Process for the preparation of sulfamide derivatives

Description

1 / 21 PROCESS FOR THE PREPARATION OF SULFAMIDE DERIVATIVES TECHNICAL AREA

[0001] The present invention provides a process for the preparation of sulfonamide derivatives, which are useful for the preparation of sulfonamide-based compounds, such as sulfonamide-based herbicidal active ingredients. PRECEDENT TECHNIQUE

[0002] Sulfamide derivatives, such as N,N-disubstituted sulfamides, are important chemical intermediates in organic synthesis.

[0003] Specifically, such derivatives can be used for the preparation of sulfonamide-based compounds with multiple substitutions, which are commonly used in fields such as medicine and agricultural chemicals.

[0004] For example, saflufenacil (2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1-(2H)pyrimidin1]-4fluoro-N-[[methyl(1-methylethyl)amino]sulfonyl]benzamide), which belongs to the class of substituted sulfonamides, is a herbicide particularly useful for pre-planting applications and selective control of pre-emergent weeds in multiple crops. It is absorbed by the foliage and roots with translocation in the apoplast and limited movement in the phloem. Saflufenacil is applied to the foliage and is used for residual control of broadleaf weeds, including glyphosate- and ALS-resistant biotypes. Saflufenacil is applied pre-emergence in maize and sorghum at 50-125 grams / hectare (g / ha); Pre-planting application for rapid leaf burn in soybeans, cereals, cotton, and legumes; and post-directed application in fruit and nut trees at 18-25 g / ha, and in sugarcane at 24.5-96 g / ha. Petition 870250088405, dated 09 / 30 / 2025, page 16 / 44 2 / 21

[0005] Saflufenacil belongs to the group of protoporphyrinogen oxidase (PPO) inhibitors, more specifically it is a pyrimidinedione-based PPO inhibitor and was described in WO 01 / 083459. Additional processes for its preparation are described in documents WO 03 / 097589, WO 05 / 054208, WO 06 / 097589, WO 06 / 125746, WO 08 / 043835, and WO 08 / 043836.

[0006] WO 2001 / 083459 discloses the preparation of N,N-disubstituted sulfonamides, firstly by reacting chlorosulfonyl isocyanate with formic acid to obtain S-chlorosulfonamide. Then, S-chlorosulfonamide is reacted with a secondary amine to obtain the desired product.

[0007] WO 03 / 097589 discloses a process for the preparation of sulfamoyl halides from primary or secondary amines, comprising: (i) reacting a primary or secondary amine with SO3 or a source of SO3 in the presence of a tertiary amine such as α-picoline; and (ii) reacting the reaction mixture obtained in step (i) with a phosphorus halide such as phosphorus pentachloride. The sulfamoyl halides obtained can also be reacted with ammonia, such as aqueous ammonia, to obtain N,N-disubstituted sulfonamides.

[0008] WO 2009 / 050120 discloses a process for the preparation of N,N-disubstituted sulfonamides having the formula R1R2NS(O)2-NH2 by reacting sulfamoyl chloride having the formula R1R2N-S(O)2-Cl with ammonia, wherein said sulfamoyl chloride is used in the form of a solution in an inert solvent, such as an aromatic solvent. According to WO 2009 / 050120, the ammonia required for the reaction may be supplied in gaseous form or in the form of a solution. Petition 870250088405, dated 09 / 30 / 2025, page 17 / 44 3 / 21 generally a non-aqueous solution, provided that, when ammonia is supplied in the form of a solution, the solvent generally contains less than 1% of protic components, such as water.

[0009] There is a continuing need to develop new and improved synthetic processes for preparing sulfonamide derivatives, more specifically N,N-disubstituted sulfonamides, thus providing alternative routes that allow, for example, the use of milder reaction conditions and overcoming limitations in previously disclosed processes. SUMMARY OF THE INVENTION

[0010] The Experimental section in this document shows the preparation of N-methyl-N-(1-methylethyl)aminosulfonamide. Specifically, sulfuryl chloride was added to a solution of N-isopropylmethylamine in a solvent, more specifically toluene, to obtain Nisopropylmethylsulfamoyl chloride. The Nisopropylmethylsulfamoyl chloride was then mixed with an ammonia-based solution, more specifically, an ammonia-in-water solution or an ammonia-in-methanol solution. The resulting solution was allowed to react, yielding N-methyl-N-(1-methylethyl)aminosulfonamide.

[0011] In one aspect, the present invention relates to a process for the preparation of a compound of formula I in which: Petition 870250088405, dated 09 / 30 / 2025, p. 18 / 44 4 / 21 R1 and R2 are, each independently, alkyl (C1-C12), alkenyl (C2-C6), cycloalkyl (C3-C8), aryl, heteroaryl, or R1 and R2, together with the nitrogen atom to which they are attached, form a 5- to 8-membered ring optionally substituted by one or more groups, each independently selected from alkyl (C1-C12), cycloalkyl (C3-C8), aryl and heteroaryl, and optionally further interrupted by one or more atoms, each independently selected from -O- and -S-, wherein said alkyl, alkenyl and cycloalkyl are each independently optionally interrupted by one or more groups, each independently selected from -O- and -S-, the said process comprising: react a compound of formula II R1„„NH R2 II with sulfuryl chloride (SO2Cl2) in a solvent, to obtain a compound of the formula III R1 / Cl R2S / f (Co III. React the compound of formula III with an ammonia-based solution to obtain the compound of formula I.

[0012] In certain embodiments, a process for preparing the compound of formula I, as defined above, is disclosed in this document, wherein said ammonia-based solution is a solution of ammonia in a solvent. Petition 870250088405, dated 09 / 30 / 2025, page 19 / 44 5 / 21 protic, such as an ammonia solution in water and an ammonia solution in methanol.

[0013] In another aspect, the present invention provides a process for the preparation of a compound of formula IV R1 and R2 are, each one, as defined above; R3 and R4 are each independently H or halogen; R5e H or alkyl (C1-C6); and R6e H, alkyl (C1-C6) or haloalkyl (C1-C6); the aforementioned process comprising the preparation of compound formula I in accordance with the process disclosed above and the transformation of said compound formula I into compound formula IV. DETAILED DESCRIPTION

[0014] In one aspect, a process for the preparation of N,N-disubstituted sulfonamides of formula I, as defined above, is disclosed in this document, comprising said process: (I) reacting a compound of formula II, as defined above, with sulfuryl chloride in a solvent, thereby obtaining a compound of formula III, as defined above; and (ii) reacting the compound of formula III with an ammonia-based solution, thereby obtaining the compound of formula I. Petition 870250088405, dated 09 / 30 / 2025, p. 20 / 44 6 / 21

[0015] The term alkyl typically means a linear or branched hydrocarbon group having.* Particular alkyl groups are (C1-C12) alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, n-octyl, and the like. (C1Cs) alkyl, (C1-C6) alkyl, or (C1-C4) alkyl groups are preferred.

[0016] The term alkenyl typically means a linear or branched hydrocarbon group having one or more double bonds. Particular alkenyl groups are (C2-C6) alkenyl groups, such as ethenyl, propenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-octen-1-yl and the like. (C2-C4) alkenyl groups are preferred.

[0017] The term cycloalkyl means a saturated mono- or bicyclic hydrocarbyl group having, for example, 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, which may be substituted, for example, by one or more alkyl groups.

[0018] The term aromatic ring refers to an aromatic carbocyclic ring having, for example, 6-14 carbon atoms, and consisting of a single ring or multiple rings condensed or linked by a covalent bond. Non-limiting examples of aromatic rings include benzene, naphthalene, anthracene, naphthacene, phenanthrene, pyrene, chrysene, tetracene, and triphenylene. The term “aryl” as used in this document refers to any univalent group derived from a heterocyclic ring, as defined in this document, by the removal of a hydrogen atom from any of the ring atoms. Aryl (C6-C10) groups are preferred. Petition 870250088405, dated 09 / 30 / 2025, p. 21 / 44 7 / 21

[0019] The term heteroaromatic ring refers to a mono-, bi-, or polycyclic aromatic ring having, for example, 4 to 12 atoms and consisting of at least one carbon atom and at least one heteroatom selected from oxygen, sulfur, or nitrogen. Heteroaromatic rings with 5 or 6 members are preferred. Non-limiting examples of heteroaromatic rings include thiophene, imidazole, pyridine, furan, pyrrole, oxazole, thiazole, purine, indole, pyrrole, pyrazine, isoquinoline, pyrazole, isoxazole, thiazole, isothiazole, pyrazine, pyrimidine, pyridazine, and carbazole. The term heteroaryl, as used in this document, refers to a univalent radical derived from a heteroaromatic ring, as defined herein, by the removal of a hydrogen atom from any of the ring atoms.

[0020] Each of the above-defined alkyl, alkenyl and cycloalkyl groups may be interrupted with one or more atoms, each independently selected from -O- and -S.

[0021] In certain embodiments, step (i) of the process of the invention comprises reacting the compound of formula II with sulfuryl chloride in said solvent, wherein the molar ratio between the sulfuryl chloride and the compound of formula II is about 1: at least 1.8 (i.e., the number of moles of the compound of formula II is at least 1.8 times the number of moles of sulfuryl chloride), e.g., about 1:1.8, about 1:1.9, about 1:2.0, about 1:2.0 or more, respectively. According to the invention, the secondary amine of formula II, which is reacted with the sulfuryl chloride in step (i) of the process disclosed herein, may be added in molar excess compared to the sulfuryl chloride, e.g., at least 1.8 equivalents. Petition 870250088405, dated 09 / 30 / 2025, p. 22 / 44 8 / 21 molar relative to the moles of sulfuryl chloride, thus acting as a nucleophilic source (reacting with sulfuryl chloride) and base (necessary to capture the HCl formed during said reaction), thereby eliminating the need for an additional base source that would add further complexity to the processing. The excess secondary amine can be recovered and reused.

[0022] In certain embodiments, step (i) of the invention process comprises reacting the compound of formula II with sulfuryl chloride in said solvent in the presence of an organic base. Particular embodiments are those in which said organic base is a tertiary amine-based base. Non-limiting examples of tertiary amine-based bases include a trialkylamine, such as trimethylamine, triethylamine, dimethylethylamine and a combination thereof; an N-cycloalkyl-N,N-dialkylamine, such as dimethylcyclohexylamine, diethylcyclohexylamine and a combination thereof; benzyldimethylamine; pyridine; imidazole; and a combination thereof. According to the invention, step (i) of the process disclosed in this document could comprise the use of an organic base, such as a tertiary amine, for example, to capture the HCl formed during said reaction, for example, when the molar ratio between sulfuryl chloride and the compound of formula II is from about 1:0.8 to about 1:1.5, for example., about 1:0.8, about 1:1, about 1: 1.2-1.5, respectively.

[0023] In certain embodiments, the process of the present invention is a process as defined in any of the embodiments above, wherein step (i) is carried out at a temperature ranging from about -15 °C to about 10 °C, Petition 870250088405, dated 09 / 30 / 2025, p. 23 / 44 9 / 21 for example, from about -10 °C to about 8 °C, or from about -5 °C to about 0 °C or about 5 °C.

[0024] In certain embodiments, the process of the present invention is a process as defined in any of the embodiments above, wherein step (i) comprises adding sulfuryl chloride to a solution of the compound of formula II in said solvent, that is, the sulfuryl chloride is added, for example, drop by drop, to a solution of the compound of formula II in said solvent. In such particular embodiments, the addition of sulfuryl chloride is carried out for a period of at least 30 minutes, for example, for at least 45 minutes, for at least 1 hour, for at least 1.5 hours, for at least 2 hours, for at least 2.5 hours or for at least 3 hours; and / or at a temperature ranging from about -15 °C to about 10 °C, for example, from about -10 °C to about 8 °C, or from about -5 °C to about 0 °C or about 5 °C.

[0025] In certain embodiments, the process of the present invention is a process as defined in any of the embodiments above, wherein the solvent used in step (i) is an aprotic organic solvent. Such particular embodiments are those in which said aprotic organic solvent is a benzene-based solvent or a halogen-containing solvent. Non-limiting examples of benzene-based solvents include toluene, xylene, benzene, chlorobenzene and mixtures thereof; and non-limiting examples of halogen-containing solvents include dichloromethane, dichloroethane and mixtures thereof.

[0026] In certain embodiments, the process of the present invention is a process as defined in any of the Petition 870250088405, dated 09 / 30 / 2025, page 24 / 44 10 / 21 embodiments above, wherein the ammonia-based solution reacted with the compound of formula III, as defined above in step (ii), is an ammonia solution in a protic solvent. The term “protic solvent,” as used in this document, refers to any solvent containing an unstable H+, and non-limiting examples of such solvents include water and alcohols such as methanol.

[0027] In particular, in such embodiments, the ammonia-based solution is aqueous ammonia, that is, a solution of ammonia in water, for example, having a concentration in the range of about 15% to about 70%, for example, from about 17% to about 65%, from about 19% to about 60%, from about 20% to about 55%, from about 20% to about 30%, from about 35% to about 55%, about 25% or about 50%.

[0028] In other particular embodiments, the ammonia-based solution is methanolic ammonia, that is, a solution of ammonia in methanol, for example, having a concentration in the range of about 10% to about 30%, for example, from about 12% to about 30%, from about 12% to about 25%, or about 7M, of ammonia in methanol.

[0029] As is generally known, a one percent solution is defined as 1 gram of solute per 100 milliliters of final volume, e.g., one gram of ammonia per 100 milliliters of protic solvent, as defined above, is equivalent to an ammonia solution in a protic solvent having a concentration of 1%.

[0030] In certain embodiments, the process of the present invention is a process as defined in any of the embodiments above, wherein step (ii) is carried out at a temperature ranging from about -30 °C to about 10 °C, Petition 870250088405, dated 09 / 30 / 2025, page 25 / 44 11 / 21 for example, from about -25°C to about 8°C, from about 20°C to about 7°C, from about -15°C to about 6°C, or from about -10°C to about 0°C or 5°C.

[0031] In certain embodiments, the process of the present invention is a process as defined in any of the embodiments above, wherein step (ii) further comprises the addition of a cosolvent. The term cosolvent, as used herein, refers to an organic solvent that is miscible in the solvent of the ammonia-based solution reacted in step (ii) of the process disclosed herein.

[0032] In such particular embodiments, the cosolvent is a polar organic solvent. Non-limiting examples of polar organic solvents include acetonitrile, acetone, dimethylformamide, dimethyl sulfoxide, and a combination thereof.

[0033] In certain embodiments, the process of the present invention is a process as defined in any of the embodiments above, wherein step (ii) further comprises adding a cosolvent in an amount up to about 30%, for example, up to about 20%, or up to about 10%, for example, from about 5% to about 25%, or from about 10% to about 20%, relative to the amount of the ammonia-based solution, by volume.

[0034] In certain embodiments, the process of the present invention is a process as defined in any of the embodiments above, wherein the compound of formula III is obtained in step (i) in the form of a solution in said solvent; and said solution is reacted with said ammonia-based solution in step (ii). In such particular embodiments, the compound of formula II is reacted with sulfuryl chloride. Petition 870250088405, dated 09 / 30 / 2025, p. 26 / 44 12 / 21 in said solvent to obtain a solution of the compound of formula III in said solvent, wherein said solution is then washed with an acidic aqueous solution, e.g., an aqueous solution of HCl, to remove water-miscible byproducts, such as unreacted compound of formula II in the form of a salt, e.g., an HCl salt of compound of formula II, to obtain an organic phase consisting essentially of compound of formula III; and said organic phase is further reacted with the ammonia-based solution in step (ii). The term “consisting essentially of”, as used herein in relation to the organic phase containing compound of formula III obtained after acid washing of the solution containing compound of formula III obtained in step (i), means that said organic phase contains at least 80%, preferably at least 90%, of compound of formula III by weight, i.e., said organic phase may contain up to about 20%, e.g., no more than 15%, preferably up to about 10%, of compounds other than compound of formula III, by weight.

[0035] In certain embodiments, the process of the present invention is a process as defined in any of the embodiments above, wherein the compound of formula III is obtained in step (i) in the form of a solution in said solvent; and said solution is concentrated under reduced pressure before being reacted with the ammonia-based solution in step (ii). In such particular embodiments, the compound of formula II is reacted with sulfuryl chloride in said solvent to thereby obtain a solution of the compound of formula III in said solvent, wherein said solution is then washed with an aqueous acidic solution, for example, an aqueous solution of Petition 870250088405, dated 09 / 30 / 2025, p. 27 / 44 13 / 21 HCl, to remove water-miscible byproducts, such as unreacted compound of formula II in the form of a salt, e.g., an HCl salt of compound of formula II, thereby obtaining an organic phase consisting essentially of compound of formula III; said organic phase is further concentrated under reduced pressure thereby obtaining compound of formula III in a pure form; and said pure compound of formula III reacts with the ammonia-based solution in step (ii).

[0036] In certain embodiments, the ammonia-based solution reacted in step (ii) of the invention process is an ammonia solution in water having a concentration in the range of about 15% to about 70%, e.g., from about 20% to about 55%.

[0037] Such particular embodiments are those in which: (a) the said ammonia-based solution is aqueous ammonia having a concentration in the range of about 15% to about 35%, e.g., about 20% to about 30%, or about 25%; (b) step (ii) further comprises the addition of a co-solvent; and / or (c) the compound of formula II is reacted with sulfuryl chloride in said solvent to obtain a solution of the compound of formula III in said solvent, wherein said solution is then washed with an aqueous acidic solution, e.g., an aqueous solution of HCl, to remove water-miscible by-products, such as unreacted compound of formula II in the form of a salt, e.g., an HCl salt of compound of formula II, to obtain an organic phase consisting essentially of compound of formula III; said organic phase is further concentrated under reduced pressure to obtain the compound of Petition 870250088405, dated 09 / 30 / 2025, p. 28 / 44 14 / 21 formula III in a pure form; and said pure compound of formula III reacts with the ammonia-based solution in step (ii).

[0038] Other such particular embodiments are those in which: (a) said ammonia-based solution is an ammonia-in-water solution having a concentration in the range of about 40% to about 60%; and / or (b) the compound of formula II is reacted with sulfuryl chloride in said solvent to obtain a solution of compound of formula III in said solvent, wherein said solution is then washed with an acidic aqueous solution, e.g., an aqueous solution of HCl, to remove water-miscible byproducts, such as unreacted compound of formula II in the form of a salt, e.g., an HCl salt of compound of formula II, to obtain an organic phase consisting essentially of compound of formula III; said organic phase is further concentrated under reduced pressure to obtain compound of formula III in a pure form; and said pure compound of formula III is reacted with the ammonia-based solution in step (ii).

[0039] In certain embodiments, the ammonia-based solution reacted in step (ii) of the invention process is an ammonia-in-methanol solution.

[0040] These particular embodiments are those in which: (a) step (ii) further comprises the addition of a cosolvent; and / or (b) the compound of formula III is obtained in step (i) in the form of a solution in said solvent; and said solution is reacted with said ammonia-based solution in step (ii). Petition 870250088405, dated 09 / 30 / 2025, p. 29 / 44 15 / 21

[0041] In certain embodiments, the process disclosed herein, according to any of the embodiments above, is for the preparation of a compound of formula I, wherein R1 and R2 are each independently alkyl (C1-C6), such as methyl ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2,2-dimethylpropyl, and n-hexyl. In such particular embodiments, R1 is methyl and R2 is isopropyl.

[0042] The process disclosed in this document, according to any of the embodiments above, may be carried out with different efficiencies, depending on the reagents and conditions used. In other words, the product of this process could comprise different percentages of the desired compound I, as well as certain amounts of other compounds, such as unreacted starting material. Thus, in certain embodiments, the yield of the compound of formula I obtained by the process of the present invention is from about 40% to about 60%, from about 60% to about 80%, from about 80% to about 90%, or greater than 90%.

[0043] The N,N-disubstituted sulfonamides of formula I prepared by the process disclosed in this document according to any of the embodiments above could be useful for the preparation of sulfonamide-based compounds, for example, sulfonamide-based herbicidal active ingredients.

[0044] In another aspect, the present invention thus provides a process for the preparation of a compound of formula IV Petition 870250088405, dated 09 / 30 / 2025, p. 30 / 44 16 / 21 R1 and R2, each independently, are alkyl (C1-C12), alkenyl (C2-C6), cycloalkyl (C3-C8), aryl, heteroaryl, or R1 and R2, together with the nitrogen atom to which they are attached, forming a 5- to 8-membered ring optionally substituted by one or more groups, each independently selected from alkyl (C1-C12), cycloalkyl (C3-C8), aryl and heteroaryl, and optionally further interrupted by one or more atoms, each independently selected from -O- and -S-, wherein said alkyl, alkenyl and cycloalkyl, each independently, are optionally interrupted by one or more groups, each independently selected from -O- and -S-; R3 and R4 are each independently H or halogen; R5 is H or alkyl (C1-C6); and R6e H, alkyl (C1-C6) or haloalkyl (C1-C6); the aforementioned process comprising the preparation of compound formula I in accordance with the process disclosed in this document, in accordance with any of the embodiments described above, and the transformation of said compound formula I into compound formula IV (also referred to herein as “a process for the preparation of compound formula IV”). Petition 870250088405, dated 09 / 30 / 2025, p. 31 / 44 17 / 21

[0045] The term halogen as used in this document refers to a halogen and includes fluorine, chlorine, bromine and iodine, but is preferably fluorine or chlorine.

[0046] The term haloalkyl typically means an alkyl as defined herein, substituted with one or more groups, each independently selected from a halogen.

[0047] According to the invention, the process for preparing the compound of formula IV could include, in addition to the step of preparing the compound of formula I according to the process disclosed in this document, any step (or steps) disclosed in the literature for preparing the compound of formula IV as defined above, for example, as disclosed in WO 2001 / 083459.

[0048] In certain embodiments, the process for preparing the compound of formula IV disclosed in this document is for preparing a compound of formula IV in which R1 and R2 are each independently alkyl (C1-C4), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2,2-dimethylpropyl and hexyl; R3 and R4 are each independently halogens, such as Cl and F; R5 is H or alkyl (C1-C4) and R6 is haloalkyl (C1-C6). Such particular embodiments are those in which R1 is methyl; R2 is isopropyl; R3 is Cl; R4 is F; R5 is methyl; and R6 is CF3 (saflufenacil).

[0049] Unless otherwise indicated, all numbers expressing, for example, quantities of components and ratios between components, used in this specification, should be understood as if they were modified in all cases by the term approximately. Accordingly, unless otherwise indicated Petition 870250088405, dated 09 / 30 / 2025, pages 32 / 44 18 / 21 Conversely, the numerical parameters presented in this descriptive report are approximations that may vary by up to plus or minus 10% depending on the desired properties to be obtained by the present invention.

[0050] The invention will now be illustrated by the following non-limiting Examples. EXAMPLES Materials and methods

[0051] Materials. All reagents and starting materials were purchased from Sigma Aldrich, Acros Organics, and Alfa Aesar. Example 1. Synthesis of N-methyl-N-(1-methylethyl)aminosulfonamide using 50% ammonia in water.

[0052] In a clean, dry 0.5 L round-bottom flask, toluene (120 mL, 5 vol.) and N-isopropylmethylamine (26.1 g, 2 eq.) were loaded under a nitrogen atmosphere at 25–30 °C. The mixture was stirred for 15 minutes and cooled to -5–0 °C. Sulfuryl chloride (24 g, 1 eq.) was then added dropwise to the reaction mass over 3 hours. Once the addition was complete, the reaction was maintained at this temperature for a further 30 minutes, during which time complete conversion to the intermediate nisopropylmethylsulfamoyl chloride was observed. The reaction mixture was then held at 0 °C and washed twice with dilute HCl (1%, 37.5 mL, 1.5 vol.) while maintaining temperatures between 0 and 5 °C. The organic layer was then concentrated under reduced pressure (45-50 °C, 40 mbar) to yield the crude intermediate as a light yellow oil. In a separate 500 ml round-bottom flask, NH4OH (50%) (120 ml, 5 V) was added and cooled to an internal temperature of -10 °C. Petition 870250088405, dated 09 / 30 / 2025, pages 33 / 44 19 / 21 to the cold solution, and the intermediate N-isopropylmethylsulfamoyl chloride was added dropwise over 5 minutes and the solution was mixed for 4 hours, during which time it was gradually heated to 0 °C and held at this temperature. Once the conversion was complete, the solution was extracted with EtOAc (240 ml, 10 V) and the combined organic layers were reduced under pressure to yield the desired N-methyl-N-(1-methylethyl)aminosulfonamide product as a light yellow oil, which crystallized after standing. The desired product was obtained with an isolated yield of 83%. Example 2. Synthesis of N-methyl-N-(1-methylethyl)aminosulfonamide using 25% ammonia in water.

[0053] In a clean, dry 0.5 L round-bottom flask, toluene (120 mL, 5 vol) and N-isopropylmethylamine (26.1 g, 2 eq) were loaded under a nitrogen atmosphere at 25–30 °C. The mixture was stirred for 15 min and cooled to -5 °C. Sulfuryl chloride (24 g, 1 eq.) was then added dropwise to the reaction mass at 0–10 °C over 3 hours. Once the addition was complete, the reaction was maintained at this temperature for a further 30 minutes, during which time complete conversion to the intermediate nisopropylmethylsulfamoyl chloride was observed. The reaction mixture was then cooled to 0 °C and washed twice with dilute HCl (1%, 37.5 mL, 1.5 vol) while maintaining temperatures at 5 °C. The organic layer was then concentrated under reduced pressure (45-50 °C, 40 mbar) to yield the crude intermediate as a light yellow oil.In a separate 500 ml round-bottom flask, NH4OH (25%) (120 ml, 5 V) was charged and cooled to an internal temperature of 10 °C. Once the solution was cold, the solution was added dropwise. Petition 870250088405, dated 09 / 30 / 2025, pages 34 / 44 20 / 21 intermediate N-isopropylmethylsulfamoyl chloride was mixed for 5 minutes followed by acetonitrile (24 mL, 1 V) and the solution was stirred for 4 hours, during which time it was gradually heated to 0 °C and held at this temperature. Once the conversion was complete, the solution was extracted with EtOAc (240 mL, 10 V) and the combined organic layers were reduced under pressure to yield the desired N-methyl-N-(1-methylethyl)aminosulfonamide product as a light yellow oil, which crystallized after standing. The desired product was obtained with an isolated yield of 75%. Example 3. Synthesis of N-methyl-N-(1-methylethyl)aminosulfonamide using 7 M ammonia in methanol.

[0054] In a clean, dry 0.5 L round-bottom flask, toluene (120 mL, 5 vol) and N-isopropylmethylamine (26.1 g, 2 eq) were loaded under a nitrogen atmosphere at 25–30 °C. The mixture was stirred for 15 min and cooled to -5 °C. Sulfuryl chloride (24 g, 1 eq.) was then added dropwise to the reaction mass at 0–10 °C over 3 hours. Once the addition was complete, the reaction was maintained at this temperature for a further 30 minutes, during which time complete conversion to the intermediate nisopropylmethylsulfamoyl chloride was observed. The reaction mixture was then cooled to 0 °C and washed twice with dilute HCl (1%, 37.5 mL, 1.5 vol) while maintaining temperatures at 5 °C. The organic layer was then transferred to a 500 mL flask containing 7M methanolic ammonia (240 mL, 10 V), which had been previously cooled to -5°C.Acetonitrile (24 mL, 1 V) was added and the solution was stirred overnight, during which time it was gradually heated to 0°C and held at that temperature. A. Petition 870250088405, dated 09 / 30 / 2025, pages 35 / 44 21 / 21 Once the conversion was complete, the reaction mixture was concentrated under reduced pressure and the resulting crude suspension was dissolved with a 1% HCl solution at 5 V, extracted with EtOAc (240 mL, 10 V), and the combined organic layers were reduced under pressure to yield the desired N-methyl-N-(1-methylethyl)aminosulfonamide product as a light yellow oil that crystallized upon standing. The desired product was obtained with an isolated yield of 63%. Petition 870250088405, dated 09 / 30 / 2025, pages 36 / 44

Claims

1 / 7 Claims:

1. Process for the preparation of a compound of formula I R1 characterized in that: R1 and R2 are each independently alkyl (C1-C12), alkenyl (C2-C6), cycloalkyl (C3-C8), aryl, heteroaryl, or R1 and R2, together with the nitrogen atom to which they are attached, form a 5- to 8-membered ring optionally substituted by one or more groups, each independently selected from alkyl (C1-C12), cycloalkyl (C3-C8), aryl and heteroaryl, and optionally further interrupted by one or more atoms, each independently selected from -O- and -S-, wherein said alkyl, alkenyl and cycloalkyl are each independently optionally interrupted by one or more groups, each independently selected from -O- and -S-, the said process comprising: (i) reaction of a compound of formula II R1 R2 ,NH 11 with sulfuryl chloride in a solvent,to obtain a compound of formula III R1 III Petition 870250088405, dated 09 / 30 / 2025, page 37 / 44 2 / 7 (ii) react the compound of formula III with an ammonia-based solution, to obtain the compound of formula I., 2. Process according to claim 1, characterized in that the molar ratio between sulfuryl chloride and the compound of formula II is 1: at least 1.8, respectively.

3. Process according to claim 1, characterized in that step (i) comprises reacting the compound of formula II with sulfuryl chloride in said solvent in the presence of an organic base, such as a tertiary amine-based base.

4. Process according to claim 3, characterized in that said tertiary amine base is selected from the group consisting of a trialkylamine, such as trimethylamine, triethylamine, dimethylethylamine and a combination thereof; an N-cycloalkylN,N-dialkylamine, such as dimethylcyclohexylamine, diethylcyclohexylamine and a combination thereof; benzyldimethylamine; pyridine; imidazole; and a combination thereof.

5. Process, according to any one of claims 1, 2, 3 or 4, characterized in that step (i) is carried out at a temperature ranging from about -15 °C to about 10 °C, preferably from about -5 °C to about 5 °C.

6. Process according to any one of claims 1, 2, 3, 4 or 5, characterized in that step (i) comprises adding sulfuryl chloride to a solution of the compound of formula II in said solvent. Petition 870250088405, dated 09 / 30 / 2025, p. 38 / 44 3 / 7 7. Process according to claim 6, characterized in that the addition of sulfuryl chloride is carried out over a period of at least 60 minutes; and / or at a temperature ranging from about -15 °C to about 10 °C, preferably from about -5 °C to about 5 °C.

8. Process according to any one of claims 1, 2, 3, 4, 5, 6 or 7, characterized in that said solvent is an aprotic organic solvent, such as a benzene-based solvent and a halogen-containing solvent.

9. Process according to claim 8, characterized in that the benzene-based solvent is selected from the group consisting of toluene, xylene, benzene, chlorobenzene and a mixture thereof; and said halogen-containing solvent is selected from the group consisting of dichloromethane and dichloroethane.

10. A process according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8 or 9, characterized in that the ammonia-based solution is a solution of ammonia in a protic solvent.

11. Process according to claim 10, characterized in that the ammonia-based solution is an ammonia solution in water having a concentration in the range of about 15% to about 70%.

12. Process according to claim 10, characterized in that the ammonia-based solution is a solution of ammonia in methanol.

13. Process, according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, characterized by Petition 870250088405, dated 09 / 30 / 2025, page 39 / 44 4 / 7 the fact that step (ii) is carried out at a temperature ranging from about -30 °C to about 10 °C, preferably from about -15 °C to about 0 °C.

14. Process according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, characterized in that step (ii) further comprises the addition of a cosolvent.

15. Process according to claim 14, characterized in that the cosolvent is a polar organic solvent, such as acetonitrile, acetone, dimethylformamide, dimethyl sulfoxide and a combination thereof.

16. Process according to claim 14 or 15, characterized in that the cosolvent constitutes up to about 20% by volume of the ammonia-based solution.

17. Process according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, characterized in that the compound of formula III is obtained in step (i) in the form of a solution in said solvent; and said solution reacts with said ammonia-based solution in step (ii).

18. Process according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, characterized in that the compound of formula III is obtained in step (i) in the form of a solution in said solvent; and said solution is concentrated under reduced pressure before reacting with said ammonia-based solution in step (ii). Petition 870250088405, dated 09 / 30 / 2025, pp. 40 / 44 5 / 7 19. Process according to claim 1, characterized in that the ammonia-based solution is an ammonia solution in water having a concentration in the range of about 15% to about 70%.

20. Process according to claim 19, characterized in that: a) said ammonia-based solution is an ammonia-in-water solution having a concentration in the range of about 15% to about 35%; b) step (ii) also comprises the addition of a cosolvent; and / or c) the compound of formula III is obtained in step (i) in the form of a solution in said solvent; said solution is then washed with an acidic aqueous solution to obtain an organic phase consisting essentially of the compound of formula III; said organic phase is further concentrated under reduced pressure to obtain the compound of formula III in a pure form; and said pure compound of formula III is reacted with said ammonia-based solution in step (ii).

21. Process according to claim 19, characterized in that: a) said ammonia-based solution is an ammonia-in-water solution having a concentration in the range of about 40% to about 60%; and / or b) the compound of formula III is obtained in step (i) in the form of a solution in said solvent; said solution is then washed with an acidic aqueous solution to obtain an organic phase consisting essentially of the compound of formula III; said organic phase is further concentrated under reduced pressure to obtain the compound of formula III in a pure form; and said pure compound of formula III is reacted with said ammonia-based solution in step (ii).

22. Process according to claim 1, characterized in that the ammonia-based solution is a solution of ammonia in methanol.

23. Process according to claim 22, characterized in that: a) step (ii) further comprises the addition of a cosolvent; and / or b) the compound of formula III is obtained in step (i) in the form of a solution in said solvent; and said solution is reacted with said ammonia-based solution in step (ii).

24. Process according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23, characterized in that R1 and R2 are each independently alkyl (C1-C6), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2,2-dimethylpropyl and n-hexyl.

25. Process for preparing compound of formula IV Petition 870250088405, dated 09 / 30 / 2025, page 42 / 44 7 / 7 IV characterized in that: R1 and R2 are each as defined in claim 1; R3 and R4 are each independently H or halogen; R5 is H or alkyl (C1-C6); and R6 is H, alkyl (C1-C6) or haloalkyl (C1-C6); The aforementioned process comprises the preparation of compound formula I, according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24, and the transformation of said compound formula I into compound formula IV. Petition 870250088405, dated 09 / 30 / 2025, pp. 43 / 44