Process for preparation of thienones

Abstract

The present invention relates to a process for the preparation of thiophene-3-ones by the simultaneous addition of a tri-substituted ketone and a sulfide or hydrosulfide anion followed by the addition of a base. 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 preparing dimethenamid usually involves the construction of a thiophene ring (usually thiophene-3-one), followed by the introduction of 2-methoxy-2-propylamine (or 2-methoxyisopropylamine), also known as 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 the preparation of 2,4-dimethyl-2,3-dihydrothiophen-3-one by reacting 1,2,4-trichloro-2-methylpentan-3-one with H2S / NaOH (Examples 3a and 3d), Na2S (Example 3b) and NaHS (Example 3c), 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-2,3-dihydrothiophene-3-one. There is a need for more efficient methods for providing 2,4-dimethyl-3-thiophene-one, such as improved yield, reduced impurities and / or milder conditions. SUMMARY OF THE INVENTION

[0011] The inventors have now realized that the order of addition of the reagents is the key to obtaining good yields in the reaction between 1,2,4-trichloro-2-methylpentan-3-one and sulfide anions, and reducing impurities (mainly intermolecular coupling products and polymers thereof). In the embodiments of US5,703,248, the sulfide anions (H2S, Na2S or NaHS) are either added to 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 the intermolecular coupling products, which resulted in dimers, oligomers and polymer by-products. Among other possible solutions, the inventors tested the inversion order and confirmed that adding 1,2,4-trichloro-2-methylpentan-3-one to the sulfide anion solution did not solve the problem and even further reduced the yield. However, studies conducted by the inventors showed that adding the two compounds simultaneously surprisingly increased the yield.

[0012] Therefore, a first aspect of the present invention is a method for preparing a 2,3-dihydrothiophen-3-one compound of formula (I),

[0013]

[0014] in

[0015] 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;

[0016] The method comprises

[0017] (i) reacting a sulfide or hydrosulfide anion with a compound of formula (II) in the presence of a solvent system comprising an organic solvent

[0018]

[0019] in

[0020] L 1 , L 2 and L 3 Each of is independently selected from a leaving group; and

[0021] R 1 and R 2 As defined above;

[0022] and

[0023] (ii) reacting the mixture obtained from step (i) with a base;

[0024] The sulfide or hydrosulfide anion and the compound of formula (II) are added simultaneously.

[0025] The inventors have found that the method improves yield and reduces the formation of intermolecular by-products and oligomers / polymers.

[0026] 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 of formula (I) (2,4-dimethyl-2,3-dihydrothiophene-3-one) 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 alternatives for generating dimethenamid are described in US5,703,248, EP210320, EP296463, US2011077418, CN108299221 or CN113024505. DETAILED DESCRIPTION OF THE INVENTION

[0028] definition

[0029] In this document, the following terms are given the following meanings.

[0030] 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.

[0031] The compound of formula (I) exists in two tautomeric forms

[0032]

[0033] The ratio between the two tautomeric forms depends on different factors. For the purposes of this application, they are considered equivalent.

[0034] The term "C1-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.

[0035] The term "C2-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.

[0036] The term "C2-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.

[0037] "C6-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.

[0038] "C7-C 15 "Arylalkyl" refers to an aryl group attached to the rest of the molecule through an alkyl group, for example, benzyl and phenethyl.

[0039] “C2-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.

[0040] The "leaving group" in the context of this application refers to a group that is removed by the sulfide anion (S 2- ) or sulfhydride anion (RS - ) replaces an atom or group of atoms. These are SN2 or SN1 type reactions, for which those skilled in the art can find suitable reagents. Sulfides are considered to contain S 2- Any salt of an anion, such as sodium sulfide (Na2S) (which is commercially available in varying degrees of solvation), hydrogen sulfide H2S (usually used in the presence of a base such as NaOH), (NH4)2S or K2S. Hydrosulfides are considered to contain HS - The reaction described herein is first carried out via an intermolecular reaction, wherein the sulfide displaces the leaving group L in the compound of formula (II) 1 or L 2 The obtained RS - Substance replaces the remaining L in intramolecular reaction 1 or L 2 In the case of a sulfhydride, the sulfhydride first displaces the leaving group L in the compound of formula (II) in an intermolecular reaction. 1 or L 2 The resulting RSH group is converted to RS by a base. - Substance, the RS - Substance replaces the remaining L in intramolecular reaction 1 or L 2, thereby closing the ring. Examples of leaving groups are halogens, such as fluorine, chlorine, bromine or iodine, with chlorine being the most common. Other leaving groups may be methoxy or sulfonates, such as tosylate (TsO - , -OSO2-toluene), mesylate (MsO - , -OSO2-Me) or triflate (TfO - , -OSO2-CF3). Those skilled in the art can find other examples in textbooks or reference books such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure. In order to complete the reaction, it is necessary to 3 to one of the hydrogens at the α position (i.e., attached to the initial L 2 This is done in the presence of an alkaline medium. This elimination can occur after or simultaneously with ring closure.

[0041] The reaction does not necessarily require special equipment, and any container commonly used for chemical reactions should be suitable. In cases where some pressure buildup is expected, an autoclave vessel or other means to cope with the pressure may be used. The process may be run in a batch, semi-batch or continuous mode, with batch mode being preferred.

[0042] The reaction is preferably carried out in an inert atmosphere, for example, in an argon or nitrogen atmosphere.

[0043] Step (i)

[0044] In step (i), the sulfide or hydrosulfide anion reacts with a compound of formula (II) as defined above. Typically, the method comprises preparing a first solution of the sulfide or hydrosulfide anion (e.g. in water, or in a water-soluble organic solvent, or in a mixture of the two), 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 the two). The first and second solutions are then fed into a container (e.g., a flask or a reactor) which typically already contains a solvent and other optional additives. The container may include means for controlling temperature, pressure, pH and other reaction variables. For example, a cooling / heating device is typically used to cool the reaction mixture in the exothermic step and to heat it when necessary.

[0045] For example, R 1 and R 2 Each is independently selected from C1-C6 alkyl, such as C1-C3 alkyl, more preferably ethyl or methyl. 1 and R 2are all methyl, that is, so as to provide the compound 2,4-dimethyl-2,3-dihydrothiophen-3-one of formula (I).

[0046] Leaving group L 1 , L 2 and L 3 can be any group displaced by a sulfide or hydrosulfide reagent, such as a halogen, such as chlorine, bromine or iodine. Any or all leaving groups L 1 , L 2 and L 3 can be the same or different, but all the same is more practical and is therefore the preferred choice. 1 , L 2 and L 3 Either all bromine, or all iodine, or all chlorine, usually all chlorine.

[0047] Compounds of formula (II) can be prepared according to methods known in the literature, for example US 5,703, 248. Sulfide and hydrosulfide anions are known in the art and can be obtained from various suppliers.

[0048] The temperature in step (i) is typically maintained at -10°C to 30°C, such as -5°C to 25°C, such as 0°C to 25°C, or 10°C to 25°C, or 10°C to 15°C.

[0049] The reaction can be carried out 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. The reaction can also be carried out in the presence of an organic solvent and water, wherein preferably the organic solvent is at least partially soluble in water. Therefore, the solvent system can be a mixture of alcohol and water, for example C1-C6-alcohol, for example C1-C4 alcohol. A particularly preferred solvent system is a combination of water with one of methanol, ethanol, 1-propanol, 2-propanol or pentanol. The ratio between the organic solvent and water is not particularly relevant. The main purpose of water is to dissolve the hydrosulfide anion, and the organic solvent helps to dissolve the compound of formula (I) and the compound of formula (II), and the entire solvent system surprisingly prevents the formation of oligomers and polymers, and thus helps to improve the yield. The volume ratio of the organic solvent to water may be from 10:1 to 1:10, for example from 8:1 to 1:8, or from 7:1 to 1:5, or from 5:1 to 1:2.

[0050] The theoretical molar ratio between the sulfide or hydrosulfide anion and the compound of formula (II) is 1:1. Each sulfide anion molecule reacts with one molecule of the compound of formula (II). The reaction is usually carried out in excess of sulfide or hydrosulfide anion, and thus the typical molar ratio (S) between the total sulfide or hydrosulfide anion added and the total compound of formula (II) is 2- / HS - :compound of formula (II)) is 5:1 to 1:1, for example 3:1 to 1:1, or 2:1 to 1:1, or 1.7:1 to 1:1, or 1.4:1 to 1:1, or 1.25:1 to 1:1, or 1.2:1 to 1:1, or 1.2:1 to 1.1:1.

[0051] Sulfide or hydrosulfide anion and the compound of formula (II) are added simultaneously over a period of time, rather than one being added to the other. Typically, sulfide or hydrosulfide is dissolved in a solvent such as alcohol (e.g., methanol), water or a mixture of the two, and the compound of formula (II) is dissolved in the same or different solvent. In a typical setting, both are added simultaneously at a rate that roughly maintains the molar ratio between sulfide or hydrosulfide anion and the compound of formula (II). The actual addition rate depends on specific conditions (scale, available equipment, temperature). Both additions may require several minutes or several hours. Under normal conditions, both are added within a time of 1 minute to 48 hours, such as 10 minutes to 12 hours or 20 minutes to 8 hours, such as 1 to 4 hours.

[0052] In order to better control the reaction and ensure maximum consumption of the compound of formula (II), step (i) can be divided into two sub-steps, wherein

[0053] Step (ia) comprises adding the sulfide or hydrosulfide anion and the compound of formula (II) simultaneously at a temperature of -10°C to 20°C, such as -5°C to 15°C, such as 5°C to 15°C or 10°C to 15°C, over a period of 1 minute to 24 hours, such as 10 minutes to 12 hours or 20 minutes to 8 hours; and

[0054] Step (ib) comprises reacting the mixture obtained from step (ia) at a temperature of 0°C to 70°C, or 5°C to 25°C, or 10°C to 25°C, for 1 minute to 24 hours, 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.

[0055] The sulfide or hydrosulfide anion may be a 2-Any compound of an anion, such as sodium sulfide (Na2S) (which is commercially available in different degrees of solvation), hydrogen sulfide H2S (usually in the presence of a base such as NaOH), (NH4)2S, NaHS or K2S, preferably selected from sodium sulfide (Na2S), sodium hydrosulfide (NaHS) and mixtures thereof. Sulfide or hydrosulfide anions are commercially available. Sulfide or hydrosulfide anions can be added in pure form, or more typically in the form of a solution, so that they can be added simultaneously with the compound of formula (II) in the correct dosage.

[0056] Step (ii)

[0057] Step (ii) is usually triggered when most of the compound of formula (II) has been consumed. This can be monitored by conventional means, for example, by submitting a sample to HPLC. At this stage, the reaction mixture contains some compound of formula (I) and a number of intermediates, such as thiophenone, where L 3 Still not undergoing elimination. In step (ii) of the method, pH is increased to ensure that the reaction is complete. This is achieved by adding a base. The step generally includes adding a base to the already existing mixture to keep the pH within an optimal range. The pH in step (ii) is generally maintained at 7 to 12, such as 8 to 12, such as 7 to 11, such as 9 to 11.5, such as 10 to 11.5 or 10 to 11. The base can be an inorganic or organic base, such as an inorganic base, such as an alkali metal or alkaline earth metal hydroxide, such as LiOH, NaOH, KOH, or carbonates and bicarbonates, such as Na2CO3, NaHCO3, K2CO3 or KHCO3, preferably NaOH or KOH, preferably NaOH. The example of an organic base can be a primary amine, a secondary amine or a tertiary amine, such as methoxypropylamine, dimethylamine or triethylamine. The pH value can be continuously monitored using known equipment such as a pH meter, wherein there are a variety of commercial options.

[0058] The temperature in step (ii) may be the same as in step (i), but is typically raised to a temperature of 30 to 70°C, such as 35 to 60°C, such as 35 to 50°C, or 40 to 50°C, or 40 to 45°C.

[0059] The reaction time in step (ii) depends on other reaction conditions, such as temperature or the concentration of reagent. Taking these factors into account, step (ii) may require 1 minute to several hours or days, such as 48 hours, although the typical time requires 10 minutes to 24 hours. Conventional techniques (such as gas chromatography) can be used to track the progress of the reaction.

[0060] Step (iii)

[0061] After the majority of the compound of formula (II) is converted into the compound of formula (I), the solvent is usually removed, for example, by distillation, and the pH is lowered by adding an acid (e.g., dilute hydrochloric acid or sulfuric acid). The pH is usually 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 with common organic solvents such as ethers (e.g., diethyl ether or tert-butyl dimethyl ether).

[0062] The obtained compound of formula (I) can then be purified according to standard conditions (distillation, gel chromatography, recrystallization, etc.) or can be used directly in the next step.

[0063] The present disclosure has described how to adjust different variables of the method within certain ranges. The present disclosure also encompasses combinations of different ranges of these variables. For example, one skilled in the art will recognize that the present disclosure encompasses a method for preparing a compound of formula (I) as defined elsewhere in this specification, the method comprising

[0064] (i) reacting a sulfide or hydrosulfide anion with a compound of formula (II) as defined elsewhere in this specification in the presence of a solvent system comprising an organic solvent; and

[0065] (ii) reacting the mixture obtained from step (i) with a base;

[0066] The sulfide or hydrosulfide anion and the compound of formula (II) are added simultaneously.

[0067] Furthermore, the method may include

[0068] (i) reacting a sulfide or hydrosulfide anion with a compound of formula (II) as defined elsewhere in this specification in the presence of a solvent system comprising an organic solvent and water; and

[0069] (ii) reacting the mixture obtained from step (i) with a base;

[0070] wherein the sulfide or hydrosulfide anion and the compound of formula (II) are added simultaneously; and

[0071] Where R 1 and R 2 Each of which is independently selected from C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl; and

[0072] Where L 1 , L 2 and L 3 Each of which is independently selected from fluorine, chlorine, bromine or iodine, methoxy, tosylate (TsO- , -OSO2-toluene), mesylate (MsO - , -OSO2-Me) and trifluoromethanesulfonate (TfO - , -OSO2-CF3).

[0073] For example, one skilled in the art will recognize that the present disclosure encompasses a process for preparing a compound of formula (I) as defined elsewhere in this specification, the process comprising

[0074] (i) reacting a sulfide or hydrosulfide anion selected from sodium sulfide (Na2S), hydrogen sulfide H2S (typically used in the presence of a base such as NaOH), (NH4)2S and K2S with a compound of formula (II) as defined elsewhere in this specification in the presence of a solvent system comprising an organic solvent; and

[0075] (ii) reacting the mixture obtained from step (i) with a base;

[0076] The sulfide or hydrosulfide anion and the compound of formula (II) are added simultaneously.

[0077] For example, the method comprises

[0078] (i) reacting a sulfide or hydrosulfide anion selected from sodium sulfide (Na2S) with a compound of formula (II) as defined elsewhere in this specification in the presence of a solvent system comprising an organic solvent; and

[0079] (ii) reacting the mixture obtained from step (i) with a base selected from the group consisting of LiOH, NaOH, KOH, Na2CO3, NaHCO3, K2CO3 and KHCO3;

[0080] The sulfide or hydrosulfide anion and the compound of formula (II) are added simultaneously.

[0081] For example, the method comprises

[0082] (i) reacting sodium sulfide (Na2S) with a compound of formula (II) as defined elsewhere in this specification in the presence of a solvent system comprising an organic solvent; and

[0083] (ii) reacting the mixture obtained 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;

[0084] wherein the sulfide or hydrosulfide anion and the compound of formula (II) are added simultaneously;

[0085] Where R1 and R 2 Each of which is independently selected from C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, preferably C1-C6 alkyl; and

[0086] Where L 1 , L 2 and L 3 Each of which is independently selected from fluorine, chlorine, bromine or iodine, methoxy, tosylate (TsO - , -OSO2-toluene), mesylate (MsO - , -OSO2-Me) and trifluoromethanesulfonate (TfO - , -OSO2-CF3).

[0087] For example, the method comprises

[0088] (i) reacting a sulfide or hydrosulfide anion selected from sodium sulfide (Na2S), sodium hydrosulfide (NaHS) and mixtures thereof with a compound of formula (II) as defined elsewhere in this specification at a temperature of -10°C to 30°C in the presence of a solvent system comprising an organic solvent and optionally comprising water; and

[0089] (ii) reacting the mixture obtained 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 of 30°C to 70°C;

[0090] wherein the sulfide or hydrosulfide anion and the compound of formula (II) are added simultaneously;

[0091] Where R 1 and R 2 Each of which is independently selected from C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, preferably C1-C6 alkyl; and

[0092] Where L 1 , L 2 and L 3 Each of which is independently selected from fluorine, chlorine, bromine or iodine, methoxy, tosylate (TsO - , -OSO2-toluene), mesylate (MsO - , -OSO2-Me) and trifluoromethanesulfonate (TfO - , -OSO2-CF3).

[0093] For example, the method comprises

[0094] (i) reacting a sulfide or hydrosulfide anion with a compound of formula (II) as defined elsewhere in this specification at a temperature of from -10°C to 30°C in the presence of a solvent system comprising an organic solvent and optionally water; and

[0095] (ii) reacting the mixture obtained from step (i) with a base at a pH of 8 to 12 at a temperature of 30° C. to 70° C.;

[0096] wherein the sulfide or hydrosulfide anion and the compound of formula (II) are added simultaneously;

[0097] Where R 1 and R 2 Each of which is independently selected from C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, preferably C1-C6 alkyl; and

[0098] Where L 1 , L 2 and L 3 Each of which is independently selected from fluorine, chlorine, bromine or iodine, methoxy, tosylate (TsO - , -OSO2-toluene), mesylate (MsO - , -OSO2-Me) and trifluoromethanesulfonate (TfO - , -OSO2-CF3).

[0099] For example, the method comprises

[0100] (i) reacting a sulfide or hydrosulfide anion selected from sodium sulfide (Na2S), sodium hydrosulfide (NaHS) and mixtures thereof with a compound of formula (II) as defined elsewhere in this specification at a temperature of -10°C to 30°C in the presence of a solvent system comprising an organic solvent and optionally comprising water; and

[0101] (ii) reacting the mixture obtained 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 of 30°C to 70°C;

[0102] wherein the sulfide or hydrosulfide anion and the compound of formula (II) are added simultaneously;

[0103] Where R 1 and R 2 Each of is independently selected from C1-C6 alkyl; and

[0104] Where L 1 , L 2 and L 3 Each of which is independently selected from chloro, bromo, methoxy, tosylate (TsO - , -OSO2-toluene), mesylate (MsO - , -OSO2-Me) and trifluoromethanesulfonate (TfO - , -OSO2-CF3), preferably chlorine.

[0105] For example, the method comprises

[0106] (i) reacting sodium sulfide (Na2S) with a compound of formula (II) as defined elsewhere in this specification at a temperature between -10°C and 30°C in the presence of a solvent system comprising an organic solvent and optionally water; and

[0107] (ii) reacting the mixture obtained from step (i) with a base at a pH of 8 to 12 at a temperature of 30° C. to 70° C.;

[0108] wherein sodium sulfide (Na2S) and the compound of formula (II) are added simultaneously;

[0109] Where R 1 and R 2 Each of is independently selected from C1-C6 alkyl; and

[0110] Where L 1 , L 2 and L 3 Each of which is chlorine.

[0111] For example, the method is a method for preparing 2,4-dimethyl-2,3-dihydrothiophen-3-one, which comprises

[0112] (i) reacting a sulfide or hydrosulfide anion selected from sodium sulfide (Na2S), sodium hydrosulfide (NaHS) and mixtures thereof with a compound of formula (II) as defined elsewhere in this specification at a temperature of -10°C to 30°C in the presence of a solvent system comprising an organic solvent and optionally comprising water, wherein R 1 and R 2 Each of is methyl, preferably 1,2,4-trichloro-2-methylpentan-3-one; and

[0113] (ii) reacting the mixture obtained from step (i) with a base at a pH of 8 to 12 at a temperature of 30° C. to 70° C.;

[0114] The sulfide or hydrosulfide anion and the compound of formula (II) are added simultaneously. Example

[0115] Example 1: Preparation of 2,4-dimethyl-2,3-dihydrothiophen-3-one (compound of formula (I)) from 1,2,4-trichloro-2-methylpentan-3-one (compound of formula (II))

[0116] Step (i)

[0117] A four-necked flask was equipped with a thermometer, a pH meter, a magnetic stirrer and flushed with nitrogen. Methanol (13 mL) was added to the flask and degassed, then filled with nitrogen. At 20-25° C., 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 added simultaneously over a period of 1 hour (Na2S: compound of formula (II) = 1.2:1). A pump was used to meter the solution in both cases. After the addition was complete, the pH was about 8.3. The reaction mixture was stirred at 20-25° C. for another hour, after which the pH dropped to about 7.1, and less than 2% of the initial 1,2,4-trichloro-2-methylpentan-3-one remained.

[0118] Step (ii)

[0119] The pH was then adjusted to 11-11.5 by adding 15% NaOH at 20-25° C. The reaction mixture was stirred at 20-25° C. for 0.5 h and the pH was maintained at 10.5-11 by adding 15% NaOH when necessary. The reaction mixture was then warmed to 40° C. and stirred for 1 h while maintaining the pH at 10.5-11.

[0120] Step (iii)

[0121] The reaction mixture was then cooled to a temperature below 35°C and methanol was removed by vacuum distillation (40-50 mbar) under nitrogen. Once the distillation was complete, the flask was filled with nitrogen again. 10 mL of water and 20 mL of MTBE were added, and the pH was adjusted to 8-8.5 by dropping 2N HCl at 20-30°C. The mixture was transferred to a separatory funnel filled with nitrogen, and the upper organic layer was 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 give crude 2,4-dimethyl-2,3-dihydrothiophene-3-one (5.90 g, 83% yield).

[0122] If any water remained, it was removed under higher vacuum (in a larger scale plant it can be simply separated). The crude 2,4-dimethyl-2,3-dihydrothiophen-3-one was distilled (bp. 58° C. at 1-2 mbar) and was ready for the next step. As described above, all processes were carried out under nitrogen, including solvent removal, extraction and phase separation.

[0123] Example 2: Preparation of 2,4-dimethyl-2,3-dihydrothiophen-3-one (compound of formula (I)) from 1,2,4-trichloro-2-methylpentan-3-one (compound of formula (II)) using different addition orders and conditions

[0124] Following the experimental procedure of Example 1, the preparation of 2,4-dimethyl-2,3-dihydrothiophen-3-one (compound of formula (I)) from 1,2,4-trichloro-2-methylpentan-3-one (compound of formula (II)) and Na2S·9H2O was repeated using the conditions and addition order shown in Table 1 below.

[0125] Table 1

[0126]

[0127] In Comparative Example 1 (Comp. 1), 1,2,4-trichloro-2-methylpentan-3-one (compound of formula (II)) was added on Na2S·9H2O. In Comparative Example 2 (Comp. 2), Na2S·9H2O was added on 1,2,4-trichloro-2-methylpentan-3-one (compound of formula (II)). Example A of the present invention was carried out under the same conditions, but 1,2,4-trichloro-2-methylpentan-3-one and Na2S·9H2O were added simultaneously. As shown in Table 1 above, the yield increased when the two starting materials were added simultaneously. Examples B, C, D and E of the present invention used different ratios of reagents, temperatures and pH values, and all examples were still better than Comp. 1 or Comp. 2.

[0128] The use of only water as solvent in Comp. 3 resulted in low yields and many oligomeric and polymeric products despite the simultaneous addition of 1,2,4-trichloro-2-methylpentan-3-one (compound of formula (II)) and Na2S·9H2O.

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 method comprises (i) reacting a sulfide or hydrosulfide anion with a compound of formula (II) in the presence of a solvent system comprising an organic solvent in L 1 , L 2 and L 3 Each of is independently selected from a leaving group; and R 1 and R 2 As defined above; and (ii) reacting the mixture obtained from step (i) with a base; The sulfide or hydrosulfide anion and the compound of formula (II) are added simultaneously.

2. The method according to claim 1, wherein R 1 and R 2 Each is independently selected from C1-C6 alkyl.

3. The method according to claim 2, wherein R 1 and R 2 All are methyl.

4. A method according to any one of the preceding claims, wherein L 1 , L 2 and L 3 Each is independently selected from chlorine, bromine and iodine.

5. A process according to any one of the preceding claims, wherein the temperature in step (i) is maintained at -10°C to 30°C.

6. A process according to any one of the preceding claims, wherein the temperature in step (ii) is maintained at 30 to 70°C.

7. A process according to any one of the preceding claims, wherein the pH in step (ii) is maintained at 7 to 12.

8. A process according to any one of the preceding claims, wherein the pH is maintained in step (ii) by adding an alkali metal or alkaline earth metal hydroxide or carbonate or bicarbonate.

9. A method according to any one of the preceding claims, wherein step (i) comprises step (ia), which comprises simultaneously adding the sulfide or hydrosulfide anion and the compound of formula (II) at a temperature of -10°C to 20°C over a period of 1 minute to 24 hours; and Step (ib) comprising reacting the mixture obtained from step (ia) at a temperature of 0°C to 30°C for a period of 1 minute to 24 hours.

10. A process according to any one of the preceding claims, wherein the sulfide or hydrosulfide anion is selected from sodium sulfide, sodium hydrosulfide and mixtures thereof.

11. The process according to any one of the preceding claims, wherein the process is a batch, semi-batch or continuous process.

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 a compound as defined in claim 1 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.

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