Route for preparing thiophenones

Abstract

The present invention refers to a new synthetic process for preparing thiophen-3-ones and to the intermediates of said synthetic process. The application further refers to methods of obtaining active ingredients, such as dimethenamid.

Description

[0001] ROUTE FOR PREPARING 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, also known as 2-methoxyisopropylamine or MOIPA, to finalize by coupling the 2-chloroaceto moiety. One of the key steps is therefore the construction of a 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), or 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-3-thiophenone. There is a need for processes that provide 2,4- dimethyl-3-thiophenone more efficiently, for example improving yields, reducing impurities, and / or providing milder conditions.

[0011] SUMMARY OF THE INVENTION

[0012] The inventors have developed a new strategy to access 2,4-dimethyl-3-thiophenone through a new synthetic route. This new route adds an alternative path to this key intermediate in which many of the intermediates do not require purifications. Also, this new route avoids the use of sensitive reagents, such as hot hydrogen peroxide.

[0013] Thus, a first aspect of the invention is 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 the decarboxylation of a compound of formula (II), and optionally the hydrolysis thereof (i.e. the transformation of compound of formula (II) wherein R3is not hydrogen, into one where R3is hydrogen),

[0014] CD wherein

[0015] R1and R2are as defined above; and

[0016] R3is independently selected from the group consisting of hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, Cg-Cis aryl, C2-C15 heterocyclyl and C7-C15 arylalkyl. By "hydrolysis thereof" it is meant the transformation of compound of formula (II) wherein R3is not hydrogen, into one where R3is hydrogen, that is, the hydrolyzation of the ester moiety into carboxylic acid.

[0017] A further aspect of the invention is a compound of formula (II) as defined above.

[0018] A further aspect of the invention is therefore a process for the preparation of said compound of formula (II) by dehydrating a compound of formula (III), wherein

[0019] R1and R2are as defined above; and

[0020] R3is selected from the group consisting of hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, Cg-Cis aryl, C2-C15 heterocyclyl and C7-C15 arylalkyl.

[0021] A further aspect of the invention is a compound of formula (III) as defined above.

[0022] A further aspect of the invention is therefore a process for preparing said compound of formula

[0023] (III) that comprises reacting a compound of formula (IV) with a compound of formula (V),

[0024] X U d

[0025] (IV) (V) wherein

[0026] R1and R2are as defined above;

[0027] R3is selected from the group consisting of hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, Cg-Cis aryl, C2-C15 heterocyclyl and C7-C15 arylalkyl; and

[0028] X is a halogen atom.

[0029] 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.

[0030] Therefore, a further aspect of the invention is a process for preparing dimethenamid that comprises preparing a compound of formula (I) wherein R1and R2are methyl, following the process defined elsewhere in the present specification, and then transforming said compound of formula (I) into dimethenamid.

[0031] A further aspect of the invention is also the use of a compound of formula (II) for the preparation of dimethenamid.

[0032] A further aspect of the invention is also the use of a compound of formula (III) for the preparation of dimethenamid.

[0033] DETAILED DESCRIPTION OF THE INVENTION

[0034] Definitions

[0035] In the present document the following terms are given the meaning below.

[0036] 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.

[0037] The compounds of formula (I) exist as two tautomeric forms

[0038] The proportion between both tautomeric forms depends on different factors. For the purposes of the present application, they are both considered equivalent.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] "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.

[0043] "C7-C15 Arylalkyl" refers to an aryl group linked to the rest of the molecule by an alkyl group, such as benzyl and phenethyl.

[0044] "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.

[0045] The term "halogen" refers to Fluor, chlorine, bromine or iodide.

[0046] The reactions disclosed in the present specification do 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 processes can run in batch, a semi-batch or a continuous mode, preferably in batch mode.

[0047] The reaction is preferably carried out in an inert atmosphere, e.g. under an argon or nitrogen atmosphere.

[0048] Preparing a compound of formula (I)

[0049] The preparation of a compound of formula (I) requires the decarboxylation of a compound of formula (II). The reaction typically involves heating the compound of formula (II), typically in the presence of a solvent. The temperature should be as low as possible that results in decarboxylation in a reasonable time. Appropriate temperatures are typically between 40°C and 250°C, for example, between 50°C and 200°C, for example, between 70°C and 175°C or between 90°C and 150°C. The reaction can proceed until all starting material and intermediates are consumed, in this case until all compound of formula (II) is consumed. This can be monitored following known procedures, such as liquid chromatography. Usual reaction times can be from 1 hour to 72 hours, for example, from 10 hours to 50 hours. The solvent is not particularly relevant and must be one that is inert and has a boiling point that allows heating at the particular temperature chosen, for example, an alcohol, for example a Ci-Cg alcohol (e.g. methanol, ethanol, propanol, / so-propanol, butanol, tert-butanol, pentanol or hexanol), or an aromatic solvent, for example, toluene or xylene. Alternative solvents are also water, chlorobenzene, DMF, DMSO, NMP, or DMAC.

[0050] When R3is different from hydrogen the compound of formula (II) is an ester, and the reaction can proceed, first by hydrolyzation of the ester, and then decarboxylating the resulting carboxylic acid. Typically, the reaction mixture will contain at any given time during the reaction a mixture of a compound of formula (I), the corresponding carboxylate of formula (II) and the carboxylic acid thereof. Alternatively, the reaction may proceed in two stages so that in the first step (i) a compound of formula (II) wherein R3is not hydrogen is heated to a temperature of 40°C to 250°C to obtain a compound of formula (II) wherein R3is hydrogen; and a second step (ii) in which the compound of formula (II) obtained in step (i) is further heated to a temperature of 40°C to 250°C to provide the compound of formula (I).

[0051] The reaction to yield the compound of formula (I) from a compound of formula (II) can take place in the presence of an organic or inorganic base. Examples of inorganic bases are alkaline and an alkaline-earth hydroxides, for example, LiOH, NaOH, or KOH, as well as carbonates and bicarbonates, such as NajCOs, NaHCOs, K2CO3, or KHCO3. For example, the base can be NaOH or KOH, preferably NaOH. Thus, the process may comprise heating a compound of formula (II) to a temperature of 40°C to 250°C in a solvent in the presence of a base. For example, the process comprises heating a compound of formula (II) wherein each of R1, R2and R3are selected from the group consisting of C1-C12 alkyl, C2-C12 alkenyl, and C2-C12 alkynyl to a temperature of 50°C to 150°C in the presence of a solvent and a base. Also, the process may comprise heating a compound of formula (II) to a temperature of 40°C to 250°C in an aromatic solvent in the presence of a base selected from the group consisting of alkaline and an alkaline-earth hydroxides, for example, LiOH, NaOH, or KOH, as well as carbonates and bicarbonates. Also, the process may comprise heating a compound of formula (II) wherein each of R1, R2and R3are selected from the group consisting of C1-C12 alkyl, C2-C12 alkenyl, and C2-C12 alkynyl, to a temperature of 40°C to 250°C in a solvent and in the presence of a base selected from the group consisting of alkaline and an alkaline-earth hydroxides, carbonates and bicarbonates.

[0052] To provide the intermediate 2,4-dimethyl-3-thiophenone necessary to prepare dimethenamid the process may comprise heating a compound of formula (II) wherein each of R1and R2are methyl, to a temperature of 40°C to 250°C in a solvent and in the presence of a base selected from the group consisting of alkaline and an alkaline-earth hydroxides, carbonates and bicarbonates.

[0053] Preparing a compound of formula (II)

[0054] The compounds of formula (II) are prepared by dehydration of a compound of formula (III). The reaction typically involves mixing the compound of formula (III) with a solvent and heating, preferably in the presence of an acid or a base. Any acid or base can perform the catalysis. Examples of organic acids that can be used are pyridinium p-toluenesulfonate (PPTS), p- toluenesulfonic acid, acetic acid, propionic acid, 4-methoxybenzoic acid, benzoic acid, formic acid, chloroacetic acid, trifluoroacetic acid, methanesulfonic acid, or trifluoroacetic acid. Examples of inorganic acids are sulfuric acid, or hydrochloric acid. Any base can also perform the catalysis, such as alkaline or alkaline-earth hydroxides (e.g. NaOH or KOH) or alcoxides (e.g. NaOMe or NaOEt). Usual conditions involve the use of catalytic amounts of the acid or the base. Thus, the acid or the base can be added in a molar equivalent amount of 0.01 to 0.9, with respect to the total amount of compound of formula (III), for example, between 0.1 and 0.5 or between 0.15 and 0.4, with respect to the total amount of compound of formula (III).

[0055] The temperature should be as low as possible that results in dehydration in a reasonable time. Appropriate temperatures are typically between 40°C and 250°C, for example, between 50°C and 200°C, or between 40°C and 200°C, for example, between 70°C and 150°C or between 80°C and 130°C. Usual reaction times can be from 1 hour to 72 hours, for example, from 10 hours to 50 hours. The solvent is not particularly relevant and must be one that is inert and has a boiling point that allows heating, for example, an alcohol, for example a Ci-Cg alcohol (e.g. methanol, ethanol, propanol, / so-propanol, butanol, tert-butanol, pentanol or hexanol), or an aromatic solvent, for example, toluene or xylene.

[0056] For example, the reaction may proceed by combining a compound of formula (III) with an acid in a solvent and heating the mixture for 1 to 72 hours. The reaction can thus proceed by combining a compound of formula (III) wherein each of R1, R2and R3is independently selected from the group consisting of C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, Cg-Cis aryl, C2-C15 heterocyclyl and C7-C15 arylalkyl with an acid selected from the group consisting of pyridinium p- toluenesulfonate (PPTS), p-toluenesulfonic acid, acetic acid, propionic acid, 4-methoxybenzoic acid, benzoic acid, formic acid, chloroacetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, and hydrochloric acid in a solvent and heating the mixture for 1 to 72 hours. For example, the reaction may proceed by combining a compound of formula (III) wherein each of R1, R2and R3is selected from the group consisting of C1-C12 alkyl, C2-C12 alkenyl and C2-C12 alkynyl, with an acid in a solvent and heating the mixture for 1 to 72 hours to a temperature of 40°C to 200°C.

[0057] To provide the intermediate methyl 3,5-dimethyl-4-oxo-4,5-dihydrothiophene-2-carboxylate necessary to prepare dimethenamid the process may comprise heating a compound of formula (III) wherein each of R1and R2are methyl, to a temperature of 40°C to 250°C in a solvent and in the presence of an acid.

[0058] Preparing a compound of formula (III)

[0059] The compound of formula (III) is prepared by reacting a compound of formula (IV) with a compound of formula (V), typically in the presence of a base. The reaction involves the nucleophilic substitution of the halogen in a compound of formula (V) and the condensation between the alpha acidic carbon of the compound of formula (IV) and the ketone of the compound of formula (V). As a result of these two processes the thiophenone ring is formed.

[0060] The compound of formula (IV) wherein R3is hydrogen is thioglycolic acid, which is commercially available and can be transformed into the corresponding esters (R3different from hydrogen) through different process known to the skilled person, for example, that described below in example 2 of the present application.

[0061] The reaction typically takes place in the presence of a base, whether inorganic or organic. Examples of organic bases are trialkyl amines, such as triethyl amine.

[0062] The temperature should be controlled. Appropriate temperatures are typically between -78°C and 40°C, for example, between -10°C and 30°C, or between -5°C and 25°C. Usual reaction times can be from 1 hour to 72 hours, for example, from 10 hours to 50 hours. The solvent is not particularly relevant, for example, an alcohol, for example a Ci-Cg alcohol (e.g. methanol, ethanol, propanol, / so-propanol, butanol, tert-butanol, pentanol or hexanol) or acetonitrile.

[0063] Thus, the processes may comprise mixing a compound of formula (IV) with a compound of formula (V) in the presence of a solvent and a base. Typically, the process may comprise mixing a compound of formula (IV) with a base in a solvent, and then adding a compound of formula (V), while maintaining a temperature of 0°C to 40°C. For example, the process comprises contacting a compound of formula (IV) and a compound of formula (V), wherein each of R1, R2and R3is independently selected from the group consisting of C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, and Cg-Cis aryl, in the presence of a base at a temperature between -78°C and 40°C.

[0064] Preparing a compound of formula (IV)

[0065] The compound of formula (IV) wherein R3is hydrogen, thioglycolic acid, is commercially available. The corresponding esters wherein R3is different from hydrogen can be easily prepared through esterification processes known to the skilled person. Examples of esterification processes can be found in "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", fourth edition, J. March (for example, pages 393-396). Examples of known procedures are the esterification in the presence of an alcohol in acid media (see example 2 below). The reaction may be facilitated in the presence of a dehydrating agent, such as dicyclohexylcarbodiimide (DCC), dicyclohexylurea (DHU) or N,N'-carbonyldiimidazole.

[0066] Preparing a compound of formula (V)

[0067] The compound of formula (V) is readily prepared by halogenation of the corresponding diketone of formula (VI), which are commercially available or obtainable by known processes. For example, chlorination can take place in the presence of sulfuryl chloride in a reaction that may or may not require heating. Bromination can take place in the presence of bromine (Br2). A number of methods are available for halogenation in a position alpha to a carbonyl group, as discussed in many reference books such as "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", fourth edition, J. March. See for example pages 587-590.

[0068] The compounds of formula (VI) are commercially available or obtainable through different methods. These are described, for example, in reference books such as "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", fourth edition, J. March. See for example page 490 (de-halogenation coupling), 493 (acylation of ketones an nitriles by carboxylic Esters), 1188 (oxidation of a ketone in the presence of selenium dioxide).

[0069] Therefore, the process of the invention may comprise dehydrating a compound of formula (III), followed by decarboxylation of the resulting compound of formula (II) to yield a compound of formula (I), wherein the compounds of formula (I), (II) and (III) are as defined elsewhere in the present application. Alternatively, the process may comprise contacting a compound of formula (IV) and a compound of formula (V) to provide a compound of formula (III), dehydrating said compound of formula (III), followed by decarboxylation of the resulting compound of formula (II) to yield a compound of formula (I), wherein the compounds of formula (I), (II), (III), (IV) and

[0070] (V) are as defined elsewhere in the present application.

[0071] Compounds of formula (II) and of formula (III)

[0072] As mentioned above, further aspects of the invention are the compounds of formula (II) and of formula (III). These compounds can be used for the preparation of dimethenamid and are therefore compounds in which R1and R2are typically methyl. However, the reactions described in the present document can also be useful for the preparation of further compounds wherein each of R1and R2is independently selected from the group consisting of hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, Cg-Cis aryl, C2-C15 heterocyclyl and C7-C15 arylalkyl. For example, each of R1and R2can be independently selected from the group consisting of hydrogen, C1-C12 alkyl, C2-C12 alkenyl, and C2-C12 alkynyl. For example, each of R1and R2can be independently selected from the group consisting of hydrogen, C1-C12 alkyl, for example, compounds of formula (II) or (III) wherein both of R1and R2are a C1-C12 alkyl, e.g. a Ci-Cg alkyl or a C1-C4 alkyl or a C1-C3 alkyl.

[0073] R3can also be selected from the group consisting of hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, Cg-Cis aryl, C2-C15 heterocyclyl and C7-C15 arylalkyl. Since R3it is not part of the final compounds of formula (I), its specific nature is not particularly relevant as long as it does not interfere with the reactions of the invention. Esters are preferred for this position and therefore R3can be selected from the group consisting of C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, Cg-Cis aryl, C2-C15 heterocyclyl and C7-C15 arylalkyl. Any group that favors hydrolyzation of the ester and subsequent carbonylation to the yield the compound of formula (I) is preferred, for example methyl, which additionally has economic and practical advantages. Other groups may also play the same role, and R3can be selected from the group consisting of Ci-Cg alkyl or C1-C3 alkyl groups.

[0074] EXAMPLES

[0075] Example 1: Bromination of 2,3-pentadione to provide 4-bromopentane-2,3-dione

[0076] A solution of 2,3-pentanedione (1.0 g, 0.01 mol, 1.0 eq.) in chloroform was cooled to 0°C and Br2 (1.7 g, 0.01 mol, 1.07 eq.) in chloroform (4 ml) was slowly added dropwise. The mixture was stirred at 0 °C for 1 h, and after this time GC(FID) showed full conversion of the starting material. The solution was allowed to warm to room temperature and 20% aqueous sodium bisulfite solution was added to remove the excess of bromine. Then, the reaction mixture was extracted with dichloromethane. The organic phase was washed with 5% sodium thiosulfate, followed by water and brine, then dried over anhydrous Na2SO4. The solvent was removed by rotary evaporation to give the desired product 4-bromopentane-2, 3-dione as an orange oil (yield 86%). The crude material was used in the next step without further purification.

[0077] Example 2: synthesis of methyl thioglycolate

[0078] To a solution of thioglycolic acid (1.0 g, 0.01 mol, 1.0 eq.) in methanol (10 ml) was added concentrated H2SO4 (0.43 g, 0.004 mol, 0.4 eq.) and the mixture was refluxed for 4 h. After this time, the solvent was removed under reduced pressure. The residue was dissolved in diethyl ether and washed with water. The combined organic layers were dried over anhydrous NajSCU and concentrated with a rotary evaporator, giving a colorless oil (50% yield). The crude material was used without any further purification.

[0079] Example 3: synthesis of methyl 3-hvdroxy-3,5-dimethyl-4-oxotetrahydrothiophene-2- carboxylate by reaction of the 4-bromopentane-2,3-dione of Example 1 with the methyl thioglycolate of Example 2.

[0080] To a solution of methyl thioglycolate (0.30 g, 3.0 mmol, 1.0 eq.) in acetonitrile (8 ml), 0.57 g of triethylamine (6.0 mmol, 2.0 eq.) was added. Then, 4-bromopentane-2, 3-dione (0.5 g, 3.0 mmol, 1 eq.) in acetonitrile (2 ml) was added dropwise. The reaction mixture was stirred at room temperature for 24 h. After this time, the solvent was removed, and the residue was partitioned between IM HCI and ethyl acetate. The aqueous layer was extracted two more times with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous NajSC , and evaporated. The crude material (yield of 78%) was used in the next step without any further purification.

[0081] Example 4: synthesis of methyl 3,5-dimethyl-4-oxo-4,5-dihvdrothiophene-2-carboxylate by dehydration of the methyl 3-hvdroxy-3,5-dimethyl-4-oxotetrahvdrothiophene-2-carboxylate of Example 3 methyl 3-hydroxy-3,5-dimethyl-4-oxotetrahydrothiophene-2-carboxylate (0.48 g, 2.4 mmol, 1.0 eq.) from example 3 was dissolved in anhydrous toluene and 0.12 g of PPTS (4.7 mmol, 0.20 eq.) was added. The reaction mixture was refluxed for 24 h. After this time, the resulting mixture was cooled to the room temperature. The solvent was removed and the residue was partitioned between IM HCI and ethyl acetate. The aqueous layer was extracted two more times with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous NajSC , and evaporated. The desired product methyl 3,5-dimethyl-4-oxo-4,5-dihydrothiophene-2- carboxylate was isolated by FCC (0-8% EtOAc / Hexane), giving a yellow, crystalline solid in 49% yield.

[0082] Example 5: synthesis of 2,4-dimethyl-3-thiophenone by decarboxylation of the methyl 3,5- dimethyl-4-oxo-4,5-dihvdrothiophene-2-carboxylate of Example 4. methyl 3,5-dimethyl-4-oxo-4,5-dihydrothiophene-2-carboxylate (0.25 g, 1.0 mmol, 1.0 eq.) was dissolved in MeOH and 4 ml of IM NaOH (4.0 mmol, 4.0 eq.) was added. The reaction mixture was refluxed for 24 h under an argon atmosphere. After this time, LCMS showed complete consumption of the substrate and hydrolysis methyl 3,5-dimethyl-4-oxo-4,5-dihydrothiophene- 2-carboxylate to the corresponding carboxylic acid 3-hydroxy-3,5-dimethyl-4- oxotetrahydrothiophene-2-carboxylic acid. The reaction mixture was transferred to a sealed reactor and temperature of the reaction was raised to 130 °C. After stirring for 24 h at this temperature, the formation of methyl 3,5-dimethyl-4-oxo-4,5-dihydrothiophene-2-carboxylate was detected by LCMS. The reaction mixture was then cooled to room temperature, acidified with IM HCI and extracted with ethyl acetate. Organic phases were combined, washed with water and brine, dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. LCMS analysis indicated 40% of 2,4-dimethyl-3-thiophenone and 53% of 3-hydroxy- 3,5-dimethyl-4-oxotetrahydrothiophene-2-carboxylic acid in the final crude material.

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 the decarboxylation of a compound of formula (II), and optionally the hydrolysis thereof,CD whereinR1and R2are as defined above; andR3is selected from the group consisting of hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, Cg-Cis aryl, C2-C15 heterocyclyl and C7-C15 arylalkyl.

2. The process according to claim 1 wherein the compound of formula (II) is heated in a solvent to a temperature comprised between 50°C and 250°C.

3. The process according to claim 2 wherein the solvent is an alcohol, for example a Ci-Cg alcohol, or an aromatic solvent, for example, toluene or xylene.

4. The process according to any of claims 1 to 3 comprising a first step (i) wherein a compound of formula (II) wherein R3is not hydrogen is heated to a temperature of 50°C to 250°C to obtain a compound of formula (II) wherein R3is hydrogen; and a second step (ii) wherein said compound of formula (II) obtained in step (i) is further heated to a temperature of 50°C to 250°C.

5. The process according to claim 4 wherein a compound of formula (II) wherein R3is not hydrogen is heated to a temperature of 50°C to 200°C to obtain a compound of formula (I).

6. The process according to any of the previous claims, wherein the compound of formula (II) is obtained by dehydrating a compound of formula (III)wherein R1, R2and R3are as defined in any of the previous claims.

7. The process according to claim 6 wherein the reaction temperature is between 40°C and 250°C.

8. The process according to any of claims 6 or 7, wherein the reaction takes place in the presence of an acid.

9. The process according to any of the previous claims, wherein the compound of formula (III) is obtained by reacting a compound of formula (IV) with a compound of formula (V)(IV) (V) wherein R1, R2and R3are as defined in claim 1; and X is a halogen atom.

10. The process according to claim 9 wherein the reaction takes place in the presence of a base.

11. The process according to any of the previous claims, wherein the compound of formula (V) is obtained by halogenation of a compound of formula (VI)wherein R1and R2are as defined in any of the previous claims.

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 any of the previous claims wherein R1and R2are methyl following the process defined in any of the previous claims, and then transforming said compound of formula (I) into dimethenamid.

14. A compound of formula (II)(ID wherein each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, Cg-Cis aryl, C2-C15 heterocyclyl and C7-C15 arylalkyl.

15. A compound of formula (III)wherein each of R1, R2and R3is independently selected from the group consisting of hydrogen, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, Cg-Cis aryl, C2-C15 heterocyclyl and C7-C15 arylalkyl.

16. The compound according to any of claims 14 or 15, wherein R1, R2and R3are each independently selected from the group consisting of Ci-Cg alkyl groups.

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