Efficient purification of saflufenacil

Abstract

The application discloses a process for the preparation of saflufenacil comprising reacting 2-chloro-5-(2,6- dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-l(2H)-yl)-4-fluoro-N-(N-isopropyl-N- methylsulfamoyl)benzamide with a methylating agent in the presence of a phase transfer catalyst to obtain a final reaction mixture comprising saflufenacil and the phase transfer catalyst, characterized in that the phase transfer catalyst is removed or partially removed before separating or purifying saflufenacil.

Description

[0001] EFFICIENT PURIFICATION OF SAFLUFENACIL

[0002] FIELD OF THE INVENTION

[0003] The present application relates to the field of organic synthesis, specifically to the methods for the more efficient preparation of saflufenacil.

[0004] BACKGROUND saflufenacil (2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-l-(2H)pyrimidinyl]-4-fluoro- N-[[methyl(l-methylethyl)amino] sulfonyl] benzamide), which belongs to the class of substituted sulfamides, is a herbicide that is particularly useful for preplant applications and selective pre-emergence weed control in multiple crops. It is absorbed by foliage and roots with translocation in the apoplast and limited movement in the phloem. Saflufenacil is applied to foliage and is used for residual control of broadleaved weeds, including glyphosate- and ALS-resistant biotypes. Saflufenacil is applied pre-emergence in corn and sorghum, at 50-125 gram / hectare (g / ha); preplant for rapid foliar burn-down in soybeans, cereals, cotton, legumes; and post-directed in tree fruit and nuts, at 18-25 g / ha, and in sugarcane at 24.5- 96 g / ha.

[0005] Saflufenacil belongs to the group of protoporphyrinogen oxidase (PPO) inhibitors, more specifically it is a pyrimidinedione-based PPO inhibitor and it has been described in WO 01 / 083459. Processes for its preparation are described in WO 03 / 097589, US 2006 / 0293520, WO 06 / 097589, US 2008 / 0293941, US 2010 / 105562, and US 2010 / 035905.

[0006] Patent application US 2008 / 0293941 describes the preparation of saflufenacil by methylation of 2-Chloro- 4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-l(2H)-yl]-N-[methyl(propan-2- yl)sulfamoyl]benzamide (which will also be referred herein as "demethylated saflufenacil"). The reaction typically proceeds in a two-phase system comprising water, an organic solvent, an alkylating agent (typically, dimethyl sulfate or "DMS") and a phase transfer catalyst. US 2008 / 0293941 provides a detailed description of the reactants and reaction conditions. As to the workup and purification, the application contains little indications beyond customary procedures. methylating agent Phase transfer cat

[0007] Demethylated Saflufenacil SailufenaciS US 2006 / 0293520 describes a process for the preparation of saflufenacil by reacting demethylated saflufenacil with a methylation agent, typically dimethyl sulfate, in the presence of a phase transfer catalyst, typically tetrabutyl ammonium bromide. In examples 6 and 7 (page 15) US 2006 / 0293520 teaches specific embodiments of the reaction wherein the final product is purified by chromatographic methods. Crystallization is mentioned but no details are given on how to achieve such crystallization for saflufenacil. US 2010 / 105562 discloses preparation methods of saflufenacil, similar to those of US 2008 / 0293941 and US 2006 / 0293520, and the subsequent preparation of saflufenacil crystals. US2010035905 contains a similar disclosure to produce hydrates of saflufenacil.

[0008] Patent application WO2023 / 232507 deals with the problem of saflufenacil loss during workup and subsequent crystallization procedures. The application provides a process in which the mother liquor from the crystallization process is first extracted with an aqueous phase at pH 7-10, and the aqueous phase is then back-extracted by decreasing the pH below 6 in the presence of an organic solvent. The first step must be done quickly because saflufenacil readily decomposes at pH above 7 mainly into the impurity of formula (VI) depicted below, making the process difficult to implement at an industrial scale. Also, there is a risk if saflufenacil is maintained at pH above 7 for longer than recommended, and the margin of error is small.

[0009] Decomposition compound of formula (VI) described in WO2023 / 232507.

[0010] There is therefore a need in the art to find improved procedures to prepare saflufenacil.

[0011] SUMMARY OF THE INVENTION

[0012] In this context the inventors have developed a process for the preparation of saflufenacil comprising reacting 2-chloro-5-(2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-l(2H)-yl)-4-fluoro-N-(N- isopropyl-N-methylsulfamoyl)benzamide (also referred herein as "demethylated saflufenacil") with a methylating agent in the presence of a phase transfer catalyst to obtain a final reaction mixture comprising saflufenacil and the phase transfer catalyst, characterized in that the phase transfer catalyst is removed or partially removed before separating or purifying saflufenacil, typically by crystallization. The process of the invention does not require complicated operations. More importantly, the process does not require saflufenacil to be in contact with water having a pH above 7, thus preventing the decrease in yield and quality derived from its decomposition at such pH, while providing a good yield. This is especially advantageous during crystallization and re-crystallization, which involve high volumes for which a quick exchange is not efficient, and would yield unacceptable amounts of decomposition of saflufenacil. Later second or third crop recoveries may use a pH above 7 because the small quantities of saflufenacil involved allow for a short and efficient exchange even at industrial levels. The inventors have found that the removal of the phase transfer catalyst surprisingly reduces the amount of saflufenacil lost during purification. For example, the results have shown a significant reduction of saflufenacil present in the mother liquor after crystallization. The removal of the phase transfer catalyst allowed the inventors to proceed with workup, crystallization and recovery conditions, that avoid the delicate pH adjustments and back extractions described in WO2023 / 232507, and that result in the decomposition of saflufenacil to the decomposition compound of formula (VI) as described in WO2023 / 232507. Neither do other documents such as US 2010 / 105562, or US 2010 / 035905 teach the relevance of removing phase transfer catalysts.

[0013] DETEILED DESCRIPTION OF THE INVENTION

[0014] Definitions

[0015] Prior to setting forth the present subject matter in detail, it may be helpful to provide definitions of certain terms used herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this subject matter pertains.

[0016] "Alkyl" means in the present document a straight (linear) or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, having the number of carbon atoms indicated in each case, for example 1-24 carbon atoms, which is attached to the rest of the molecule by a single bond. In an embodiment of the invention the alkyl group comprises 1-20 carbon atoms. In a further embodiment it comprises 1-4 carbon atoms. Exemplary alkyl groups can be methyl, ethyl, n-propyl, i- propyl, n-butyl, t-butyl, or n-pentyl.

[0017] "Alkenyl" refers to a straight (linear) or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing at least one unsaturation, having 2 to 24, for example 2 to 20, for example 2 to 12, for example 2 to 4 carbon atoms, and which is attached to the rest of the molecule by a single bond. Exemplary alkenyl groups are vinyl, allyl, butenyl (e.g. 1-butenyl, 2-butenyl, 3-butenyl), or pentenyl (e.g. 1- pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl).

[0018] "Aryl" refers to an aromatic hydrocarbon radical having 6 to 10 carbon atoms such as phenyl or naphthyl. "Arylkyl" (or "aralkyl") refers to an aryl group linked to the rest of the molecule by an alkyl group such as benzyl and phenethyl.

[0019] The term "final reaction mass" in the present document refers to the reaction mixture after all components of the process were introduced, reaction was carried out and starting material was consumed up to the desired conversion (reaction end). The final reaction mass can be a one-phase or two-phase mixture. In the process described herein it is typically a two-phase mixture.

[0020] "Workup" in the present document refers to the all operations following the reaction end up to the preparation of the final product (saflufenacil) having the desired purity. Accordingly, it includes, but is not limited to, quenching, solvent distillations; extractions; filtrations; decantations; centrifugations; sorption - desorption processes; removal and recovery of reagents and catalysts, including the phase transfer catalysts; pH modifications; separation and purifications to obtain the final product.

[0021] "Crude product" in the present document refers to the desired material (saflufenacil) separated from the reaction mixture during the workup with the quality below the desired level and before final purification to obtain the final product.

[0022] The term "crystallization" has its usual meaning in the art and comprises separating the product (saflufenacil) from impurities accompanying it by selective precipitation of either of them during workup. Crystallization may be done once, or it may include one or more subsequent recrystallizations. Selective precipitation, and thus separation, will depend largely on the election of the solvent(s) and is typically triggered by solvent evaporation, cooling of the mixture and / or addition of an antisolvent.

[0023] Methylation of Demethylated Saflufenacil to Provide Saflufenacil

[0024] The reaction to produce saflufenacil comprises the methylation of 2-Chloro-4-fluoro-5-[2,6-dioxo-4- (trifluoromethyl)-3,6-dihydropyrimidin-l(2H)-yl]-N-[methyl(propan-2-yl)sulfamoyl]benzamide, also referred in the present applications as "demethylated saflufenacil". This demethylated saflufenacil and its preparation is well known in the art, for example, following the methods described in US 2008 / 0293941 or US 2008 / 033174.

[0025] Factors governing the outcome of the reaction are discussed below. They are discussed separately to provide an organized presentation but should not be considered as separate isolated embodiments. Thus, the skilled person is aware of the fact that the parameters can be modified within the terms of the process described herein.

[0026] Solvent Solvents suitable for these reactions are, depending on the temperature range, aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, cyclopentane, cyclohexane, toluene, or xylene; chlorinated aliphatic and aromatic hydrocarbons, such as dichloromethane, trichloromethane, 1,2- dichloroethane, 1,1,2,2-tetrachloroethane, chlorobenzene, 1,2-, 1,3- or 1,4-dichlorobenzene, chlorotoluenes, or dichlorotoluenes; open-chain dialkyl ethers, such as diethyl ether, di-n-propyl ether, diisopropyl ether, or methyl tert-butyl ether; cyclic ethers, such as tetra hydrofuran (THF), 2- methyltetrahydrofurane (2-MeTHF), 3-methyltetrahydrofurane (3-MeTHF), or 1,4-dioxane; anisole; glycol ethers, such as dimethyl glycol ether, diethyl glycol ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether; Ci-C4-alcohols, such as methanol, ethanol, n-propanol, isopropanol, or n-butanol; aliphatic Ci-C6-alkyl carboxylates, such as methyl acetate, ethyl acetate or n-butyl acetate; ketones, such as acetone, methyl ethyl ketone, methyl isopropyl ketone, or methyl isobutyl ketone; carbonates, such as dimethyl carbonate, diethyl carbonate and ethylene carbonate; N,N-dialkylamides, such as N,N- dimethylformamide or N,N-dimethylacetamide; N-alkyllactams, such as N-methylpyrrolidone; sulfoxides, such as dimethyl sulfoxide; tetraalkyl ureas, such as tetramethyl urea, tetraethyl urea, tetrabutyl ureas, dimethylethylene urea, or dimethylpropylene urea or mixtures of these solvents.

[0027] Preferred solvents are N,N-dimethylformamide, N-methylpyrrolidone, acetone, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, chlorobenzene, methyl acetate, ethyl acetate, butyl acetate, or methyl ethyl ketone, or mixtures of these solvents. It is preferred that the solvent is a mixture of an aromatic hydrocarbon, such as toluene or a xylene; or a chlorinated aromatic hydrocarbon, such as chlorobenzene (monochlorobenze or MCB), 1,2-, 1,3- or 1,4-dichlorobenzene, a chlorotoluene, or a dichlorotoluene; with a ketone, such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, or butanone; or a cyclic ether, such as tetra hydrofuran (THF), 2-methyltetrahydrofurane (2-MeTHF), 3-methyltetrahydrofurane (3-MeTHF), or 1,4-dioxane. Typical conditions described in the art will use a mixture of an aromatic hydrocarbon, usually toluene, and a cyclic ether, typically THF.

[0028] The inventors have found that a mixture of an aromatic hydrocarbon, for example, toluene, and a ketone, for example methyl ethyl ketone provide good to excellent yields, and safer conditions that avoid the production of peroxides. Such solvent mixtures have the additional advantage as being suitable for the subsequent crystallization (and optional recrystallization(s)) of the saflufenacil product.

[0029] Temperature and Pressure

[0030] The reaction typically requires heating but is not always mandatory and it can proceed at temperatures between -5°C and 120°C, preferably at temperatures between 0°C and 80 °C. The solvent or mixture of solvents can also influence the choice of reaction temperature. For example, if the solvent is a mixture of toluene and THF (boiling point of 66°C), the reaction temperature can be between 20°C and 60°C. If the solvent of choice is a mixture of toluene and methyl ethyl ketone (boiling point of 79°C) the temperature of the reaction is preferably between 20°C and 75°C, for example, between 40°C and 70°C, although it is also possible to perform the reaction at lower temperatures, for example, between 20°C and 50°C or between 30°C and 45°C. The use of solvents with higher boiling points will allow higher reaction temperatures. The reaction time can be determined by the person skilled in the art in a manner that is customary. It will typically involve measuring the amount of starting material (demethylated saflufenacil) left in the reaction mixture. The reaction can be carried out at atmospheric pressure, reduced pressure or under elevated pressure, if appropriate under an inert gas, continuously or batchwise.

[0031] Methylation Agent

[0032] The are many methylating agents known in the art. Exemplary methylating agents are methyl halides, dimethyl sulfate (DMS), dimethyl carbonate, methylsulfonic acid, methyl Ci-C6-alkylsulfonates, methyl Ci- Ce-haloalkyllsulfonates or methyl phenylsulfonate, wherein the phenyl ring may carry one or more substituents from the group consisting of halogen, nitro, Ci-Ce-alkyl and Ci-Ce-haloalkyl. Preferred methylating agents are methyl halides, dimethyl sulfate (DMS), methyl Ci-C6-alkylsulfonates or methyl phenylsulfonates.

[0033] Particularly preferred methylating agents are dimethyl sulfate and methyl halides, such as methyl iodide, methyl bromide, methyl chloride; most preferably dimethyl sulfate.

[0034] In the process described herein, the methylating agent can be employed both in an equimolar amount, based on the amount of demethylated saflufenacil, and in a substoichiometric amount or superstoichiometric amount.

[0035] Usually, at least an equimolar amount of the methylating agent is used, based on the initial demethylated saflufenacil. Typically, the methylating agent will be used in a superstoichioetric amount with respect to demethylated saflufenacil. The molar ratios of demethylated saflufenacil to methylating agent are generally in the range from 1:1 to 1:5 or from 1:1 to 1:3, or from 1:1 to 1:2, or from 1:1 to 1:1.5, preferably from 1:1 to 1: 1.3.

[0036] Base and pH of the reaction

[0037] Suitable bases for the reaction according to the invention are all customary organic and inorganic bases.

[0038] Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide; alkaline earth metal oxides, such as calcium oxide and magnesium oxide; alkali metal and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride; alkali metal and alkaline earth metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate and calcium carbonate; and also alkali metal bicarbonates, such as sodium bicarbonate; organometallic compounds, in particular alkali metal and alkaline earth metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, potassium tert-pentoxide and dimethoxymagnesium; moreover organic bases, for example tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine, tributylamine, and N-methylpiperidine, pyridine; substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine; and also bicyclic amines, such as 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diaza-bicyclo[4.3.0]-non-5-ene (DBN) or 1,4- diazabicyclo[2.2.2]octane (DABCO).

[0039] Preferred bases are selected from the group consisting of alkali metal and alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkaline earth metal oxides, such as calcium oxide; alkali metal and alkaline earth metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, zinc carbonate; alkali metal bicarbonates, such as sodium bicarbonate; and also tertiary amines, such as triethylamine. Particularly preferred bases are selected from the group consisting of alkali metal and alkaline earth metal hydroxides and also tertiary amines. Especially preferred are bases selected from the group consisting of alkali metal and alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkaline earth metal oxides, such as calcium oxide; alkali metal and alkaline earth metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, zinc carbonate; and also alkali metal bicarbonates, such as sodium bicarbonate.

[0040] In a particularly preferred embodiment of the process according to the invention, the base used is sodium hydroxide or potassium hydroxide, sodium carbonate or potassium carbonate or sodium bicarbonate or potassium bicarbonate. In a very preferred embodiment of the process according to the invention, the base used is an alkali metal hydroxide or alkaline earth metal hydroxide, preferably an alkali metal hydroxide.

[0041] The bases are generally employed in equimolar amounts, based on the demethylated saflufenacil; however, they can also be employed in excess or, if appropriate, as solvent.

[0042] Preferably, at least an equimolar amount of base, based on the demethylated saflufenacil, is used. The amount of base is generally not more than 1.3 mol per mole of demethylated saflufenacil. Buffers can also be added to the reaction media in addition to or as substitutes of bases. The buffer to be used can be any that maintains an acid pH. Exemplary buffers are phosphate salts, citrate and acetate, such as those base on NaH2PC>4.

[0043] Phase transfer catalyst

[0044] Examples of phase-transfer catalysts are quaternary ammonium salts, phosphonium salts, crown ethers or polyglycols.

[0045] Suitable quaternary ammonium salts comprise, for example, tetra-(Ci-Ci8)-alkylammonium fluorides, chlorides, bromides, iodides, tetrafluoroborates, diborates, sulfates, hydroxides, perchlorates and borates, such as, for example, tetramethylammonium fluoride tetrahydrate, tetramethylammonium fluoride, tetrabutylammonium fluoride, tetrabutylammonium fluoride trihydrate, tetramethylammonium chlorine, tetraethylammonium chloride, tetrapropylammonium chloride, tetrabutylammionium chloride, dodecyltrimethylammonium chloride, methyltributylammonium chloride, methyltrioctylammonium chloride, methyltricaprylammonium chloride; tetraethylammonium chloride hydrate, tetraethylammonium bromide, tetrapropylammonium bromide (TPAB), tetrabutylammonium bromide (TBAB), tetrahexylammonium bromide, tetraoctylammonium bromide, cetyltrimethylammonium bromide (CTAB), dodecyltrimethylammonium bromide, tetramethylammonium bromide tetrabutylammonium iodide, tetrahexylammonium iodide, tetrabutylammonium tetrafluoroborate, C12-C14- trimethylammonium diborate, tetrabutylammonium hydrogensulfate (TBAHS), tetramethylammonium hydroxide (TMAOH), tetraethylammonium hydroxide, tetrapropylammonium hydroxide, tetrabutylammonium hydroxide, tetrabutylammonium perchlorate, Ci2-Ci4-alkyltrimethylammonium borate, Ci2-Ci4-alkyltrimethylammonium diborate; N-benzyltri-(Ci-C3o)-alkylammonium chlorides, such as N-benzyltri-(Ci-Ci8)-alkylammonium chlorides, bromides or fluorides, such as, for example, benzyltrimethylammonium chloride (BTMAC), benzyltriethylammonium chloride (BTEAC), benzyltriethylammonium bromide, benzyltributylammonium chloride, benzyltributylammonium bromide, or benzalkonium chloride (benzyldimetylalkylammonium chloride), wherein the alkyl chain can have different lengths, such as C8 to C20, for example C8, CIO, C12, C14, C16, C18, C20 or mixtures thereof); phenyltri-(Ci-Ci8)-alkylammonium chlorides, bromides or fluorides, such as, for example, phenyltrimethylammonium chloride (PTMAC); aromatic ammonium salts, such as, for example, hexadecylpyridinium chloride, N,N-dimethylpiperidinium hydroxide, pyridinium fluorides, chlorides or bromides, such as, for example, 1-cetylpyridinium chloride monohydrate, cetylpyridinium bromide. Preferably, the phase transfer catalyst is selected from a quaternary ammonium salt wherein one of the groups is an aralkyl or aryl group and another group is a C4-C3o-alkyl group, e.g. benzalkonium. For example, the phase transfer catalyst can be a quaternary ammonium salt of formula (I)

[0046] (R1)(R2)(R3)(R4)N+X" (I)

[0047] R1and R2are independently selected from the group consisting of Ci-C8(linear) alkyl groups, C2- C8(linear) alkenyl groups, preferably a C1-C4 alkyl groups, preferably methyl or ethyl, preferably methyl (preferably R1and R2are both methyl);

[0048] R3is selected from the group consisting of C4-C30 (linear) alkyl groups, C4-C30 alkenyl groups, preferably a C6-C2o alkyl groups, preferably selected from the group consisting of octyl, decyl, dodecyl, tetradecyl, hexadecyl, and octadecyl;

[0049] R4is selected from the group consisting of C4-C30 (linear) alkyl groups, C6-Cis aryl and C7-Ci5-aryl alkyl, preferably C6-Cis aryl and C7-Ci5-aryl alkyl, for example, benzyl; and

[0050] X is a counter anion selected from the group consisting of halogens, hydrogensulfate, hydroxide (OH"), perchlorate, borate and diborate, for example a halogen atom, for example bromide or chloride.

[0051] For example, the phase transfer catalyst can be a quaternary ammonium salt of formula (I) (RT)(R2)(R3)(R4)N+X- (I)

[0052] R1and R2are independently selected from the group consisting of Ci-C6(linear) alkyl groups, C2- C6(linear) alkenyl groups, preferably a C1-C4 alkyl groups, preferably methyl or ethyl, preferably methyl (preferably R1and R2are both methyl);

[0053] R3is selected from the group consisting of C6-C3o (linear) alkyl groups, C6-C3o alkenyl groups, preferably a C6-C20alkyl groups, preferably selected from the group consisting of octyl, decyl, dodecyl, tetradecyl, hexadecyl, and octadecyl;

[0054] R4is selected from the group consisting of C6-Cis aryl and C7-Ci5-aryl alkyl, for example, benzyl; and X is a counter anion selected from the group consisting of halogens, hydrogensulfate, hydroxide (OH"), perchlorate, borate and diborate, for example a halogen atom, for example bromide or chloride.

[0055] For example, the phase transfer catalyst can be a quaternary ammonium salt of formula (I) wherein

[0056] R1and R2are independently selected from the group consisting of C1-C4 alkyl groups, preferably methyl or ethyl;

[0057] R3is selected from the group consisting of C4-C30 (linear) alkyl groups, preferably methyl or ethyl;

[0058] R4is selected from the group consisting of C4-C30 (linear) alkyl groups, preferably methyl or ethyl; and X is a counter anion selected from the group consisting of halogens, hydrogensulfate, hydroxide (OH"), perchlorate, borate and diborate, for example a halogen atom, for example chloride.

[0059] For example, the phase transfer catalyst can be a quaternary ammonium salt of formula (I) wherein

[0060] R1and R2are independently selected from the group consisting of Ci-C8(linear) alkyl groups, preferably a C2-C5alkyl groups, preferably butyl;

[0061] R3and RR4 are independently selected from the group consisting of C4-C6(linear) alkyl groups, preferably butyl; and

[0062] X is a counter anion selected from the group consisting of halogens, for example bromide.

[0063] For example, the phase transfer catalyst can be a quaternary ammonium salt of formula (I) wherein

[0064] R1and R2are independently selected from the group consisting of C1-C4 alkyl groups, preferably methyl or ethyl;

[0065] R3is selected from the group consisting of C6-C20alkyl groups, preferably selected from the group consisting of octyl, decyl, dodecyl, tetradecyl, hexadecyl, and octadecyl;

[0066] R4is selected from the group consisting of C6-Cis aryl and C7-Ci5-aryl alkyl, preferably a C7-C15- arylalkyl such as benzyl; and

[0067] X is a counter anion selected from the group consisting of halogens, hydrogensulfate, hydroxide (OH"), perchlorate, borate and diborate, for example a halogen atom, for example chloride.

[0068] Suitable phosphonium salts comprise, for example, Ci-Cig-alkyltriphenylphosphonium chlorides, bromides, acetates, such as, for example, methyltriphenylphosphonium bromide, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, ethyltriphenylphosphonium acetate, butyltriphenylphosphonium chloride, butyltriphenylphosphonium bromide; or tetra-(Ci-Cig)- alkylphosphonium chloride or bromide, such as tetrabutylphosphonium bromide, tetraphenylphosphonium chloride or bromide, benzyltriphenylphosphonium chloride or bromide.

[0069] Suitable crown ethers comprise, for example, 18-crown-6, dibenzo-18-crown-6.

[0070] Suitable polyglycols comprise, for example, diethyleneglycoldibutyl ether (butyl diglyme), tetraethylene glycol dimethyl ether (tetraglyme), triethylene glycol dimethyl ether (triglyme), polyglycol dimethyl ether. In general, the phase-transfer catalyst is employed in an amount of up to 20 mol percent, preferably between 1 and 15 mol percent and in particular between 2 and 12 mol percent, based on the demethylated saflufenacil.

[0071] For the reaction, the demethylated saflufenacil, the phase transfer catalyst, the alkylating agents and base(s) / buffer(s) can be brought into contact in any way. Preferably, the demethylated saflufenacil, the phase transfer catalyst, a buffer and the alkylating agent are initially charged in a reaction vessel, if appropriate with the desired solvent, and the pH is thereafter adjusted with a base (e.g. an alkaline hydroxide such as sodium hydroxide).

[0072] As already mentioned, many combinations of the above discussed solvents, temperature, pressure, methylating agents, bases, pH control, and phase transfer catalysts can be used. A typical reaction set up may include providing a mixture of demethylated saflufenacil, a phase transfer catalyst, and a base in a solvent system comprising water and an organic solvent or mixture of solvents. The reaction can then be started by adding the methylating agent. During the reaction the pH is typically maintained at a pH between 1 and 6 and the temperature at 20°C to 50°C.

[0073] For example, the reaction may include providing a mixture of demethylated saflufenacil, a phase transfer catalyst selected from a quaternary ammonium salt, and a base in a solvent system comprising water and an organic solvent, wherein the organic solvent is a mixture of an aromatic hydrocarbon with a cyclic ether or a ketone. The reaction can then be started by adding a methylating agent, typically a methyl halide or dimethyl sulfate (DMS). During the reaction the pH is typically maintained at a pH of 2 to 5 and the temperature at 20°C to 50°C.

[0074] Alternatively, the reaction may include providing a mixture of demethylated saflufenacil, a phase transfer catalyst, and a base in a solvent system comprising water and an organic solvent, wherein the organic solvent is preferably a mixture of toluene with THF or methyl ethyl ketone, and wherein the phase transfer catalyst is a compound of formula (I)

[0075] (R1)(R2)(R3)(R4)N+X" (I) wherein

[0076] R1and R2are independently selected from the group consisting of Ci-C8(linear) alkyl groups, C2- C8(linear) alkenyl groups, preferably a C1-C4 alkyl groups, preferably methyl or ethyl, preferably methyl (preferably R1and R2are both methyl);

[0077] R3is selected from the group consisting of C4-C30 (linear) alkyl groups, C4-C30 alkenyl groups, preferably a C6-C2o alkyl groups, preferably selected from the group consisting of octyl, decyl, dodecyl, tetradecyl, hexadecyl, and octadecyl;

[0078] R4is selected from the group consisting of C4-C30 (linear) alkyl groups, C6-Cis aryl and C7-Ci5-aryl alkyl, preferably C6-Cis aryl and C7-Ci5-aryl alkyl, for example, benzyl; and

[0079] X is a counter anion selected from the group consisting of halogens, hydrogensulfate, hydroxide (OH"), perchlorate, borate and diborate, for example a halogen atom, for example bromide or chloride. The reaction ca then be started by adding a methylating agent, typically a methyl halide or dimethyl sulfate (DMS), and during the reaction the pH is typically maintained at a pH of 2 to 5 and the temperature at 30°C to 50°C. Removal of the Phase Transfer

[0080] Once finished, the reaction is typically quenched, for example by the addition of acid (e.g. aqueous mineral acid such as HCI or sulfuric acid) in order to neutralize any remaining methylating agent, typically, DMS. As a result, the reaction vessel would contain a two-phase mixture, wherein the aqueous phase has an acidic pH.

[0081] In the process of the invention the phase transfer catalyst is subsequently removed or at least partially removed. There are different techniques that can be used to remove the phase transfer catalyst, ion exchange processes being preferred. It is preferred that the mixture contains water to dissolve any salts formed during the ion exchange. According to this embodiment, to the quenched reaction mixture an ion exchange resin is added to start an ion exchange process by which the phase transfer catalyst is removed from the mixture. After quenching, the pH of the aqueous phase is typically below 3, for example below 2 or below 1. Before submitting the mixture to the ion exchange process, the pH can be adjusted to suitable levels for the ion exchange resin. Each ion exchange resin may require different optimum pH values. Alternatively, the mixture resulting from the reaction can be separated, and the aqueous phase discarded, and then water at an appropriate pH is added.

[0082] The temperature is not critical during the ion exchange process and heating may be used to ensure that all the saflufenacil remains dissolved during the process.

[0083] Once the pH has been adjusted, the mixture is submitted to an ion exchange process. Optimal pH may depend on the ion exchange resin used, and it is typically maintained throughout the ion exchange process between 1 and 6, preferably, between 2 and 5, preferably between 2.5 and 4.5, preferably between 3 and 4, by addition of a base or a buffer, to prevent reaching an equilibrium before the phase transfer catalyst is removed to acceptable levels. Said base can be an alkaline or alkaline-earth hydroxide, for example, one selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, beryllium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide and mixtures thereof, preferably sodium hydroxide.

[0084] Alternatively, the inventors have found that the process is surprisingly efficient even if the pH is not controlled during the ion exchange process. Thus, the pH of the water phase during the ion exchange process may not be corrected so that it is allowed to decrease. Without wanting to be bound by theory, it is believed that allowing free variation of the pH prevents the production sodium sulfate, which could interfere with the ion exchange process by competing for sorption with the phase transfer catalyst and / or driving the equilibrium towards desorption of the phase transfer catalyst. In such cases, the stabilization of the pH signals the end of the ion exchange process.

[0085] The process may comprise adding an ion exchange resin and mixing until sorption of all the phase transfer catalyst is complete or has reached desired levels. The temperature can be comprised between 10°C and 120°C, for example, between 20°C and 110°C, or between 30°C and 100°C, preferably between 40°C and 80°C, or between 50°C and 70°C, preferably between 60°C and 70°C. The main objective is to maintain saflufenacil dissolved. The resin is then separated from the mixture. The ion exchange resin is typically added in the form of pearls or particles, which can be filtered out or removed by suction once the process is complete. Other forms are however possible, such as ion exchange columns through which the mixture is circulated.

[0086] There are several types of ion exchange resins, depending on the substrate used as support, the acidity and the functional group responsible for the sequestration of the cations, and the pore size. Attending to the acidity and functional group, the resins can be divided into (i) strongly acidic cation (SAC), typically featuring sulfonic acid groups, e.g. sodium polystyrene sulfonate or polyAMPS; (ii) strongly basic anion (SBA), typically featuring quaternary amino groups, for example, trimethylammonium groups, e.g. polyAPTAC); (iii) weakly acidic cation (WAC), typically featuring carboxylic acid groups; and (iv) weakly basic anion (WBA), typically featuring primary, secondary, and / or tertiary amino groups, e.g. polyethylene amine. It is preferred that an ion exchange resin selected from strongly acidic cation (SAC) or weakly acidic cation (WAC), preferably a strongly acidic cation (SAC) containing sulfonate groups, polyAMPS groups (poly(2-acrylamido-2-methyl-l-propanesulfonic acid)).

[0087] The most common support for ion exchange resins are styrene-divinylbenzene co-polymers, also referred to as polystyrene crosslinked with divinyl benzene.

[0088] Attending to the pore size, the ion exchange resins can be divided into (i) micropore, with a Slit width less than 2 nm; (ii) mesopore, with a Slit width between 2 and 50 nm; and (iii) macropore, with a Slit width bigger than 50 nm. The ion exchange resin used is preferably a macropore.

[0089] The ion exchange resin can be regenerated using known procedures to recover the expensive and valuable phase transfer catalyst.

[0090] The more phase transfer catalyst is removed, the better the results in the later separation, typically a crystallization. Thus, it is preferred that 20 w / w% (by weight) or more of the phase transfer catalyst initially added in the reaction is removed. For example, in the process of the invention 30 w / w% or more of the phase transfer catalyst initially added to the reaction is removed, for example 40 w / w% or more, or 50 w / w% or more, or 60 w / w% or more, or 70 w / w% or more, or 80 w / w% or more, or 90 w / w% or more, or 95 w / w% or more, or 98 w / w% or more, for example, between 30 w / w% and 100 w / w%, or between 50 w / w% and 99 w / w%, or between 60 w / w% and 99 w / w%, or between 70 w / w% and 99 w / w%, or between 80 w / w% and 99 w / w%, or between 90 w / w% and 99 w / w%, or between 50 w / w% and 100 w / w%, or between 90 w / w% and 100 w / w%.

[0091] Therefore, the process of the invention for the preparation of saflufenacil may comprise

[0092] (a) reacting 2-chloro-5-(2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-l(2H)-yl)-4-fliioro-N-(N- isopropyl-N-methylsulfamoyl)benzamide with a methylating agent in the presence of a phase transfer catalyst to obtain a final reaction mixture comprising saflufenacil and the phase transfer catalyst; and

[0093] (b) removing or partially removing the phase transfer catalyst during the subsequent workup from the final reaction mixture obtained in the previous step.

[0094] For example, the process for the preparation of saflufenacil may comprise

[0095] (a) reacting 2-chloro-5-(2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-l(2H)-yl)-4-fluoro-N-(N- isopropyl-N-methylsulfamoyl)benzamide with a methylating agent in the presence of a phase transfer catalyst to obtain a final reaction mixture comprising saflufenacil and the phase transfer catalyst;

[0096] (b) removing or partially removing the phase transfer catalyst during the subsequent workup from the final reaction mixture obtained in the previous step; and

[0097] (c) crystallizing saflufenacil from the mixture obtained from step (b), to obtain solid saflufenacil and a mother liquor.

[0098] For example, the process for the preparation of saflufenacil may comprise

[0099] (a) reacting 2-chloro-5-(2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-l(2H)-yl)-4-fluoro-N-(N- isopropyl-N-methylsulfamoyl)benzamide with a methylating agent in the presence of a phase transfer catalyst to obtain a final reaction mixture comprising saflufenacil and the phase transfer catalyst;

[0100] (b) removing or partially removing the phase transfer catalyst during the subsequent workup from the final reaction mixture obtained in the previous step;

[0101] (c) crystallizing saflufenacil from the mixture obtained from step (b), to obtain solid saflufenacil and a mother liquor; and

[0102] (d) extracting the mother liquor of step (c) with an aqueous phase having a pH of 7 or less to provide an aqueous phase comprising saflufenacil and demethylated saflufenacil. For example, the process for the preparation of saflufenacil may comprise

[0103] (a) reacting 2-chloro-5-(2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-l(2H)-yl)-4-fliioro-N-(N- isopropyl-N-methylsulfamoyl)benzamide with a methylating agent in the presence of a phase transfer catalyst to obtain a final reaction mixture comprising saflufenacil and the phase transfer catalyst;

[0104] (b) removing or partially removing the phase transfer catalyst during the subsequent workup from the final reaction mixture obtained in the previous step;

[0105] (c) crystallizing saflufenacil from the mixture obtained from step (b), to obtain solid saflufenacil and a mother liquor;

[0106] (d) extracting the mother liquor of step (c) with an aqueous phase having a pH of 7 or less to provide an aqueous phase comprising saflufenacil and demethylated saflufenacil; and

[0107] (e) adding said aqueous phase to the reaction in a later batch.

[0108] The crystallization process can proceed according to any of the generally known methodologies. For example, saflufenacil can be crystallized or recrystallized following the method described in US 2010 / 105562, or US 2010 / 035905. The crystallization process will result in solid saflufenacil and a mother liquor. The crystallization process can be repeated one or more times until a saflufenacil of the desired purity is obtained. Many different solvents can be used but it is preferred to use the same solvent or solvents used in the reaction to prepare saflufenacil. Preferably, the crystallization is done in a mixture of an apolar and polar solvents, for example, in a mixture of an aromatic solvent and a polar solvent selected from the group consisting of ethers and ketones, preferably, a mixture of toluene and a polar solvent selected from the group consisting of methyl ethyl ketone, tetra hydrofurane or 2- or 3- methyltetrahydrofurane.

[0109] Recovery from Mother Liquor

[0110] The process may comprise a step of extracting the mother liquor from the previous crystallization step with an aqueous phase having a pH of 7 or less to provide an aqueous phase comprising saflufenacil and demethylated saflufenacil. As discussed in the examples below, the amount of saflufenacil present in this mother liquor is surprisingly low due to the high efficiency of the crystallization. This recovered saflufenacil and demethylated saflufenacil can be recycled for use in subsequent batches.

[0111] EXAMPLES

[0112] Example 1: first batch. Does not use in the starting materials any phase transfer catalyst, demethylated Saflufenacil nor Saflufenacil recovered from previous batches. To a four-neck flask were added 412 g of toluene, 178 g of methyl ethyl ketone (MEK), 98.7 g (200 mmol) of 2-chloro-5-(2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-l(2H)-yl)-4-fluoro-N-(N-isopropyl-N- methylsulfamoyl)benzamide (demethylated saflufenacil), 95 g of a 3 % aqueous solution of NaH2PC>4 and 10.2 g (15 mmol) of 50 % aqueous solution of Benzalkonium Chloride (BzC).

[0113] To the prepared mixture at room temperature with good stirring were added 33.1 g (260 mmol) of dimethyl sulfate (DMS). The reaction mixture was heated to 35-39°C and stirred for lOh. 15% NaOH was added to control pH at 4.2±0.1.

[0114] After reaction ended to the mixture was added about 15 g (0.12 mol) of 30% HCI to achieve pH below 1.0 and the solution was stirred for 2h at 35-39°C to destroy any unreacted DMS. The reaction mixture was then heated to 65-70°C until all solid (mostly saflufenacil) dissolved, after which the aqueous phase was separated.

[0115] To the organic phase was added 95 g of water and pH was adjusted to 4 at 65-70°C with 15% NaOH. To the prepared mixture was added ion exchange resin of macroporous type, styrene-divinylbenzene copolymer, strong acid in H+ Form in an amount containing 0.075 equivalents of sulfonic groups. The mixture was stirred for 2h at 65-70°C with pH control between 3 to 4 by addition of 15% NaOH up to full sorption of BzC. The resin was filtered, and the aqueous phase was separated at 65-70°C.

[0116] The organic phase was washed with 95 g of water and concentrated at the atmospheric pressure. About 470 g of the solvent was distilled out at the temperature between 100°C and 112°C. To the concentrated solution was added 5 g of MEK at 112°C and the mixture was cooled to -5°C within 3h. Crystallized crude product was filtered and rinsed with 35 g of cooled toluene.

[0117] In another flask were added 590 g of toluene and the above crude product. The mixture was heated to reflux until all solid was dissolved. About 500 g of toluene was distilled out at atmospheric pressure and to the solution was added 5 g of MEK at the temperature 112°C and the mixture was cooled to -5°C within 3h.

[0118] Recrystallized Saflufenacil was filtered and rinsed with 35 g of cooled toluene. Final material was dried at 60-70°C to obtain Saflufenacil with assay more than 97 % and yield 83%. The saflufenacil contained less than 0.4 w / w% of demethylated saflufenacil and no detectable amount of the decomposition compound of Formula (VI) as described in WO2023 / 232507.

[0119] The mother liquor from the first crystallization contained only about 3.5% of produced saflufenacil. That means that the crystallization process, including the removal of phase transfer catalyst, was extremely efficient. In WO2023 / 232507 about 7% to 10% of the saflufenacil remained in the mother liquor after crystallization. The remaining saflufenacil and starting material were further recovered in two steps, a recovery of demethylated Saflufenacil and Saflufenacil from mother liquors of crystallization and recrystallization, and recovery of the "second crop".

[0120] Saflufenacil and Saflufenacil from mother liquors of crystallization and

[0121] To said mother liquor of the crude material, 10 % aq. NaHCCh was added to adjust pH=6.8-7.0 at room temperature. After stirring for 10 min the phases were separated and aqueous phase containing about 1.3 g of demethylated saflufenacil (2.7 mmol, 1.3% with respect to that initially added and more than 95% of that present in the mother liquor) and 0.7 g of Saflufenacil (1.4 mmol, 0.7% with respect to the starting material) together with mother liquor from recrystallization, containing about 1.5 % of Saflufenacil with respect to the starting material and very small amount of impurities, were delivered to the next batch of synthesis. The organic phase was delivered to the next step.

[0122] Recovery of a "second crop" Saflufenacil from mother liquor after recovery of demethylated saflufenacil The mother liquor (organic phase) of the previous phase was mixed with 50 g of water and 15 % aq. NaOH was dropped into the mixture to adjust pH=8.8-9.0 at the temperature 5 - 10°C. After stirring for 10 min at the same temperature the phases were separated and the aqueous phase was fed to the excess of cooled 15 % aq. solution of HCI with good mixing and keeping the temperature between 5 and 10°C. Saflufenacil precipitated from the aqueous solution as a crystal product with a purity about 75 % and a content of demethylated saflufenacil below 1 % . Yield of Saflufenacil in this "second crop" material about 2.5 %. This "second crop" material may be collected from a few batches and easily recrystallized to obtain a saflufenacil with appropriate quality.

[0123] Recovery of BzC and resin regeneration

[0124] To a four-neck flask were added ion exchanged resin containing BzC, 80 g MEK and 10 g of 30% HCI. The mixture was stirred for 0.5h at room temperature and filtered. Regenerated resin was used on the next batch of synthesis.

[0125] Liquid phase was concentrated to recover about 65 % of BzC for the next batch. Thus, in addition to the efficiency in the crystallization, the process described herein recovers part of BzC, facilitating subsequent waste management.

[0126] Example 2: Use as part of the starting materials of phase transfer catalyst, demethylated Saflufenacil and Saflufenacil recovered from previous batches. To a four-neck flask were added 412 g of toluene recovered from the first batch, 146 g of recovered and 32 g of fresh methyl ethyl ketone (MEK), 98.7 g (0.2 mol) of demethylated saflufenacil, 95 g of 3 % aqueous solution of NaH2PO4, aqueous solution and mother liquor containing demethylated saflufenacil and Saflufenacil from previous batch, recovered BzC and 3.8 g (0.0048 mol) of 50 % aqueous solution of BzC.

[0127] To the prepared mixture at room temperature with good stirring were added 33.1 g (0.26 mol) of dimethyl sulfate (DMS).

[0128] The reaction mixture was heated to 35-39°C and stirred for lOh. 15% NaOH was added to control pH = 4.2±0.1. After reaction ended to the mixture was added about 15 g (0.12 mol) of 30% HCI to achieve pH below 1.0 and the solution was stirred for 2h at 35-39°C to destroy any unreacted DMS. The reaction mixture was then heated to 65-70°C until all solid dissolved and the aqueous phase was separated.

[0129] To the organic phase was added 95 g of water and pH was adjusted to 4 at 65-70°C with 15% NaOH. To the prepared mixture was added ion exchange resin of macroporous type, styrene-divinylbenzene co-polymer, strong acid in H+ Form in amount containing 0.075 equivalents of sulfonic groups. The mixture was stirred for 2h at 65-70°C with pH control between 3 to 4 by addition of 15% NaOH up to full sorption of BzC.

[0130] The resin was filtered, and aqueous phase was separated at 65-70°C.

[0131] The organic phase was washed with 95 g of water and concentrated at atmospheric pressure. About 470 g of the solvent was distilled out at 100°C to 112°C. To the concentrated solution was added 5 g of MEK at 112°C and the mixture was cooled to -5°C within 3h. Crystallized crude product was filtered and rinsed with 35 g of cooled toluene.

[0132] In another flask were added 590 g of toluene and the above crude product. The mixture was heated to reflux until all solid was dissolved. About 500 g of toluene was distilled out at atmospheric pressure and to the solution was added 5 g of MEK at 112°C and the mixture was cooled to -5°C within 3h.

[0133] Recrystallized Saflufenacil was filtered and rinsed with 35 g of cooled toluene. Final material was dried at 60-70°C to obtain Saflufenacil with assay more than 97 % and yield 86.5 %.

[0134] The same recovery process was followed as in example 1, with analogous results.

[0135] Example 3: first batch. Does not use in the starting materials any phase transfer catalyst, demethylated Saflufenacil nor Saflufenacil recovered from previous batches. Separation of phase transfer catalyst without pH correction.

[0136] To a four-neck flask were added 412 g of toluene, 178 g of methyl ethyl ketone (MEK), 98.7 g (200 mmol) of 2-chloro-5-(2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-l(2H)-yl)-4-fluoro-N-(N-isopropyl-N- methylsulfamoyl)benzamide (demethylated saflufenacil), 95 g of a 3 % aqueous solution of NaHzPC and 10.2 g (15 mmol) of 50 % aqueous solution of Benzalkonium Chloride (BzC).

[0137] To the prepared mixture at room temperature with good stirring were added 33.1 g (260 mmol) of dimethyl sulfate (DMS). The reaction mixture was heated to 35-39°C and stirred for lOh. 15% NaOH was added to control pH at 4.2±0.1.

[0138] After reaction ended to the mixture was added about 15 g (0.12 mol) of 30% HCI to achieve pH below 1.0 and the solution was stirred for 2h at 35-39°C to destroy any unreacted DMS. The reaction mixture was then heated to 65-70°C until all solid (mostly saflufenacil) dissolved, after which the aqueous phase was separated.

[0139] To the organic phase were added 95 g of water and ion exchange resin of macroporous type, styrene- divinylbenzene co-polymer, strong acid in H+ Form in an amount containing 0.075 equivalents of sulfonic groups. The mixture was stirred for 20 min at 65-70°C. Within this time pH went down and was stabilized. The stirring was stopped, and lower aqueous phase was taken out from the flask by vacuum through dip pipe with the filter on the end to prevent exit of ion exchange resin. To the organic phase 95 g of the fresh water were added and the mixture was stirred for 20 min at 65-70°C. Within this time pH went down and was stabilized. The stirring was stopped, and lower aqueous phase was taken out from the flask by vacuum through dip pipe with the filter on the end to prevent exit of ion exchange resin. Such washing with water was repeated overall 4 times up to full sorption of BzC. The resin was filtered, and the organic phase was concentrated at the atmospheric pressure. About 470 g of the solvent was distilled out at the temperature between 100°C and 112°C. To the concentrated solution was added 5 g of MEK at 112°C and the mixture was cooled to -5°C within 3h. Crystallized crude product was filtered and rinsed with 35 g of cooled toluene.

[0140] In another flask were added 590 g of toluene and the above crude product. The mixture was heated to reflux until all solid was dissolved. About 500 g of toluene was distilled out at atmospheric pressure and to the solution was added 5 g of MEK at the temperature 112°C and the mixture was cooled to -5°C within 3h.

[0141] Recrystallized Saflufenacil was filtered and rinsed with 35 g of cooled toluene. Final material was dried at 60-70°C to obtain Saflufenacil with assay more than 97 % and yield 84 %. The saflufenacil contained less than 0.4 % of demethylated saflufenacil and no detectable amount of the decomposition compound of Formula (VI) as described in WO2023 / 232507. The mother liquor from the first crystallization contained only about 3.0 % of produced saflufenacil. That means that the crystallization process, including the removal of phase transfer catalyst, was extremely efficient.

[0142] Recovery of demethylated Saflufenacil and Saflufenacil from mother liquors of crystallization and recrystallization, likewise recovery of BzC and resin regeneration was done as described in Example 1.

[0143] Example 4: first batch. Does not use in the starting materials any phase transfer catalyst, demethylated Saflufenacil nor Saflufenacil recovered from previous batches. Separation of phase transfer catalyst using column with ion exchange resin without pH correction.

[0144] To a four-neck flask were added 412 g of toluene, 178 g of methyl ethyl ketone (MEK), 98.7 g (200 mmol) of 2-chloro-5-(2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-l(2H)-yl)-4-fluoro-N-(N-isopropyl-N- methylsulfamoyl)benzamide (demethylated saflufenacil), 95 g of a 3 % aqueous solution of NaHzPC and 10.2 g (15 mmol) of 50 % aqueous solution of Benzalkonium Chloride (BzC).

[0145] To the prepared mixture at room temperature with good stirring were added 33.1 g (260 mmol) of dimethyl sulfate (DMS). The reaction mixture was heated to 35-39°C and stirred for lOh. 15% NaOH was added to control pH at 4.2±0.1.

[0146] After reaction ended to the mixture was added about 15 g (0.12 mol) of 30% HCI to achieve pH below 1.0 and the solution was stirred for 2h at 35-39°C to destroy any unreacted DMS. The reaction mixture was then heated to 65-70°C until all solid (mostly saflufenacil) dissolved, after which the aqueous phase was separated.

[0147] To the organic phase were added 95 g of water and intensive stirring was resumed at the temperature 65- 70°C.

[0148] To the flask were connected column containing ion exchange resin of macroporous type, styrene- divinylbenzene co-polymer, strong acid in H+ Form in an amount containing 0.075 equivalents of sulfonic groups. The column was heated through the jacked to the temperature 65-70°C.

[0149] Inlet of the circulating pump was connected to the dip pipe inside of the flask and outlet to the upper side of the column. Circulating of the two-phase mixture in the flask through the column was done with the rate about 2 liters per hour. The mixture was circulated for 20 min at 65-70°C. Within this time pH went down and was stabilized. The circulating and the stirring were stopped, the phases in the flask were separated. Acidic aqueous phase was taken out from the flask and to the organic phase 95 g of the fresh water were added. First intensive stirring and after that recirculating of the mixture through the column were resumed. Such circulating cycles was repeated overall 4 times up to full sorption of BzC. After forth phase separation the organic phase was concentrated at the atmospheric pressure. About 470 g of the solvent was distilled out at the temperature between 100°C and 112°C. To the concentrated solution was added 5 g of MEK at 112°C and the mixture was cooled to -5°C within 3h. Crystallized crude product was filtered and rinsed with 35 g of cooled toluene.

[0150] In another flask were added 590 g of toluene and the above crude product. The mixture was heated to reflux until all solid was dissolved. About 500 g of toluene was distilled out at atmospheric pressure and to the solution was added 5 g of MEK at the temperature 112°C and the mixture was cooled to -5°C within 3h.

[0151] Recrystallized Saflufenacil was filtered and rinsed with 35 g of cooled toluene. Final material was dried at 60-70°C to obtain Saflufenacil with assay more than 97 % and yield 84.5 %. The saflufenacil contained less than 0.4 % of demethylated saflufenacil and no detectable amount of the decomposition compound of Formula (VI) as described in WO2023 / 232507.

[0152] The mother liquor from the first crystallization contained only about 2.5 % of produced saflufenacil. That means that the crystallization process, including the removal of phase transfer catalyst, was extremely efficient.

[0153] Recovery of demethylated Saflufenacil and Saflufenacil from mother liquors of crystallization and recrystallization, was done as described in Example 1.

[0154] Recovery of BzC and resin regeneration.

[0155] The column with ion exchange resin was disconnected from the reaction flask and connected to the pure empty two-neck flask. Inlet of the pump was introduced to the vessel containing solution of sulfuric acid in MEK and about 100 ml of the solution containing 7.5 g of sulfuric acid were delivered through the column in one pass with the rate about 130 ml / h.

[0156] Column with regenerated resin was used on the next batch of synthesis. Liquid phase was concentrated to recover more than 90 % of BzC for the next batch. Thus, in addition to the efficiency in the crystallization, the process described herein recovers most of BzC, facilitating subsequent waste management.

[0157] Example 5: second batch. Use as part of the starting materials of phase transfer catalyst, demethylated Saflufenacil and Saflufenacil recovered from previous batches. Separation of phase transfer catalyst using column with ion exchange resin without pH correction in one pass delivery.

[0158] To a four-neck flask were added 412 g of toluene recovered from the previous batch, 178 g of recovered methyl ethyl ketone (MEK), 98.7 g (200 mmol) of 2-chloro-5-(2,6-dioxo-4-(trifluoromethyl)-3,6- dihydropyrimidin-l(2H)-yl)-4-fluoro-N-(N-isopropyl-N-methylsulfamoyl)benzamide (demethylated saflufenacil), 95 g of a 3 % aqueous solution of NaHzPC , aqueous solution and the last mother liquor containing demethylated saflufenacil and Saflufenacil from previous batch, recovered BzC and 1 g (1.5 mmol) of 50 % aqueous solution of Benzalkonium Chloride (BzC).

[0159] To the prepared mixture at room temperature with good stirring were added 33.1 g (260 mmol) of dimethyl sulfate (DMS). The reaction mixture was heated to 35-39°C and stirred for lOh. 15% NaOH was added to control pH at 4.2±0.1.

[0160] After reaction ended to the mixture was added about 15 g (0.12 mol) of 30% HCI to achieve pH below 1.0. The reaction mixture was then heated to 65-70°C and stirred for 2h to destroy any unreacted DMS. The stirring was stopped, and the aqueous phase was separated. The organic phase was washed with additional 95 g of water at the same temperature.

[0161] To the organic phase were added 150 g of water and intensive stirring was resumed at the temperature 65-70°C.

[0162] To another (receiving) flask was connected column containing ion exchange resin of macroporous type, styrene-divinylbenzene co-polymer, strong acid in H+ Form in an amount containing 0.125 equivalents of sulfonic groups. The column was heated through the jacked to the temperature 65-70°C.

[0163] Inlet of the delivering pump was connected to the dip pipe inside of the flask with reaction mass and outlet to the upper side of the column. Delivery of the two-phase mixture to the receiving flask through the column was done with the rate about 130 ml per hour. After delivery the mixture aqueous phase was separated from the organic phase at the temperature 65-70°C. Organic phase was concentrated at the atmospheric pressure. About 500 g of the solvent was distilled out at the temperature between 100°C and 112°C. To the concentrated solution was added 5 g of MEK at 112°C and the mixture was cooled to -5°C within 3h. Crystallized crude product was filtered and rinsed with 35 g of cooled toluene.

[0164] In another flask were added 590 g of toluene and the above crude product. The mixture was heated to reflux until all solid was dissolved. About 500 g of toluene was distilled out at atmospheric pressure and to the solution was added 5 g of MEK at the temperature 112°C and the mixture was cooled to -5°C within 3h.

[0165] Recrystallized Saflufenacil was filtered and rinsed with 35 g of cooled toluene. Final material was dried at 60-70°C to obtain Saflufenacil with assay more than 97 % and yield 88 %. The saflufenacil contained less than 0.4 % of demethylated saflufenacil and no detectable amount of the decomposition compound of Formula (VI) as described in WO2023 / 232507. The mother liquor from the first crystallization contained only about 1.8 % of produced saflufenacil. That means that the crystallization process, including the removal of phase transfer catalyst, was extremely efficient.

[0166] Recovery of demethylated Saflufenacil and Saflufenacil from mother liquors of crystallization and recrystallization, was done as described in Example 1.

[0167] Recovery of BzC and resin regeneration was done as described in Example 4.

[0168] Column with regenerated resin was used on the next batch of synthesis.

Claims

CLAIMS1 - A process for the preparation of saflufenacil comprising reacting 2-chloro-5-(2,6-dioxo-4- (trifluoromethyl)-3,6-dihydropyrimidin-l(2H)-yl)-4-fluoro-N-(N-isopropyl-N-methylsulfamoyl)benzamide with a methylating agent in the presence of a phase transfer catalyst to obtain a final reaction mixture comprising saflufenacil and the phase transfer catalyst, characterized in that the phase transfer catalyst is removed or partially removed before separating or purifying saflufenacil.2.- The process of claim 1 comprising(a) reacting 2-chloro-5-(2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-l(2H)-yl)-4-fluoro-N-(N- isopropyl-N-methylsulfamoyl)benzamide with a methylating agent in the presence of a phase transfer catalyst to obtain a final reaction mixture comprising saflufenacil and the phase transfer catalyst; and(b) removing or partially removing the phase transfer catalyst during the subsequent workup from the final reaction mixture obtained in the previous step.3.- The process of any of claims 1 or 2, wherein the phase transfer catalyst is removed or partially removed in an ion exchange process by contacting the mixture with an ion exchange resin, an ion exchange column or an ion exchange membrane.4.- The process of claim 3 wherein the ion exchange resin is a Strong acid (SAC) cation exchange resin.5.- The process of any of claims 3 or 4, wherein the ion exchange resin comprises a support matrix of styrene-divinylbenzene co-polymer.6.- The process of any of claims 3 to 5, wherein the ion exchange resin comprises sulfonate groups, polyAMPS groups (poly(2-acrylamido-2-methyl-l-propanesulfonic acid)) or a mixture thereof.7.- The process of any of claims 3 to 6, wherein the pH of the water phase during the ion exchange process is maintained between 1 and 6, preferably, between 2 and 5, preferably between 2.5 and 4.5, preferably between 3 and 4, by addition of a base or a buffer.8.- The process of any of claims 3 to 6, wherein the pH of the water phase during the ion exchange process is not corrected, and it is allowed to decrease.9.- The process of claim 1 or any of claims 2 to 8, wherein the phase transfer catalyst is selected from the group consisting of phosphonium salts, quaternary ammonium salts, crown ether, polyglycols and mixtures thereof.10.- The process of claim 9, wherein the phase transfer catalyst is a quaternary ammonium salt of formula (I)(R1)(R2)(R3)(R4)N+X" (I) whereinR1and R2are independently selected from the group consisting of Ci-C8linear alkyl groups, C2-C8(linear) alkenyl groups;R3is selected from the group consisting of C4-C30 linear alkyl groups, C4-C30 alkenyl groups;R4is selected from the group consisting of C4-C30 (linear) alkyl groups, C6-Ci5aryl and C7-Ci5-aryl alkyl; andX is a counter anion selected from the group consisting of halogens, hydrogensulfate, sulfate, hydroxide (OH"), perchlorate, borate and diborate.11.- The process of claim 10, whereinR1and R2are independently selected from the group consisting of C1-C4 alkyl groups;R3is selected from the group consisting of C4-C30 (linear) alkyl groups;R4is selected from the group consisting of C4-C30 (linear) alkyl groups; andX is a counter anion selected from the group consisting of halogens, hydrogensulfate, hydroxide (OH"), perchlorate, borate and diborate.12.- The process of claim 10, whereinR1and R2are independently selected from the group consisting of C1-C4 alkyl groups;R3is selected from the group consisting of C6-C20alkyl groups;R4is selected from the group consisting of C6-Ci5aryl and C7-Ci5-arylalkyl; andX is a counter anion selected from the group consisting of halogens, hydrogensulfate, hydroxide (OH"), perchlorate, borate and diborate.13.- The process of any of the previous claims, comprising crystallizing saflufenacil from the mixture obtained after removing or partially removing the phase transfer catalyst, to obtain solid saflufenacil and a mother liquor.14.- The process of claim 13, wherein the crystallization takes place in the same solvent or solvents used in the reaction to prepare saflufenacil.15.- The process of any of the previous claims, comprising extracting the mother liquor resulting from the crystallization with an aqueous phase having a pH of 7 or less to provide an aqueous phase comprising saflufenacil and demethylated saflufenacil.16.- The process of claim 15, wherein said aqueous phase is added to the reaction in a later batch.

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