Method for preparing an n-cyano sulfilimine compound

Abstract

The instant invention relates to a method for preparing N-cyano sulfilimine compounds and derivatives thereof, such as N-cyano sulfoximines. In particular, it has been found that a N-cyano sulfilimine compound may be prepared by mixing in a solvent a sulfide compound (i), cyanamide (ii), and an oxidizing agent (iii) in the presence of compound (iv) comprising an alkali metal hydroxide, a hydrogen carbonate salt, a mixture of hydrogen carbonate salt and a carbonate salt, and / or a mixture of phosphate salts, whereby the yields of N-cyano sulfilimine compound production are increased.

Description

[0001] METHOD FOR PREPARING AN N-CYANO SULFILIMINE COMPOUND

[0002] TECHNICAL FIELD

[0003] The instant invention relates to a method for preparing N-cyano sulfilimine compounds and derivatives thereof, such as N-cyano sulfoximines.

[0004] BACKGROUND

[0005] N-cyano sulfilimine compounds are intermediates used in the preparation of organic compounds containing sulfur-to-nitrogen bonds, such as N-cyano sulfoximines. Sulfoximine compounds, also referred to as sulfilimine or sulfimide compounds, and in particular N- cyano sulfoximine compounds, have several applications including their use as insecticidal agents. Reference is made to, e.g., U.S. Patent Application publication No. 2005 / 0228027, which describes N-substituted sulfoximines as being effective for controlling insects. Reference is also made to International Patent Application publication No. 2008 / 106006, which shows the preparation of N-cyano sulfoximines from N-cyano sulfilimines.

[0006] Known processes for preparing N-cyano sulfilimine compounds are based on the reaction of sulfide with cyanamide and an oxidant like iodobenzene diacetate also known as (diacetoxyiodo)benzene or DIB, sodium hypochlorite (NaOCI) or bromine under basic conditions. Reference is made to, for instance, International Patent Application publication No. 2008 / 106006 which describes the production of cyano-substituted sulfilimines from the corresponding sulfides by reaction with cyanamide and hypochlorite and International Patent Application publication No. 2013 / 123349 which describes methods of producing a sulfilimine compound, combining a sulfide compound, cyanamide, a hypochlorite compound, and a base, which may include sodium hydroxide, and wherein a buffer may optionally be used to improve the storage stability of the starting material cyanamide and to neutralize acidic impurities. Trisodium phosphate or sodium dihydrogen phosphate, with sufficient sodium hydroxide used to generate the trisodium salt, are mentioned to be used as a phosphate buffer.

[0007] Such preparations have difficulties to be implemented on an industrial scale due to their exothermicity and the low stability of the N-cyano sulfilimine product under the reaction conditions, and the formation of by-products such as sulfoxides and sulfones, resulting in low yields of N-cyano sulfilimine when the reaction is scaled-up.

[0008] Accordingly, there is a need for improved processes for the preparation of N-cyano sulfilimine, for N-cyano sulfilimine to be obtained in high yields in particular for its industrialscale implementation. SUMMARY

[0009] The instant invention relates to such a process. In particular, it has been found that a N-cyano sulfilimine compound may be prepared by mixing in a solvent a sulfide compound (i), cyanamide (ii), and an oxidizing agent (iii) in the presence of a compound (iv) comprising an alkali metal hydroxide, a hydrogen carbonate salt, a mixture of hydrogen carbonate salt and a carbonate salt, and / or a mixture of phosphate salts, whereby the yields of N-cyano sulfilimine compound production are increased. Particular embodiments and advantages of a such method are further described in the following detailed description.

[0010] The instant invention further relates to the preparation of derivatives of N-cyano sulfilimine and of N-cyano sulfoximines in particular.

[0011] DETAILED DESCRIPTION

[0012] The instant invention particularly relates to a method for preparing a N-cyano sulfilimine compound comprising: mixing in a solvent i) a sulfide compound, ii) cyanamide, and iii) an oxidizing agent in the presence of iv) a compound comprising an alkali metal hydroxide, a hydrogen carbonate salt, a mixture of hydrogen carbonate salt and a carbonate salt, and / or a mixture of phosphate salts.

[0013] Mixing in a solvent the sulfide compound (i), cyanamide (ii) and the oxidizing agent (iii), in the presence of the compound (iv) provides a reaction mixture. Mixing further results in the formation of the N-cyano sulfilimine compound. Accordingly, mixing typically provides a reaction mixture which, upon formation of N-cyano sulfilimine, will comprise the N-cyano sulfilimine compound.

[0014] In particular, a method as described herein is applicable for preparing N-cyano sulfilimine compounds from sulfide compounds by the transformation of the sulfide group of the sulfide compound to a N-cyano sulfilimine group of the N-cyano sulfilimine compound, by reaction with cyanamide (ii) in oxidizing conditions due to mixing with an oxidizing agent (iii). In a method as described herein this reaction takes place by mixing in the presence of a compound (iv). Such reaction may be generally depicted as follows:

[0015] Salt (iv) N-cyano sulfilimine

[0016] Such method has been found to improve the yield of preparation of the N-cyano sulfilimine compound when compared to, e.g., the same method carried out in absence of a compound (iv). Without being bound to any theory, mixing in the presence of a compound (iv) as described herein it is believed to stabilize the N-cyano sulfilimine compound and / or reaction intermediate / s formed by the reaction of (i), (ii) and (iii), and thereby improving the yield of the reaction.

[0017] For the purpose of the present description (i), (ii), and (iii) may be jointly referred to as the reagents or the starting materials.

[0018] The solvent, the reagents (i), (ii) and the compound (iv) may be mixed in any suitable order. Further, all or part of the solvent, the reagents (i), (ii) and (iii), and the compound (iv) may be mixed in a single step or in different steps. Mixing will be described in further detail below.

[0019] In a method as described herein the solvent may comprise a polar organic solvent and optionally may comprise water. It may be preferred for the solvent not to comprise water. However, the solvent may comprise water if present in the solvents used themselves, or if purposedly added as such or in admixture with the compound (iv) and / or with one or more of the reagents (i), (ii), and (iii).

[0020] Preferably a polar organic solvent may be selected from acetonitrile (ACN); an ester such as ethyl acetate or butyl acetate; an ether such as methyl t-butyl ether, 1 ,4-dioxane, tetrahydrofuran (THF), 2-methyl THF; an alcohol such as methanol, ethanol or isopropyl alcohol (IPA); dimethyl acetamide (DMAc); dimethyl sulfoxide (DMSO) and mixtures thereof. More preferably the polar organic solvent may be acetonitrile. Acetonitrile advantageously has been found to provide the best results with complete conversion of the starting sulfide compound, superior selectivity for the target N-cyano sulfilimine, and higher purity of the product obtained, when compared to other solvents. Furthermore, acetonitrile is easily available and facilitates downstream processing. In several embodiments the solvent may comprise acetonitrile and water or may consist of acetonitrile.

[0021] The amount of solvent that may be used in a method as described herein may depend on the scale of the reaction and the concentration of the reagents (i), (ii), and (iii) and compound (iv) to be used in the preparation of the N-cyano sulfilimine compound, such as detailed further below. As a mode of example, the solvent may be used in a volume amount from 0.25 L to 4 L of total solvent per mol of sulfide compound (i), in particular from 0.5 L to 3 L, more in particular from 0.75 to 2 L of solvent, yet more in particular from 1 L to 1 .5 L of total solvent per mol of sulfide compound (i).

[0022] A sulfide compound (i) used in a method as described herein may be commercially available or may be prepared by methods know in the art. In a method as described herein the specific structure of a N-cyano sulfilimine compound will depend on the structure of the starting sulfide compound (i). Suitable specific structures for the sulfide compound and the N-cyano sulfilimine compound will be explained in more detail below.

[0023] The amount of sulfide compound (i) used in a method as described herein will depend on the scale of the preparation of the N-cyano sulfilimine compound. As a mode of example, in a process wherein mixing is performed in batch mode a sulfide compound may be used in a molar amount from 0.01 mol to 30000 mol per batch, in particular from 30 to 15000 mol and more in particular from 2000 to 10000 mol per batch. Alternatively, in a process wherein mixing is performed in continuous mode flow rates from 0.01 mol to 1000 mol per hour, in particular from 5 to 800 mol per hour and more in particular from 100 to 700 mol per hour, may be used.

[0024] The sulfide compound (i) may be used as such, e.g., in solid or liquid form or in solution in an appropriate solvent, e.g., acetonitrile. In a method as described herein the sulfide compound (i) may be preferably used in solution in a suitable solvent, such as acetonitrile. In particular, the sulfide compound (i) may be added to the reaction mixture as a solution, e.g., in acetonitrile, in a concentration of, e.g., from 1 to 50 % w / w based on the weight of sulfide compound (i) and the total weight of the solution, in particular from 5 to 40 % w / w, more in particular from 10 to 25 % w / w and yet more in particular from 15 to 20 % w / w.

[0025] A method as described herein comprises mixing an oxidizing agent (iii) together with the sulfide compound (i) and cyanamide (ii). In the reaction between the sulfide compound (i) and cyanamide (ii), the presence of the oxidizing agent (iii) provides the oxidizing conditions required for the formation of the N-cyano sulfilimine compound.

[0026] In a method as described herein cyanamide (ii) may be used in a molar equivalent amount from 0.5 to 3 equivalents of cyanamide (ii) per equivalent of sulfide compound (i). In several embodiments the equivalent amount may be from 0.75 to 2 equivalents of cyanamide (ii) per equivalent of sulfide compound (i), in particular from 1 to 1.75 equivalents, more in particular from 1.1 to 1.6 equivalents.

[0027] Cyanamide may be used as such, e.g., in solid form or in solution in an appropriate solvent, e.g., water. Cyanamide (ii) may be preferably used in solution, more preferably in water. In several particular embodiments, cyanamide (ii) may be added to the reaction mixture as a solution, e.g., an aqueous solution, in a concentration from 20 to 80 % w / w based on the weight of cyanamide and the total weight of the solution, in particular from 25 to 75 % w / w, and more in particular from 40 to 60 % w / w.

[0028] Cyanamide (ii) may be prepared by methods known in the art or may be commercially available.

[0029] In several embodiments the oxidizing agent (iii) may comprise bromine, hypochlorite, (diacetoxyiodo)benzene (DIB), and / or a monopersulfate compound (e.g., potassium peroxymonosulfate or the triple potassium salt of peroxymonosulfate, hydrogen sulfate and sulfate of formula 2*KHSO5 KHSO4 K2SC>4 also known as oxone). Preferably, the oxidizing agent may comprise bromine and / or hypochlorite.

[0030] In several particularly preferred embodiments the oxidizing agent may comprise bromine (Br2). Under aqueous basic conditions, e.g., when an alkali metal hydroxide, such as sodium hydroxide, is used as a compound (iv), bromine is converted to unstable hypobromite, also an oxidizing agent.

[0031] Accordingly, when the oxidizing agent (iii) comprises bromine, it may be preferred for the compound (iv) to be an alkali metal hydroxide, preferably sodium hydroxide (iv). When the oxidizing agent comprises bromine, the formation of hypobromite may take place in situ, during mixing or bromine may be pre-reacted, e.g., with an alkali metal hydroxide such as sodium hydroxide, to form hypobromite, prior to mixing with other reagents (i), (ii). Since hypobromite itself it is not stable it is generally preferred not to previously form hypobromite (e.g., from bromine). Accordingly, when the oxidizing agent comprises bromine, it may be preferred to form hypobromite in situ during mixing, by e.g., the alkali metal hydroxide as the compound (iv), the cyanamide (ii), and the sulfide compound (i) and subsequently mixing the bromine as oxidizing agent (iii). These and other specific modes of addition will be discussed in more detail below.

[0032] In several particularly preferred alternative embodiments the oxidizing agent may comprise hypochlorite. A hypochlorite may be selected from potassium hypochlorite and sodium hypochlorite.

[0033] Sodium hypochlorite may be preferred because it is easily available and because it has been found to provide good yields in combination with the use of a compound (iv) as described herein. Further, the use of sodium hypochlorite is easy to handle in an industrial scale. In particular, quenching of sodium hypochlorite prior to disposal results in sodium chloride which is not toxic and easily disposable. A method as described herein has also been found to solve some of the problems associated to the use of hypochlorite such as a reduction of the yield of the reaction when the reaction is scaled up. Nonetheless, mixing in the presence of a compound (iv) in a method as described herein advantageously improves the preparation of N-cyano sulfilimine compound, also when oxidizing agents other than hypochlorite are used.

[0034] The use of (diacetoxyiodo)benzene (DIB) as oxidizing agent (iii) in a method as described herein, wherein mixing is performed in the presence of a compound (iv), has also been found to significantly improve the preparation of the N-cyano sulfilimine compound by improving yield of reaction. Accordingly, a method as described herein may also advantageously improve scaling-up of the preparation of a N-cyano sulfilimine compound when DIB is used.

[0035] In a method as described herein an oxidizing agent (iii) may be used in a molar equivalent amount from 0.9 to 7 equivalents of oxidizing agent per equivalent of sulfide compound (i). Lower equivalent amounts (e.g., from 0.9 to 2 equivalents) may be preferred to facilitate downstream processing of the reaction mixture. Higher equivalent amounts (e.g., from 2 to 7 equivalents) may be preferred to speed up the reaction. In several embodiments the equivalent amount may be from 1 to 6 equivalents of oxidizing agent per equivalent of sulfide compound (i), in particular from 1.1 to 5 equivalents, more in particular from 1.3 to 4 equivalents, yet more in particular from 1.4 to 3 equivalents.

[0036] In a method as described herein an oxidizing agent (iii) may be used in solution in a suitable solvent, such as water. In particular embodiments the oxidizing agent (iii) may be added to the reaction mixture as a solution, e.g., an aqueous solution, in a concentration from 2 to 25 % w / w based on the weight of oxidizing agent (e.g., sodium hypochlorite) and the total weight of the solution, in particular from 5 to 20 % w / w, and more in particular from 10 to 15 % w / w. Aqueous solutions of the oxidizing agent may be commercially available, such as sodium hypochlorite aqueous solutions having a 12-15% w / w concentration.

[0037] In a method as described herein the compound (iv) comprises an alkali metal hydroxide, a hydrogen carbonate salt, a combination of hydrogen carbonate salt and a carbonate salt, and / or a combination of phosphate salts. As indicated above mixing in the presence of a compound (iv) as described herein it is believed to stabilize the N-cyano sulfilimine compound and / or reaction intermediate / s formed by the reaction of (i), (ii) and (iii), and thereby improving the yield of the reaction. Furthermore, in the presence of water, e.g., wherein the solvent comprises water, the compound (iv) may advantageously contribute to maintaining a specific pH for the reaction mixture.

[0038] In several embodiments, a combination of compounds (iv) may be used. A compound (iv) may be used in solid form or in solution, e.g., as a saturated solution, in appropriate solvent (such as water). For instance, a compound (iv) may be added to the reactor wherein mixing takes place as a solid or in solution, e.g., as a saturated solution. Such compounds are commercially available. A saturated solution may be prepared by methods known in the art. For instance, the compound may be added to an appropriate solvent (e.g., water) until saturation of the solution is observed, e.g., by formation of a precipitate of the compound (iv).

[0039] In several embodiments the compound (iv) may comprise an alkali metal hydroxide. An alkali metal hydroxide may preferably be selected from sodium hydroxide or potassium hydroxide, and more preferably is sodium hydroxide. When the compound (iv) comprises alkali metal hydroxide, and sodium hydroxide in particular, mixing may comprise adding the alkali metal hydroxide as a solid or as an aqueous solution of alkali metal hydroxide in concentration from 5 to 50 %. In several embodiments, mixing may preferably comprise adding the alkali metal hydroxide as an aqueous solution from 10 to 40 %.

[0040] In the presence of water, e.g., when the solvent comprises water, an alkali metal hydroxide, and sodium hydroxide in particular, may advantageously contribute to maintaining a specific pH for the reaction mixture.

[0041] In several embodiments the compound (iv) may comprise a hydrogen carbonate salt, also referred to in the art as a bicarbonate salt. A hydrogen carbonate salt may be selected from an alkali metal hydrogen carbonate salt and may be particularly selected from sodium hydrogen carbonate and potassium hydrogen carbonate. The compound (iv) may preferably comprise sodium hydrogen carbonate, which is widely available at low cost.

[0042] When the compound (iv) comprises a hydrogen carbonate salt, and sodium hydrogen carbonate in particular, mixing may comprise adding the hydrogen carbonate salt as a solid hydrogen carbonate salt, as a saturated aqueous solution of the hydrogen carbonate salt or as an aqueous slurry of the hydrogen carbonate salt. In several embodiments, mixing may preferably comprise adding the hydrogen carbonate salt as a solid hydrogen carbonate salt.

[0043] Adding a hydrogen carbonate salt or, in particular, sodium hydrogen carbonate as a solid or as a saturated aqueous solution advantageously reduces the use of solvent (e.g., water), as no solvent or a minimal amount of solvent is added in admixture with the salt in the preparation of the N-cyano sulfilimine compound. This may facilitate dosing of the compound (iv) and reduce solvent, e.g., aqueous waste. Furthermore, using hydrogen carbonate salt or, in particular, sodium hydrogen carbonate, as a solid has been found to provide N-cyano sulfilimine compounds in very good yields.

[0044] In several alternative embodiments the compound (iv) may preferably comprise a combination of phosphate salts, preferably a combination of alkali metal phosphate salts. The alkali metal may be preferably selected from sodium and potassium and is preferably sodium. The phosphate may preferably be a combination of dihydrogen phosphate and monohydrogen phosphate or a combination of monohydrogen phosphate and orthophosphate, more preferably a combination of dihydrogen phosphate and hydrogen phosphate. Yet more preferably the combination of alkali metal phosphate salts may be a combination of sodium dihydrogen phosphate and disodium monohydrogen phosphate.

[0045] Where the compound (iv) comprises a combination of phosphate salts as defined above, in a method as described herein mixing may comprise adding the combination of phosphate salts as an aqueous solution of the combination of phosphate salts.

[0046] In the presence of water, a combination of phosphate salts and in particular a combination sodium dihydrogen phosphate and disodium monohydrogen phosphate, may advantageously contribute to maintaining a specific pH for the reaction mixture.

[0047] The amount of compound (iv) mixed in a method as described herein may vary depending on the nature of the compound, the amount of solvent, the nature of the solvent and the amount of sulfide compound (i) used in the preparation of the N-cyano sulfilimine compound.

[0048] As a person skilled in the art will understand, the amount of each of reagents (i), (ii) and (iii) and compound (iv) mixed in a method described herein corresponds to the amount of reagents and compound added to, e.g., a reactor wherein they are mixed.

[0049] The amount of compound (iv) with respect to the amount of sulfide compound (i), may be from 0.01 to 6 molar equivalents of compound (iv) with respect each molar equivalent of sulfide compound (i), in particular from 0.02 to 5, more in particular from 0.05 to 4, and yet more in particular from 0.1 to 3.5 molar equivalents.

[0050] In several embodiments, the amount of compound (iv) may be in excess with respect to the amount of sulfide compound (i). For instance, mixing may comprise mixing 1.05 to 6 molar equivalents of compound (iv) with respect each molar equivalent of sulfide compound (i), more in particular from 1.5 to 4 molar equivalents, more in particular from 2 to 4 equivalents, yet more in particular from 2.5 to 3.5 equivalents of compound (iv) per each equivalent of sulfide compound (i). An excess of compound (iv) may be particularly preferred, e.g., where the compound comprises an alkali metal hydroxide, e.g., sodium hydroxide, or a hydrogen carbonate salt, e.g., sodium hydrogen carbonate.

[0051] In several embodiments, the amount of sulfide compound (i) may be in excess with respect to the amount of compound (iv). For instance, mixing may comprise mixing from 0.01 to 0.90 molar equivalents of the compound (iv) with respect to each molar equivalent of sulfide compound (i), more in particular from 0.02 to 0.75 molar equivalents, more in particular from 0.05 to 0.5 molar equivalents and more in particular from 0.1 to 0.4 molar equivalents of the compound (iv) with respect to each molar equivalent of sulfide compound (i). An excess of sulfide compound (i) with respect to the compound (iv) may be particularly preferred, e.g., where the compound comprises a combination of phosphate salts. Where a combination of phosphate salts is used, the molar amount of phosphate refers to the total mols of phosphate ions present in the combination of phosphate salts in any form, including dihydrogen phosphate, monohydrogen phosphate and orthophosphate.

[0052] In a method as described wherein a compound (iv) is used in solution in a suitable solvent, such as water, the compound (iv) may be added to the reaction mixture as a solution or slurry, e.g., an aqueous solution or slurry, in a concentration of, e.g., from 5 to 40 % w / w based on the weight of compound (iv) and the total weight of the solvent, e.g., water, in particular from 7 to 35 % w / w, and more in particular from 25 to 30 % w / w.

[0053] In a method as described herein mixing, cooling, and heating (heating may be performed, for instance, at the end of the reaction, in the working up of the reaction mixture to improve solubility of the salts as detailed further below), may be performed using means known to the person in the art according to the production scale. For instance, the solvent, the reagents (i), (ii) and (iii) and the compound (iv) may be added to a reactor and mixed therein. In several embodiments, the reactor may be provided with stirring means and the solvent, reagents and compound mixed by stirring. Optionally, a suitable reactor may be provided with cooling and / or heating means. Preferably, a suitable reactor may be provided with at least cooling means.

[0054] Even though a method as described herein is particularly suitable for industrial-scale preparations, it may also be used in a lab-scale preparations. Accordingly, suitable reactors may be selected from lab-scale reactors (e.g., a reaction flask such as a two or a three neck round bottom flask, which may be provided with a stirrer, a thermometer, and / or a condenser) or industrial-scale reactors (such as a stirred batch reactor or a continuous stirred tank reactor).

[0055] Mixing may be performed in batch or in continuous mode.

[0056] All or part of the solvent may be added to a reactor in a single step or in different steps. For instance, the solvent may be added, e.g., to a reactor, prior to, simultaneously with and / or after one or more of the reagents (i), (ii), (iii), and / or the compound (iv).

[0057] In several embodiments, the solvent may be added to a reactor and then (i), (ii), (iii) and (iv) may be added subsequently to the reactor comprising the solvent. Additionally, or alternatively all or part of the solvent may be added in admixture with one or more of (i), (ii) (iii) and / or (iv), e.g., with (i), (ii), (iii) and / or (iv) previously mixed or dissolved with the solvent. Thereby, the addition of (i), (ii), (iii) and / or (iv) premixed with a solvent may add all the solvent to the reactor or may add further solvent to any solvent previously present in the reactor or subsequently added to the reactor.

[0058] If the solvent is added in different seps, the solvent added in one step may be the same as or different from the solvent added in other steps. For instance, the solvent added to a reactor prior to or after the addition of (i), (ii), (iii) and (iv) may be different or may have a different composition from the solvent added in admixture with one or more of (i), (ii), (iii) and (iv). Similarly, the solvent added in admixture with one or more of (i), (ii), (iii) and (iv), in one step may be the same as or different from the solvent added in admixture with one or more of (i), (ii), (iii) and (iv) added in another step.

[0059] In several embodiments, the sulfide compound (i) may be added to the reactor prior to the other reagents (ii) and (iii) and the compound (iv) in a first mixing step. For instance, mixing may be performed by adding a sulfide compound (i) in admixture with a first solvent (e.g., acetonitrile alone or in combination with water) to a reactor in the first mixing step.

[0060] In several particular embodiments, in a mode of addition (A), after the first mixing step (wherein the sulfide compound (i) is added to the reactor) a compound (iv) may be subsequently added, as such (e.g., as a solid) or in admixture with a second solvent (e.g., water) in a second mixing step; followed by the addition of cyanamide (ii) as such (e.g., as a solid) or in admixture with a third solvent (e.g., water) in a third mixing step; and by the addition of the oxidizing agent (iii) as such (e.g., as a solid) or in admixture with a fourth solvent (e.g., water) in a fourth mixing step. In several more particular embodiments, mixing may be performed by adding a sulfide compound (i) in admixture with acetonitrile alone or in combination with water to a reactor in a first mixing step; subsequently adding a compound (iv) as a solid or in admixture with water in a second mixing step; followed by adding cyanamide (ii) in admixture with a water in a third mixing step; and by adding the oxidizing agent (iii) in admixture with water in a fourth mixing step.

[0061] Alternatively, in several particular embodiments, in a mode of addition (B), after the first mixing step (wherein the sulfide compound (i) is added to the reactor) cyanamide (ii) may be added in a second mixing step; the compound (iv) may be added in a third mixing step and the oxidizing agent (iii) may be added in a fourth mixing step. The form of addition of the different reagents (ii), (iv), and (iii) may be the same as described above.

[0062] In several embodiments, the oxidizing agent (iii) may be added to the reactor prior to the other reagents (i) and (ii) and the compound (iv) in a first mixing step. For instance, mixing may be performed by adding the oxidizing agent (iii) to a reactor in admixture with a first solvent (e.g., water) in the first mixing step.

[0063] In several particular embodiments, in a mode of addition (C), after the first mixing step (wherein the oxidizing agent (iii) is added to the reactor) cyanamide (ii) may be added as such (e.g., as a solid) or in admixture with a second solvent (e.g., water) in a second mixing step; and subsequently a compound (iv) may be added, as such (e.g., as a solid) or in admixture with a third solvent (e.g., water), in a third mixing step. A sulfide compound (i) in admixture with a third solvent (e.g., acetonitrile alone or in combination with water) may be subsequently added in a fourth mixing step.

[0064] Alternatively, in further several particular embodiments, in a mode of addition (D) after the second mixing step (wherein the cyanamide (ii) is added after the oxidizing agent (iii) as described above); the sulfide compound (i) may be added in a third mixing step; and the compound (iv) may be added in a fourth mixing step. The form of addition of the different reagents (i) and (iv) may be the same as described above.

[0065] Alternatively, in several particular embodiments, in a mode of addition (E), after the first mixing step (wherein the oxidizing agent (iii) is added to the reactor) the compound (iv) may be added in a second mixing step; in a third mixing step cyanamide (ii) may be added; and the sulfide compound (i) may be added in a fourth mixing step. The form of addition of the different reagents (iv), (ii) and (i) may be the same as described above.

[0066] In several embodiments, the compound (iv) may be added to the reactor prior to the other reagents (i), (ii) and (iii) in a first mixing step. For instance, mixing may be performed by adding the compound (iv) to a reactor in admixture with a first solvent (e.g., water) in the first mixing step.

[0067] In several particular embodiments, in a mode of addition (F), after the first mixing step (wherein the compound (iv) is added to the reactor) cyanamide (ii) may be added in a second mixing step; the sulfide compound (i) may be added in a third mixing step and the oxidizing agent (iii) may be added in a fourth mixing step. The form of addition of the different reagents (iv), (i) and (iii) may be the same as described above.

[0068] In several embodiments, the cyanamide (ii) may be added to the reactor prior to the other reagents (i), (iii) and (iv) in a first mixing step. For instance, mixing may be performed by adding the cyanamide (ii) to a reactor in admixture with a first solvent (e.g., water) in the first mixing step.

[0069] In several particular embodiments, in a mode of addition (G), after the first mixing step (wherein the cyanamide (ii) is added to the reactor) the compound (iv) may be added in a second mixing step; the oxidizing agent (iii) may be added in a third mixing step and the sulfide compound (i) may be added in a fourth mixing step. The form of addition of the different reagents (iv), (iii) and (i) may be the same as described above.

[0070] Several examples of modes of addition may be summarized in the following table: It has been found that all modes of addition result in the formation of the N-cyano sulfilimine in good yields.

[0071] Different modes of addition may be preferred for, e.g., certain combinations of reagents. For instance, a mode of addition (B) may be particularly preferred, e.g., when an hypocholite is used as oxidizing agent (iii) and hydrogen carbonate is used as a compound (iv). A mode of addition (F) may be particularly preferred, e.g., when bromine is used as oxidizing agent (iii) and an alkali metal hydroxide, sodium hydroxide in particular, is used as a compound (iv).

[0072] A specific mode of addition, as defined above, does not preclude mixing further amounts of any of the reagents (i), (ii), (iii) or (iv) at any other stage. For instance, in the mode of addition (E), the compound (vi) may be added in the second mixing step and may be further added in other mixing steps, e.g., concomitantly with or after the cyanamide (ii) or the sulfide compound (i).

[0073] Mixing may be typically performed under controlled conditions, e.g., of temperature and, if applicable, of pH.

[0074] Generally, the reaction of the reagents (i), (ii) and (iii) in the presence of the compound (iv) is exothermic. Accordingly, mixing may be preferably performed under cooling to control the mixing temperature. For instance, a reactor provided with mixing means and cooling means may be used. Cooling means may be external cooling means or cooling means integrated to the reactor. Suitable reactors may further comprise means for measuring the temperature of the reaction mixture.

[0075] As a mode of example mixing may be performed at a temperature from -20 to 20 °C, preferably from -15 to 15 °C, more preferably from -5 to 10 °C, and yet more preferably from 0 to 5 °C. In a method as described herein, such temperatures have been found to provide the N-cyano sulfilimine compound in particularly good yields.

[0076] Where the solvent comprises water, mixing may be performed by controlling the pH of the reaction mixture obtained by mixing the reagents (i), (ii) and (iii) and the compound (iv) in the solvent. For instance, controlling the pH may be performed by measuring the pH of the reaction mixture. If necessary, controlling the pH of the reaction mixture obtained may further comprise maintaining the pH within a specific range, by adding a base or an acid as required. Suitable bases may be selected from sodium or potassium hydroxide or carbonate. Preferably the base may be sodium hydroxide due to its availability, price, ease of use and downstream processing. Accordingly, a compound (iv) as disclosed herein, such as alkali metal hydroxide, a hydrogen carbonate salt, and / or a combination of hydrogen carbonate salt and a carbonate salt, may also be useful as a base to control the pH of the reaction. Accordingly, in several embodiments a compound (iv) or combinations of compounds (iv) may be particularly used for such pH control. Suitable acids may be selected from hydrochloric, phosphoric, or sulfuric acid.

[0077] In several embodiments, the compound (vi) may act as a buffer and mixing the reagents (i), (ii) and (iii) and the compound (iv) may provide a reaction mixture with a pH suitable for the formation of the N-cyano sulfilimine compound and which is stable within a specific pH range, throughout the mixing time (e.g., whilst the reaction progresses and until the desired product and the reaction is considered to be completed). Accordingly, controlling the pH may not require the addition of an acid or a base to maintain the pH within a specific range.

[0078] In several other embodiments, mixing the reagents (i), (ii) and (iii) and the compound (iv) may provide a reaction mixture wherein the pH is outside a specific range and / or the pH of the reaction mixture increases or decreases as the reaction progresses and falls outside a specific range. Accordingly, controlling the pH may comprise adding a base or an acid as required to obtain a reaction mixture with a pH and / or to maintain the pH of the reaction mixture within a specific range.

[0079] For instance, in a method as described herein, wherein the solvent comprises water, the reaction mixture obtained may have a pH from 7 to 13, preferably from 8 to 13. Such pH may be directly obtained by mixing the reagents (i), (ii) and (iii) and the compound (iv). Alternatively, if by mixing the reagents (i), (ii) and (iii) and the compound (iv), the pH is outside of this range or if the pH changes and falls outside of such ranges as mixing (and the reaction) progresses, the pH may be maintained within this range by adding a base or an acid as required, such as the acids and bases indicated above.

[0080] In several particular embodiments, wherein the compound (iv) comprises an alkali metal hydroxide, and in particular sodium hydrogen carbonate, the reaction mixture obtained may have a pH from 7 to 13, preferably from 8 to 13, and addition of a base or an acid may not be required.

[0081] Similarly, in several other particular embodiments, wherein the compound (iv) comprises a hydrogen carbonate salt, and in particular sodium hydrogen carbonate, the reaction mixture obtained may have a pH from 7 to 13, preferably from 8 to 13, and addition of a base or an acid may not be required.

[0082] In several particular embodiments, wherein the compound (iv) comprises a mixture of phosphate salts, the reaction mixture obtained may have a pH from 7 to 13, preferably from 8 to 13, but the pH may fall below the specific range (or preferred range) as the reaction progresses. Accordingly, wherein the compound (iv) comprises a mixture of phosphate salts, mixing may be performed in the presence of a further compound (iv) acting as a base, such as alkali metal hydroxide, to assist in increasing the pH and maintaining it within the specific (or preferred) range. Other bases may also be alternatively or additionally used as indicated above.

[0083] Similarly, where the compound (iv) comprises a mixture of phosphate salts mixing in a solvent the reagents (i), (ii) and (iii) and the compound (iv) may result in a reaction mixture with a pH above the specific range from 7 to 13 or the preferred range of 8 to 13, and an acid may be added to bring the pH within said specific or preferred range.

[0084] As indicated above, mixing in a solvent the sulfide compound (i), cyanamide (ii) and the oxidizing agent (iii), in the presence of the compound (iv) results in the formation of the N-cyano sulfilimine compound. Mixing is typically performed for a sufficient amount of time to allow such formation of the N-cyano sulfilimine compound, particularly in a satisfactory yield.

[0085] The formation of N-cyano sulfilimine and the evolution of the reaction may be monitored by determining and / or measuring the presence of the starting materials and / or the product formed by means known in the art, e.g., thin layer chromatography (TLC), high performance liquid chromatography (HPLC). HPLC may also be used to determine the yield of the reaction as explained in more detail below. Other tools that may be used to monitor the reaction and identify the products of the reaction may be Liquid chromatography-mass spectrometry (LCMS).

[0086] For instance, mixing may be carried out until the signal of the starting sulfide compound (i) is no longer observed and the signal of the N-cyano sulfilimine remains constant (i.e., no longer increases). The signal observed may be, e.g., the corresponding peak in a chromatogram or the corresponding spot in a TLC. At this point the reaction may be regarded as having been completed. Once the reaction is deemed completed the reaction may be stopped and the N-cyano sulfilimine compound may be recovered by means known in the art.

[0087] As a mode of example mixing may be performed for 0.25 to 5 hours, in particular for 0.5 to 4 hours, more in particular for 1 to 3 hours and more in particular for 1.25 to 2.5 hours. Without being bound to any theory, such mixing times have been found to allow the formation of the N-cyano sulfilimine compound without suffering from degradation and thereby ensuring satisfactory yields when the reaction is carried out in a large scale.

[0088] Once the signal of starting sulfide compound (i) is no longer observed for the reaction mixture, the yield of the reaction for the formation of the N-cyano sulfilimine compound can be estimated from the % of the area of the peak of the N-cyano sulfilimine compound in the HPLC chromatogram obtained from a sample of the reaction mixture when the reaction is regarded to have been completed.

[0089] For instance, the yield of the reaction may be expressed as a % with respect to the theoretical maximum N-cyano sulfilimine compound obtainable from the initial amount of sulfide compound (i) used in the reaction, and based. on the % of N-cyano sulfilimine compound measured in the corresponding HPLC chromatogram of a sample of the crude of the reaction, and the mass of the product obtained at the end of the reaction after isolation and after evaporation of the solvent. In other words, the yield was calculated based on the mass and purity of the crude obtained as determined by HPLC.

[0090] A HPLC chromatogram for determining the yield of the reaction may be obtained from a sample of the reaction mixture when the reaction is regarded to have been completed, i.e., when the peak of the starting sulfide compound (i) is no longer observable. As a mode of example, the HPLC chromatogram may be registered by any available equipment known in the art, for example, Agilent, using suitable column (e.g., reversed- phase column, in particular packed with high-performance C-8 packing HPLC, such as Agilent’s ZORBAX RR SB C8, 80A° (4.6 x150 mm), 3.5pm) and mobile phase (e.g., a mixture of water (with a 0.15% of TFA), acetonitrile and methanol in a suitable gradient). For instance, a sample of the reaction mixture may be diluted in a mixture of ACN and water (e.g., 1 :1 v / v), the flow rate of the mobile phase may be of 1.2 mL / min and the temperature of 40 °C.

[0091] An LCMS may be used to identify the products of the reaction and the corresponding peaks in the chromatogram. As a mode of example, the LCMS chromatogram may be registered by any available equipment known in the art, for example. The conditions used for recording the LCMS chromatogram may be the same as those described above for HPLC.

[0092] The % of the area of the peak of the N-cyano sulfilimine compound in the HPLC, chromatogram may be calculated relative to the total area of all the peaks present in the chromatogram obtained, using any available software known in the art, for example, Empower software from Waters.

[0093] It has been found that a method as described herein may provide the N-cyano sulfilimine compound in good yields in conditions which are adequate for scaling-up the reaction for industrial application. For instance, the yield of the reaction may be from 65 to 99 %, as determined by HPLC from a sample taken from the reaction mixture when the reaction is deemed complete as explained above. In particular, the yield of the reaction may be from 70 to 98 %, more in particular from 75 to 96 %.

[0094] A method described herein may comprise isolating the N-cyano sulfilimine from the reaction mixture, e.g., once the reaction is deemed to have been completed. The N-cyano sulfilimine may be isolated from the reaction mixture by means known in the art.

[0095] Where the reaction mixture obtained comprises N-cyano sulfilimine and unreacted oxidizing agent and the method may further comprise quenching unreacted oxidizing agent with a reducing agent to provide a quenched reaction mixture and isolating the N-cyano sulfilimine from the quenched reaction mixture. Accordingly, in such embodiments, isolating the N-cyano sulfilimine from the reaction mixture comprises quenching the reaction mixture and isolating the N-cyano sulfilimine from the quenched reaction mixture.

[0096] The reducing agent used in quenching may preferably comprise a sulfo-compound, more preferably sodium sulfite or metabisulfite. Such reducing agents are easily available and both the reducing agents as such and the product of quenching (sodium sulphate) display low toxicity.

[0097] Quenching may be performed by adding and mixing the reducing agent to the reaction mixture obtained once the reaction is deemed to have been completed. The reducing agent may be added as, e.g., an aqueous solution, to provide the quenched reaction mixture. The N-cyano sulfilimine may then be isolated from the quenched reaction mixture by means known in the art.

[0098] As a mode of example, N-cyano sulfilimine may be isolated from the reaction mixture or the quenched reaction mixture, by known means of separation. For instance, the reaction mixture or the quenched reaction mixture may have two or more phases, e.g., two liquid phases such as an organic phase and aqueous phase, or a solid phase and a liquid phase, or two liquid phases and a solid phase. The different phases may be separated, whereby one of the separated phases may comprise a major fraction of the N-cyano sulfilimine compound. A major fraction of the N-cyano sulfilimine compound is understood as the majority of the N-cyano sulfilimine compound obtained in the reaction mixture. Residual N- cyano sulfilimine present in other phases may be recovered and added to the phase comprising a major fraction of the N-cyano sulfilimine compound.

[0099] Separating may comprise heating the reaction mixture prior to separation to increase the solubility of the salts and facilitate the separation. Heating may be performed to a temperature from 30 to 60 °C.

[0100] The separated phase comprising the major fraction of the N-cyano sulfilimine compound may be washed and / or extracted, to provide a clean phase comprising the major fraction of the N-cyano sulfilimine compound.

[0101] In several particular embodiments, a reaction mixture or quenched reaction mixture having two liquid phases and a solid phase may be first subject to filtration to remove the solid phase, and the two liquid phases may be separated by methods known in the art. The separated liquid phase comprising the major fraction of the N-cyano sulfilimine compound may be washed and / or extracted, to provide a clean liquid phase comprising the major fraction of the N-cyano sulfilimine compound dissolved in an organic solvent (e.g., acetonitrile).

[0102] Were a N-cyano sulfilimine compound obtained in a method as described herein is to be used in the preparation of a derivative thereof, such as a N-cyano sulfoximine, the N- cyano sulfilimine compound may be typically directly used dissolved in the liquid phase, e.g., obtained after washing, without needing further isolation from the solvent or further purification.

[0103] If further isolation of the N-cyano sulfilimine compound, e.g., from the solvent is desired this may be achieved by means known in the art. For instance, the clean liquid phase comprising the major fraction of the N-cyano sulfilimine compound may be dried by evaporating the organic solvent thereby providing the isolated N-cyano sulfilimine compound. If desired the isolated N-cyano sulfilimine compound may be further purified by means known in the art, e.g., chromatographic or crystallization methods. However, as discussed above, the N-cyano sulfilimine compound may be typically used without isolation from the liquid phase.

[0104] In a method as described herein the specific structure of a N-cyano sulfilimine compound will depend on the structure of the starting sulfide compound (i).

[0105] In several embodiments, the N-cyano sulfilimine compound may be of formula (I): wherein Het represents one of

[0106] X represents halogen, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 haloalkenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CN, NO2, SOmR6where m is an integer from 0 to 2, COOR4, CONR4R5, aryl or heteroaryl; Y represents hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 haloalkenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CN, NO2, SOmR1where m is an integer from 0 to 2, COOR4, CONR4R5, aryl or heteroaryl; n is an integer from 0 to 3;

[0107] L represents either a single bond; -CH(CH2)P- where R1, S and L taken together represent a 4-, 5-, or 6-membered ring and p is an integer from 1 to 3, - CH(CH2OCH2)- where R1, S and L taken together represent a 6-membered ring, or -CH- where L, R2and the common carbon to which they connect taken together represent a 4-, 5-, or 6-membered ring with up to, but no more than, 1 heteroatom;

[0108] R1represents C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3- Ce haloalkenyl, arylalkyl, heteroarylalkyl, or -CH2- in cases where R1, S and L taken together represent a 4-, 5-, or 6-membered ring;

[0109] R2and R3independently represent hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 haloalkenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CN, SOmR6where m is an integer from 0 to 2, COOR4, CONR4R5, arylalkyl, heteroarylalkyl, or R2and R3taken together and the common carbon to which they attach form a 3-6 membered ring;

[0110] R4and R5independently represent hydrogen, C1-C4 alkyl, C1-C4 haloalkyl; C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 haloalkenyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl; and

[0111] R6represents C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3- Ce haloalkenyl, arylalkyl or heteroarylalkyl; and the sulfide compound (i) is of formula (II) wherein

[0112] R1, R2, R3, L, Het and n are as previously defined.

[0113] In several embodiments, in the N-cyano sulfilimine compound of formula (I) and the sulfide compound (i) of formula (II):

[0114] Het represents: X represents halogen, C1-C4 haloalkyl, C2-C4 haloalkenyl, or C1-C4 haloalkoxy, preferably represents C1-C4 haloalkyl, more preferably represents C1-C4 perhalogenated alkyl, and yet more preferably represents CF3;

[0115] Y represents hydrogen n is an integer from 0 to 3;

[0116] L is a single bond;

[0117] R1represents C1-C4 alkyl, C3-C6 alkenyl or C3-C6 alkynyl, preferably represents C1-C4 alkyl, yet more preferably represents methyl; and

[0118] R2and R3independently represent hydrogen or C1-C4 alkyl, preferably, one of R2or R3represents hydrogen and the other one of R2or R3represents methyl.

[0119] In several embodiments the N-cyano sulfilimine compound of formula (I) is of structure (la) and the sulfide compound (i) of formula (II) is of structure (Ila):

[0120] Structure la Structure Ila

[0121] The N-cyano sulfilimine compound of structure (la) is N-[methyl[1-[6- (trifluoromethyl)-3-pyridinyl]ethyl]-A4-sulfanylidene]cyanamide (IIIPAC name, CAS No. 1046119-63-4).

[0122] The sulfide compound of structure (Ila) is 5-[1-(methylthio)ethyl]-2- trifluoromethylpyridine (IIIPAC name, CAS No. 1005489-34-8).

[0123] As indicated above, N-cyano sulfilimine compounds as described herein may be used for the preparation of derivatives thereof and in particular sulfoximines, which may be particularly used as insecticidal compounds. The structure of a particular slufoximine will depend on the structure of the starting N-cyano sulfilimine compound. A sulfoximine compound of particular interest may be sulfoxaflor of structure (Illa) (IIIPAC name [methyl- oxo-[1-[6-(trifluoromethyl)pyridin-3-yl]ethyl]-A6-sulfanylidene]cyanamide and CAS No. 946578-00-3), which is useful as an insecticide:

[0124] Structure Illa

[0125] Sulfoxaflor may be derived from a N-cyano sulfilimine compound of structure (la), which therefore it may be of particular interest. Accordingly, the instant invention further relates to a method of preparation of a derivative of a N-cyano sulfilimine compound. As a mode of example, such a derivative may be a sulfoximine compound, more in particular N-cyano sulfoximine and yet more in particular may be sulfoxaflor.

[0126] Such a method comprises preparing a N-cyano sulfilimine compound using a method as described herein in a first step and subsequent steps for the formation of said derivative, e.g., a sulfoximine compound such as sulfoxaflor. The preparation of sulfoximines, and sulfoxaflor in particular, from a N-cyano sulfilimine compound may be performed by methods known in the art. For instance, sulfoxaflor may be prepared from N- cyano sulfilimine by oxidation. Suitable oxidants or oxidizing agents that may be used include m-chloroperoxybenzoic acid (m-CPBA), as described in, e.g., US patent No. 8,193,364, alkali metal permanganate as described in, e.g., EP patent No. 2 114 885, or other oxidants such as monopersulfate, perborate, or percarbonate.

[0127] Accordingly, a method for preparing a N-cyano sulfoximine, and sulfoxaflor in particular, may comprise: preparing a N-cyano sulfilimine compound using a method as described herein, oxidizing the N-cyano sulfilimine compound obtained by mixing the N-cyano sulfilimine compound with an oxidizing agent, e.g., selected from m- chloroperoxybenzoic acid (m-CPBA), alkali metal permanganate, monopersulfate, perborate, percarbonate and mixtures thereof.

[0128] As indicated above, the N-cyano sulfilimine compound may be typically used directly as obtained in a method for its preparation as described herein without further purification, e.g., in solution in an organic solvent such as acetonitrile as described above.

[0129] In several embodiments, the oxidizing agent may be added to a solution of the N- cyano sulfilimine compound. Alternatively, a solution of the N-cyano sulfilimine compound may be added to a solution of the oxidizing agent and mixed until formation of N-cyano sulfoximine is obtained.

[0130] A base (e.g., a carbonate, such as a hydrogen carbonate and more in particular potassium and / or sodium hydrogen carbonate, yet more in particular potassium hydrogen carbonate may be preferred) may be optionally used to neutralize, e.g., m-chlorobenzoic acid (m-CBA) generated from using m-CPBA as oxidizing agent.

[0131] The reaction may be monitored by means known in the art, e.g., as described above for the preparation of the N-cyano sulfilimine compound, and mixing may be continued until the reaction is regarded to be complete, e.g., when the presence of the starting N-cyano sulfilimine is no longer observed. As a mode of example, mixing may be carried out for 0.25 to 3 hours, in particular for 0.5 to 2 hours. Mixing may be performed at a temperature from -15 to 45° C, in particular from 0 to 30° C, more in particular from 5 to 20 °C. A method as described herein provides N-cyano sulfoximines, and sulfoxaflor in particular, in very good yields, as determined from the weight and assay of final isolated product with respect to of the theoretical amount of product obtainable from the initial amount of sulfide compound. For instance, in methods described herein the final yield of the N-cyano sulfoximine, and sulfoxaflor in particular, obtain may be from 50 to 97%, in particular from 60 to 95 %, more in particular from 65 to 90 % and yet more in particular from 70 to 85.

[0132] In the present specification, the term “includes”, “comprises” and derivations thereof (such as “including”, “comprising”, etc.) should not be understood in an excluding sense, that is, these terms should not be interpreted as excluding the possibility that what is described and defined may include further elements, steps, etc. Nonetheless, the term “includes”, “comprises” and derivations thereof should be interpreted to encompass term “consists of” and derivations thereof (such as “consisting of”), which should be interpreted as excluding the possibility that what is described and defined may include further elements, steps, etc.

[0133] On the other hand, the disclosure is obviously not limited to the specific embodiment(s) described herein, but also encompasses any variations that may be considered by a person skilled in the art within the general scope of the invention as defined in the claims.

[0134] The instant invention is further illustrated by the following examples without being limited thereto or thereby.

[0135] EXAMPLES

[0136] In the current examples, the indicated molar equivalent amounts (equiv.) of the reagents used are indicated with respect to the starting material, i.e. , the sulfide compound (i). Accordingly, the number of equivalents given for a specific reagent indicate the mols of the reagent used per each mol of sulfide compound (i). The indicated concentration of the solutions is expressed as % by weight (w / w) referring to the grams (g) of solute per 100 g of the weight of the solution. The solvents, reagents (i), (ii), (iii) and the compound (iv) used are commercially available.

[0137] HPLC of samples containing a N-cyano sulfilimine compound were performed using a mixture of ACN and Water (1 :1) v / v as diluent of the sample to be analyzed, in an Agilent HPLC apparatus using a ZORBAX RR SB C8, 80A° (4.6 x150 mm), 3.5pm reversed- phase column from Agilent in the following conditions:

[0138] Mobile Phase (A): 0.15% TFA in Water Mobile Phase (B): Acetonitrile

[0139] Mobile Phase (C): Methanol

[0140] Gradient (T / % B): 0 / 2.5, 2.3Z2.5, 14 / 3.3, 24 / 43, 29 / 80, 34 / 80, 34.5 / 2.5, 40 / 2.5 Gradient (T / % C): 0 / 14.5, 2.3 / 14.5, 14 / 18.7, 24 / 0, 29 / 0, 34 / 0, 34.5 / 14.5, 40 / 14.5 Flow Rate: 1.2 mL / min Temperature: 40 °C

[0141] The % of N-cyano sulfilimine compound in the samples analyzed was determined using Empower software.

[0142] LCMS were performed for the identification of the peaks in the chromatogram in the same conditions as described above for HPLC.

[0143] Example 1 : Preparation of a N-cyano sulfilimine compound with NaOCI as oxidizing agent (iii) and in the presence of sodium hydrogen carbonate as a salt (iv).

[0144] A 1 L three-neck round-bottom flask (RFB) was fitted with a thermometer, a mechanical stirrer, and an addition funnel. The flask was loaded with a solution of 5-[1- (methylthio)ethyl]-2-trifluoromethylpyridine, i.e., a sulfide compound (i) of structure (Ila) (75 g, 0.34 mol) in acetonitrile (525 ml). NaHCOs was used as a compound (iv) and was added as a solid (71.2 g, 0.83 mol, 2.45 equiv.) to the flask containing the sulfide compound (i) whilst stirring. Then a 35 % aqueous solution of cyanamide (ii) NH2CN (59.1 g of solution, 0.49 mol, 1.45 equiv.) was added dropwise over 15 min at a temperature from 25-30 °C. Then the reaction mixture comprising (i), (ii), and (iv) was cooled to 0-5 °C and a 12 % aqueous solution of NaOCI (463 g, 0.75 mol, 2.2 equiv.) was added as oxidizing agent (iii) at 0-5 °C. The reaction mixture was stirred at 0-5 °C for an additional 2-2.2 h. The reaction was monitored by TLC and HPLC until the absence of the sulfide compound (i) was observed. Finally, the reaction mixture was quenched using aqueous sodium metabisulfite (25.6 g, 0.13 mol, 0.76 equiv.). The quenched reaction mixture was filtered to discard undissolved inorganic salts and the filtrate was phase separated. The top organic layer was concentrated to dryness obtaining 88.5 g of a solid having a pale yellow to brown color comprising N-cyano sulfilimine compound N-[methyl[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]- A4-sulfanylidene]cyanamide. The yield of the reaction based on the isolated crude product comprising the N-cyano sulfilimine compound was of 82.8 %, based on the mass and purity of the crude obtained as determined by HPLC, namely a purity of 85.35 %, and the theoretical maximum N-cyano sulfilimine compound obtainable from the initial amount of sulfide compound (i) (namely 0.34 mol). For the subsequent preparation of sulfoxaflor, the same example was performed but the acetonitrile layer containing N-[methyl[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]-A4- sulfanylidene]cyanamide after separation from aqueous phase, before quenching with sodium metabisulfite, was used as starting material in Example 11.

[0145] Example 1a: Stability of a N-cyano sulfilimine compound

[0146] The stability under reaction conditions of the N-cyano sulfilimine compound obtained according to the same procedure of Example 1 was evaluated by monitoring the reaction mixture after the reaction was regarded to have been completed. The monitoring was done following the area % of the N-cyano sulfilimine compound on a HPLC chromatogram.

[0147] The reaction mixture was analyzed at the end of the reaction and after 24 h, 48 h, 72 h and 5 days of maintaining a sample of the reaction mixture at the temperature indicated in the following table (Table 1).

[0148] Table 1 : Stability of N-cyano sulfilimine compound in the reaction mixture

[0149] As it can be seen from Table 1 , percentage of the N-cyano sulfilimine compound remains stable at least 48 hours and after that decreases very slightly. This is an indication that N-cyano sulfilimine compound obtained by a method as described herein has good stability in the reaction mixture and that the process used for its preparation is suitable for industrial-scale applications.

[0150] The stability of the N-cyano sulfilimine compound, was also evaluated in the solvent of the separated top organic layer, after quenching and after separation from the reaction mass of the separated top organic layer, after quenching, at the elevated temperature indicated in Table 2.

[0151] Table 2: Stability of N-cyano sulfilimine compound in organic solvent

[0152] As it can be seen from Table 2 percentage of the N-cyano sulfilimine compound remains stable at least 24 hours and after that decreases very slightly. This is an indication that N-cyano sulfilimine compound is relatively stable when stored in a solvent and that the process used for its preparation is suitable for industrial-scale applications.

[0153] Example 1 b: Impact of addition sequence in the reaction

[0154] Example 1 was repeated pre-loading the reactor with acetonitrile (525 ml) using the previously indicated equivalent amounts of each of (ii), (iii), and (iv) with respect to the sulfide compound (i), but varying the order of addition of the different reagents (i), (ii), (iii), and (iv) as indicated in the following table:

[0155] It can be observed that all modes of addition show good yields of formation of the N-cyano sulfilimine comound (of 70% and above based on the HPLC Area % of the N-cyano sulfilimine compound), and the yields obtained are significantly superior to the yield obtained without addition of a compound (iv) (last entry of the table). Nonetheless, the addition of the sulfide compound (i) in a first mixing step, followed by cyanamide (ii) in a second mixing step, the compound (iv) in a third mixing step and the oxidizing agent (iii) in a fourth mixing step, was found to provide the highest yield.

[0156] Examples 2-7: Preparation of a N-cyano sulfilimine compound with NaOCI as oxidizing agent (iii) in the presence of sodium hydrogen carbonate as a compound (iv), using different proportions of cyanamide (ii), oxidizing agent (iii), compound (iv) and solvent.

[0157] Example 1 was repeated as described above varying the equivalent amounts of the reagents (ii) and (iii), volumes of acetonitrile, and temperature as indicated in the following table (Table 3), which for reference also includes the conditions and results of Example 1.

[0158] Amount of solvent in every experiment is presented as a number of volumes where 1 volume in ml is equivalent to the amount of sulfide compound (i) in g, i.e. , in experiment 1 for 75 g of sulfide compound (i) 525 ml of acetonitrile or 7 volumes were used.

[0159] The yield of the reaction is expressed in % based on the % of N-cyano sulfilimine compound measured in the corresponding HPLC chromatogram of a sample of the crude of the reaction obtained after evaporation of the solvent. In particular, the yield was calculated based on the mass and purity of the crude obtained as determined by HPLC, and the theoretical maximum N-cyano sulfilimine compound obtainable from the initial amount of sulfide compound (i) used in each reaction.

[0160] Table 3: Reaction conditions and results of examples 1 - 7.

[0161] Comparative Examples 1-4: Preparation of a N-cyano sulfilimine compound with NaOCI as oxidizing agent (iii) and in the absence of a compound (iv). A two-necked round bottom flask fitted with a thermometer and a stirrer, was loaded with 5-[1-(methylthio)ethyl]-2-trifluoromethylpyridine, i.e., a sulfide compound (i) of structure (Ila) (0.5 g, 2 mmol) dissolved in 5 ml of acetonitrile. The solution was cooled to -15 °C and then immediately a cyanamide (ii) as an aqueous 50 % solution (0.28 g, 3.35 mmol, 1.63 equiv.) was added dropwise over 3 minutes, under stirring keeping the temperature at -10 to -20 °C. Then of the oxidizing agent (iii) was added as a 12 % aqueous NaOCI solution dropwise over 5 min keeping the temperature at -15 °C. The amount of oxidizing agent was varied in the different comparative examples as indicated in the table below (Table 4). The amount of NaOCI is indicated in equivalents of NaOCI with respect to one equivalent of sulfide compound (i) and in mmols. Further the mass of the 12% solution of NaOCI is also indicated. The reaction mixture was stirred at -20 °C for additional 2 h. The reaction mixture was quenched with excess of sodium metabisulfite. The reaction mixture was extracted with EtOAc (2x10 mL), organic phase was washed with water (2x20 ml), and brine (20 mL). After solvent evaporation under vacuum the crude product was analyzed by HPLC. Area % of the N-cyano sulfilimine compound corresponding to the varying amounts of oxidizing agents is detailed in Table 4.

[0162] Table 4: HPLC Area % of N-cyano sulfilimine compound in comparative examples with different amounts of oxidizing agent (iii).

[0163] *mass of 12% aqueous solution of NaOCI

[0164] As it can be seen from Table 4, in absence of a compound (iv) increasing amount of oxidizing agent (iii) increases the area % of N-cyano sulfilimine compound in the isolated crude product, to some extent. However, the maximum concentration of the N-cyano sulfilimine compound is well below the results observed for the reactions performed in the presence of a compound (iv) of examples 1-7 (Table 3).

[0165] This results in a much lower yield of reaction when compared to the use of a compound (iv). Examples 8-9: Preparation of a N-cyano sulfilimine compound with (diacetoxyiodo) benzene (DIB) as oxidizing agent (iii) and the presence of sodium hydrogen carbonate as a compound (iv).

[0166] A two-necked round bottom flask fitted with a thermometer and a stirrer, was loaded with 5-[1-(methylthio)ethyl]-2-trifluoromethylpyridine a sulfide compound (i) of structure (Ila) (0.5 g, 2 mmol) in 10 ml of acetonitrile and with cyanamide (ii) as an aqueous 50 % solution under stirring (0.28 g of the solution, i.e., 3.38 mmol and 1 .64 equiv. of NH2CN with respect to one equivalent of sulfide compound (i)). Subsequently the compound (iv) NaHCOs was added to the reaction mixture in solid form (0.35 g, 4.1 mmol, 2 equiv.). The mixture was cooled to 0 °C, by placing it in an ice bath, and then DIB as oxidizing agent (iii) was added all at once in solid form (having a 98% purity), in the proportions indicated in the table below (Table 5). A yellow slurry was obtained which was mixed at 0-5 °C for 10 min, and then cooling was stopped by removing the ice bath. The reaction mixture was allowed to slowly warm up to room temperature over 1.5 h and subsequently slowly warmed from 25 to 30 °C over the next 0.5 h. The reaction mixture was allowed to return to room temperature. Excess oxidant was destroyed by aqueous solution of sodium metabisulfite. The reaction mixture was extracted with EtOAc (3x20 mL), organic phase was washed with water (2x20 ml), and brine (20 mL). After solvent evaporation under vacuum the crude product was analyzed by HPLC. The results of the HPLC analysis are shown in Table 5.

[0167] Table 5: HPLC Area % of N-cyano sulfilimine compound using different amounts of oxidizing agent (iii), in the presence of a compound (iv)

[0168] *mass of solid DIB with a purity of 98%

[0169] Comparative examples 5-8: Preparation of a N-cyano sulfilimine compound with (diacetoxyiodo) benzene (DIB) as oxidizing agent (iii) in absence of a compound (iv).

[0170] The procedure described for examples 8 and 9 was used for preparation of a N- cyano sulfilimine compound with (diacetoxyiodo)benzene (DIB) as oxidizing agent (iii) in absence of a compound (iv) in the comparative examples 5-8 with the difference that the step of adding NaHCOs (or any other compound (iv)) was omitted and that the oxidizing agent (iii) and the cyanamide (ii) were added in the amounts indicated in the table below (Table 6). The results of the HPLC analysis of the crude products obtained, is also included in Table 6.

[0171] Table 6: HPLC Area % of N-cyano sulfilimine compound using different amounts of oxidizing agent (iii) and cyanamide (ii), in absence of a compound (iv).

[0172] *mass of solid DIB with a purity of 98% **mass of 50% NH2CN aqueous solution

[0173] From Examples 8-9 and comparative examples 5-9 it can be clearly seen that mixing the reagents (i), (ii), (iii) in the presence of a compound (iv) improves the concentration of N-cyano sulfilimine compound in the crude product, advantageously resulting in a preparation of N-cyano sulfilimine with improved yield.

[0174] Example 10: Preparation of a N-cyano sulfilimine compound with bromine as oxidizing agent (iii) and in the presence of sodium hydroxide as a compound (iv).

[0175] A two-necked RBF fitted with a thermometer was loaded with 15 % NaOH (37.32 g, 140 mmol, 3.5 equiv.). The solution was cooled to 0-5 °C (in an ice bath). Then, bromine (0.97 g, 60 mmol, 1.5 eq) was added dropwise over 5 min keeping the temperature at 0 °C. Then 50 % aqueous NH2CN solution (5.45 g, 65.2 mmol, 1.63 eq) was added keeping the temperature at 0-5 °C. Then a solution of 5-[1-(methylthio)ethyl]-2-trifluoromethylpyridine a sulfide compound (i) of structure (Ila) (10 g, 40 mmol) in 5 volumes of acetonitrile (i.e. 50 ml) at 0-5 °C was added. The reaction mixture was stirred at 0-5 °C for additional 30 min.

[0176] Acetonitrile layer was separated from the aqueous phase and was analyzed by HPLC showing 96.5 % of desired N-cyano sulfilimine compound, based on the % area of the N-cyano sulfilimine compound peak relative to the total area of other peaks in the chromatogram.

[0177] Example 10a: Lower equivalents of NaOH

[0178] The same preparation as described for Example 10 was performed using lower equivalents of NaOH (e.g. 2.5 and 3 equiv.) and, even though very good yields were obtained (e.g. of 91.5 and 96.1 % respectively as determined by HPLC, based on the % area of the N-cyano sulfilimine compound peak relative to the total area of other peaks in the chromatogram).

[0179] The best results were obtained with 3.5 equiv. of NaOH.

[0180] Example 10b: with hypobromite preparation in advance and its feeding as the last reagent When the preparation was repeated with the same ratio of the reagents, but bromine was added to solution of compound (iv) (NaOH), in order to form hypobromite prior to the start of the reaction, and solution of sodium hypobromide was fed to the solution of sulfide (i) and cyanamide (ii), relatively good yields were obtained (67-77 % as determined by HPLC). However, the yields were lower than those obtained in Example 10 and in Example 10a above.

[0181] Example 11 : Preparation of sulfoxaflor with previous preparation of a N-cyano sulfilimine compound with bromine as oxidizing agent (iii) and in the presence of sodium hydroxide as a compound (iv).

[0182] N-cyano sulfilimine was prepared as described above in Example 10.

[0183] The ACN layer comprising the N-cyano sulfilimine compound, as separated at the end of Example 10, was directly used in the following step, using the following equivalents of reagents based on the starting molar amount of sulfide compound (i).

[0184] A two-necked RBF fitted with a thermometer, was loaded with the ACN layer comprising the N-cyano sulfilimine compound. m-CPBA (2.10 equiv.) was added to the ACN comprising the N-cyano sulfilimine compound and the temperature was maintained at 10-15 °C. 15 % aqueous solution of KHCO3 (2.65 equiv.) was subsequently added at the same temperature, and mixing was maintained at 10-15 °C for 1 hour. The formation of sulfoxaflor was monitored by HPLC.

[0185] When the reaction was deemed completed, the acetonitrile was distilled out under the vacuum. The residue was cooled to 0-5 °C and filtered to provide an isolated product (Sulfoxaflor). After vacuum drying 10.3 g of the product with assay 96.5 % were prepared. Yield 81 % on sulfide compound (i).

[0186] Yields obtained with similar preparations on a similar scale and conditions but wherein the intermediate N-cyano sulfilimine compound was prepared with NaCIO as oxidizing agent (iii) and Hydrogen carbonate as a compound (iv) according to Example 1 , was of about 70 % (data not shown).

[0187] The overall yields obtained for the preparation of sulfoxaflor, both using bromine or hypochlorite as the oxidizing agent for the preparation of the intermediate N-cyano sulfilimine compound, were good and superior to those previously reported in similar scale and conditions. The use of bromine as oxidizing agent (iii) for the preparation of the intermediate N-cyano sulfilimine compound was found to provide particularly good overall yields in the preparation of sulfoxaflor.

Claims

CLAIMS1 . A method for preparing a N-cyano sulfilimine compound comprising: mixing in a solvent i) a sulfide compound, ii) cyanamide, and iii) an oxidizing agent in the presence of iv) a compound comprising an alkali metal hydroxide, a hydrogen carbonate salt, a mixture of hydrogen carbonate salt and a carbonate salt, and / or a combination of phosphate salts.

2. The method of claim 1 , wherein the solvent comprises a polar organic solvent and optionally comprises water, preferably the polar organic solvent is selected from acetonitrile; an ester such as ethyl acetate or butyl acetate; an ether such as methyl t-butyl ether, an alcohol such as methanol or ethanol, and mixtures thereof, more preferably the polar organic solvent is acetonitrile.

3. The method of claim 1 or 2, wherein the oxidizing agent (iii) comprises bromine, hypochlorite, (diacetoxyiodo) benzene (DIB), and / or monopersulfate, preferably the oxidizing agent comprises bromine and / or hypochlorite, and more preferably comprises bromine.

4. The method of any one of claims 1 to 3, wherein the compound (iv) comprises an alkali metal hydroxide and preferably comprises sodium hydroxide.

5. The method of any one of claims 1 to 3, wherein the compound (iv) comprises a hydrogen carbonate salt, and preferably comprises sodium hydrogen carbonate.

6. The method of any one of claims 1 to 3, wherein the compound (iv) comprises a combination of at least two different phosphate salts, preferably a combination of alkali metal phosphate salts, wherein the alkali metal is preferably selected from sodium and potassium, and is preferably sodium, and the phosphate is a combination of dihydrogen phosphate and monohydrogen phosphate or a combination of monohydrogen phosphate and orthophosphate, preferably is a combination of dihydrogen phosphate and monohydrogen phosphate, and yet more preferably the combination of alkali metalphosphate salts is a combination of sodium dihydrogen phosphate and disodium monohydrogen phosphate.

7. The method of any one of the preceding claims, comprising mixing from 0.01 to 6 molar equivalents of compound (iv) per each molar equivalent of the sulfide compound (i), preferably from 0.02 to 5 molar equivalents, more preferably from 0.05 to 4 molar equivalents, yet more preferably from 0.1 to 3.5 molar equivalents.

8. The method of any one of claims 1-7, wherein the solvent comprises water and the reaction mixture obtained has a pH from 7 to 13, preferably from 8 to 13.

9. The method of any one of claims 1-8, wherein mixing is performed at a temperature from -20 to 20 °C, preferably from -15 to 15 °C, more preferably from -5 to 10 °C, and yet more preferably from 0 to 5 °C.

10. The method of any one of claims 1 to 9, wherein the reaction mixture obtained comprises N-cyano sulfilimine and unreacted oxidizing agent and the method further comprises: quenching unreacted oxidizing agent with a reducing agent, the reducing agent preferably comprises a sulfo-compound, more preferably comprises sodium sulfite or metabisulfite, to provide a quenched reaction mixture, and isolating the N-cyano sulfilimine from the quenched reaction mixture.

11. The method of any one of claims 1 to 10 wherein the N-cyano sulfilimine compound is of formula (I):wherein Het representsX represents halogen, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 haloalkenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CN, NO2, SOmR6where m is an integer from 0 to 2, COOR4, CONR4R5, aryl or heteroaryl;Y represents hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 haloalkenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CN, NO2, SOmR1where m is an integer from 0 to 2, COOR4, CONR4R5, aryl or heteroaryl; n is an integer from 0 to 3;L represents either a single bond, -CH(CH2)P- where R1, S and L taken together represent a 4-, 5-, or 6-membered ring and p is an integer from 1 to 3, -CH(CH2OCH2)- where R1, S and L taken together represent a 6-membered ring, or -CH- where L, R2and the common carbon to which they connect taken together represent a 4-, 5-, or 6-membered ring with up to, but no more than, 1 heteroatom;R1represents C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl,C3-C6 haloalkenyl, arylalkyl, heteroarylalkyl, or -CH2- in cases where R1, S and L taken together represent a 4-, 5-, or 6-membered ring;R2and R3independently represent hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 haloalkenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CN, SOmR6where m is an integer from 0 to 2, COOR4, CONR4R5, arylalkyl, heteroarylalkyl, or R2and R3and the common carbon to which they attach form a 3-6 membered ring;R4and R5independently represent hydrogen, C1-C4 alkyl, C1-C4 haloalkyl; C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 haloalkenyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl; andR6represents C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 haloalkenyl, arylalkyl or heteroarylalkyl;and the sulfide compound (i) is of formula (II)whereinR1, R2, R3, L, Het and n are as previously defined.

12. The method of any one of claims 1 to 11 wherein the N-cyano sulfilimine compound of formula (I) is of structure (la) and the sulfide compound (i) of formula (II) is of structure(Ha)Structure la Structure Ila13. A method for preparing a N-cyano sulfoximine compound comprising: preparing a N-cyano sulfilimine compound according to any one of claims 1 to 12, and oxidizing the N-cyano sulfilimine compound obtained by mixing the N-cyano sulfilimine compound with an oxidizing agent, to provide the N-cyano sulfoximine compound.

14. The method of claim 13 wherein the oxidizing agent is selected from m- chloroperoxybenzoic acid (m-CPBA), alkali metal permanganate, monopersulfate, perborate, percarbonate and mixtures thereof.

15. The method of claim 13 or 14 wherein the N-cyano sulfoximine compound is sulfoxaflor.

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