Preparation method and intermediate of sulfonepyraclostrobin

Abstract

The present invention provides a method, which includes the step of thiomethylating pyrazole to generate an R2-C(O)-S-CH2-functional group at the 4-position of the pyrazole ring. The method can be used to prepare sulfone pyrazoline. The present invention also provides an intermediate of formula (III).

Description

[0001] Pyroxasulfone is a potent pre-emergence herbicide that belongs to the class of 3-([(hetero)aryl]methanesulfonyl)-4,5-dihydro-1,2-oxazoles. It has the following chemical structure:

[0002]

[0003] Sulfonepyrazoline [chemical name: 3-([5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methanesulfonyl)-5,5-dimethyl-4,5-dihydro-1,2-oxazole] was first described in WO 2002 / 062770 (≡EP 1364946). It is commercially available as water-dispersible granules and suspension concentrates.

[0004] A useful precursor of sulfonepyraclostrobin is the corresponding sulfide of formula I:

[0005]

[0006] The sulfide of formula I is converted into sulfonepyrazol either directly or via the corresponding sulfoxide by oxidation. The synthesis of the sulfide of formula I is reported in WO 2004 / 013106 (≡EP1541561), where thiourea is used to incorporate the sulfide functionality into the molecule. The reaction of thiourea and 4-bromomethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole displaces the bromine and then generates the hydrobromide form of 2-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-isothiourea (Example 10 of EP 1541561). This salt is then combined with 3-chloro-5,5-dimethyl-2-isoxazoline in the presence of a base to give the sulfide of formula I (Reference Example 1 of EP 1541561).

[0007] From the above chemical structure, it can be found that the sulfide of formula I consists of two key fragments, isoxazole and pyrazole rings, which are bridged together by -S-CH2-. The inventors have currently discovered a short and concise synthetic route to prepare the sulfide of formula I; in fact, this new synthetic route can be used for a wider range of sulfide classes of formula I:

[0008]

[0009] Wherein R1 is C1-C3 alkyl. As indicated above, R1 is preferably methyl. The chemical name of the sulfide of formula I (R1 is methyl) is 3-[[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]thio]-4,5-dihydro-5,5-dimethylisoxazole}.

[0010] The sulfide of formula I can be obtained by synthesis via a class of thioester intermediates of formula III:

[0011]

[0012] wherein R1 is a C1-C3 alkyl group, R2 is an alpha hydrogen-containing group (e.g., Y2Y1H*C*-, wherein the alpha carbon and alpha hydrogen are marked with asterisks, e.g., R2 is -CH3 or -CH2C6H5), and R3 is selected from hydrogen and a C1 group that can be directly converted to -CHF2, as described in detail below.

[0013] Particularly preferred are thioesters of formula III in which R2 is methyl and R3 is hydrogen, ie thioacetates of formula 3 in which R1 is also methyl:

[0014]

[0015] The synthetic route of the sulfide of formula I is detailed as follows:

[0016] Plan A

[0017]

[0018] The general synthetic route is reduced to the following preferred scheme (ie, R1 = R2 = methyl; R3 = H):

[0019]

[0020] It can be seen that the synthetic route contains two alternative routes:

[0021] II→III→IV→I (e.g., 2→3→4→1); or

[0022] II→III→VI→I (e.g., 2→3→6→1)

[0023] In the sequential reactions shown in Scheme A, each individual step is described in detail below. It should be noted that the synthetic routes described above include keto-enol tautomerism where appropriate.

[0024] II→III→IV→I (e.g., 2→3→4→1)

[0025] II→III (e.g., 2→3)

[0026] One main aspect of the present invention is a process comprising the step of thiomethylating a pyrazole of formula II to generate a R2-C(O)-S-CH2-functional group at position 4 of the pyrazole ring, thereby obtaining and preferably isolating a thioester of formula III:

[0027]

[0028] wherein R1 is a C1-C3 alkyl group;

[0029] R2 is an alpha hydrogen-containing group [e.g., Y2Y1H*C*-, such that R2 is preferably C1-C3 alkyl (Y1 and Y2 are independently selected from hydrogen and C1-C2 alkyl) or R2 is benzyl, (i.e., Y1 is hydrogen and Y2 is -C6H5); and

[0030] R3 is hydrogen or a C1 group that can be converted to F2HC-, wherein the C1 group is Y3Y4HC-, wherein Y3 and Y4 are selected from halogen (except Y3=Y4=F, of course), alkoxy, or the Y3 and Y4 together are =O (making the C1 group a formyl group).

[0031] Thus, in its most general form, the thioester of Formula III is a thioacetate (Y1 and Y2 are both hydrogen, such that R2 is methyl), or an alpha-substituted thioacetate (at least one of Y1 and Y2 is not hydrogen).

[0032] A method for the thiomethylation of pyrazoles of formula II comprises reacting with a compound of formula MSC(O)-R2, wherein M is hydrogen or a metal cation, such as an alkali metal cation, and R2 is as defined above, in the presence of a formaldehyde source, preferably under basic conditions.

[0033] As for the pyrazole starting material of formula II, it is commercially available or can be prepared by methods known in the art, such as described in WO 2004 / 013106 (≡EP 1541561), prepared by the ring-closing reaction of methylhydrazine and ethyl 4,4,4-trifluoro-3-oxobutanoate. Exemplary steps can be found in US 2013 / 015804 and US 7,488,831.

[0034] With respect to the MSC(O)-R2 compound, thioacetic acid and α-substituted thioacetic acids (e.g., R2, respectively, -CH3 or -CH2C6H5) can be used for the reaction, most conveniently in the form of their salts (e.g., potassium thioacetate). Salts of thioacetic acid and α-substituted thioacetic acids are commercially available and their preparation is well known [e.g., Org. Synth 32, 101 (1952)]. Typically, the molar ratio of the MSC(O)-R2 compound to the pyrazole of formula II is approximately stoichiometric. A slight excess of MSC(O)-R2 may be used, e.g., up to about 1.5:1, e.g., 1.1:1 to 1.3:1, with a ratio of about 1.2:1 being most preferred.

[0035] Formaldehyde sources include aqueous formaldehyde solution and paraformaldehyde. Paraformaldehyde (formula HOCH2(OCH2) n-2The polymer of OCH2OH) slowly dissolves in an alkaline environment and undergoes depolymerization to give formaldehyde, which participates in the reaction. For example, paraformaldehyde with a degree of polymerization (n) between 8 and 100 in powder / flake / granular form can be used in the method. Another compound that can provide paraformaldehyde in situ is 1,3,5-trioxane. A slight molar excess of formaldehyde relative to the pyrazole starting material is often advantageous in the reaction, i.e., up to 1.2:1.

[0036] Although alkaline environment (e.g., pH range 9 to 11) is not mandatory, it is very conducive to the reaction. Suitable bases for generating alkaline environment in the reaction mixture include alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides, alkali metal hydrides, alkali metal phosphates, and corresponding alkaline earth metal bases where applicable. Alkaline reagents can be added to the reaction vessel in the form of solid or concentrated aqueous solution. Organic bases, i.e., pyridine derivatives and alkylamines can be used to replace inorganic bases. The amount of alkali relative to the pyrazole starting material is between 5:100-300:100.

[0037] The thiomethylation reaction includes the use of HCHO / MSC(O)-R2 pairs, and the reaction is carried out in water or an organic solvent, wherein the organic solvent is a protic solvent, a polar aprotic solvent, including halogenated hydrocarbons and aromatic solvents and mixtures thereof. It is found that aqueous solvents are particularly advantageous, i.e., water alone and a solvent mixture consisting of water and an organic solvent miscible with water (particularly a polar aprotic solvent, such as acetonitrile, dimethylformamide). Other types of organic solvents are also suitable, such as aqueous mixtures of lower alkanols or ethers. The mixture (e.g., water / acetonitrile) can be used to provide the pyrazole of formula II to the reaction vessel in the form of a solution to help the reactant feed to the reaction vessel. Therefore, the reaction medium of the appropriate ratio is composed of a water / organic solvent in a weight ratio of 9:1-1:9. It is often preferred that a solvent mixture of approximately equal proportions or slightly water is the main component.

[0038] The reactants and reagents may be added to the reaction vessel sequentially; simultaneous addition of two or more reactants is also possible. There is no particular requirement for the order of addition, except that the pyrazole starting material is contacted with the formaldehyde source in an alkaline environment in the reaction vessel, or in the presence of at least a portion of the MSC(O)-R2 compound previously added to the reaction vessel.

[0039] To meet this requirement, a sequential addition may be employed, wherein the pyrazole of formula II is the last reactant added. For example, the experimental results reported below show that the thiomethylation reaction is effectively carried out by slowly adding the pyrazole of formula II (preferably dissolved in water, an organic solvent or a mixture thereof) to a reaction vessel which has previously been charged with a compound of formula MSC(O)-R2, a formaldehyde source and a base. For example, at a laboratory scale, the addition rate may be adjusted according to the process, wherein the pyrazole is added over a period of 30 minutes to 10 hours.

[0040] Therefore, a specific aspect of the present invention is a method, which comprises charging water, an organic solvent or a mixture thereof into a reaction vessel, dissolving a compound of formula MSC(O)-R2 and polymethanol in an alkaline environment (generated by adding a base), gradually feeding a pyrazole of formula II, i.e., in the form of a liquid stream consisting of pyrazole dissolved in water, dissolved in the organic solvent or dissolved in a mixture thereof, allowing the reaction to be completed, and then obtaining a reaction product of formula III (e.g., compound 3).

[0041] The reaction is carried out under stirring at a temperature of -20 to 80°C, most conveniently at 0 to 25°C, for example at about 15°C, by gradually adding the pyrazole, and then substantially reaching complete reaction at the end of the addition period. The reaction mixture can be kept under stirring for an additional period of time. The reaction mixture is then post-treated to obtain the product of formula III, for example by removing the organic solvent (if present), then acidifying the aqueous medium with an inorganic acid or an organic acid (e.g., acetic acid) to precipitate the reaction product of formula III, and then the reaction product of formula III is separated from the liquid phase (e.g., by filtration), washed with water, and dried.

[0042] The thiomethylation of the pyrazole of formula II by means of the HCHO / MSC(O)-R2 pair requires relatively simple post-treatment steps to collect the solid reaction product, which exhibits high yields. The reaction product, i.e. the compound of formula III, in particular S-(5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl-methyl)thioacetate of formula 3, constitutes a further aspect of the present invention. It can be used in the next step of the continuous reaction without further purification, or it can be purified, for example, by crystallization, grinding, etc.

[0043]

[0044] It should be noted that the present invention further contemplates the use of other binary reagent systems to accomplish the thiomethylation reaction:

[0045] H2C(OR4)2 / MSC(O)-R2 pair (R4 is alkyl, perfluoroalkyl or aryl);

[0046] H2C(CO2R4)2 / MSC(O)-R2 pair (R4 is alkyl, perfluoroalkyl or aryl); and

[0047] CH2=NR5 / MSC(O)-R2 (R5 is alkyl, perfluoroalkyl, aryl, -SO2R' or -C(O)R' (R' is alkyl, perfluoroalkyl, alkyl or aryl).

[0048] As an alternative to the thiomethylation reaction based on the use of the HCHO / MSC(O)-R2 pair, the pyrazole of formula II can be directly thiomethylated with the aid of a single reagent of formula X-CH2-SC(O)-R2 or a salt thereof, wherein R2 is as defined above (e.g., -CH3, -CH2C6H5), X is a hydroxyl group or a leaving group, preferably a halogen (e.g., chlorine or bromine), -O-SO2R' (R' is alkyl, perfluoroalkyl or aryl), -OC(O)R' (R' is alkyl, perfluoroalkyl or aryl), -N + R'3 (R' is hydrogen and alkyl; the quaternary ammonium ion can be part of the ring system). The reagent of formula X-CH2-SC(O)-R2 is used in a molar excess relative to the pyrazole of formula II, for example, a molar excess of up to 50%. Exemplary reagents include:

[0049] HO-CH2-SC(O)-CH3 (S-hydroxymethylthioacetate; described in Angew. Chem. Int. Ed. 2017, 56, 9891);

[0050] Br-CH2-SC(O)-CH3 (S-bromomethylthioacetate, described in Angew. Chem. Int. Ed. 2017, 56, 9891); and

[0051] (R2 is methyl or benzyl; described in The Journal of Organic Chemistry 1965 30(1), 300-301).

[0052] The reaction can use different types of solvents, for example, 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. The reaction is preferably carried out under an inert atmosphere, optionally under heating.

[0053] For example, the pyrazole of formula II is thiomethylated using S-bromomethylthioacetate or S-(1-piperidinylmethyl)thioacetate hydrochloride in dioxane at a temperature between 50° C. and reflux. The reaction mixture is then subjected to extractive work-up and chromatography to obtain the compound of formula III.

[0054] III→IV (e.g., 3→4)

[0055] The thioester of formula III (wherein R3 is hydrogen) undergoes difluoromethylation of the alcohol function at the 5-position of the pyrazole ring to generate the corresponding etherified thioester of formula IV,

[0056]

[0057] wherein R1 and R2 are as defined above; specifically, difluoromethylation of 3 affords 4:

[0058]

[0059] For this purpose, the thioester of formula III, wherein R3 is hydrogen, is reacted with a difluoromethylating agent in an organic solvent, usually in the presence of a base. Useful difluoromethylating agents are described, for example, in Hu et al., Chem. Commun. 2009, pp. 7465-7478.

[0060] Most conveniently, F2HC- is introduced into the alcohol function by means of a compound of formula F2X'C-L1, wherein X' is hydrogen or halogen (Cl, Br), and L1 is a leaving group. L1 is preferably chlorine, bromine or iodine. L1 may also be:

[0061] -COOR", wherein R" is an alkyl group, such as methyl or ethyl, or a corresponding alkali metal, for example, reagents such as ClCF2COOMe, ClCF2COONa and BrCF2COOEt can be used;

[0062] -C(O)R"', wherein R"' is alkyl or phenyl; for example, a reagent such as ClCF2C(O)Ph can be used;

[0063] -P(O)(O-alkyl)2, for example, a reagent such as BrCF2PO(OEt)2 can be used.

[0064] The preferred reagent is F2HC-L1, in particular chlorodifluoromethane. The displacement of L1 in F2HC-L1 by the action of the thioester of formula III under strongly basic conditions can be carried out in different solvents [polar aprotic solvents such as dimethylformamide, dimethylacetamide, acetonitrile and dimethyl sulfoxide, cyclic carbonates (propylene carbonate, ethylene carbonate, and generally preferably NMP] in the presence of a base (alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides, alkali metal hydrides, alkali metal phosphates, nitrogen-containing organic bases (i.e., trialkylamines and pyridine derivatives)) or treated with sodium metal. The difluoromethylating agent, such as F2HC-L1, is preferably used in excess. The amount of base introduced into the reaction vessel is preferably 1 to 10 equivalents relative to 1 equivalent of the thioester of formula III.

[0065] The formation of the etherified thioester of formula IV is usually carried out under heating, i.e., 40-100° C. The reaction can be promoted by adding a catalyst, such as a quaternary ammonium salt containing a halogen counterion, such as tetraalkylammonium bromide or ammonium iodide (e.g., tetra-n-butylammonium bromide or ammonium iodide) and an inorganic iodine salt. These compounds can be used in a catalytically effective amount of 0.01:1-10:1 relative to the thioester of formula III.

[0066] Although it is very satisfactory to form the etherified thioester of formula IV in an open reactor with chlorodifluoromethane continuously or intermittently sparged through the liquid reaction mixture, a more efficient reaction under pressure in an autoclave is preferred, using F2HC-L1 as defined above (e.g. chlorodifluoromethane) as a pressurizing agent, or alternatively, using an inert gas to increase the pressure in the reaction vessel. Thus, the difluoromethylation of the alcohol at the 5-position of the pyrazole ring can be carried out at ambient pressure or higher pressure.

[0067] The present invention particularly provides a method comprising charging an organic solvent, a thioester of formula III and a base into a pressure chamber / autoclave, pressurizing the autoclave (to an internal pressure of, for example, 1.5 to 100 atmospheres) with a difluoromethylating agent (e.g., F2HC-L1), reacting under heating and optionally stirring, and obtaining an etherified thioester of formula IV from the reaction mixture. The method is not limited to any particular order of reactant / reagent addition. For a variant of the difluoromethylation reaction of the thioester of formula III at high temperature and pressure, the solvent of choice is dimethylformamide, which has shown good results, especially in combination with an alkali metal carbonate (e.g., sodium carbonate) or an alkali metal phosphate base (e.g., tripotassium phosphate).

[0068] After cooling the reaction vessel and reducing the pressure, the etherified thioester of formula IV is obtained by conventional techniques.

[0069]

[0070] For example, the reaction mixture is concentrated, and the residue is then treated with a mixture of water and a water-immiscible organic solvent to partition the intermediate of Formula IV into the organic solvent, and the organic layer is then evaporated to obtain a crude product. The crude ether of Formula IV may be subjected to the next step, or may be purified by standard techniques (e.g., chromatography and / or crystallization) to collect a purified solid intermediate.

[0071] The difluoromethylation reaction of the thioester of formula III is carried out satisfactorily at room temperature / below room temperature (e.g. below 10° C.) using F2HC-L1 (e.g. chlorodifluoromethane) as defined above as a pressurizing agent in a pressure reactor filled with an organic solvent and a base. Suitable solvents for this variant of the invention include, in addition to the polar aprotic solvents mentioned above, aqueous mixtures thereof, and lower alkanols C1-C3. Particularly suitable polar aprotic solvents are nitrile solvents, such as acetonitrile, and preferred bases are alkali metal hydroxides. The inventors have found that this combination (nitrile solvent and alkali metal hydroxide) is suitable for variants of the difluoromethylation reaction at room temperature / below room temperature.

[0072] For example, the thioester of formula III is added to a pressure reactor that has been previously charged with a solvent (e.g., acetonitrile) and an alkali metal hydroxide (e.g., KOH). The reaction mixture is cooled to about -5 to 15°C, e.g., about 5°C, and then the thioester is added. A difluoromethylating agent (e.g., chlorodifluoromethane) is gradually fed to the reactor. On a laboratory scale, the addition rate of chlorodifluoromethane is 0.1 equivalents per minute to 0.005 equivalents per minute, relative to the thioester of formula III. The reaction mixture is maintained under stirring at a slightly elevated temperature (but still below room temperature, e.g., up to 20°C), for example, for several hours, and then the reaction is complete. The reaction product is separated from the reaction mixture using conventional techniques described below.

[0073] The thioester of formula III (wherein R3 is not hydrogen, i.e., R3 is a C1 group of formula Y3Y4HC-, wherein Y3 and Y4 are both halogen or both alkoxy) can be converted into a difluoromethyl moiety using a fluorine-containing reagent (i.e., a nucleophilic fluorine source, such as tetra-n-butylammonium fluoride, pyridine·HF complex or cesium fluoride). When R3 is a formyl group, it can be converted into a difluoromethyl moiety by conventional deoxyfluorination methods using sulfur tetrafluoride or a fluorine sulfur complex.

[0074] Ethers of formula IV, such as S-(5-difluoromethoxy-1-alkyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)thioacetate, in particular S-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)thioacetate (compound 4 above), form a further aspect of the invention.

[0075] It should be noted that the conversion of compound 3 to 4 in a pressure reactor at high temperature (e.g. in the presence of an alkali carbonate or phosphate base with DMF as solvent), and the conversion of compound 3 to 4 at ambient / low temperature (e.g. in the presence of an alkali hydroxide base with acetonitrile as solvent) form further independent aspects of the present invention.

[0076] IV→I (e.g., 4→1)

[0077] Next, the method of the present invention comprises the step of reacting the etherified thioester of formula IV with the 4,5-dihydroisoxazole of formula V,

[0078]

[0079] wherein L2 is a leaving group, as mentioned previously in various contexts, in particular halogen (eg chlorine or bromine),

[0080] To obtain the sulfide of formula I, the preferred reaction is as follows:

[0081]

[0082] This step of the reaction comprises charging an organic solvent (e.g., a lower alkanol, such as MeOH, EtOH, and isopropanol; or a polar aprotic solvent, such as acetonitrile and dimethylformamide; or a mixture of these solvents), a reactant of formula IV (e.g., 4) and a reactant of formula V (e.g., 5), and a base (alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, alkali metal alkoxide, alkali metal hydride, alkali metal phosphate, nitrogen-containing organic base (i.e., trialkylamine and pyridine derivative)) into a reaction vessel, and reacting under (optional) stirring and heating, for example, in a refluxing alkanol (e.g., methanol). The progress of the reaction can be followed by conventional chromatography.

[0083] Equimolar amounts of etherified thioester VI and 4,5-dihydroisoxazole V, or an excess (eg, up to 50% molar excess) of 4,5-dihydroisoxazole V are added to the reaction vessel. The amount of base may vary from 1 to 3 equivalents.

[0084] After the reaction is complete, the reaction mixture can be post-processed to collect the sulfide of formula I, for example, removing the reaction solvent and then repeating the extraction step with a mixture of water / a water-immiscible solvent (e.g., ethyl acetate). The organic extracts are combined and washed. Next, the phases are separated and the volatile components are removed to collect the oily sulfide of formula I.

[0085] II→III→VI→I (e.g., 2→3→6→1)

[0086] As indicated above, the present invention provides an alternative method to obtain the sulfide of formula I by transposing the steps of difluoromethylation of the 5-position of the pyrazole ring and incorporation of 4,5-dihydroisoxazole into the molecule.

[0087] III→VI (e.g., 3→6)

[0088] The reaction of the thioester of formula III with the 4,5-dihydroisoxazole of formula V, specifically, the reaction of 3 with 5 is set forth above for step IV→I (e.g., 4→1) under refluxing ethanol for 30 min:

[0089]

[0090] Work-up involves acidification of the reaction mass with aqueous mineral acid followed by the extraction step described above and illustrated in the Examples below.

[0091] VI→I (for example, 6→1)

[0092] The conditions for the difluoromethylation of VI to produce I are as described above for step III→IV (e.g., 3→4) of.

[0093] Finally, the sulfide of formula I is subjected to oxidation to obtain a herbicidally active compound, i.e., sulfonepyraclostrobin. The oxidation reaction is completed by methods known in the art, using oxidants such as organic and inorganic peroxides; available oxidants include hydrogen peroxide, metachloroperbenzoic acid, peracetic acid, peroxybenzoic acid, magnesium monoperoxyphthalate, potassium peroxymonosulfate, potassium permanganate and sodium periodate. As an alternative to the direct conversion of the sulfide functional group into sulfone-SO2, technicians may consider oxidation through the corresponding sulfoxide (-SO), that is, separation of the sulfoxide and subsequent oxidation to sulfone. The oxidation reaction is carried out in an organic solvent or in a mixture of an organic solvent and water, an organic solvent such as a halogenated hydrocarbon (halogenated aliphatic hydrocarbons (e.g., dichloromethane and chloroform) and halogenated aromatic hydrocarbons (e.g., chlorobenzene)); ethers, such as dioxane, tetrahydrofuran (THF) and ether; C1-C4 alkanols; ketones; and amides. Exemplary procedures can be found in WO 2004 / 013106 (≡EP 1541561). Example

[0094] method

[0095] NMR spectra were recorded using a Bruker 400 MHz spectrometer.

[0096] Melting points were determined using a Büchi B-545 melting point apparatus.

[0097] Example 1

[0098] Preparation of S-(5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)thioacetate

[0099]

[0100] Potassium thioacetate (31.8 g, 0.278 mol, 1.05 equiv) was dissolved in water (300 g) and acetonitrile (100 g), then paraformaldehyde (10.0 g, 0.333 mol, 1.26 equiv) and potassium hydroxide (1.56 g, 0.0278 mol, 0.10 equiv) were added. The solution was stirred until the paraformaldehyde was completely dissolved, then a solution of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol (2, 44.0 g, 0.265 mol, 1.0 equiv) in acetonitrile (200 g) and water (40 g) was added over 3 h. The acetonitrile was removed in vacuo at 30 °C, then hydrochloric acid (4 M, 130 g) was slowly added. The mixture was stirred (15 min) and then filtered. The crude product was resuspended in water (200 g), and the mixture was stirred (0.5 h), then filtered and dried in vacuo at 25° C. to give the title compound 3 (64 g, 91%); melting point (mp) 85-87° C.; 1 H NMR (400MHz, CDCl3) 9.10 (1H, s), 3.88 (2H, s), 3.68 (3H, s), 2.42 (3H, s); 13 C NMR (100MHz, CDCl3)204.1(s), 151.0(s), 137.6(q, J C-F 37), 121.5(q, J C-F 270), 96.7(s), 34.3(s), 30.5(s), 22.2(s); 19 F NMR (376MHz, CDCl3)-62.3 (3F, s).

[0101] Example 2

[0102] Preparation of S-(5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)thioacetate

[0103]

[0104] S-Hydroxymethylthioacetate (1.92 g, 18.1 mmol, 1.5 equivalents; Synthesis reference Z. Sofer, J. Luxa, D. D. P. Lazar, T. Hartman, H. Hardtdegen, M. Pumera, Angew. Chem. Int. Ed. 2017, 56, 9891) was dissolved in water (200 g), and then a solution of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol (2, 2.0 g, 12.0 mmol, 1.0 equivalent) in DMF (10 g) was added within 3 h. The pH was adjusted to 2 using hydrochloric acid (4 M), and then brine (50 mL) was added. The product was extracted with (3×50 mL). The volatile components were removed in vacuo to give compound 3 (3.78 g, 82%).

[0105] Example 3

[0106] Preparation of S-(5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)thioacetate

[0107]

[0108] S-bromomethylthioacetate (2.34 g, 13.8 mmol, 1.15 equivalents; synthesis reference Z. Sofer, J. Luxa, D. D. P. Lazar, T. Hartman, H. Hardtdegen, M. Pumera, Angew. Chem. Int. Ed. 2017, 56, 9891) was dissolved in dioxane (50 g) dried over alumina, and then 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol (2, 2.0 g, 12.0 mmol, 1.0 equiv) was added. The solution was stirred at 80 ° C under a nitrogen atmosphere (2 h), then concentrated to about 10 mL, and then water (100 g) was added. The pH was adjusted to 2 using hydrochloric acid (4 M), and then brine (50 mL) was added. The product was used i PrOH / CH2Cl2: 1 / 9 extraction (3×50 mL). The volatile components were removed in vacuo to give compound 3 (2.26 g, 64%).

[0109] Example 4

[0110] Preparation of S-(5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)thioacetate

[0111]

[0112] S-(1-piperidinylmethyl)thioacetate hydrochloride (2.67 g, 12.7 mmol, 1.06 equiv.; synthesis reference Edward E. Smissman and John RJ Sorenson, The Journal of Organic Chemistry 1965 30 (1), 300-301) was dissolved in dioxane (50 g) dried over alumina, and then 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol (2, 2.0 g, 12.0 mmol, 1.0 equiv.) was added. The solution was stirred at 80° C. under a nitrogen atmosphere (2 h), then concentrated to about 10 mL, and then water (100 g) was added. The pH was adjusted to 2 using hydrochloric acid (4 M), and then brine (50 mL) was added. The product was used i PrOH / CH2Cl2: 1 / 9 extraction (3 x 50 mL). The volatile components were removed in vacuo to give compound 3 (2.14 g, 66%).

[0113] Example 5

[0114] Preparation of S-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)thioacetate

[0115]

[0116] Compound 3 (4.0 g, 0.016 mol, 1.0 equiv) was dissolved in DMF (80 g), and sodium carbonate (5.0 g, 0.047 mol, 3.0 equiv) was then added. The mixture was pressurized to 2.5 atmospheres using chlorodifluoromethane in a 400 mL autoclave under stirring. The mixture was heated to 80 ° C under stirring (3 h). Heating was stopped, the reaction was continued to stir, and the temperature was lowered to ambient temperature. The autoclave was vented to atmospheric pressure, and the mixture was then concentrated in vacuo to a weight of about 12 g. Water (50 g) and hexane (50 g) were added, and the mixture was then stirred vigorously (15 min). The mixture was separated, and the hexane layer was then concentrated in vacuo to give a crude sample of compound 4 as an orange oil (3.63 g, 76%), which was used without further purification. Analytical sample 4 was obtained by flash column chromatography on silica gel, eluting with EtOAc / hexane: 1 / 4; mp 33-35°C; 1 H NMR (400MHz, CDCl3) 6.68 (1H, t, J H-F 72), 4.04 (2H, s, CH2), 3.81 (3H, s, CH3), 2.35 (3H, s, CH3); 13 C NMR (100MHz, CDCl3)194.7(s), 142.8(s), 139.0(q, JC-F 37), 120.9(q, J C-F 270), 115.6(t, J C-F 270), 104.9(s), 35.8(s), 30.1(s), 20.1(s); 19 F NMR (376MHz, CDCl3)-62.3 (3F, s), -81.6 (2F, d, J H-F 72).

[0117] Example 6

[0118] Preparation of S-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)thioacetate

[0119]

[0120] Compound 3 (7.30 g, 28.7 mmol, 1.0 equivalent) was added to DMF (70 g) and tripotassium phosphate (11.9 g, 86.1 mmol, 3.0 equivalent). The mixture was pressurized to 5 atmospheres of pressure using chlorodifluoromethane in a 400 mL autoclave under stirring. The mixture was heated to 80 ° C under stirring (3 h). Heating was stopped, the reaction was stirred and cooled to room temperature. The autoclave was ventilated to atmospheric pressure, and the mixture was then discharged into a mixture of water (300 g) and hexane (300 g). The mixture was stirred vigorously (15 minutes). The mixture was separated. The organic layer (upper layer) was collected, and the lower layer (aqueous layer) was then washed with hexane (50 g). The hexane wash was combined with the previously collected organic layer (upper layer), and the combined hexane fractions were washed with water (100 mL) and then concentrated under vacuum to give compound 4 (8.71 g, 80 purity, 79% yield) as an orange oil, which was used without further purification.

[0121] Example 7

[0122] Preparation of S-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)thioacetate

[0123]

[0124] Potassium hydroxide (13.3 g, 0.24 mol, 2.0 equivalents) and acetonitrile (100 mL) were charged into a pressure vessel and then cooled to 5°C. Compound 3 (30 g, 0.12 mol, 1.0 equivalents) was added at 5°C and the slurry was stirred for 15 minutes. Chlorodifluoromethane (30.6 g, 0.35 mol, 3.0 equivalents) was continuously charged to the reaction mixture at 5°C over 3 hours. The reaction mixture was warmed to 10°C and then stirred at this temperature for 5 hours. Ethyl acetate (100 mL) and water (200 mL) were added and then stirred at 10°C for another 20 minutes. Stirring was stopped and the mixture was separated into an organic layer and an aqueous layer, the aqueous layer was extracted with ethyl acetate (100 mL), and the ethyl acetate extract and the organic layer of the reaction mixture were combined and washed with water (2×100 mL). The volatile components of the mixture were removed in vacuo to give compound 4 (32.3 g, 90% purity, 81%).

[0125] Example 8

[0126] Preparation of 3-[[[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]thio]-4,5-dihydro-5,5-dimethylisoxazole

[0127]

[0128] Compound 4 (1.31 g, 80% purity, 3.4 mmol, 1.0 equiv) was dissolved in methanol (20 g), and 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole (5, 0.63 g, 4.7 mmol, 1.4 equiv) was added, followed by sodium carbonate (1.37 g, 13 mmol, 3.8 equiv). The mixture was heated to 50 ° C (6 h) with stirring. Methanol (10 mL) was removed under vacuum, and water (100 g) was added. The mixture was extracted with ethyl acetate (2×30 g). The combined ethyl acetate extracts were washed with water (100 mL), brine (50 mL), and the volatile components were removed under vacuum to give 1 (1.62 g, 59% purity, 78% yield) as a yellow oil.

[0129] Example 9

[0130] Preparation of 3-[[[5-(Hydroxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]thio]-4,5-dihydro-5,5-dimethylisoxazole

[0131]

[0132] Compound 3 (0.50 g, 2.0 mmol, 1.0 equiv) was dissolved in ethanol (10 g), and 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole (5, 0.30 g, 2.2 mmol, 1.1 equiv) was added, followed by potassium carbonate (0.54 g, 3.9 mmol, 2.0 equiv). The mixture was heated to reflux under stirring (16 h). The mixture was acidified to pH 3 with 1 M HCl. The resulting mixture was then extracted with ethyl acetate (2×50 g). The combined ethyl acetate extracts were washed with hydrochloric acid (1 M, 100 mL), brine (50 mL), and the volatile components were removed in vacuo to give 6 (385 mg, 79% purity, 50% yield) as a yellow oil.

Claims

1. A process comprising the step of thiomethylating a pyrazole of formula II to produce a R2-C(O)-S-CH2-functional group at position 4 of the pyrazole ring, thereby obtaining and optionally isolating a thioester of formula III: in R1 is C1-C3 alkyl; R2 is an alpha hydrogen-containing group Y2Y1H*C*-, wherein the alpha carbon and the alpha hydrogen are marked with an asterisk, wherein Y1 and Y2 are independently selected from hydrogen, C1-C2 alkyl; and R3 is hydrogen or a C1 group which can be converted to F2HC-, said C1 group being Y3Y4HC-, wherein Y3 and Y4 are halogen or alkoxy, or said Y3 and Y4 together are =O, The method comprises reacting a pyrazole of formula II with a compound of formula MSC(O)-R2 in an alkaline environment in the presence of a formaldehyde source, wherein M is hydrogen or a metal cation, or wherein the pyrazole of formula II is thiomethylated with the aid of a reagent of formula X-CH2-SC(O)-R2 or a salt thereof, wherein X is a hydroxyl group or a leaving group selected from: halogen; -O-SO2R', wherein R' is an alkyl group, a perfluoroalkyl group or an aryl group; -OC(O)R', wherein R' is alkyl, perfluoroalkyl or aryl; or -N + R'3, wherein R' is hydrogen and alkyl.

2. The method of claim 1, wherein R2 is -CH3 and R3 is hydrogen.

3. The method according to claim 1 or 2, wherein an alkaline environment is created in the reaction vessel or in the presence of at least a portion of the MSC(O)-R2 compound pre-charged into the reaction vessel, and then the pyrazole of formula II is contacted with the formaldehyde source in the reaction vessel.

4. The method according to claim 3, comprising charging water or an organic solvent or a mixture thereof into a reaction vessel, adding the MSC(O)-R2 compound, then dissolving the paraformaldehyde in an alkaline environment generated by adding a base, gradually feeding the pyrazole of formula II to complete the reaction, and then collecting the reaction product of formula III.

5. The method according to claim 1 or 2, wherein the reagent of formula X-CH2-SC(O)-R2 is selected from: HO-CH2-SC(O)-CH3; Br-CH2-SC(O)-CH3; and Wherein R2 is methyl.

6. The method according to claim 1 or 2, wherein the pyrazole of formula II is: And, the thioester of formula III is:

7. The method according to claim 1 or 2, further comprising the step of reacting the thioester of formula III wherein R3 is hydrogen with a difluoromethylating agent to produce and optionally isolate the corresponding etherified thioester of formula IV wherein R1 and R2 are as defined in claim 1 or 2.

8. The method of claim 7, wherein the difluoromethylating agent is F2X'C-L1, wherein X' is hydrogen or halogen, and L1 is a leaving group selected from: chlorine, bromine or iodine; -COOR", wherein R" is an alkyl group or a corresponding alkali metal; -C(O)R'', wherein R''' is alkyl or phenyl; or -P(O)(O-alkyl)2.

9. The method according to claim 8, wherein the difluoromethylating agent is a compound of formula F2HC-L1.

10. The method according to claim 9, which comprises charging an organic solvent, a thioester of formula III and a base into an autoclave, pressurizing the autoclave with F2HC-L1, reacting under heating and optionally stirring, and then obtaining an etherified thioester of formula IV from the reaction mixture.

11. The method according to claim 10, wherein the organic solvent is dimethylformamide and the base is an alkali metal carbonate or an alkali metal phosphate.

12. The method according to claim 9, comprising charging an organic solvent, a thioester of formula III and a base into an autoclave, pressurizing the autoclave with F2HC-L1, wherein the reaction temperature is below 10°C, and then obtaining an etherified thioester of formula IV from the reaction mixture.

13. The process of claim 12, wherein the organic solvent is acetonitrile and the base is an alkali metal hydroxide, and the reaction mixture is then cooled to below 10°C.

14. The method of claim 7, wherein the thioester of formula III is: And the etherified thioester of formula IV is:

15. The process according to any one of claims 1 to 2, further comprising reacting a thioester of formula III wherein R3 is a C1 group convertible to F2HC- with a fluorine-containing reagent to produce and optionally isolate the corresponding etherified thioester of formula IV, wherein R1 and R2 are as defined in claim 1 or 2.

16. The method according to claim 7, further comprising the step of reacting the etherified thioester of formula IV with the 4,5-dihydroisoxazole of formula V to produce the sulfide of formula I: Wherein L2 is a leaving group, the leaving group is selected from chlorine or bromine; 17. The method of claim 16, wherein the reaction is 18. The method according to claim 1 or 2, further comprising the steps of: The thioester of formula III is reacted with a 4,5-dihydroisoxazole of formula V to give a compound of formula VI: Wherein L2 is a leaving group, and the leaving group is a halogen; The compound of formula VI is reacted with a difluoromethylating agent to obtain a compound of formula I:

19. The method of claim 16, further comprising oxidizing the compound of formula I to the corresponding sulfoxide or sulfone.

20. The process according to claim 19, wherein the oxidation gives sulfonepyraclostrobin:

21. Compounds of formula III: in: R1 is C1-C3 alkyl; R2 is an alpha hydrogen-containing group Y2Y1H*C*-, wherein the alpha carbon and alpha hydrogen are marked with an asterisk, wherein Y1 and Y2 are independently selected from hydrogen, C1-C2 alkyl; and R3 is hydrogen or a C1 group which can be converted to F2HC-, wherein the C1 group is Y3Y4HC-, wherein Y3 and Y4 are halogen or alkoxy, or wherein Y3 and Y4 together are =0.

22. The compound according to claim 21, which is:

23. Compounds of formula IV: in R1 is C1-C3 alkyl; R2 is an alpha hydrogen-containing group Y2Y1H*C*-, wherein the alpha carbon and alpha hydrogen are marked with an asterisk, and wherein Y1 and Y2 are independently selected from hydrogen, C1-C2 alkyl.

24. The compound according to claim 23, which is:

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