New route for preparation of thienones

Abstract

The invention relates to a novel synthesis method for preparing thiophene-3-ketone and an intermediate of the synthesis method. The invention also relates to a method for obtaining an active ingredient, such as dimethenamid.

Description

Technical Field

[0001] The present invention relates to the field of organic compound synthesis, and more particularly to a method for preparing thiophenone, wherein the thiophenone can be used for preparing dimethenamid. Background Art

[0002] The agrochemical industry is constantly searching for more efficient methods for preparing its active ingredients (AIs). The ability to provide an economical and clean synthesis of an AI is one of the key factors determining the commercialization of an AI.

[0003] Dimethenamid is a herbicide belonging to the class of chloroacetamides, which inhibits lipid synthesis. It is included in group 15 of the WSSA classification. It is commonly applied to the soil to control a variety of broadleaf weeds and grasses. It is a chiral molecule with two isomeric forms commonly known as M and P stereoisomers, with dimethenamid-P being more biologically active.

[0004]

[0005] The synthetic scheme for the preparation of dimethenamid usually involves the construction of a thiophene ring (usually thiophene-3-one) followed by the introduction of 2-methoxy-2-propylamine (also known as 2-methoxyisopropylamine or MOIPA) by coupling the 2-chloroacetyl moiety. Therefore, one of the key steps is the construction of the thiophene-3-one ring that exists in two tautomeric forms.

[0006]

[0007] In the case of dimethenamid, the desired intermediate is 2,4-dimethyl-2,3-dihydrothiophen-3-one (also found in the literature as 2,4-dimethylthiophen-3-one), which may be present in a mixture with its tautomeric form 2,4-dimethyl-3-hydroxythiophenone (also known as 3-thiophene alcohol).

[0008] US5,703,248 discloses a method for preparing a novel nanostructured carbonyl ... 2 S / NaOH (Examples 3a and 3d), Na 2 S (Example 3b) or NaHS (Example 3c) to prepare 2,4-dimethyl-2,3-dihydrothiophen-3-one, as well as the continuous preparation in the presence of NaHS.

[0009] The methods disclosed in the prior art are not satisfactory, and the yield can be improved. Therefore, there is a need in the art to provide alternative methods for obtaining dimethenamid and its intermediate 2,4-dimethyl-3-thiophenone. There is a need for a more efficient method for providing 2,4-dimethyl-3-thiophenone, such as improving the yield, reducing impurities and / or providing milder conditions. SUMMARY OF THE INVENTION

[0011] The inventors have developed a new strategy to obtain 2,4-dimethyl-3-thiophenone via a novel synthetic route. This new route adds an alternative route to this key intermediate, many of which do not require purification. In addition, this new route avoids the use of sensitive reagents such as hot hydrogen peroxide.

[0012] Therefore, a first aspect of the present invention is a process for preparing a compound of formula (I),

[0013]

[0014] in

[0015] R 1 and R 2 Each of which is independently selected from hydrogen, C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, C 6 -C 15 Aryl, C 2 -C 15 Heterocyclic and C 7 -C 15 Arylalkyl;

[0016] The process comprises decarboxylation and optionally hydrolysis of a compound of formula (II) (ie wherein R 3 The compound of formula (II) which is not hydrogen is converted into a compound in which R 3 is a compound of formula (II) wherein

[0017]

[0018] in

[0019] R 1 and R 2 As defined above; and

[0020] R 3 are independently selected from hydrogen, C 1 -C 12 Alkyl, C 2 -C12 Alkenyl, C 2 -C 12 Alkynyl, C 6 -C 15 Aryl, C 2 -C 15 Heterocyclic and C 7 -C 15 Arylalkyl.

[0021] "Hydrolysis thereof" refers to the hydrolysis of 3 The compound of formula (II) which is not hydrogen is converted into a compound in which R 3 The compound of formula (II) which is hydrogen, ie the ester portion, is hydrolyzed to the carboxylic acid.

[0022] Another aspect of the invention are compounds of formula (II) as defined above.

[0023] Therefore, another aspect of the present invention is a process for preparing the compound of formula (II), which is carried out by dehydrating the compound of formula (III).

[0024]

[0025] in

[0026] R 1 and R 2 As defined above; and

[0027] R 3 Selected from hydrogen, C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, C 6 -C 15 Aryl, C 2 -C 15 Heterocyclic and C 7 -C 15 Arylalkyl.

[0028] Another aspect of the invention are compounds of formula (III) as defined above.

[0029] Therefore, another aspect of the present invention is a process for preparing a compound of formula (III), which comprises reacting a compound of formula (IV) with a compound of formula (V).

[0030]

[0031] in

[0032] R 1 and R2 As defined above;

[0033] R 3 Selected from hydrogen, C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, C 6 -C 15 Aryl, C 2 -C 15 Heterocyclic and C 7 -C 15 Arylalkyl; and

[0034] X is a halogen atom.

[0035] The compounds of formula (I) encompass the thiophene-3-one intermediate, 2,4-dimethyl-2,3-dihydrothiophene-3-one, required for the preparation of dimethenamid. Therefore, another aspect of the present invention is a process for preparing dimethenamid, the process comprising preparing according to the process defined herein wherein R 1 and R 2 The compound of formula (I) is a methyl compound, and then the compound of formula (I) is converted into dimethenamid. The preparation of dimethenamid can be achieved in different ways. The compound (2,4-dimethyl-2,3-dihydrothiophene-3-one) of formula (I) can react with 1-methoxy-2-propylamine to generate N-(1-methoxyprop-2-yl)-2,4-dimethylaminothiophene, which can then react with the acyl chloride of 2-chloroacetate to generate dimethenamid. Examples of this method and other alternative schemes for generating dimethenamid are described in US5,703,248, EP210320, EP296463, US2011077418, CN108299221 or CN113024505.

[0036] Therefore, another aspect of the present invention is a process for preparing dimethenamid, said process comprising preparing according to the process defined elsewhere in this specification wherein R 1 and R 2 A compound of formula (I) having a methyl group, and then converting the compound of formula (I) into dimethenamid.

[0037] Another aspect of the present invention is also the use of the compound of formula (II) for preparing dimethenamid.

[0038] Another aspect of the present invention is also the use of the compound of formula (III) for preparing dimethenamid. DETAILED DESCRIPTION OF THE INVENTION

[0040] definition

[0041] In this document, the following terms are given the following meanings.

[0042] The compounds of the invention are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures include the replacement of hydrogen with deuterium or tritium, or the replacement of hydrogen with 13 C- or 14 C-enriched carbon replaces carbon, or uses 15 N-enriched nitrogen replaces nitrogen, or 19 F-enriched fluorine is a substitute for fluorine and is within the scope of the present invention.

[0043] The compound of formula (I) exists in two tautomeric forms

[0044]

[0045] The ratio between the two tautomeric forms depends on different factors. For the purposes of this application, they are considered equivalent.

[0046] The term "C 1 -C 12 "Alkyl" refers to a straight or branched saturated hydrocarbon chain radical having no multiple bonds and having from 1 to 12 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, such as methyl, ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, tert-butyl, sec-butyl), pentyl (e.g., 1-methylpentyl, 3-methylpentyl, n-pentyl), hexyl, octyl or dodecyl.

[0047] The term "C 2 -C 12"Alkenyl" refers to a straight or branched hydrocarbon chain radical having one or more carbon-carbon double bonds and having 2 to 12 carbon atoms, and which is attached to the rest of the molecule by a single bond. The double bond of the alkenyl group can be non-conjugated or conjugated to another unsaturated group. Suitable alkenyl groups include, but are not limited to, alkenyl, 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-1-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.

[0048] The term "C 2 -C 12 "Alkynyl" refers to a straight or branched hydrocarbon chain radical having one or more carbon-carbon triple bonds and 2 to 12 carbon atoms, and which is connected to the rest of the molecule by a single bond. The triple bond of the alkynyl group can be non-conjugated 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-1-butynyl, 4-methyl-2-heptynyl and 4-ethyl-2-octynyl.

[0049] “C 6 -C 15 "Aryl" refers to a hydrocarbon moiety having 6 to 15 carbon atoms and at least one aromatic hydrocarbon structure, such as phenyl, naphthyl or anthracenyl.

[0050] “C 7 -C 15 "Arylalkyl" refers to an aryl group attached to the rest of the molecule through an alkyl group, for example, benzyl and phenethyl.

[0051] “C 2 -C 15"Heterocyclyl" refers to a stable 3- to 16-membered ring consisting of carbon atoms (2 to 15) and 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, preferably a 4- to 8-membered ring with 1 or more heteroatoms, more preferably a 5- or 6-membered ring with 1 or more heteroatoms. For the purposes of the present invention, the heterocycle can be a monocyclic, bicyclic or tricyclic ring system, which can include fused ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl can be partially or fully saturated or aromatic. Examples of such heterocycles include, but are not limited to, azepine, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole or tetrahydrofuran.

[0052] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0053] The reactions disclosed in this specification do not necessarily require special equipment, and any container commonly used for chemical reactions should be suitable. In the case where some pressure accumulation is expected, an autoclave container or other measures can be used to cope with the pressure. The method can be operated in an intermittent, semi-batch or continuous mode, preferably in an intermittent mode.

[0054] The reaction is preferably carried out in an inert atmosphere, such as an argon or nitrogen atmosphere.

[0055] Preparation of compounds of formula (I)

[0056] The preparation of compounds of formula (I) requires decarboxylation of compounds of formula (II). The reaction generally comprises heating a compound of formula (II), usually in the presence of a solvent. The temperature should be as low as possible so as to decarboxylate within a reasonable time. Suitable temperatures are generally 40°C to 250°C, for example 50°C to 200°C, for example 70°C to 175°C or 90°C to 150°C. The reaction can be carried out until all starting materials and intermediates are consumed, in which case until all compounds of formula (II) are consumed. This can be monitored according to known methods (e.g., liquid chromatography). Typical reaction times can be 1 hour to 72 hours, for example 10 hours to 50 hours. The solvent is not particularly relevant and must be an inert solvent having a boiling point that allows heating at the selected specific temperature, such as an alcohol, for example C 1 -C 6 Alcohols (e.g. methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, pentanol or hexanol), or aromatic solvents such as toluene or xylene. Alternative solvents include water, chlorobenzene, DMF, DMSO, NMP or DMAC.

[0057] When R 3When R is not hydrogen, the compound of formula (II) is an ester, and the reaction can be carried out first by hydrolysis of the ester and then decarboxylation of the resulting carboxylic acid. Typically, the reaction mixture will contain a mixture of the compound of formula (I), the corresponding carboxylic acid ester of formula (II) and its carboxylic acid at any given time during the reaction. Alternatively, the reaction can be carried out in two stages, so that in the first step (i), R 3 The compound of formula (II) which is not hydrogen is heated to a temperature of 40°C to 250°C to obtain 3 a compound of formula (II) which is hydrogen; and a second step (ii), wherein the compound of formula (II) obtained in step (i) is further heated to a temperature of 40° C. to 250° C. to provide a compound of formula (I).

[0058] The reaction of the compound of formula (II) to produce the compound of formula (I) can be carried out in the presence of an organic base or an inorganic base. Examples of inorganic bases are alkali metal and alkaline earth metal hydroxides, such as LiOH, NaOH or KOH, and carbonates and bicarbonates, such as Na 2 CO 3 , NaHCO 3 , K 2 CO 3 or KHCO 3 For example, the base may be NaOH or KOH, preferably NaOH.

[0059] Thus, the method 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 method comprises heating a compound of formula (II) to a temperature of 40°C to 250°C in the presence of a solvent and a base. 1 , R 2 and R 3 Each of the selected 1 -C 12 Alkyl, C 2 -C 12 Alkenyl and C 2 -C 12 The method may include heating the compound of formula (II) containing an alkynyl group to a temperature of 50°C to 150°C. In addition, the method may include heating the 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 alkali metal and alkaline earth metal hydroxides (e.g., LiOH, NaOH or KOH) and carbonates and bicarbonates. In addition, the method may include heating the compound of formula (II) containing an alkynyl group to a temperature of 50°C to 150°C in an aromatic solvent in the presence of a base selected from alkali metal and alkaline earth metal hydroxides, carbonates and bicarbonates. 1 , R 2 and R 3 Each of the selected 1 -C 12 Alkyl, C 2 -C12 Alkenyl and C 2 -C 12 The alkynyl compound of formula (II) is heated to a temperature of 40°C to 250°C.

[0060] In order to provide the intermediate 2,4-dimethyl-3-thiophenone required for preparing dimethenamid, the method may include reacting R 1 and R 2 The compound of formula (II) in which each of the compounds is a methyl group is heated to a temperature of 40°C to 250°C.

[0061] Preparation of compounds of formula (II)

[0062] The compound of formula (II) is prepared by dehydrating the compound of formula (III). The reaction generally includes 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 be catalyzed. 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 be catalyzed, such as alkali metal or alkaline earth metal hydroxides (such as NaOH or KOH) or alkoxides (such as NaOMe or NaOEt). Common conditions include using a catalytic amount of acid or base. Therefore, relative to the total amount of the compound of formula (III), the acid or base can be added in a molar equivalent of 0.01 to 0.9, for example, relative to the total amount of the compound of formula (III), added in a molar equivalent of 0.1 to 0.5 or 0.15 to 0.4.

[0063] The temperature should be as low as possible so that the dehydration is carried out in a reasonable time. Suitable temperatures are generally 40°C to 250°C, for example 50°C to 200°C, or 40°C to 200°C, for example 70°C to 150°C or 80°C to 130°C. Typical reaction times may be 1 hour to 72 hours, for example 10 hours to 50 hours. The solvent is not particularly relevant and must be an inert solvent with a boiling point that allows heating, for example an alcohol, for example C 1 -C 6 Alcohols (eg methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, pentanol or hexanol), or aromatic solvents such as toluene or xylene.

[0064] For example, the reaction can be carried out by mixing a compound of formula (III) with an acid in a solvent and heating the mixture for 1 to 72 hours. 1 , R 2 and R 3Each of which is independently selected from C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, C 6 -C 15 Aryl, C 2 -C 15 Heterocyclic and C 7 -C 15 The compound of formula (III) of aralkyl is mixed 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 the mixture is heated for 1 to 72 hours. For example, the reaction can be carried out by mixing wherein R 1 , R 2 and R 3 Each of the selected 1 -C 12 Alkyl, C 2 -C 12 Alkenyl and C 2 -C 12 The alkynyl compound of formula (III) is mixed with an acid in a solvent and the mixture is heated to a temperature of 40°C to 200°C for 1 to 72 hours.

[0065] In order to provide the intermediate 3,5-dimethyl-4-oxo-4,5-dihydrothiophene-2-carboxylic acid methyl ester required for preparing dimethenamid, the method may include reacting R 1 and R 2 The compound of formula (III) in which each of the compounds is a methyl group is heated to a temperature of 40°C to 250°C.

[0066] Preparation of compounds of formula (III)

[0067] The compound of formula (III) is prepared by reacting a compound of formula (IV) with a compound of formula (V), usually in the presence of a base. The reaction involves nucleophilic substitution of the halogen in the compound of formula (V) and 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, a thiophenone ring is formed.

[0068] Where R 3 The compound of formula (IV) in which H is thioglycolic acid is commercially available and can be converted into the corresponding ester (R 3 Unlike hydrogen).

[0069] The reaction is usually carried out in the presence of an inorganic base or an organic base. An example of an organic base is a trialkylamine, such as triethylamine.

[0070] The temperature should be controlled. Suitable temperatures are generally -78°C to 40°C, such as -10°C to 30°C, or -5°C to 25°C. Typical reaction times may be 1 hour to 72 hours, such as 10 hours to 50 hours. The solvent is not particularly relevant, for example an alcohol, such as C 1 -C 6 alcohol (eg methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, pentanol or hexanol), or acetonitrile.

[0071] Thus, the method 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 method 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 method comprises contacting a compound of formula (IV) with a compound of formula (V) in the presence of a base at a temperature of -78°C to 40°C, wherein R 1 , R 2 and R 3 Each of which is independently selected from C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl and C 6 -C 15 Aryl.

[0072] Preparation of compounds of formula (IV)

[0073] Where R 3 The compound of formula (IV) wherein R is hydrogen, ie, thioglycolic acid, is commercially available. 3 The corresponding esters different from hydrogen can be easily prepared by esterification methods known to those skilled in the art. Examples of esterification methods can be found in "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", Fourth Edition, J. March (e.g., pages 393-396). An example of a known method is esterification in an acid medium in the presence of an alcohol (see Example 2 below). In the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC), dicyclohexylurea (DHU) or N, N'-carbonyldiimidazole, the reaction can be promoted.

[0074] Preparation of compounds of formula (V)

[0075] Compounds of formula (V) are readily prepared by halogenation of the corresponding diketone of formula (VI) (which is commercially available or can be obtained by known methods). For example, chlorination can be carried out in the presence of sulfonyl chloride in a reaction that may or may not require heating. Bromination can be carried out in bromine (Br 2 ) is carried out in the presence of. Many methods can be used to halogenate at the alpha position of the carbonyl group, as discussed in many reference books, such as "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", Fourth Edition, J. March. For example, see pages 587-590.

[0076] Compounds of formula (VI) are commercially available or can be obtained by different methods. These are described, for example, in reference books such as "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th edition, J. March. See, for example, page 490 (dehalogenation coupling), page 493 (acylation of ketones and nitrile by carboxylic acid esters), page 1188 (oxidation of ketones in the presence of selenium dioxide).

[0077] Therefore, the method of the present invention may include dehydrating a compound of formula (III), and then decarboxylating the resulting compound of formula (II) to produce a compound of formula (I), wherein the compounds of formula (I), (II) and (III) are as defined elsewhere in the application. Alternatively, the method may include contacting a compound of formula (IV) with a compound of formula (V) to provide a compound of formula (III), dehydrating the compound of formula (III), and then decarboxylating the resulting compound of formula (II) to produce a compound of formula (I), wherein the compounds of formula (I), (II), (III), (IV) and (V) are as defined elsewhere in the application.

[0078] The compound of formula (II) and the compound of formula (III)

[0079] As mentioned above, other aspects of the present invention are compounds of formula (II) and compounds of formula (III). These compounds can be used to prepare dimethenamid and are therefore compounds wherein R 1 and R 2 However, the reactions described in this application can also be used to prepare other compounds in which R 1 and R 2 Each of which is independently selected from hydrogen, C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12Alkynyl, C 6 -C 15 Aryl, C 2 -C 15 Heterocyclic and C 7 -C 15 Aralkyl. For example, R 1 and R 2 Each of which may be independently selected from hydrogen, C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl and C 2 -C 12 For example, R 1 and R 2 Each of which may be independently selected from hydrogen, C 1 -C 12 Alkyl, for example, a compound of formula (II) or a compound of formula (III), wherein R 1 and R 2 Both C 1 -C 12 Alkyl groups, such as C 1 -C 6 Alkyl or C 1 -C 4 Alkyl or C 1 -C 3 alkyl.

[0080] R 3 It can also be selected from hydrogen, C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, C 6 -C 15 Aryl, C 2 -C 15 Heterocyclic and C 7 -C 15 Aralkyl. 3 is not part of the final compound of formula (I), and its specific nature is therefore not particularly relevant as long as it does not interfere with the reaction of the present invention. Esters are preferred for this position, and therefore R 3 Can be selected from C 1 -C 12 Alkyl, C 2 -C 12 Alkenyl, C 2 -C 12 Alkynyl, C 6 -C 15 Aryl, C 2 -C 15Heterocyclic and C 7 -C 15 Aralkyl. Any group that facilitates the hydrolysis of the ester and the subsequent carbonylation to produce the compound of formula (I) is preferred, such as methyl, which has additional economic and practical advantages. Other groups can also play the same role, and R 3 Can be selected from C 1 -C 6 Alkyl or C 1 -C 3 alkyl. Example

[0081] Example 1: Bromination of 2,3-pentanedione to provide 4-bromopentane-2,3-dione

[0082]

[0083] A solution of 2,3-pentanedione (1.0 g, 0.01 mol, 1.0 equiv) in chloroform was cooled to 0°C and Br was slowly added dropwise. 2 (1.7 g, 0.01 mol, 1.07 equiv) in chloroform (4 ml). The mixture was stirred at 0 °C for 1 h, and after this time GC (FID) showed complete conversion of the starting material. The solution was allowed to warm to room temperature, and 20% aqueous sodium bisulfite solution was added to remove excess bromine. The reaction mixture was then extracted with dichloromethane. The organic phase was washed with 5% sodium thiosulfate, followed by water and brine, and then with anhydrous Na 2 SO 4 Drying. Removal of the solvent by rotary evaporation gave 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.

[0084] Example 2: Synthesis of Methyl Thioglycolate

[0085] To a solution of thioglycolic acid (1.0 g, 0.01 mol, 1.0 equiv) in methanol (10 ml) was added concentrated H 2 SO 4 (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 ether and washed with water. The combined organic layers were washed with anhydrous Na 2 SO 4 Drying and concentration on a rotary evaporator gave a colorless oil (50% yield). The crude material was used without further purification.

[0086] Example 3: Synthesis of methyl 3-hydroxy-3,5-dimethyl-4-oxotetrahydrothiophene-2-carboxylate by reacting 4-bromopentane-2,3-dione of Example 1 with methyl thioglycolate of Example 2.

[0087]

[0088] To a solution of methyl thioglycolate (0.30 g, 3.0 mmol, 1.0 eq) in acetonitrile (8 ml) was added 0.57 g of triethylamine (6.0 mmol, 2.0 eq). Then, a solution of 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 1 M HCl and ethyl acetate. The aqueous layer was extracted twice more with ethyl acetate, and the combined organic layers were washed with brine and washed with anhydrous Na 2 SO 4 Dried and evaporated. The crude material (78% yield) was used in the next step without further purification.

[0089] Example 4: Synthesis of 3,5-dimethyl-4-oxo-4,5-dihydrothiophene-2-carboxylic acid methyl ester by dehydration of 3-hydroxy-3,5-dimethyl-4-oxotetrahydrothiophene-2-carboxylic acid methyl ester of Example 3

[0090]

[0091] 3-Hydroxy-3,5-dimethyl-4-oxotetrahydrothiophene-2-carboxylic acid methyl ester (0.48 g, 2.4 mmol, 1.0 equiv) from Example 3 was dissolved in anhydrous toluene and 0.12 g of PPTS (4.7 mmol, 0.20 equiv) was added. The reaction mixture was refluxed for 24 h. After this time, the resulting mixture was cooled to room temperature. The solvent was removed and the residue was partitioned between 1 M HCl and ethyl acetate. The aqueous layer was extracted twice more with ethyl acetate and the combined organic layers were washed with brine and washed with anhydrous Na 2 SO 4 Dried and evaporated. The desired product, methyl 3,5-dimethyl-4-oxo-4,5-dihydrothiophene-2-carboxylate, was isolated by FCC (0-8% EtOAc / hexanes) to give a yellow crystalline solid in 49% yield.

[0092] Example 5: Synthesis of 2,4-dimethyl-3-thiophenone by decarboxylation of methyl 3,5-dimethyl-4-oxo-4,5-dihydrothiophene-2-carboxylate of Example 4.

[0093]

[0094] 3,5-dimethyl-4-oxo-4,5-dihydrothiophene-2-carboxylic acid methyl ester (0.25g, 1.0mmol, 1.0 equivalent) is dissolved in MeOH and 4ml of 1M NaOH (4.0mmol, 4.0 equivalent) is added. The reaction mixture is refluxed for 24h under an argon atmosphere. After this time, LCMS shows that the substrate is completely consumed and 3,5-dimethyl-4-oxo-4,5-dihydrothiophene-2-carboxylic acid methyl ester is hydrolyzed into the corresponding carboxylic acid 3-hydroxy-3,5-dimethyl-4-oxo-tetrahydrothiophene-2-carboxylic acid. The reaction mixture is transferred to a sealed reactor, and the reaction temperature is raised to 130 ° C. After stirring at this temperature for 24h, the formation of 3,5-dimethyl-4-oxo-4,5-dihydrothiophene-2-carboxylic acid methyl ester is detected by LCMS. The reaction mixture is then cooled to room temperature, acidified with 1MHCl and extracted with ethyl acetate. The organic phases were combined, washed with water and brine, and washed with anhydrous Na 2 SO 4 After drying, the solvent was evaporated under reduced pressure. LCMS analysis showed 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

1. A process for preparing a compound of formula (I), in R 1 and R 2 Each of which is independently selected from hydrogen, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C6-C 15 Aryl, C2-C 15 Heterocyclic and C7-C 15 Arylalkyl; The process comprises the decarboxylation of a compound of formula (II), and optionally the hydrolysis thereof, in R 1 and R 2 As defined above; and R 3 Selected from hydrogen, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C6-C 15 Aryl, C2-C 15 Heterocyclic and C7-C 15 Arylalkyl.

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

3. The process according to claim 2, wherein the solvent is an alcohol, such as a C1-C6 alcohol, or an aromatic solvent, such as toluene or xylene.

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

5. The method according to claim 4, wherein R 3 The compound of formula (II) other than hydrogen is heated to a temperature of 50°C to 200°C to obtain the compound of formula (I).

6. The process according to any one of the preceding claims, wherein the compound of formula (II) is obtained by dehydrating a compound of formula (III), Where R 1 , R 2 and R 3 As defined in any one of the preceding claims.

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

8. The process according to any one of claims 6 or 7, wherein the reaction is carried out in the presence of an acid.

9. A process according to any one of the preceding claims, wherein the compound of formula (III) is obtained by reacting a compound of formula (IV) with a compound of formula (V) Where R 1 , R 2 and R 3 As defined in claim 1; and X is a halogen atom.

10. The process according to claim 9, wherein the reaction is carried out in the presence of a base.

11. A process according to any one of the preceding claims, wherein the compound of formula (V) is obtained by halogenation of a compound of formula (VI) Where R 1 and R 2 As defined in any one of the preceding claims.

12. A process according to any one of the preceding claims, wherein the compound of formula (I) is further converted into dimethenamid, including any enantiomers thereof.

13. A process for preparing dimethenamid, said process comprising preparing according to the process defined in any one of the preceding claims a compound as defined in any one of the preceding claims wherein R 1 and R 2 A compound of formula (I) having a methyl group, and then converting the compound of formula (I) into dimethenamid.

14. Compounds of formula (II) in R 1 , R 2 and R 3 Each of which is independently selected from hydrogen, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C6-C 15 Aryl, C2-C 15 Heterocyclic and C7-C 15 Arylalkyl.

15. Compounds of formula (III) in R 1 , R 2 and R 3 Each of which is independently selected from hydrogen, C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C6-C 15 Aryl, C2-C 15 Heterocyclic and C7-C 15 Arylalkyl.

16. A compound according to any one of claims 14 or 15, wherein R 1 , R 2 and R 3 Each is independently selected from C1-C6 alkyl.

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