, R3 and R4 are H or alkyl groups.

13. The method according to any one of claims 1-2, further comprising the step of reacting the compound of formula (I) with the compound of formula F2HC-L1, wherein L1 is a leaving group, optionally followed by an oxidation step to obtain sulfonylpyrazol: 。 14. S- Substituted thioisoxazole derivatives: 2-(5,5-dimethyl-4- H- Isoxazol-3-yl)-1,3-dimethyl-isothiourea or 2-(5,5-dimethyl-4-yl)-1,3-dimethyl-isothiourea H- Isoxazol-3-yl)-1,3-dimethyl-isothiourea salt: Where X represents chloride, bromine, difluoromethanesulfonate, and methanesulfonate. Or 2-(5,5-dimethyl-4) H- Isoxazol-3-yl)-1,3-diethyl-isothiourea or 2-(5,5-dimethyl-4-yl)-1,3-diethyl-isothiourea H- Isoxazol-3-yl)-1,3-diethyl-isothiourea salt: Where X represents chloride, bromine, difluoromethanesulfonate, and methanesulfonate. or N , N- Dimethyl(5,5-dimethyl-4) H- Isoxazol-3-ylthio)methylimine or N , N- Dimethyl(5,5-dimethyl-4) H- Isoxazol-3-ylthio)methyliminoonium salt: Where X represents chloride, bromine, difluoromethanesulfinate, and methanesulfinate.

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