Process for the preparation of thiophenones

Abstract

The present invention refers to a process for preparing a thiophen-3-ones by the simultaneous addition of trisubstitued ketones and sulfide or bisulfide anion, followed by the addition of a base. The application further refers to methods of obtaining active ingredients, such as dimethenamid.

Description

[0001] PROCESS FOR THE PREPARATION OF THIOPHENONES

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to the field of synthesis of organic compounds, more specifically to a process for the preparation of thiophenones that are useful in the preparation of dimethenamid.

[0004] BACKGROUND PRIOR ART

[0005] The agrochemical industry is always in the search of more efficient processes for the preparation of its active ingredients (Als). The capability of providing economical and clean synthesis of the active ingredients is one of the key factors determining the commercialization of an active ingredient.

[0006] Dimethenamid is a herbicide belonging to the group of chloroacetamides, that inhibits lipid synthesis. It is included in group 15 of the WSSA classification. It is typically applied on the soil to control a variety of broad-leaved weeds and grasses. It is a chiral molecule having two isomeric forms commonly known as M and P stereoisomers, dimethenamid-P being more biologically active.

[0007] Dimethenamid-P

[0008] Synthetic schemes to prepare dimethenamid typically involve constructing the thiophene ring (typically a thiophen-3-one), followed by incorporating the 2-methoxy-2-propanamine (or 2- methoxyisopropylamine), also known as MOIPA, to finalize by coupling the 2-chloroaceto moiety. One of the key steps is therefore the construction of the thiophen-3-one ring, that exists in two tautomeric forms. thiophen-3-one tautomers

[0009] In the case of dimethenamid, the intermediate needed is 2,4-dimethyl-2,3-dihydrothiophen-3- one (also found in the literature as 2,4-dimethylthiophen-3-one), which can exist as a mixture with its tautomeric form 2,4-dimethyl-3-hydroxythiophenone (also known as 3-thiopheneol). US 5,703,248 discloses the preparation of 2,4-dimethyl-2,3-dihydrothiophen-3-one by reacting l,2,4-trichloro-2-methylpentan-3-one with F S / NaOH (examples 3a and 3d), NajS (example 3b), and NaHS (example 3c), as well as a continuous preparation in the presence of NaHS.

[0010] The processes disclosed in the prior art are not satisfactory and yields can improve. There is therefore in the art a need to provide alternative procedures for obtaining dimethenamid and its intermediate 2,4-dimethyl-2,3-dihydrothiophen-3-one. There is a need for processes that provide 2,4-dimethyl-3-thiophenone more efficiently, for example improving yields, reducing impurities, and / or milder conditions.

[0011] SUMMARY OF THE INVENTION

[0012] The inventors have now realized that the order of addition of the reagents is key to obtain good yields in the reaction between l,2,4-trichloro-2-methylpentan-3-one and sulfide anions, and reduces the impurities, mainly intermolecular coupling products and polymers thereof. In the examples of US 5,703,248 the sulfide anion (H2S, NajS or NaHS) is either, added over 1,2,4- trichloro-2-methylpentan-3-one, or the order of addition is not specified. The inventors observed that the yield was limited by intermolecular coupling products which lead to dimmers, oligomer and polymeric by-products. Among other possible solutions, the inventors tested inverting the order and confirmed that adding l,2,4-trichloro-2-methylpentan-3-one over a solution of the sulfide anion does not solve the problem, and even further reduces the yield. The research done by the inventors shows however that the simultaneous addition of both compounds surprisingly improves the yield.

[0013] Thus, a first aspect of the invention is a process for preparing a 2,3-dihydrothiophen-3-one compound of formula (I), wherein each of R1and R2is independently selected from the group consisting of hydrogen, Ci-

[0014] C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, Cg-Cis aryl, C2-C15 heterocyclyl and C7-C15 arylalkyl; the process comprising

[0015] (i) reacting a sulfide or bisulfide anion with a compound of formula (II) wherein each of L1, L2and L3is independently selected from the group consisting of leaving groups; and

[0016] R1and R2are as defined above; in the presence of a solvent system comprising an organic solvent; and

[0017] (ii) reacting the mixture resulting from step (i) with a base; wherein the sulfide anion or bisulfide anion and the compound of formula (II) are added simultaneously.

[0018] The inventors have found that the process increases the yield, and reduces intermolecular byproducts and oligomer / polymer formation. Also, the amount of intermediate species and byproducts is reduced, for example, the thiophenone wherein L3still has not undergone the elimination, also referred to as L3-(l), or the thiophene with no double bonds, also referred to as 2H-(I):

[0019] L3-(l) 2H-(I) wherein R1, R2and L3are as defined elsewhere in the present document.

[0020] The compound of formula (I) encompasses the thiophen-3-one intermediate necessary for preparing dimethenamid, 2,4-dimethyl-2,3-dihydrothiophen-3-one. It is therefore a further aspect of the invention a process for preparing dimethenamid, the process comprising preparing a compound of formula (I) wherein R1and R2are methyl following the process defined herein, and then transforming said compound of formula (I) into dimethenamid. The preparation of dimethenamid can be achieved in different ways. The compound of formula (I) (2,4-dimethyl- 2,3-dihydrothiophen-3-one) can be reacted with l-methoxy-2-propylamine to produce N-(l- methoxyprop-2-yl)-2,4-dimethylaminothiophene, which can then be reacted with the acyl chloride of 2-chloroacetate to yield dimethenamid. Examples of this procedure and other alternative schemes to dimethenamid are described in US 5,703,248, EP210320, EP296463, US2011077418, CN108299221 or CN113024505.

[0021] DETAILED DESCRIPTION OF THE INVENTION

[0022] Definitions

[0023] In the present document the following terms are given the meaning below.

[0024] The compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon, or the replacement of a nitrogen by a15N-enriched nitrogen, or the replacement of a fluorine by a19F-enriched fluorine are within the scope of this invention.

[0025] The compounds of formula (I) exist as two tautomeric forms

[0026] The proportion between both tautomeric forms depends on different factors. For the purposes of the present application, they are both considered equivalent.

[0027] The term "C1-C12 alkyl" means a linear or branched saturated hydrocarbon chain radical having no multiple bonds and having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Suitable groups include, but are not limited to alkyl groups such as methyl, ethyl, propyl (e.g. n-propyl or / so-propyl), butyl (e.g. n-butyl, t-butyl, sec-butyl), pentyl (e.g. 1-methylpentyl, 3-methylpentyl, n-pentyl), hexyl, octyl, or dodecyl.

[0028] The term "C2-C12 alkenyl" means a linear or branched hydrocarbon chain radical having one or more carbon-carbon double bonds therein and having from two to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Suitable alkenyl groups include, but are not limited to alkenyl groups such as vinyl, allyl, butenyl (e.g. 1-butenyl, 2- butenyl, 3-butenyl), pentenyl (e.g. 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl), hexenyl (e.g. 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl), butadienyl, pentadienyl (e.g. 1,3- pentadienyl, 2,4-pentadienyl), hexadienyl (e.g. 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, 2,5-hexadienyl), 2-ethylhexenyl (e.g. 2-ethylhex-l-enyl, 2-ethylhex-2-enyl, 2- ethylhex-3-enyl, 2-ethylhex-4-enyl, 2-ethylhex-5-enyl), 2-propyl-2-butenyl, 4,6-Dimethyl-oct-6- enyl.

[0029] The term "C2-C12 alkynyl" means a linear or branched hydrocarbon chain radical having one or more carbon-carbon triple bonds therein and from two to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. The triple bond of an alkynyl group can be unconjugated or conjugated to another unsaturated group. Suitable alkynyl groups include, but are not limited to alkynyl groups such as ethynyl, propynyl (e.g. 1-propynyl, 2-propynyl), butynyl (e.g. 1-butynyl, 2-butynyl, 3-butynyl), pentynyl (e.g. 1-pentynyl, 2-pentynyl, 3-pentynyl, 4- pentynyl), hexynyl (e.g. 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl), methylpropynyl, 3-methyl-l-butynyl, 4-methyl-2-heptynyl , and 4-ethyl-2-octynyl.

[0030] "Cg-Cis Aryl" refers to a hydrocarbon moiety having six to fifteen carbon atoms and at least one aromatic hydrocarbon structure, such as phenyl, naphthyl or anthracyl.

[0031] "C7-C15 Arylalkyl" refers to an aryl group linked to the rest of the molecule by an alkyl group, such as benzyl and phenethyl.

[0032] "C2-C15 Heterocyclyl" refers to a stable 3- to 16- membered ring which consists of carbon atoms (between 2 and 15) and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulphur, preferably a 4- to 8-membered ring with one or more heteroatoms, more preferably a 5- or 6-membered ring with one or more heteroatoms. For the purposes of this invention, the heterocycle may be a monocyclic, bicyclic or tricyclic ring system, which may include fused ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidised; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated or aromatic. Examples of such heterocycles include, but are not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, or tetrahydrofuran.

[0033] "Leaving group" in the context of the present application refers to atoms or groups of atoms that are displaced by sulfide anions (S2j or by a bisulfide anion (R-Sj under reaction conditions. These are SN2 or SN1 type reactions for which the skilled person can find suitable reagents. Sulfides are considered any salt that contains an S2' anion, for example sodium sulfide (Na2S), which is commercialized in different solvation degrees, hydrogen sulfide H2S (usually used in the presence of a base such as NaOH), (Nl- hS, or K2S. Bisulfides are considered salts containing the HS' group. The reaction described herein proceeds first through an intermolecular reaction in which a sulfide displaces one of the leaving groups L1or L2in the compound of formula (II). The resulting RS' specie displaces the remaining L1or L2in an intramolecular reaction to close the ring. In the case of performing the reaction with a bisulfide, the bisulfide first displaces one of the leaving groups L1or I in the compound of formula (II) in an intermolecular reaction. The resulting RSH group is transformed by a base into an RS- specie that displaces the remaining L1or L2in an intramolecular reaction to close the ring. Examples of leaving groups are halogens, for example, fluor, chlorine, bromo or Iodide, chlorine being the most frequent. Other leaving groups can be methoxy or Sulfonic esters, for example, tosylate (TsO-, -OSO2-p-toluene), mesylate (MsO-, -OSO2-Me) or triflates (TfO-, -OSO2-CF3). The skilled person can find other examples in textbooks or reference books, such as, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. For the completion of the reaction, it is necessary that L3is eliminated together with one of the hydrogens in alpha position (that is, one of the hydrogen atoms attached to the carbon atom initially holding L2). This is accomplished in the presence of a basic medium. Such elimination can take place after or at the same time the ring is being closed.

[0034] The reaction does not necessarily require special equipment and any vessel typically used for chemical reactions should be appropriate. In case some pressure is expected to build up, autoclave vessels or other measures to deal with pressure can be used. The process can run in batch, a semi-batch or a continuous mode, preferably in batch mode.

[0035] The reaction is preferably carried out in an inert atmosphere, e.g. under an argon or nitrogen atmosphere.

[0036] In Step (i) a sulfide or bisulfide anion is reacted with a compound of formula (II) as defined above. Typically, the process comprises preparing a first solution (e.g. in water, or in a water-soluble organic solvent or in a mixture of both) of the sulfide or bisulfide anion, and a second solution of the compound of formula (II) (e.g. in water, or in a water-soluble organic solvent or in a mixture of both). The first and second solutions are then fed to a recipient (e.g. flask or reactor) which typically already contains a solvent and other optional additives. The recipient may contain means for controlling the temperature, the pressure, pH and other variables of the reaction. For example, cooling / heating means are typically used to cool the reaction mixture in exothermic steps and to heat when required.

[0037] For example, R1and R2are each independently selected from the group consisting of Ci-Cg alkyl groups, for example C1-C3 alkyl groups, more preferably ethyl or methyl. It is preferred that R1and R2are both methyl, that is, so as to provide the compound of formula (I) 2,4-dimethyl-2,3- dihydrothiophen-3-one.

[0038] The leaving groups L1, L2and L3can be any group that it is displaced by the sulfide or the bisulfide reagent, for example, a halogen such as chloride, bromine or iodide. Any or all of the leaving groups L1, L2and L3can be the same or different, although being all the same is more practical and it is therefore a preferred option. For example, L1, L2and L3or are all bromine, or are all iodide, or are all chlorine, typically, all chlorine.

[0039] The compounds of formula (II) can be prepared according to methods known in the literature, for example US 5,703,248. Sulfide and bisulfide anions are known in the art and are available from different vendors.

[0040] The temperature in step (i) is typically maintained between -10°C and 30°C, for example, between -5°C and 25°C, for example between 0°C and 25°C, or between 10°C and 25°C or between 10°C and 15°C.

[0041] The reaction can proceed in the presence of a polar organic solvent. Examples of polar organic solvents that can be used are ethers, alcohols, such as methanol or ethanol, acetonitrile, ethyl acetate, DMF, or DMSO. It is preferred that the organic solvent is partially soluble in water, for example, at least 5% soluble in water at 25°C. It is also possible to perform the reaction in the presence of an organic solvent and water, wherein the organic solvent is preferably at least partially soluble in water. Therefore, the solvent system can be a mixture of an alcohol and water, for example, Ci-Cg-alcohol, for example a C1-C4 alcohol. Solvent systems that are particularly preferred are the combinations of water with one of methanol, ethanol, 1-propanol, 2-propanol or pentanol. The proportion between the organic solvent and water is not particularly relevant. The main purpose of water is to dissolve the disulfide anion, and the organic solvent helps solubilize the compounds of formula (I) and the compound of formula (II), the whole solvent system surprisingly preventing the formation of oligomers and polymers and thus contributing to increasing the yield. The volume proportion between the organic solvent and water can be comprised between 10:1 and 1:10, for example between 8:1 and 1:8 or between 7:1 and 1:5 or between 5:1 and 1:2.

[0042] The theoretical molar proportion between the sulfide or bisulfide anions and the compound of formula (II) is 1:1. Each molecule of sulfide anion reacts with one molecule of compound of formula (II). The present reaction typically proceeds with an excess of sulfide or bisulfide anion, and therefore typical molar proportions between the total sulfide or bisulfide anion and the total compound of formula (II) (S27HS :compound of formula (II)) added are between 5:1 and 1:1, for example between 3:1 and 1:1 or between 2:1 and 1:1 or between 1.7:1 and 1:1, or between 1.4:1 and 1:1 or between 1.25:1 to 1:1 or between 1.2:1 and 1:1 or between 1.2:1 and 1.1:1. Step (i) may comprise the simultaneous addition of at least 1 equivalent of sulfide or bisulfide, for example 1 to 1.5 equivalent amounts. Once the simultaneous addition is complete, a small amount of additional (e.g. 0.05-0.5 equivalents, or 0.05-0.2 equivalents) sulfide or bisulfide may be added. The sulfide or bisulfide anions and the compound of formula (II) are added simultaneously over a period of time, rather than one being added over a the other. Typically, the sulfide or bisulfide is dissolved in a solvent such as an alcohol (e.g. methanol), water or a mixture of both, and the compound of formula (II) in the same or in a different solvent. In a typical setup both are added at the same time at a rate that approximately maintains the molar proportion between the sulfide or bisulfide anion and the compound of formula (II). The actual rate of addition depends on the specific conditions (scale, equipment available, temperature). The addition of both can take a few minutes or several hours. Under normal conditions both are added over a period of time of between 1 minute and 48 hours, for example between 10 minutes and 12 hours or between 20 minutes and 8 hours, for example between 1 and 4 hours.

[0043] To better control the reaction and ensure the maximum consumption of the compound of formula (II), step (i) can be divided into two sub-steps, wherein step (ia) comprises the simultaneous addition of the sulfide or bisulfide anion and the compound of formula (II) over a period of between 1 minute and 24 hours, for example between 10 minutes and 12 hours or between 20 minutes and 8 hours, at a temperature between -10°C and 20°C, for example, between -5°C and 15°C, for example between 5°C and 15°C, or between 10°C and 15°C; and step (ib) comprises reacting the mixture resulting from step (ia) for a period between 1 minute and 24 hours at a temperature between 0°C and 70°C or between 5°C and 25°C or between 10°C and 25°C, until most of the compound of formula (II) has been consumed, for example until more than 95% of the initial compound of formula (II) has been consumed.

[0044] The sulfide or bisulfide anion can be any compound that contains an S2-anion, for example sodium sulfide (NajS), which is commercialized in different solvation degrees, hydrogen sulfide H2S (usually in the presence of a base such as NaOH), (NF hS, NaHS, or K2S, preferably, selected from the group consisting of sodium sulfide (Na2$), sodium hydrogen sulfide (NaHS) and mixtures thereof. Sulfide or bisulfide anion are commercially available. The sulfide or bisulfide anion can be added neat or more typically in a solution in order to facilitate the simultaneous addition with the compound of formula (II) in the correct dosage.

[0045] Step (ii) is typically triggered when most of the compound of formula (II) is consumed. This can be monitored through the usual means, for example, by submitting samples to HPLC. At this stage the reaction mixture contains some compound of formula (I) and many intermediates, such as the compounds of formula L3-( I ) or of formula 2 H -( I ) described elsewhere in the present document. In step (ii) of the process the pH is increased to ensure completion of the reaction. This is achieved by addition of a base. This step typically comprises adding the base to the already existing mixture to maintain the pH within optimal ranges. The pH in step (ii) is typically maintained between 7 and 12 or between 7 and 13, for example between 8 and 12, for example between 7 and 11, for example between 9 and 11.5, for example between 10 and 11.5 or between 10 and 11, for example between 10 and 13 or between 11 and 13, for example, about 12-12.5. A pH above 12 in this stage reduces the amount of L3-(l) or 2H-(I) (e.g. 2,4- Dimethyldihydrothiophen-3(2H)-one). The base can be an inorganic or an organic base, for example an inorganic base, such as an alkaline or an alkaline-earth hydroxide, for example, LiOH, NaOH, KOH, or carbonates and bicarbonates, such as NajCOs, NaHCOs, K2CO3, or KHCO3, preferably NaOH or KOH, preferably NaOH. Examples of organic bases can be primary, secondary or tertiary amines, such as methoxypropylamine, dimethylamine or triethylamine. The pH can be continuously monitored using known equipment, such as pH-meters, of which there are multiple commercial options.

[0046] The temperature in step (ii) can be the same as in step (i), but it is typically increased to a temperature between 30°C and 70°C, for example, between 35°C and 60°C, for example between 35°C and 50°C, or between 40°C and 50°C or between 40°C and 45°C. The temperature can also be comprised between 50°C and 70°C or between 55°C and 70°C.

[0047] The reaction time in step (ii) depends on other reaction conditions such as temperature or concentration of the reagents. Considering these factors step (ii) can take from 1 minute to several hours or days, for example 48 hours, although typical times take from 10 minutes to 24 hours. The progress of the reaction can be followed using customary techniques (e.g. gas chromatography).

[0048] Step (iii)

[0049] After most of the compound of formula (II) is converted into compound of formula (I), the solvent is typically removed, for example, through distillation, and the pH reduced by addition of an acid (e.g. diluted hydrochloric acid or sulfuric acid). The pH is typically 7 to 10, for example, 7 to 9 or 7.5 to 9 or 7.5 to 8.5. At this pH the compound of formula (I) can be extracted using common organic solvents, such as ethers (e.g. ethyl ether or tert-butyldimethyl ether).

[0050] The resulting compound of formula (I) can be then purified following standard conditions (distillation, gel chromatography, recrystallization, etc...), or can be used directly for the next step.

[0051] The present disclosure has described how different variables of the process can be tuned within certain ranges. The present disclosure also encompasses combinations of different ranges of these variables. For example, the skilled person can recognize that the present disclosure covers a process for preparing a compound of formula (I), as defined elsewhere in the present specification, the process comprising

[0052] (i) reacting a sulfide or bisulfide anion with a compound of formula (II), as defined elsewhere in the present specification, in the presence of a solvent system comprising an organic solvent; and

[0053] (ii) reacting the mixture resulting from step (i) with a base; wherein the sulfide or bisulfide anion and the compound of formula (II) are added simultaneously.

[0054] Also, the process can comprise

[0055] (i) reacting a sulfide or bisulfide anion with a compound of formula (II), as defined elsewhere in the present specification in the presence of a solvent system comprising an organic solvent and water; and

[0056] (ii) reacting the mixture resulting from step (i) with a base; wherein the sulfide or bisulfide anion and the compound of formula (II) are added simultaneously; and wherein each of R1and R2is independently selected from the group consisting of C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl; and wherein each of L1, L2and L3is independently selected from the group consisting of fluor, chlorine, bromo or Iodide, methoxy, tosylate (TsO-, -OSCh-p-toluene), mesylate (MsO-, - OSO2-Me) and triflates (TfO -OSO2-CF3).

[0057] For example, the skilled person can recognize that the present disclosure covers a process for preparing a compound of formula (I), as defined elsewhere in the present specification, the process comprising

[0058] (i) reacting a sulfide or bisulfide anion selected from the group consisting of sodium sulfide (Na2$), hydrogen sulfide H2S (usually used in the presence of a base such as NaOH), (NF hS, and K2S with a compound of formula (II), as defined elsewhere in the present specification, in the presence of a solvent system comprising an organic solvent; and

[0059] (ii) reacting the mixture resulting from step (i) with a base; wherein the sulfide or bisulfide anion and the compound of formula (II) are added simultaneously.

[0060] For example, the process comprises

[0061] (i) reacting a sulfide or bisulfide anion selected from the group consisting of sodium sulfide (Na2$) with a compound of formula (II), as defined elsewhere in the present specification, in the presence of a solvent system comprising an organic solvent; and (ii) reacting the mixture resulting from step (i) with a base selected from the group consisting of LiOH, NaOH, KOH, Na2CO3, NaHCO3, K2CO3, and KHCO3; wherein the sulfide or bisulfide anion and the compound of formula (II) are added simultaneously.

[0062] For example, the process comprises

[0063] (i) reacting sodium sulfide (Na2S) with a compound of formula (II), as defined elsewhere in the present specification, in the presence of a solvent system comprising an organic solvent; and

[0064] (ii) reacting the mixture resulting from step (i) with a base selected from the group consisting of LiOH, NaOH, KOH, Na2CO3, NaHCO3, K2CO3, and KHCO3, at a pH of 8 to 12; wherein the sulfide or bisulfide anion and the compound of formula (II) are added simultaneously; wherein each of R1and R2is independently selected from the group consisting of Ci-Ci2alkyl, C2-Ci2alkenyl, C2-Ci2alkynyl, preferably a Ci-Cg alkyl; and wherein each of L1, L2and L3is independently selected from the group consisting of fluor, chlorine, bromo or Iodide, methoxy, tosylate (TsO-, -OSO2-p-toluene), mesylate (MsO-, - OSO2-Me) and triflates (Tf0‘, -OSO2-CF3).

[0065] For example, the process comprises

[0066] (i) reacting a sulfide or bisulfide anion selected from the group consisting of sodium sulfide (Na2S), sodium hydrogen sulfide (NaHS) and mixtures thereof with a compound of formula (II), as defined elsewhere in the present specification, in the presence of a solvent system comprising an organic solvent and optionally water, at a temperature between -10°C and 30°C; and

[0067] (ii) reacting the mixture resulting from step (i) with a base selected from the group consisting of LiOH, NaOH, KOH, Na2CO3, NaHCO3, K2CO3, and KHCO3, at a pH of 8 to 12, at a temperature between 30°C and 70°C; wherein the sulfide or bisulfide anion and the compound of formula (II) are added simultaneously; wherein each of R1and R2is independently selected from the group consisting of Ci-Ci2alkyl, C2-Ci2alkenyl, C2-Ci2alkynyl, preferably a Ci-Cg alkyl; and wherein each of L1, L2and L3is independently selected from the group consisting of fluor, chlorine, bromo or Iodide, methoxy, tosylate (TsO-, -OSO2-p-toluene), mesylate (MsO-, - OSO2-Me) and triflates (TfO -OSO2-CF3).

[0068] For example, the process comprises (i) reacting a sulfide or bisulfide anion with a compound of formula (II), as defined elsewhere in the present specification, in the presence of a solvent system comprising an organic solvent and optionally water, at a temperature between -10°C and 30°C; and

[0069] (ii) reacting the mixture resulting from step (i) with a base, at a pH of 8 to 12, at a temperature between 30°C and 70°C; wherein the sulfide or bisulfide anion and the compound of formula (II) are added simultaneously; wherein each of R1and R2is independently selected from the group consisting of C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, preferably a Ci-Cg alkyl; and wherein each of L1, L2and L3is independently selected from the group consisting of fluor, chlorine, bromo or Iodide, methoxy, tosylate (TsO-, -OSCh-p-toluene), mesylate (MsO-, - OSO2-Me) and triflates (TfO -OSO2-CF3).

[0070] For example, the process comprises

[0071] (i) reacting a sulfide or bisulfide anion selected from the group consisting of sodium sulfide (Na2$), sodium hydrogen sulfide (NaHS) and mixtures thereof with a compound of formula (II), as defined elsewhere in the present specification, in the presence of a solvent system comprising an organic solvent and optionally water, at a temperature between -10°C and 30°C; and

[0072] (ii) reacting the mixture resulting from step (i) with a base selected from the group consisting of LiOH, NaOH, KOH, Na2CO3, NaHCO3, K2CO3, and KHCO3, at a pH of 8 to 12, at a temperature between 30°C and 70°C; wherein the sulfide or bisulfide anion and the compound of formula (II) are added simultaneously; wherein each of R1and R2is independently selected from the group consisting of Ci-Cg alkyl groups; and wherein each of L1, L2and L3is independently selected from the group consisting of chlorine, bromo, methoxy, tosylate (TsO-, -OSO2-p-toluene), mesylate (MsO-, -OSO2-Me) and triflates (TfO-, -OSO2-CF3), preferably chlorine.

[0073] For example, the process comprises

[0074] (i) reacting sodium sulfide (Na3S) with a compound of formula (II), as defined elsewhere in the present specification, in the presence of a solvent system comprising an organic solvent and optionally water, at a temperature between -10°C and 30°C; and

[0075] (ii) reacting the mixture resulting from step (i) with a base at a pH of 8 to 12, at a temperature between 30°C and 70°C; wherein sodium sulfide (Na3S) and the compound of formula (II) are added simultaneously; wherein each of R1and R2is independently selected from the group consisting of Ci-Cg alkyl groups; and wherein each of L1, L2and L3is chlorine.

[0076] For example, the process is a process for preparing 2,4-dimethyl-2,3-dihydrothiophen-3-one that comprises

[0077] (i) reacting a sulfide or bisulfide anion selected from the group consisting of sodium sulfide (NajS), sodium hydrogen sulfide (NaHS) and mixtures thereof with a compound of formula (II), as defined elsewhere in the present specification wherein each of R1and R2is methyl, preferably l,2,4-trichloro-2-methylpentan-3-one, in the presence of a solvent system comprising an organic solvent and optionally water, at a temperature between -10°C and 30°C; and

[0078] (ii) reacting the mixture resulting from step (i) with a base at a pH of 8 to 12, at a temperature between 30°C and 70°C; wherein the sulfide or bisulfide anion and the compound of formula (II) are added simultaneously.

[0079] EXAMPLES

[0080] Example 1: Preparation of 2,4-dimethyl-2,3-dihydrothiophen-3-one (compound of formula (I)) from l,2,4-trichloro-2-methylpentan-3-one (compound of formula

[0081] Step (i)

[0082] A four-neck flask was equipped with a thermometer, a pH meter, a magnetic stirrer and flushed with nitrogen. The flask was charged with methanol (13 mL) and degassed and refilled with nitrogen. A solution of Na2S.9H2O (6.72 g, 0.028 mol) in H2O (10.0 g) and a solution of 1,2,4- trichloro-2-methylpentan-3-one (5.00 g, 0.023 mol) in methanol (2 mL) were simultaneously added over a period of 1 hour at 20-25°C (Na2S:compound of formula (ll)= 1.2:1). Pumps were used in both cases to dose the solutions. After the addition had finished, the pH was around 8.3. The reaction mixture was stirred for another 1 hr at 20-25°C, after which period the pH had dropped to around 7.1 and less than 2% of the initial l,2,4-trichloro-2-methylpentan-3-one was left.

[0083] Step (ii)

[0084] Then, pH was adjusted to 11-11.5 by adding 15% NaOH at 20-25 °C. The reaction mixture was stirred 0.5 hr at 20-25 °C and while maintaining pH at 10.5-11 by adding 15% NaOH when needed. The reaction mixture was then brought to 40°C and stirred for 1 hr while maintaining the pH at 10.5-11. Step (Hi)

[0085] The reaction mixture was then cooled to a temperature below 35°C, and the methanol removed by distillation under vacuum under nitrogen (40-50 mbar). Once distillation was complete, the flask was filled with nitrogen again. 10 mL of water and 20 mL of MTBE were added, and pH was adjusted to 8-8.5 by dropwise addition of 2N HCI at 20-30°C. The mixture was transferred to a separation funnel filled with nitrogen and the upper organic layer collected. The aqueous phase was extracted again with MTBE (20 mL). The combined organic layers were concentrated under vacuum (25-35 mbar, 20-25°C) to provide crude 2,4-dimethyl-2,3-dihydrothiophen-3-one (5.90 g, yield 83%).

[0086] If any water remained, it was removed under higher vacuum (in larger scale setups, it can be simply separated). Crude 2,4-dimethyl-2,3-dihydrothiophen-3-one was distilled (bp. 58°C at 1-2 mbar) and was ready for use in the next step. As can be seen above, all processes were carried out under nitrogen including solvent removal, extraction and phase separation.

[0087] Example 2: Preparation of 2,4-dimethyl-2,3-dihydrothiophen-3-one (compound of formula (I)) from l,2,4-trichloro-2-methylpentan-3-one (compound of formula (II)) using different addition orders and conditions

[0088] The preparation of 2,4-dimethyl-2,3-dihydrothiophen-3-one (compound of formula (I)) from l,2,4-trichloro-2-methylpentan-3-one (compound of formula (II)) and Na2S -9^0 was repeated following the experimental procedure of Example 1, using the conditions and order of addition shown in Table 1 below.

[0089] Table 1

[0090] In Comparative example 1 (Comp. 1) l,2,4-trichloro-2-methylpentan-3-one (compound of formula (II)) was added over the Na2S-9H2O. In Comparative example 2 (Comp. 2) Na2S-9H2O was added over l,2,4-trichloro-2-methylpentan-3-one (compound of formula (II)). The inventive example A was performed under the same conditions, but with the simultaneous addition of l,2,4-trichloro-2-methylpentan-3-one and Na2S-9H2O. As seen in Table 1 above, the yield improved with the simultaneous addiction of both starting materials. Inventive examples B, C, D, and E used different proportions of reagents, temperatures and pH values, and all still performed better than Comp. 1 or Comp. 2.

[0091] The use of only water as a solvent in Comp. 3 lead to a low yield and many oligomerization and polymerization products, despite the simultaneous addition l,2,4-trichloro-2-methylpentan-3- one (compound of formula (II)) and Na2S-9H2O.

[0092] Example 3: Preparation of 2,4-dimethyl-2,3-dihydrothiophen-3-one (compound of formula (I)) from l,2,4-trichloro-2-methylpentan-3-one (compound of formula (II))

[0093] Step (i)

[0094] A IL four-neck flask was equipped with a temperature pocket, a pH meter, an overhead stirrer, and connected to a Schlenk line and flushed with nitrogen. The flask was charged with methanol (50 mL) and cooled to 5°C with an ice bath. When the reaction mass reached 5°C, a first solution of l,2,4-trichloro-2-methylpentan-3-one (50.0 g, 96% w / w assay) in Methanol (50 mL), and a second solution of Na2S.5H2O (48.8g, 1.2 eq., 98% w / w assay) in Methanol (180 mL) and Water (20.5g) were added simultaneously dropwise under N2. During the addition, the temperature of reaction mass was maintained at 5-20°C (exothermicity was observed). Once the addition of both the solutions was complete, the reaction mass was maintained at 5-20°C for 30 min under N2. Then Na2S.5H2O (4.1g, 0.1 eq., 98% w / w assay) in Methanol (20 mL) and Water (1.7g) was added in the reaction mass under N2. Once addition was complete, the reaction mass maintained at 5-20°C for 30 min under N2.

[0095] Step (ii) Then, the pH of the reaction mass was adjusted to 12-12.5 by addition of 30% NaOH solution at 5-20°C. The reaction mass was then maintained at 5-20°C for lh under nitrogen. The temperature was raised to 40-45°C, pH (12-12.5) of the reaction mass was adjusted by addition of 30% NaOH solution. The color of the reaction mass changed from yellow to orange / brown. The temperature was maintained at 40-45°C for 1 h; during this time the pH of the reaction mass was monitored and maintained at 12-12.5 by addition of a 30% NaOH solution.

[0096] The reaction mass was heated to 60-65°C and maintained at 60-65°C for 1 h; during this time the pH of the reaction mass was monitored and maintained at 12-12.5 by addition of a 30% NaOH solution. After lh at 60-65°C a sample quenched with 2 N HCI was analyzed by gas chromatography: 2,4-dimethyl-2,3-dihydrothiophen-3-one: 94.4%; 2,4-

[0097] Dimethyldihydrothiophen-3(2H)-one: 1.7%).

[0098] Step (Hi)

[0099] The reaction mixture was then cooled to a temperature below 35°C, and the methanol removed by distillation under vacuum under nitrogen (40-50 mbar). Once distillation was complete, the flask was filled with nitrogen again. When the temperature reached 20-30°C, 2N HCI started was added dropwise until a pH of 7-8 was reached.

[0100] The mixture was transferred to a separation funnel filled with nitrogen and extracted twice with MTBE (100 mL each time). The combined organic layers were concentrated under vacuum (25- 35 mbar, 25-30 °C ) to provide crude 2,4-dimethyl-2,3-dihydrothiophen-3-one (36.5g; assay 71.12%; yield 85.5%).

Claims

CLAIMS1. A process for preparing a compound of formula (I),wherein each of R1and R2is independently selected from the group consisting of hydrogen, Ci-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, Cg-Cis aryl, C2-C15 heterocyclyl and C7-C15 arylalkyl; the process comprising(i) reacting a sulfide or bisulfide anion with a compound of formula (II)wherein each of L1, L2and L3is independently selected from the group consisting of leaving groups; andR1and R2are as defined above; in the presence of a solvent system comprising an organic solvent; and(ii) reacting the mixture resulting from step (i) with a base; wherein the sulfide or bisulfide anion and the compound of formula (II) are added simultaneously.

2. The process according to claim 1, wherein R1and R2are each independently selected from the group consisting of Ci-Cg alkyl groups.

3. The process according to claim 2, wherein R1and R2are both methyl.

4. The process according to any of the previous claims, wherein L1, I and L3are each independently selected from chloride, bromine and iodide.

5. The process according to any of the previous claims, wherein the temperature in step (i) is maintained between -10°C and 30°C.

6. The process according to any of the previous claims, wherein the temperature in step (ii) is maintained between 30°C and 70°C.

7. The process according to any of the previous claims, wherein the pH in step (ii) is maintained between 11 and 13.

8. The process according to any of the previous claims, wherein the pH is maintained in step (ii) by addition of an alkaline or an alkaline-earth hydroxide or carbonates or bicarbonates.

9. The process according to any of the previous claims, wherein step (i) comprises step (ia) comprising the simultaneous addition of the sulfide or bisulfide anion and the compound of formula (II) over a period of between 1 minute and 24 hours, at a temperature between -10°C and 20°C; and step (ib) comprising reacting the mixture resulting from step (ia) for a period between 1 minute and 24 hours at a temperature between 0°C and 30°C.

10. The process according to any of the previous claims, wherein the sulfide or bisulfide anion is selected from the group consisting of sodium sulfide, sodium hydrogen sulfide and mixtures thereof.

11. The process according to any of the previous claims, wherein the process is a batch, a semibatch or a continuous process.

12. The process according to any of the previous claims, wherein the compound of formula (I) is further transformed into dimethenamid, including any of the enantiomers thereof.

13. A process for preparing dimethenamid that comprises preparing a compound of formula (I) as defined in claim 1 wherein R1and R2are methyl following the process defined in any of the previous claims, and then transforming said compound of formula (I) into dimethenamid.

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