Method for preparing dimethenamid

Abstract

The present invention relates to a process for the preparation of N-(1-methoxypropyl-2-yl)-2, 4-dimethyl-3-aminothiophene or a salt thereof, the process comprising reacting 2, 4-dimethyl-2, 3, 4-triazolo [3, 4-b] pyrimidine-2-one or a salt thereof in an organic solvent, 3-thiophene-3-one is contacted with 2-methoxyisopropylamine in the presence of one or more compounds selected from the group consisting of an acidic salt of 2-methoxyisopropylamine, a Lewis acid, trifluoromethanesulfonic acid, gaseous hydrochloric acid, and a mixture of hydrochloric acid and a C1-C6-alkyl alcohol.

Description

Technical Field

[0001] The present invention relates to the field of synthesis of organic compounds, and more particularly to a method for preparing dimethenamid and its intermediates. 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 active ingredient is one of the key factors determining the commercialization of an active ingredient.

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

[0004]

[0005] The synthetic scheme for preparing dimethenamid typically involves the construction of a thiophene ring (typically thiophene-3-one) followed by the incorporation of 2-methoxy-2-propylamine (or 2-methoxyisopropylamine (also known as MOIPA)) to complete by coupling a 2-chloroacetamide moiety. One of the key steps is the incorporation of the MOIPA moiety, typically by condensation of 2,4-dimethyltetrahydrothiophene-3-one and / or 2,4-dimethyl-2,3-dihydrothiophene-3-one with S-2-methoxyisopropylamine (also known as S-MOIPA) to obtain N-(1-methoxypropan-2-yl)-2,4-dimethyl-3-aminothiophene.

[0006]

[0007] For example, EP 0 210 320 prepares the desired 2,4-dimethyltetrahydrothiophene-3-one and then proceeds to react it with S-MOIPA in cyclohexene under heating and in the presence of molecular sieves (see Example 1). The resulting imine is reacted under a number of different oxidation conditions to provide N-(1-methoxypropan-2-yl)-2,4-dimethyl-3-aminothiophene.

[0008] Later methods sought the coupling of S-MOIPA to obtain N-(1-methoxypropan-2-yl)-2,4-dimethyl-3-aminothiophene in a single step. EP 0296463 discloses the reaction of a mixture of 2,4-dimethyl-2,3-dihydrothiophene-3-one and 2,4-dimethyl-3-hydroxythiophene with MOIPA in the presence of concentrated hydrochloric acid in Example 4. After work-up, the reaction directly provides N-(1-methoxypropan-2-yl)-2,4-dimethyl-3-aminothiophene.

[0009] US 5,457,085 discloses a method for preparing N-(1-methoxyprop-2-yl)-2,4-dimethyl-3-aminothiophene by reacting 2,4-dimethyl-2,3-dihydrothiophene-3-one (a compound of formula (II) which may exist as a mixture with its tautomeric form 2,4-dimethyl-3-hydroxythiophene) with S-MOIPA (a compound of formula (III)). The reaction may use S-MOIPA as a solvent and a strong acid (such as hydrochloric acid, acetic acid or trifluoroacetic acid). Example 7 discloses a method in which S-MOIPA is used as a solvent and concentrated hydrochloric acid is used in a stoichiometric amount relative to 2,4-dimethyl-3-thiophene.

[0010] In CN 113024505, the strategy is similar, but instead of S-MOIPA, the corresponding alcohol without a methyl group is used for coupling with 2,4-dimethyl-3-thiophenone. The resulting product is then methylated to obtain N-(1-methoxyprop-2-yl)-2,4-dimethyl-3-aminothiophene.

[0011] None of these methods are completely satisfactory. Therefore, there is a need in the art to provide alternative procedures for obtaining dimethenamid and its intermediates. There is a need to provide a more efficient coupling between MOIPA and 2,4-dimethyl-3-thiophenone, such as a method that provides higher yields, improved enantiomeric excess, milder conditions and / or easier workup. Summary of the invention

[0012] The inventors have now realised that the choice of acid is key to obtaining good yields in the reaction to obtain N-(1-methoxypropan-2-yl)-2,4-dimethyl-3-aminothiophene.

[0013] Therefore, a first aspect of the present invention is a method for preparing N-(1-methoxyprop-2-yl)-2,4-dimethyl-3-aminothiophene or a salt thereof, which comprises contacting 2,4-dimethyl-2,3-dihydrothiophene-3-one with 2-methoxyisopropylamine in the presence of one or more acid compounds selected from the group consisting of: gaseous hydrochloric acid, an acid salt of 2-methoxyisopropylamine, a Lewis acid, trifluoromethanesulfonic acid, and a mixture of hydrochloric acid and a C1-C6-alkyl alcohol.

[0014] Typically, the 2-methoxyisopropylamine is S-2-methoxyisopropylamine.

[0015] The methods disclosed herein provide N-(1-methoxyprop-2-yl)-2,4-dimethyl-3-aminothiophene, salts, in good to excellent yields and without (or with very little) loss of enantiomeric excess. To obtain dimethenamid (typically, dimethenamid-P), only the 2-chloroacetyl moiety needs to be added. Therefore, another aspect is a method for preparing dimethenamid-P, the method comprising

[0016] (i) preparing N-(1-methoxypropan-2-yl)-2,4-dimethyl-3-aminothiophene and its salts according to the method defined above; and

[0017] (ii) The obtained N-(1-methoxypropan-2-yl)-2,4-dimethyl-3-aminothiophene or a salt thereof is reacted with 2-chloroacetyl chloride.

[0018] A further aspect is the use of 2-methoxyisopropylamine for stabilizing, storing, packaging or transporting 2,4-dimethyl-2,3-dihydrothiophen-3-one.

[0019] Another aspect is a method comprising storing, packaging or transporting 2,4-dimethyl-2,3-dihydrothiophen-3-one in contact with 2-methoxyisopropylamine, a salt thereof. The inventors have observed that storing 2,4-dimethyl-2,3-dihydrothiophen-3-one overnight in the presence of air results in a loss of 10% to 20% of the material. On the other hand, when 2,4-dimethyl-2,3-dihydrothiophen-3-one was stored in the presence of 2-methoxyisopropylamine under the same conditions, no loss of material was observed.

[0020] In view of the literature, it is unexpected that such acids provide good yields and at the same time there is no loss of enantiomeric excess. For example, the use of concentrated hydrochloric acid reported in the literature produces a significant loss of enantiomeric excess. However, the use of gaseous hydrochloric acid or any of the acids mentioned above prevents this problem. An additional benefit observed is that the reaction is carried out at a lower temperature. For example, similar reactions in US 5,457,085 (Example 7) require greater than 200 ° C in order to proceed, while the method of the present invention is carried out to completion at a temperature as low as 120 ° C. DETAILED DESCRIPTION

[0021] definition

[0022] In this document, the following terms have the following meanings.

[0023] As noted, the present invention also provides salts of compounds. For example, the salts of compounds provided herein can be acid addition salts, and they can be synthesized from parent compounds containing basic moieties by conventional chemical methods. Typically, such salts are prepared, for example, by reacting the free alkali forms of these compounds with a stoichiometric amount of an appropriate acid in water or in an organic solvent or in a mixture of the two. Typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Examples of acid addition salts include mineral acid addition salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; and organic acid addition salts, such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate.

[0024] The compounds of the invention are also intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, a structure having the present invention except for the replacement of hydrogen by deuterium or tritium, or by an isotopically enriched 13 C or 14 C replaces carbon, or is rich in 15 N, or rich in 19 Compounds containing fluorine (except fluorine) in the above-mentioned compound are within the scope of the present invention.

[0025] The starting material 2,4-dimethyl-2,3-dihydrothiophen-3-one also exists in its tautomeric form 2,4-dimethyl-3-hydroxythiophenone. The ratio between the two tautomeric forms depends on different factors. For the purposes of this application, they are both considered equivalent.

[0026]

[0027] acid

[0028] The process of the present invention is carried out in the presence of one or more acids (preferably in catalytic amounts). The acid is selected from the group consisting of acid salts of 2-methoxyisopropylamine, Lewis acids, trifluoromethanesulfonic acid, gaseous hydrochloric acid and a mixture of hydrochloric acid and C1-C6-alkyl alcohol.

[0029] It is known that the reaction of 2,4-dimethyltetrahydrothiophene-3-one with MOIPA is carried out in the presence of concentrated hydrochloric acid (e.g. US5,457,085). The inventors have found that the use of concentrated hydrochloric acid is unsatisfactory, mainly due to the loss of enantiomeric excess in the final product N-(1-methoxyprop-2-yl)-2,4-dimethyl-3-aminothiophene. It has been found that the use of an acid selected from the group consisting of an acid salt of 2-methoxyisopropylamine, a Lewis acid, trifluoromethanesulfonic acid, gaseous hydrochloric acid and a mixture of hydrochloric acid with a C1-C6-alkyl alcohol is surprisingly effective in preventing this problem.

[0030] For example, the acid salt of 2-methoxyisopropylamine (preferably used in catalytic amounts) completely prevents the loss of enantiomeric excess under many conditions. The added benefit is that the reaction is carried out at a lower temperature. Before reacting with 2,4-dimethyltetrahydrothiophene-3-one, the corresponding salt of 2-methoxyisopropylamine is prepared and then added as any other reactant, rather than adding an aqueous acid solution to the reaction together with 2-methoxyisopropylamine. Preferably, the preparation of the salt of 2-methoxyisopropylamine includes contacting 2-methoxyisopropylamine with the corresponding acid in a solvent, preferably a non-aqueous solvent, followed by drying to remove excess water. The inventors have found that if the water content in the salt of 2-methoxyisopropylamine is 5% or less or less than 5% as measured by Karl-Fischer titration, the reaction is carried out with better enantiomeric excess. Any addition salt is suitable, for example a salt of 2-methoxyisopropylamine selected from the group consisting of: HX, wherein X is a halogen (e.g. hydrochloride, hydrobromide, hydroiodide), sulfate, nitrate, phosphate, organic acid addition salt (such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate or p-toluenesulfonate). Preferably, the salt is HX, wherein X is a halogen, such as hydrochloride, hydrobromide or hydroiodide.

[0031] Thus, for example, the methods disclosed herein include

[0032] a) providing an acid salt of 2-methoxyisopropylamine;

[0033] b) contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with an acid salt of neutral 2-methoxyisopropylamine in the presence of said 2-methoxyisopropylamine.

[0034] For example, the methods disclosed herein include

[0035] a) providing an acid salt of 2-methoxyisopropylamine;

[0036] b) contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with at least one equivalent of 2-methoxyisopropylamine and a catalytic or stoichiometric amount of an acid salt of 2-methoxyisopropylamine.

[0037] Other acids useful for the methods of the present invention are Lewis acids. The inventors have found that a wide range of Lewis acids improves the yield of the reaction and simultaneously prevents the loss of enantiomeric excess. An added benefit of using a Lewis acid is that the reaction is carried out at a lower temperature. The inventors have tested many Lewis acids, such as Zn(OAc)2, ZnCl2, FeCl2, FeCl3, TiCl4, Fe(OTf)3 or BF3.OEt2, with good to excellent results. Therefore, Lewis acids useful in the methods disclosed herein are substances that can accept electron pairs, such as cations of some metals, such as alkali metals (e.g., Li + ) and alkaline earth metals (such as Mg 2+ ) cations, or cations of transition metals or rare earth elements (such as Fe 2+ , Fe 3+ 、Zn 2+ Sc 3+ , Cu 2+ 、Ti 4+ 、Al 3+ Sn 2+ Sn 4+ 、Ni 2+ ,La 3+ 、In 3+ 、Ce 3+ or Ce 4+ ). Thus, the Lewis acid useful in the methods disclosed herein can be a cation of a metal selected from the group consisting of: Fe 2+ , Fe 3+ 、Zn 2+ Sc 3+ , Cu 2+ 、Ti 4 + 、Al 3+ Sn 2+ Sn 4+ 、Ni 2+ ,La 3+ 、In 3+ 、Ce 3+ 、Ce 4+ , Li + and Mg 2+Other Lewis acids are, for example, borane derivatives such as BF3.OEt2 or BCl3 or other substances such as tributylphosphine, triphenylphosphine or TMSOTf (trimethylsilyl trifluoromethanesulfonate). Typically, the Lewis acid is a halide, acetate or -OTf salt of the above cations. Therefore, in the present invention, the Lewis acid is typically a halide, acetate or -OTf salt of a metal cation or a rare earth element, such as a chloride, acetate or -OTf. Non-limiting examples of Lewis acids useful in the methods disclosed herein are Lewis acids selected from the group consisting of Zn(OAc)2, ZnCl2, ZnBr2, FeCl2, FeCl3, TiCl4, Fe(OTf)3, BF3.OEt2, BCl3, SnCl4, Ni(OTf)2 (OTf=trifluoromethanesulfonate), Zn(OTf)2, Sc(OTf)3, Sn(OTf)2, Cu(OTf)2, La(OTf)3, In(OTf)3, CeCl3, CuCl2, LiBr, LiI, LiCl, MgCl2, MgBr2, MgSO4, AlCl3, AlMeCl2, and AlMe2Cl. Typical examples according to the present disclosure are Zn(OAc)2, ZnBr2, FeCl2, FeCl3, TiCl4, Fe(OTf)3, BF3.OEt2, BCl3, SnCl4, Ni(OTf)2 (OTf=trifluoromethanesulfonate), Zn(OTf)2, Sc(OTf)3, Sn(OTf)2, Cu(OTf)2, La(OTf)3, In(OTf)3, CeCl3, CuCl2, LiBr, LiI, LiCl, MgCl2, MgBr2, MgSO4, AlCl3, AlMeCl2, and AlMe2Cl. 2+ , Fe 2+ , Fe 3+ 、Ti 4+ 、Al 3+ Cu 2+ A preferred Lewis acid is a Lewis acid selected from the group consisting of ZnCl2, ZnBr2, FeCl2, FeCl3, TiCl4, Fe(OTf)3, BF3.OEt2, SnCl4, CuCl2 and AlCl3.

[0038] Another acid that has shown excellent results is trifluoromethanesulfonic acid (trifluoromethanesulfonic acid or F3C-S(O)2OH). Although concentrated aqueous hydrochloric acid results in a significant loss of enantiomeric excess of the product N-(1-methoxypropan-2-yl)-2,4-dimethyl-3-aminothiophene, gaseous hydrochloric acid provides excellent yields.

[0039] The acid may be added in a catalytic amount or in a stoichiometric amount or in excess. The acid is preferably added in a catalytic amount, typically in an amount between 0.01 and 0.9 equivalents relative to the 2,4-dimethyl-2,3-dihydrothiophene-3-one used as a reactant. Typical catalytic amounts of the acid are included between 0.01 and 0.5 equivalents, such as between 0.02 and 0.4 equivalents, preferably between 0.3 and 0.3 equivalents relative to the 2,4-dimethyl-2,3-dihydrothiophene-3-one used as a reactant.

[0040] The amount of S-MOIPA required for the reaction to proceed to completion is 1 equivalent relative to the 2,4-dimethyl-2,3-dihydrothiophen-3-one used as a reactant, although an excess can be used to maximize conversion, such as from greater than 1 to 10 equivalents, such as from greater than one to 5 equivalents, or from 1.1 to 4 equivalents, or from 1.5 to 4 equivalents, such as greater than 1.2 equivalents or greater than 1.5 equivalents or greater than 1.8 equivalents relative to the 2,4-dimethyl-2,3-dihydrothiophen-3-one starting material. It may be advantageous to use an excess of S-MOIPA so that it acts as a solvent.

[0041] Coupling of 2,4-dimethyl-2,3-dihydrothiophen-3-one with S-MOIPA

[0042] The reaction is preferably carried out at a temperature of from 50° C. to 250° C., more preferably from 100° C. to 250° C., more preferably from 80° C. to 230° C., more preferably from 120° C. to 200° C., in particular from 110° C. to 210° C., for example from 150° C. to 190° C. For example, the reaction temperature is higher than 100° C., preferably higher than 110° C., more preferably higher than 120° C., more preferably higher than 150° C., more preferably higher than 160° C., more preferably higher than 170° C.

[0043] The reaction pressure is not critical. The temperature used is sometimes higher than the boiling point of at least one of the solvents, and the reaction is then carried out in a closed container. This results in an inherent pressure higher than 1 bar, for example, from 1.1 to 20 bar, particularly from 1.5 to 15 bar, for example, in the range of 3 to 12 bar. The reaction is preferably carried out in a pressure vessel (e.g., autoclave).

[0044] The reaction can be carried out in the presence of a solvent or neat (without a solvent). Preferred solvents are organic solvents, such as aliphatic hydrocarbons (e.g., hexane, heptane, cyclohexane, etc. ...) or aromatic hydrocarbons (e.g., toluene, xylene, etc.). Other organic solvents are also useful, such as ethers (e.g., diethyl ether, tert-butyl methyl ether, diphenyl ether, etc. ...) or amides (e.g., dimethylformamide (DMF), dimethylacetamide (DMA) or N-methylpyrrolidone (NMP)). Generally, since the reaction typically occurs at a temperature between 50° C. and 250° C., the solvent (if used) preferably has a high boiling point (e.g., above 90° C., such as above 100° C., typically between 90° C. and 300° C. or between 100° C. and 250° C.). Therefore, a solvent can be added to the reaction, but no solvent can be added so that an excess of S-MOIPA is used and acts as a solvent.

[0045] The time required for the reaction can vary depending on many factors, such as the amount of acid added (the more acid, the faster the reaction), the temperature, or the amount of S-MOIPA used. Taking these factors into account, the method disclosed herein can take from 1 minute to several hours or days, typically from one hour to 5 days, such as 48 hours, although typical times take from 2 hours to 36 hours, such as from 4 hours to 24 hours. The progress of the reaction can be tracked using common techniques (e.g., gas chromatography).

[0046] The reaction does not necessarily require special equipment, and any vessel typically used for chemical reactions should be suitable. In cases where some pressure buildup is expected, an autoclave vessel or other means of handling the pressure may be used.

[0047] The reaction is preferably carried out in an inert atmosphere to avoid the presence of oxygen, for example under an argon or nitrogen atmosphere.

[0048] The order of adding reagents is not critical. However, the inventors have found that neutral S-MOIPA has an unexpected stabilizing effect on 2,4-dimethyl-2,3-dihydrothiophene-3-one. Therefore, it is preferred to add both together. It is even possible to produce a stock solution of S-MOIPA and 2,4-dimethyl-2,3-dihydrothiophene-3-one that can be used in the reaction. Therefore, another aspect of the present invention is a method that includes storing, packaging or transporting 2,4-dimethyl-2,3-dihydrothiophene-3-one contacted with 2-methoxyisopropylamine, its salt. The method therefore includes contacting 2,4-dimethyl-2,3-dihydrothiophene-3-one with 2-methoxyisopropylamine, its salt in the absence of other reagents or solvents, and storing the two together for an extended period of time, for example, greater than 1 hour, or greater than 6 hours, or greater than 12 hours, or greater than 18 hours, or greater than 24 hours, or greater than 36 hours or greater than 48 hours. The mixture stabilizes 2,4-dimethyl-2,3-dihydrothiophen-3-one and can be packaged and transported without decomposing 2,4-dimethyl-2,3-dihydrothiophen-3-one. Therefore, a further aspect of the present invention is the use of 2-methoxyisopropylamine for stabilizing, storing, packaging or transporting 2,4-dimethyl-2,3-dihydrothiophen-3-one.

[0049] After the reaction is complete, the reaction mixture is post-processed and N-(1-methoxyprop-2-yl)-2,4-dimethyl-3-aminothiophene, its salt are separated in the usual manner. For example, the acid can be neutralized with a base (e.g., NaOH) to stop the reaction, and the solvent and / or excessive S-MOIPA are removed, for example, under reduced pressure. If desired, the addition of a base can be avoided, and post-processed without the addition of a base, for example, by removing a solvent and / or excessive S-MOIPA (e.g., under reduced pressure), followed by the addition of water to remove any remaining salt. Standard conditions (distillation, gel chromatography, recrystallization, etc.) can then be followed to purify the resulting N-(1-methoxyprop-2-yl)-2,4-dimethyl-3-aminothiophene.

[0050] The method of the present invention can be performed in different variations. Thus, for example, the method disclosed herein can include providing a mixture (preferably preformed) of 2,4-dimethyl-2,3-dihydrothiophene-3-one and MOIPA (preferably S-MOIPA), and contacting them with a preformed salt of S-methoxyisopropylamine S-MOIPA·HX (preferably in a catalytic amount relative to 2,4-dimethyl-2,3-dihydrothiophene-3-one), wherein X is chlorine, bromine or fluorine, and the salt has a water content of less than 5%, preferably less than 3%, as measured by Karl-Fischer titration. The salt is preferably the hydrochloride of S-MOIPA (S-MOIPA·HCl). The temperature is preferably included between 120°C and 200°C, and the reaction time is typically 6 to 36 hours.

[0051] For example, the methods disclosed herein may include providing a mixture (preferably a preformed mixture) of 1 equivalent of 2,4-dimethyl-2,3-dihydrothiophen-3-one and 1 to 5 equivalents of MOIPA (preferably S-MOIPA), and contacting them with 0.01 to 1.0, such as 0.01 to 0.9, preferably 0.01 to 0.6, 0.05 to 0.5 or preferably 0.1 to 0.4 or 0.1 to 0.3 equivalents of S-methoxyisopropylamine, a preformed salt S-MOIPA.HX (wherein X is chlorine, bromine or fluorine), relative to 2,4-dimethyl-2,3-dihydrothiophen-3-one, the salt having a water content of less than 5%, preferably less than 3%, as measured by Karl-Fischer titration. The salt is preferably the hydrochloride salt of S-MOIPA (S-MOIPA.HCl). The temperature is preferably comprised between 120°C and 200°C, and the reaction time is typically 6 to 36 hours.

[0052] For example, the methods disclosed herein may include providing a mixture (preferably a preformed mixture) of 1 equivalent of 2,4-dimethyl-2,3-dihydrothiophen-3-one and 1 to 5 equivalents of MOIPA (preferably S-MOIPA), and contacting them with a solvent (preferably an aromatic hydrocarbon (e.g., toluene or xylene) or an ether (e.g., THF, MeTHF, or diphenyl ether)) and 0.01 to 0.9 (preferably 0.01 to 0.6, or preferably 0.01 to 0.4) equivalents of a preformed salt of S-methoxyisopropylamine S-MOIPA.HX (wherein X is chlorine, bromine, or fluorine) relative to 2,4-dimethyl-2,3-dihydrothiophen-3-one, the salt having a water content of less than 5%, preferably less than 3%, as measured by Karl-Fischer titration. The salt is preferably the hydrochloride salt of S-MOIPA (S-MOIPA.HCl). The temperature is preferably comprised between 120° C. and 200° C., and the reaction time is typically between 6 and 36 hours.

[0053] In another example, the method disclosed herein may include providing a mixture (preferably a preformed mixture) of 1 equivalent of 2,4-dimethyl-2,3-dihydrothiophen-3-one and 1.5 to 4 equivalents of MOIPA (preferably S-MOIPA), and contacting them with 0.05 to 0.6 equivalents of a preformed salt of S-methoxyisopropylamine, S-MOIPA.HX (wherein X is chlorine, bromine or fluorine), relative to 2,4-dimethyl-2,3-dihydrothiophen-3-one, the salt having a water content of less than 5%, preferably less than 3%, as measured by Karl-Fischer titration, and wherein no solvent is added. The salt is preferably the hydrochloride salt of S-MOIPA (S-MOIPA.HCl).

[0054] The use of the term "preformed mixture" refers to a mixture of 2,4-dimethyl-2,3-dihydrothiophen-3-one and 2-methoxyisopropylamine (preferably S-MOIPA) that has been prepared prior to the reaction. The mixture of these two components can be prepared immediately prior to the reaction, or it can be prepared and stored prior to, for example, greater than 1 hour, or greater than 6 hours, or greater than 12 hours, or greater than 18 hours, or greater than 24 hours, or greater than 36 hours, or greater than 48 hours.

[0055] Additional examples of the methods disclosed herein include providing a mixture of 2,4-dimethyl-2,3-dihydrothiophene-3-one, MOIPA (preferably S-MOIPA) and a Lewis acid (preferably a catalytic amount), optionally in the presence of a solvent. The temperature is preferably comprised between 120° C. and 200° C., and the reaction time is typically 6 to 36 hours.

[0056] For example, the method may include providing a mixture of 2,4-dimethyl-2,3-dihydrothiophen-3-one, MOIPA (preferably S-MOIPA) and 0.01 to 0.9 equivalents (relative to 2,4-dimethyl-2,3-dihydrothiophen-3-one), preferably 0.01 to 0.6, or preferably 0.01 to 0.4 equivalents of a Lewis acid selected from the group consisting of: Fe 2+ , Fe 3+ 、Zn 2+ Sc 3+ , Cu 2+ 、Ti 4+ 、Al 3+ Sn 2+ Sn 4+ 、Ni 2+ ,La 3+ 、In 3+ 、Ce 3+ 、Ce 4+ , Li + Mg 2+ , BF3.OEt2, BCl3, tributylphosphine, triphenylphosphine and TMSOTf (trimethylsilyl trifluoromethanesulfonate). The temperature is preferably comprised between 120° C. and 200° C. and the reaction time is typically between 6 and 36 hours.

[0057] For example, the method may include providing 1 equivalent of 2,4-dimethyl-2,3-dihydrothiophen-3-one, between 1 and 10 equivalents, preferably greater than 1 and 4 equivalents of MOIPA (preferably S-MOIPA), and 0.01 to 0.9 equivalents (relative to 2,4-dimethyl-2,3-dihydrothiophen-3-one), preferably 0.01 to 0.6, or preferably 0.01 to 0.4 equivalents of a Lewis acid selected from the group consisting of: Fe 2+ , Fe 3+ 、Zn 2+ Sc 3+ , Cu 2+ 、Ti 4+ 、Al 3+ Sn 2+ Sn 4+ 、Ni 2+ ,La 3+ 、In 3 + 、Ce 3+ 、Ce 4+ , Li + Mg 2+, BF3.OEt2, BCl3, tributylphosphine, triphenylphosphine and TMSOTf (trimethylsilyl trifluoromethanesulfonate). The temperature is preferably between 120°C and 200°C, and the reaction time is typically 6 to 36 hours. Although the reaction can be carried out in the absence of a solvent (neat), it is optionally carried out in the presence of a solvent selected from the group consisting of: aromatic hydrocarbons (e.g. toluene or xylene) and ethers (e.g. THF, MeTHF or diphenyl ether).

[0058] For example, the method may include providing 1 equivalent of 2,4-dimethyl-2,3-dihydrothiophen-3-one, between 1 and 10 equivalents, preferably greater than 1 and 4 equivalents of MOIPA (preferably S-MOIPA), and 0.01 to 0.4 equivalents (relative to 2,4-dimethyl-2,3-dihydrothiophen-3-one) of a mixture of a Lewis acid selected from the group consisting of: Zn(OAc)2, ZnCl2, ZnBr2, FeCl2, FeCl3, TiCl 4, Fe(OTf)3, BF3.OEt2, BCl3, SnCl4, Ni(OTf)2 (OTf=trifluoromethanesulfonate), Zn(OTf)2, Sc(OTf)3, Sn(OTf)2, Cu(OTf)2, La(OTf)3, In(OTf)3, CeCl3, CuCl2, LiBr, LiI, LiCl, MgCl2, MgBr2, MgSO4, AlCl3, AlMeCl2 and AlMe2Cl. The temperature is preferably comprised between 120°C and 200°C and the reaction time is typically 6 to 36 hours. Although the reaction can be carried out in the absence of a solvent (neat), it is optionally carried out in the presence of a solvent selected from the group consisting of an aromatic hydrocarbon (e.g. toluene or xylene) and an ether (e.g. THF, MeTHF or diphenyl ether).

[0059] For example, the method disclosed herein comprises providing 2,4-dimethyl-2,3-dihydrothiophen-3-one, MOIPA (preferably S-MOIPA) and a catalytic amount of Zn in the presence of a solvent. 2+ The temperature is preferably comprised between 120° C. and 200° C., and the reaction time is typically between 6 and 36 hours.

[0060] For example, the method may include providing 1 equivalent of 2,4-dimethyl-2,3-dihydrothiophen-3-one, between 1 and 10 equivalents, preferably greater than 1 and 4 equivalents of MOIPA (preferably S-MOIPA), and 0.01 to 0.6 equivalents (relative to 2,4-dimethyl-2,3-dihydrothiophen-3-one), preferably 0.01 to 0.6, or preferably 0.01 to 0.4 equivalents of Zn 2+The reaction is preferably carried out in the absence of a solvent (neat), but it is optionally carried out in the presence of a solvent selected from the group consisting of aromatic hydrocarbons (e.g. toluene or xylene) and ethers (e.g. THF, MeTHF or diphenyl ether).

[0061] For example, the method may include providing 1 equivalent of 2,4-dimethyl-2,3-dihydrothiophen-3-one, between 1 and 10 equivalents, preferably greater than 1 and 4 equivalents of MOIPA (preferably S-MOIPA), between 0.5 and 5 equivalents of water (preferably 0.8 to 1.5 equivalents), and 0.01 to 0.4 equivalents (relative to 2,4-dimethyl-2,3-dihydrothiophen-3-one) of Zn 2+ (e.g., ZnCl2 or ZnBr2). The temperature is preferably comprised between 120°C and 200°C, and the reaction time is typically 6 to 36 hours. Although the reaction can be carried out in the absence of a solvent (neat), it is optionally carried out in the presence of a solvent selected from the group consisting of: aromatic hydrocarbons (e.g., toluene or xylene) and ethers (e.g., THF, MeTHF or diphenyl ether).

[0062] For example, the method disclosed herein comprises providing 2,4-dimethyl-2,3-dihydrothiophen-3-one, MOIPA (preferably S-MOIPA) and a catalytic amount of Fe 2+ or Fe 3+ The temperature is preferably comprised between 120° C. and 200° C., and the reaction time is typically between 6 and 36 hours.

[0063] For example, the method may include providing 1 equivalent of 2,4-dimethyl-2,3-dihydrothiophen-3-one, between 1 and 10 equivalents, preferably greater than 1 and 4 equivalents of MOIPA (preferably S-MOIPA), and 0.01 to 0.9 equivalents (relative to 2,4-dimethyl-2,3-dihydrothiophen-3-one), preferably 0.01 to 0.6, or preferably 0.01 to 0.4 equivalents of Fe 2+ or Fe 3+ (e.g., a mixture of FeCl2, FeCl3, Fe(OTf)3). The temperature is preferably comprised between 120°C and 200°C, and the reaction time is typically 6 to 36 hours. Although the reaction can be carried out in the absence of a solvent (neat), it is optionally carried out in the presence of a solvent selected from the group consisting of: aromatic hydrocarbons (e.g., toluene or xylene) and ethers (e.g., THF, MeTHF or diphenyl ether).

[0064] For example, the method may include providing 1 equivalent of 2,4-dimethyl-2,3-dihydrothiophen-3-one, between 1 and 10 equivalents, preferably greater than 1 and 4 equivalents of MOIPA (preferably 2S-MOIPA), and 0.01 to 0.9 equivalents (relative to 2,4-dimethyl-2,3-dihydrothiophen-3-one), preferably 0.01 to 0.6, or preferably 0.01 to 0.4 equivalents of Ti 4+ (e.g., TiCl4). The temperature is preferably comprised between 120°C and 200°C, and the reaction time is typically 6 to 36 hours. Although the reaction can be carried out without a solvent (neat), it is optionally carried out in the presence of a solvent selected from the group consisting of: aromatic hydrocarbons (e.g., toluene or xylene) and ethers (e.g., THF, MeTHF or diphenyl ether).

[0065] For example, the method may include providing 1 equivalent of 2,4-dimethyl-2,3-dihydrothiophene-3-one, between 1 and 10 equivalents, preferably greater than 1 and 4 equivalents of MOIPA (preferably S-MOIPA) and 0.01 to 0.9 equivalents (relative to 2,4-dimethyl-2,3-dihydrothiophene-3-one), preferably 0.01 to 0.6, or preferably 0.01 to 0.4 equivalents of boron (e.g., BF3.OEt2). The temperature is preferably included between 120°C and 200°C, and the reaction time is typically 6 to 36 hours. Although the reaction can be carried out in the absence of a solvent (neat), it is optionally carried out in the presence of a solvent selected from the group consisting of: an aromatic hydrocarbon (e.g., toluene or xylene) and an ether (e.g., THF, MeTHF or diphenyl ether).

[0066] For example, the method disclosed herein comprises providing a mixture of 2,4-dimethyl-2,3-dihydrothiophene-3-one, MOIPA (preferably S-MOIPA) and trifluoromethanesulfonic acid (preferably in a catalytic amount), optionally in the presence of a solvent. The temperature is preferably comprised between 120° C. and 200° C., and the reaction time is typically 6 to 36 hours.

[0067] For example, the method may include providing 1 equivalent of 2,4-dimethyl-2,3-dihydrothiophene-3-one, between 1 and 10 equivalents, preferably greater than 1 and 4 equivalents of MOIPA (preferably S-MOIPA) and 0.01 to 0.9 equivalents (relative to 2,4-dimethyl-2,3-dihydrothiophene-3-one), preferably 0.01 to 0.6, or preferably 0.01 to 0.4 equivalents of trifluoromethanesulfonic acid. The temperature is preferably included between 120°C and 200°C, and the reaction time is typically 6 to 36 hours. Although the reaction can be carried out in the absence of a solvent (neat), it is optionally carried out in the presence of a solvent selected from the group consisting of an aromatic hydrocarbon (e.g., toluene or xylene) and an ether (e.g., THF, MeTHF or diphenyl ether).

[0068] For example, the methods disclosed herein include providing a mixture of 2,4-dimethyl-2,3-dihydrothiophene-3-one, MOIPA (preferably S-MOIPA) and gaseous hydrochloric acid (e.g., in a catalytic amount), optionally in the presence of a solvent. The temperature is preferably between 120° C. and 200° C., and the reaction time is typically 6 to 36 hours.

[0069] For example, the method may include providing 1 equivalent of 2,4-dimethyl-2,3-dihydrothiophene-3-one, between 1 and 10 equivalents, preferably greater than 1 and 4 equivalents of MOIPA (preferably S-MOIPA) and 0.01 to 0.9 equivalents (relative to 2,4-dimethyl-2,3-dihydrothiophene-3-one), preferably 0.01 to 0.6, or preferably 0.01 to 0.4 equivalents of gaseous hydrochloric acid. The temperature is preferably included between 120°C and 200°C, and the reaction time is typically 6 to 36 hours. Although the reaction can be carried out in the absence of a solvent (neat), it is optionally carried out in the presence of a solvent selected from the group consisting of an aromatic hydrocarbon (e.g., toluene or xylene) and an ether (e.g., THF, MeTHF or diphenyl ether).

[0070] For example, the method disclosed herein comprises providing a mixture of 2,4-dimethyl-2,3-dihydrothiophene-3-one, MOIPA (preferably S-MOIPA) and a mixture of methanol and hydrochloric acid (preferably in a catalytic amount), optionally in the presence of a solvent. The temperature is preferably comprised between 120° C. and 200° C., and the reaction time is typically 6 to 36 hours.

[0071] For example, the method may include providing 1 equivalent of 2,4-dimethyl-2,3-dihydrothiophene-3-one, preferably in the absence of water, between 1 and 10 equivalents, preferably greater than 1 and 4 equivalents of MOIPA (preferably S-MOIPA) and 0.01 to 0.9 equivalents (relative to 2,4-dimethyl-2,3-dihydrothiophene-3-one), preferably 0.01 to 0.6, or preferably 0.01 to 0.4 equivalents of a mixture of hydrochloric acid in the form of a mixture with methanol. The temperature is preferably included between 120° C. and 200° C., and the reaction time is typically 6 to 36 hours. Although the reaction can be carried out in the absence of a solvent (neat), it is optionally carried out in the presence of a solvent selected from the group consisting of an aromatic hydrocarbon (e.g., toluene or xylene) and an ether (e.g., THF, MeTHF or diphenyl ether).

[0072] The method of the present invention may use more than one compound selected from the group consisting of an acid salt of 2-methoxyisopropylamine, a Lewis acid, gaseous hydrochloric acid, trifluoromethanesulfonic acid, and a mixture of hydrochloric acid and a C1-C6-alkyl alcohol. For example, the method may include providing a mixture (preferably a preformed mixture) of 1 equivalent of 2,4-dimethyl-2,3-dihydrothiophene-3-one and 1 to 5 equivalents of MOIPA (preferably S-MOIPA), and contacting them with a preformed salt of S-methoxyisopropylamine, S-MOIPA.HX (wherein X is chlorine, bromine or fluorine, and the salt has a water content of less than 5%, preferably less than 3%, as measured by Karl-Fischer titration) and a catalytic amount of an acid (the acid is selected from the group consisting of: a Lewis acid, gaseous hydrochloric acid, trifluoromethanesulfonic acid, and a mixture of hydrochloric acid and a C1-C6-alkyl alcohol). The salt is preferably the hydrochloride salt of S-MOIPA (S-MOIPA.HCl). The temperature is preferably comprised between 120° C. and 200° C., and the reaction time is typically 6 to 36 hours. Lewis acid, gaseous hydrochloric acid, trifluoromethanesulfonic acid, or a mixture of hydrochloric acid and C1-C6-alkyl alcohol can be added in an amount of 0.01 to 0.9 (preferably 0.01 to 0.6, or preferably 0.01 to 0.4) equivalents relative to the amount of 2,4-dimethyl-2,3-dihydrothiophene-3-one. The preformed salt of S-methoxyisopropylamine, S-MOIPA·HX, can be added in a catalytic amount or in a stoichiometric amount.

[0073] Thus, the method may include contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with 2-methoxyisopropylamine, an acid salt of 2-methoxyisopropylamine, and a Lewis acid.

[0074] Thus, the method may include contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with 2-methoxyisopropylamine, an acid salt of 2-methoxyisopropylamine, and gaseous hydrochloric acid.

[0075] Thus, the method may include contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with 2-methoxyisopropylamine, an acid salt of 2-methoxyisopropylamine, and trifluoromethanesulfonic acid.

[0076] Thus, the process may comprise contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with 2-methoxyisopropylamine, an acid salt of 2-methoxyisopropylamine and a mixture of hydrochloric acid and a C1-C6-alkyl alcohol.

[0077] For example, the method can include contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with at least one equivalent of 2-methoxyisopropylamine, a catalytic amount of an acid salt of 2-methoxyisopropylamine, and a catalytic amount of a Lewis acid, wherein the equivalents are measured relative to the amount of 2,4-dimethyl-2,3-dihydrothiophen-3-one.

[0078] For example, the method can include contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with 2-methoxyisopropylamine, at least one equivalent of an acid salt of 2-methoxyisopropylamine, and a catalytic amount of a Lewis acid, wherein the equivalents are measured relative to the amount of 2,4-dimethyl-2,3-dihydrothiophen-3-one.

[0079] Preferred Lewis acids to be mixed with the acid salt of 2-methoxyisopropylamine are those containing a cation of a metal selected from the group consisting of: Fe 2+ , Fe 3+ 、Zn 2+ Sc 3+ , Cu 2+ 、Ti 4+ 、Al 3+ Sn 2+ Sn 4+ 、Ni 2+ ,La 3+ 、In 3+ 、Ce 3+ 、Ce 4+ , Li + and Mg 2+ Thus, an alternative method of the present invention comprises contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with 2-methoxyisopropylamine, an acid salt of 2-methoxyisopropylamine, and a Lewis acid, wherein the Lewis acid is a cation of a metal selected from the group consisting of: Fe 2+ , Fe 3+ 、Zn 2+ Sc 3+ , Cu 2+ 、Ti 4+ 、Al 3+ Sn 2+ Sn 4+、Ni 2+ ,La 3+ 、In 3+ 、Ce 3+ 、Ce 4+ , Li + and Mg 2+ For example, the method may include contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with 2-methoxyisopropylamine, an acid salt of 2-methoxyisopropylamine, and a catalytic amount of a Lewis acid, wherein the Lewis acid is a cation of a metal selected from the group consisting of: Fe 2+ , Fe 3+ 、Zn 2+ Sc 3+ , Cu 2+ 、Ti 4+ 、Al 3+ Sn 2+ Sn 4+ 、Ni 2+ ,La 3+ 、In 3+ 、Ce 3+ 、Ce 4+ , Li + and Mg 2+ , and wherein these equivalents are measured relative to the amount of 2,4-dimethyl-2,3-dihydrothiophen-3-one. Preferably, the Lewis acid is selected from Zn 2+ , Fe 2+ , Fe 3+ 、Ti 4+ 、Al 3+ and Cu 2+ The method may include 0.01 to 0.9 equivalents (relative to 2,4-dimethyl-2,3-dihydrothiophene-3-one), preferably 0.01 to 0.6, or preferably 0.01 to 0.4 equivalents of Lewis acid.

[0080] Examples

[0081] Example 1: Preparation of N-(1-methoxyprop-2-yl)-2,4-dimethyl-3-aminothiophene or its salt and using General procedure for acid screening

[0082] 2,4-dimethyl-2,3-dihydrothiophene-3-one (130g, 96%, 1mol), S-MOIPA (187g, 95%, 2eq) and the acid shown in Table 1 are loaded into a 1L autoclave under a nitrogen atmosphere. The mixture is heated at the internal temperature shown in Table 1 for 6h. Then, it is cooled to room temperature, 80ml of water is added, and then 180g of 30% NaOH (1.5eq) is added. The mixture is distilled at atmospheric temperature to remove excess S-MOIPA. When cooled to room temperature again, enough water is added to dissolve the precipitated NaCl (if any). The oil layer is separated into the final product (crude product). In the case of adding a solvent, one volume is used. "One volume" means adding 1ml of solvent for each gram of 2,4-dimethyl-2,3-dihydrothiophene-3-one.

[0083]

[0084]

[0085] 1 The water content of S-MOIPA·HCl as measured by Karl-Fischer titration was 5.3%.

[0086] 2 The water content of S-MOIPA·HCl as measured by Karl-Fischer titration was 1.48%.

[0087] 3 The water content of S-MOIPA·HCl as measured by Karl-Fischer titration was 1.52%.

[0088] 4 The water content of S-MOIPA·HCl as measured by Karl-Fischer titration was 1.45%.

[0089] 5 The water content of S-MOIPA·HCl as measured by Karl-Fischer titration was 1.25%.

[0090] Table 1: Experimental summary

[0091] As can be observed in Table 1, the comparative examples provide poor yields or significant losses of enantiomeric excess. For example, p-toluenesulfonic acid provides a yield of less than 2%. The use of concentrated HCl reported in the literature provides a good yield (85%), but at the same time provides a significant loss of enantiomeric excess (85% ee). Some acids even provide lower yields than experiments without acid. On the other hand, the use of acids according to the method of the present invention provides good to excellent yields and at the same time provides excellent enantiomeric excess.

[0092] Example 2: Use of solvent

[0093] Following the excellent results obtained in Example 1, different solvents were tested to check the consistency of the reaction. The reaction conditions followed the same procedure described in Example 1 and one volume of solvent (as shown in Table 2). "One volume" means that 1 ml of solvent was added for each gram of 2,4-dimethyl-2,3-dihydrothiophen-3-one.

[0094]

[0095]

[0096] Table 2: Solvents

[0097] Thus, in the presence of different solvents, the reaction also proceeded with good or excellent conversions while maintaining the enantiomeric excess of the 2-methoxyisopropylamino moiety (no loss was observed).

[0098] Example 3: Reaction using ZnCl2

[0099] The same procedure as in Example 1 was followed with respect to 2,4-dimethyl-2,3-dihydrothiophene-3-one on a 2g scale with the following changes. Only 1 equivalent of S-MOIPA was added, ZnCl2 (1.0M, 0.1 equivalent) in THF was added and one volume of toluene was used as solvent. The reaction progress was monitored by GC (IPC-1, 24h). After 24 hours at 150°C, the product peak observed was 75%. Similarly, "one volume" means that 1 ml of solvent was added for each gram of 2,4-dimethyl-2,3-dihydrothiophene-3-one.

[0100] The same reaction was performed but using 2 equivalents of S-MOIPA and 1 equivalent of water. After 12 hours at 150°C, the product peak was equal to 75% with an enantiomeric excess of >99%.

[0101] Example 4: Reactions using iron halides

[0102] The same procedure of Example 1 was followed on a 2 g or 20 g scale using slightly different conditions to obtain 70%-80% yield and 99% ee. In all cases, the yields were good to excellent and no loss of enantiomeric excess was observed.

[0103] Examples 1 to 4 demonstrate that the reaction supports a wide range of Lewis acids under different conditions of temperature, solvent or ratio between reagents.

[0104] Example 5: Reaction using trifluoromethanesulfonic acid

[0105] The same procedure of Example 1 was followed using trifluoromethanesulfonic acid on a 1 gram or 20 gram scale. In each case, the amounts, reagents and solvents are shown in Table 3 below.

[0106]

[0107] Table 3: Trifluoromethanesulfonic acid

[0108] In all cases, the yields were good to excellent and no loss of enantiomeric excess was observed.

[0109] Example 6: Reaction using gaseous HCl

[0110] The same procedure of Example 1 was followed using gaseous HCl (HCl(g)) at a 1 gram or 20 gram scale. In each case, the amounts, reagents and solvents are shown in Table 4 below.

[0111]

[0112] Table 4: Gaseous HCl

[0113] In all cases, the yields were good to excellent and no loss of enantiomeric excess was observed.

[0114] Example 7: Reaction using acid salt of S-MOIPA and Lewis acid

[0115] g mmol eq M128 / S-MOIPA mixed solution 40 146.87 / 2115.73 1 / 1.47 S-MOIPA 7.00 77.84 0.53 S-MOIPA·HCl 18.62 146.87 1 <![CDATA[Zn(AcO)2]]> 2.75 14.69 0.1 30% NaOH aqueous solution 29.37 220.31 1.5 MTBE 50mL*2 NaCl aqueous solution 50mL

[0116] Table 5

[0117] Zn(AcO)2, S-MOIPA·HCl, S-MOIPA, and a preformed mixture of 2,4-dimethyl-2,3-dihydrothiophen-3-one and S-MOIPA were added to a 100 mL autoclave in the amounts shown in Table 5, which was then heated to 180°C for 15 h. After cooling, a sample was taken out for GC detection. The GC results showed that the content of 2,4-dimethyl-2,3-dihydrothiophen-3-one was less than 3% relative to the initial addition amount.

[0118] The reaction solution was transferred to a 250 mL reaction bottle, and 29.37 g of a 30% NaOH aqueous solution was added and stirred for 30 min. The mixture was extracted twice with 50 mL of MTBE (methyl tert-butyl ether), and the organic layer was combined. The resulting organic layer was washed with a saturated NaCl solution and then separated. The organic layer was distilled under vacuum, and finally kept at 50° C.-60° C. and 30-50 mbar for 30 min to obtain 41.15 g of crude N-(1-methoxyprop-2-yl)-2,4-dimethyl-3-aminothiophene. The ee value was 99.53%, and the yield was 88.96%.

[0119] Example 8: Post-treatment without alkaline washing

[0120] 2,4-Dimethyl-2,3-dihydrothiophene-3-one (30 g, 96%), S-MOIPA (2 eq) and trifluoromethanesulfonic acid (0.05 eq) were charged into an autoclave under a nitrogen atmosphere. The mixture was heated at an internal temperature of 160° for 22 h. The pressure observed during the reaction was 3-4 bar. Once the reaction was complete, the mixture was distilled at atmospheric pressure to remove excess S-MOIPA. When cooled to room temperature, enough water was added to dissolve the precipitated salt. The oil layer was separated as the final product (crude). The observed yield was 94%, with an enantiomeric excess of greater than 99%.

Claims

1. A method for preparing N-(1-methoxypropan-2-yl)-2,4-dimethyl-3-aminothiophene or a salt thereof, the method comprising contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with 2-methoxyisopropylamine in the presence of one or more components selected from the group consisting of: an acid salt of 2-methoxyisopropylamine, a Lewis acid, gaseous hydrochloric acid, trifluoromethanesulfonic acid, and a mixture of hydrochloric acid and a C1-C6-alkyl alcohol.

2. The method according to claim 1, comprising: a) providing an acid salt of 2-methoxyisopropylamine; b) contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with the acid salt of 2-methoxyisopropylamine.

3. A method according to any one of the preceding claims, wherein: The acid is added in a catalytic amount or a stoichiometric amount relative to 2,4-dimethyl-2,3-dihydrothiophen-3-one.

4. The method according to claim 3, wherein: 0.01 to 0.9 equivalents of the acid are used relative to 2,4-dimethyl-2,3-dihydrothiophen-3-one.

5. A process according to any one of the preceding claims, comprising contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with at least one equivalent of 2-methoxyisopropylamine and a catalytic amount of an acid salt of 2-methoxyisopropylamine, wherein the equivalents are measured relative to the amount of 2,4-dimethyl-2,3-dihydrothiophen-3-one.

6. A process according to any one of the preceding claims comprising contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with 2-methoxyisopropylamine, an acid salt of the 2-methoxyisopropylamine and a Lewis acid.

7. A process according to any one of the preceding claims, comprising contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with at least one equivalent of 2-methoxyisopropylamine, a catalytic amount of an acid salt of the 2-methoxyisopropylamine and a catalytic amount of a Lewis acid, wherein the equivalents are measured relative to the amount of 2,4-dimethyl-2,3-dihydrothiophen-3-one.

8. The process of any one of claims 1 or 2, comprising contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with 2-methoxyisopropylamine, at least one equivalent of an acid salt of the 2-methoxyisopropylamine, and a catalytic amount of a Lewis acid, wherein the equivalent is measured relative to the amount of 2,4-dimethyl-2,3-dihydrothiophen-3-one.

9. A method according to any one of the preceding claims, wherein: 2-Methoxyisopropylamine is S-2-methoxyisopropylamine.

10. A method according to any one of the preceding claims, wherein: The acid salt of 2-methoxyisopropylamine is the hydrochloride of 2-methoxyisopropylamine.

11. A method according to any one of the preceding claims, wherein: 2-Methoxyisopropylamine is used in an excess amount relative to 2,4-dimethyl-2,3-dihydrothiophen-3-one.

12. The method according to any one of claims 1, 3, 4 or 6-11, wherein: The Lewis acid is a cation of a metal selected from the group consisting of: Fe 2+ , Fe 3+ 、Zn 2+ Sc 3+ , Cu 2+ 、Ti 4+ 、Al 3+ Sn 2+ Sn 4+ 、Ni 2+ ,La 3+ 、In 3+ 、Ce 3+ 、Ce 4+ , Li + and Mg 2+ .

13. The method according to claim 12, wherein: The Lewis acid is a halide, acetate or -OTf salt of a cation of a metal selected from the group consisting of: Fe 2+ , Fe 3+ 、Zn 2+ Sc 3+ , Cu 2+ 、Ti 4+ 、Al 3+ Sn 2+ Sn 4+ 、Ni 2+ ,La 3 + 、In 3+ 、Ce 3+ 、Ce 4+ , Li + and Mg 2+ .

14. The method according to any one of claims 12 or 13, wherein: The Lewis acid is a Lewis acid selected from the group consisting of: Zn(OAc)2, ZnCl2, ZnBr2, FeCl2, FeCl3, TiCl4, Fe(OTf)3, BF3·OEt2, BCl3, SnCl4, Ni(OTf)2 (OTf=trifluoromethanesulfonate), Zn(OTf)2, Sc(OTf)3, Sn(OTf)2, Cu(OTf)2, La(OTf)3, In(OTf)3, CeCl3, CuCl2, LiBr, LiI, LiCl, MgCl2, MgBr2, MgSO4, AlCl3, AlMeCl2 and AlMe2Cl.

15. The method according to any one of claims 12 to 14, wherein: The Lewis acid is a halide or acetate of a metal selected from the group consisting of: Zn 2+ , Fe 2+ , Fe 3+ 、Ti 4+ 、Al 3+ and Cu 2+ .

16. The method according to any one of claims 12 to 15, wherein: The Lewis acid is a Lewis acid selected from the group consisting of Zn(OAc)2, ZnCl2, ZnBr2, FeCl2, FeCl3, TiCl4, Fe(OTf)3, BF3.OEt2, SnCl4, CuCl2 and AlCl3.

17. The method according to claims 6 and 12, comprising contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with 2-methoxyisopropylamine, an acid salt of the 2-methoxyisopropylamine, and a Lewis acid, wherein the Lewis acid is a cation of a metal selected from the group consisting of: Fe 2+ , Fe 3+ 、Zn 2+ Sc 3+ , Cu 2+ 、Ti 4+ 、Al 3+ Sn 2+ Sn 4+ 、Ni 2+ ,La 3+ 、In 3 + 、Ce 3+ 、Ce 4+ , Li + and Mg 2+ .

18. The method of claim 17, comprising contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one with 2-methoxyisopropylamine, an acid salt of the 2-methoxyisopropylamine, and a catalytic amount of a Lewis acid, wherein the Lewis acid is a cation of a metal selected from the group consisting of: Fe 2+ , Fe 3+ 、Zn 2+ Sc 3+ , Cu 2+ 、Ti 4+ 、Al 3+ Sn 2+ Sn 4+ 、Ni 2+ ,La 3+ 、In 3+ 、Ce 3+ 、Ce 4+ , Li + and Mg 2+ , and wherein the equivalent amount is measured relative to the amount of 2,4-dimethyl-2,3-dihydrothiophen-3-one.

19. The method according to claim 18, wherein: The Lewis acid is a halide or acetate of a metal selected from the group consisting of: Zn 2+ , Fe 2+ , Fe 3+ 、Ti 4+ 、Al 3+ and Cu 2+ .

20. The method according to claim 19, wherein: The Lewis acid is a Lewis acid selected from the group consisting of: Zn(OAc)2 and ZnCl2.

21. A method according to any one of the preceding claims, wherein: 2,4-dimethyl-2,3-dihydrothiophen-3-one was added as a preformed mixture of 2,4-dimethyl-2,3-dihydrothiophen-3-one and 2-methoxyisopropylamine.

22. A method according to any one of the preceding claims, wherein: No solvents added.

23. The method according to claim 22, wherein: The equivalent number of 2-methoxyisopropylamine relative to 2,4-dimethyl-2,3-dihydrothiophen-3-one is between greater than 1 and 10.

24. A method according to any one of the preceding claims, wherein: The reaction mixture is heated to a temperature comprised between 30 and 200 °C.

25. A method for preparing dimethenamid-P, the method comprising (i) preparing N-(1-methoxypropan-2-yl)-2,4-dimethyl-3-aminothiophene or a salt thereof according to any one of claims 1 to 24; and (ii) The obtained N-(1-methoxypropan-2-yl)-2,4-dimethyl-3-aminothiophene or a salt thereof is reacted with 2-chloroacetyl chloride.

26. Use of 2-methoxyisopropylamine for stabilizing, storing, packaging or transporting 2,4-dimethyl-2,3-dihydrothiophen-3-one.

27. A method comprising storing, packaging or transporting 2,4-dimethyl-2,3-dihydrothiophen-3-one or a salt thereof, the storing, packaging or transporting comprising contacting 2,4-dimethyl-2,3-dihydrothiophen-3-one or a salt thereof with 2-methoxyisopropylamine or a salt thereof.

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