Method for producing methyl-4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate

Abstract

The invention relates to a method for producing methyl-4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate of formula (I) by reacting methyl-4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) with diphosgene or triphosgene in the presence of one or more solvents and a catalyst, wherein, with respect to diphosgene, the molar ratio of the methyl-4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to diphosgene is in the range of 1.0 : 0.5 to 1.0 : 2.25; or, with respect to triphosgene, the molar ratio of the methyl-4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to triphosgene is in the range of 1.0 : 0.333 to 1.0 : 1.5; and the molar ratio of the methyl-4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is in the range of 1.0 : 0.01 to 1.0 : 2.0.

Description

[0001] Process for the preparation of methyl 4-isocvanatosulfonyl-5-methyl-thiophene-3-carboxylate

[0002] The invention relates to a novel process for the preparation of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate, which is known as an intermediate for the synthesis of the herbicide thiencarbazone-methyl (DE 19933260).

[0003] It is known that methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate can be prepared starting from methyl 4-(chlorosulfonyl)-5-methylthiophene-3-carboxylate by reaction with a metal cyanate in the presence of an imidazole (WO2018 / 153767). To prepare the target product, the sulfochloride was reacted with 1-2 equivalents of sodium cyanate in the presence of 1-1.5 equivalents of N-methylimidazole. The resulting product was converted directly to thiencarbazone-methyl either in a one-pot or a two-step process. Thiencarbazone-methyl was obtained in yields of 76%-84%.

[0004] It is also known that methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate can be prepared from the corresponding sulfonamide by phosgenation in the absence of an organic base and optionally in the presence of a catalyst (W02006 / 072376). To prepare the target product, the sulfonamide was reacted with an excess of 2.4 equivalents of phosgene in the presence of n-butyl isocyanate or pentyl isocyanate. The product was obtained in 83% yield in both cases.

[0005] In addition to phosgene, triphosgene has also been used in the literature for the synthesis of sulfonyl isocyanates. However, the reported syntheses suffer from several disadvantages. They either deliver the desired product in low yields (ChemCatChem (2020), 12(17), 4352-4372), require long reaction times (W02015 / 061518), or use large amounts of triphosgene (Nongyao (2015), 54(2), 83-87). In some cases, several of the aforementioned disadvantages apply (Journal of the American Chemical Society 2009, 131(25), 8754-8755).

[0006] Various factors must be taken into account when evaluating a chemical process. Firstly, there are many factors that influence the economic viability of a process. Important factors in this regard include the availability and price of the raw materials and solvents used, the quantities of raw materials and solvents used and, last but not least, the yield of the process and the quality of the product. Another important factor when evaluating a process is process safety. Important points with regard to the safety of a process include toxic, environmentally hazardous, physical and chemical properties of the hazardous substances used and the precise process conditions such as temperature, pressure, dosing sequences and times. These points determine the necessary safety concept for the technical implementation in a production plant.Phosgene is a highly toxic gaseous hazardous substance. Inhaling phosgene always poses an acute risk to life. Its use should therefore be kept to a minimum. It is associated with strict safety requirements, making the corresponding procedures complex and therefore expensive.

[0007] Triphosgene is also toxic. However, unlike phosgene, it is a solid. Release of phosgene from triphosgene usually only occurs in the reactor. Triphosgene can be added dropwise to a reaction solution as a solution in a controlled manner. Phosgene release is therefore local and controlled. The risk of gas release is significantly reduced.

[0008] Considering the described state of the art, there was a continuing need for an improved, technically and economically feasible process for the production of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate. The methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate obtainable by this process should preferably be obtained in high yield and with high chemical purity. Furthermore, this process should reduce the use of toxic hazardous substances (e.g., phosgene), solvents, and other additives compared to the state of the art.

[0009] Surprisingly, it has now been found that in the synthesis of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate, the yield can be increased when using the same amount of phosgene equivalents if diphosgene or triphosgene is used instead of phosgene.

[0010] It was also surprisingly found that the reaction can be carried out at increased concentration (less solvent) if the amount of catalyst used is simultaneously reduced. This is all the more surprising because increasing the concentration without simultaneously reducing the amount of catalyst leads to a reduced yield and a decrease in product purity.

[0011] The present invention accordingly relates to a process for the preparation of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate of the formula (I) by reacting methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) with diphosgene or triphosgene in the presence of one or more solvents and a catalyst, wherein, with respect to diphosgene, the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) to diphosgene is in the range from 1.0:0.5 to 1.0:2.25; or, with respect to triphosgene, the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) to triphosgene is in the range from 1.0:0.333 to 1.0:1.5; and the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) to the catalyst is in the range from 1.0:0.01 to 1.0:2.0.

[0012] To increase the yield, the molar ratio between the methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) and the catalyst can be selected depending on the concentration of the reactant of formula (II) in the reaction solvent.

[0013] At a concentration of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate at the start of the reaction in the range of > 5 wt.% to 10 wt.%, the preferred molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to catalyst is in the range of 1.0 : 0.5 to 1.0 : 2.0 and particularly preferably between 1.0 : 0.7 and 1.0 : 1.8.

[0014] At a concentration of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate at the start of the reaction in the range of > 10 wt.% to 15 wt.%, the preferred molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to catalyst is in the range of 1.0 : 0.3 to 1.0 : 1.8 and particularly preferably between 1.0 : 0.5 and 1.0 : 1.6.

[0015] At a concentration of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate at the start of the reaction in the range of > 15 wt.% to 20 wt.%, the preferred molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to catalyst is in the range of 1.0 : 0.1 to 1.0 : 1.6 and particularly preferably between 1.0 : 0.3 and 1.0 : 1.4.

[0016] At a concentration of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate at the start of the reaction in the range of > 20 wt.% to 30 wt.%, the preferred molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to catalyst is in the range of 1.0 : 0.01 to 1.0 : 1.4 and particularly preferably between 1.0 : 0.1 and 1.0 : 0.8.

[0017] At a concentration of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate at the start of the reaction in the range of > 30 wt.% to 40 wt.%, the preferred molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to catalyst is in the range of 1.0 : 0.01 to 1.0 : 1.2 and particularly preferably between 1.0 : 0.05 and 1.0 : 0.7.

[0018] At a concentration of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate at the start of the reaction in the range of > 40 wt.% to 50 wt.%, the preferred molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to catalyst is in the range of 1.0 : 0.01 to 1.0 : 1.0 and particularly preferably between 1.0 : 0.05 and 1.0 : 0.6.

[0019] Advantageously, methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate of formula (I) can be produced with very good yields and very good quality using the process according to the invention. Furthermore, the process according to the invention overcomes further disadvantages arising from the prior art.

[0020] The process according to the invention can be explained using the following scheme (1):

[0021] Scheme (1)

[0022] The compounds of formula (II) can be obtained, for example, according to the process described in DE19933260.

[0023] General definitions "Alkyl" according to the invention represents straight-chain, branched or cyclic hydrocarbons having preferably 1 to 8 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylpropyl, 1,3-dimethylbutyl, 1,4-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, 2-ethylhexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0024] In the present patent application, the term “equivalent” is generally understood to mean molar equivalent, unless otherwise stated at the respective point.

[0025] The term “phosgene equivalent” used in this patent application is based on the following ratio: 1 equivalent of triphosgene corresponds to 3 phosgene equivalents; 1 equivalent of diphosgene corresponds to 2 phosgene equivalents.

[0026] In the present patent application, the term technical xylene refers to a mixture of o-xylene, m-xylene, p-xylene and ethylbenzene.

[0027] Procedure description:

[0028] The conversion of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate (formula (II)) to methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate takes place in the presence of one or more solvents.

[0029] Suitable solvents include in particular: tetrahydrofuran (THF), dioxane, diethyl ether, diglyme, methyl tert-butyl ether (MTBE), tert-amyl methyl ether (TAME), ethylene glycol dimethyl ether (DME), 2-methyl-THF, acetonitrile (ACN), butyronitrile, ethyl acetate, isopropyl acetate, butyl acetate, pentyl acetate, methyl isobutyl ketone, ethylene carbonate, propylene carbonate, N,N-dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), N-methylpyrrolidone, sulfolane; halogenated hydrocarbons, in particular chlorinated hydrocarbons and fluorocarbons, such as tetrachloroethylene, tetrachloroethane, dichloropropane, dichloromethane (DCM), dichlorobutane, chloroform; trichlorotrifluoroethane, carbon tetrachloride, trichloroethane, trichloroethylene, pentachloroethane, 1,2-dichloroethane;aromatic hydrocarbons and halogenated hydrocarbons, such as difluorobenzene, benzotrifluoride, 4-chlorobenzotrifluoride, benzene, toluene, anisole, o-xylene, m-xylene, p-xylene, technical xylene, ethylbenzene, mesitylene, 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, chlorobenzene, bromobenzene, dichlorobenzene, in particular 1,2-dichlorobenzene, chlorotoluene, trichlorobenzene, cumene; aliphatic hydrocarbons and hydrocarbon mixtures, such as n-pentane, n-hexane, n-heptane, n-octane, 1,2,4-trimethylpentane (isooctane), petroleum ether, special gasoline; cyclohexane, methylcyclohexane.

[0030] Mixtures of the aforementioned solvents can also be used.

[0031] Preferred solvents are aromatic hydrocarbons and halogenated hydrocarbons such as difluorobenzene, benzotrifluoride, 4-chlorobenzotrifluoride, benzene, toluene, anisole, o-xylene, m-xylene, p-xylene, technical xylene, ethylbenzene, mesitylene, 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, chlorobenzene, bromobenzene, dichlorobenzene, in particular 1,2-dichlorobenzene, chlorotoluene, trichlorobenzene, cumene or mixtures thereof.

[0032] Particularly preferred solvents are chlorobenzene, toluene, o-xylene, m-xylene, p-xylene, technical xylene, ethylbenzene or mixtures thereof.

[0033] Particularly preferred solvents are o-xylene, m-xylene, p-xylene and technical xylene.

[0034] The preparation of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate of the Lormel (I) by reacting methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the Lormel (II) is carried out in the process according to the invention with diphosgene or triphosgene.

[0035] Triphosgene is preferred.

[0036] Triphosgene is preferably used as a solution in a suitable solvent. Suitable solvents include the solvents or solvent mixtures mentioned above.

[0037] Preferred solvents for the triphosgene are therefore aromatic hydrocarbons and halogenated hydrocarbons such as difluorobenzene, benzotrifluoride, 4-chlorobenzotrifluoride, benzene, toluene, anisole, o-xylene, m-xylene, p-xylene, technical xylene, ethylbenzene, mesitylene, 1,2,3-trimethylbenzene, 1,2,4-trimethylbenzene, chlorobenzene, bromobenzene, dichlorobenzene, in particular 1,2-dichlorobenzene, chlorotoluene, trichlorobenzene, cumene or mixtures thereof.

[0038] Particularly preferred solvents for the triphosgene are chlorobenzene, toluene, o-xylene, m-xylene, p-xylene, technical xylene, ethylbenzene or mixtures thereof.

[0039] Particularly preferred solvents for triphosgene are o-xylene, m-xylene, p-xylene and technical xylene.

[0040] However, triphosgene can also be used in solid form or as a melt.

[0041] If the triphosgene is used as a solution, the triphosgene concentration is in the range from 1 to 99%, preferably between 10 and 80%, more preferably between 20% and 60%, and most preferably between 30 and 50%. To increase the solubility of the triphosgene in the selected solvent, the solvent can be heated. The molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate to triphosgene is in the range from 1.0:0.333 to 1.0:1.5, preferably between 1.0:0.333 and 1.0:1.0, more preferably between 1.0:0.333 and 1.0:0.7, and most preferably between 1.0:0.4 and 1.0:0.7.

[0042] The molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate to diphosgene is in the range of 1.0 : 0.5 to 1.0 : 2.25, preferably between 1.0 : 0.5 and 1.0 : 1.5, particularly preferably between 1.0 : 0.5 and 1.0 : 1.05 and most particularly preferably between 1.0 : 0.6 and 1.0 : 1.05.

[0043] The process according to the invention is carried out in the presence of a catalyst. An alkyl isocyanate can be used as the catalyst. The molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate to alkyl isocyanate is in the range from 1.0:0.01 to 1.0:2.0, preferably between 1.0:0.05 and 1.0:2.0, and particularly preferably between 1.0:0.05 and 1.0:1.8.

[0044] Propyl isocyanate, butyl isocyanate, and pentyl isocyanate are preferred alkyl isocyanates. Butyl isocyanate is particularly preferred.

[0045] The reaction is generally carried out at a temperature between 20 °C and 200 °C, preferably between 80 °C and 160 °C, most preferably between 110 °C and 140 °C.

[0046] The reaction is typically carried out at atmospheric pressure, but can also be carried out at elevated or reduced pressure (generally between 0.1 bar and 10 bar).

[0047] As intermediates of the process for the preparation of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate of formula (I) Dimethyl 4,4'-(carbonyldisulfamoyl)bis(5-methylthiophene-3-carboxylate) is formed and in

[0048] Depending on the alkyl isocyanate used, a compound of formula (III): where in formula (III) R is alkyl. Preferably, R in formula (III) is propyl, butyl, or pentyl, particularly preferably butyl.

[0049] These intermediates also react under the reaction conditions to form the desired methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate of formula (I).

[0050] A further aspect of the present invention relates to the use of dimethyl 4,4'-(carbonyldisulfamoyl)bis(5-methylthiophene-3-carboxylate) and / or a compound of formula (III) for a process for the preparation of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate of formula (I) where in formula (III) R is alkyl, preferably propyl, butyl or pentyl, particularly preferably butyl.

[0051] The compounds of formula (I) obtained by the process according to the invention can be isolated before their use in the preparation of herbicidal end products. However, it is also possible and advantageous to further react the resulting compounds of formula (I) directly without intermediate isolation. The concentration of the reaction solution can be further increased by removing part of the solvent by distillation. In this case, the catalyst present can also be largely recovered.

[0052] In a preferred embodiment, the process for preparing methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate of the formula (I) is carried out by reacting methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) with triphosgene in the presence of one or more solvents and a catalyst, wherein the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) to triphosgene is in the range from 1.0:0.333 to 1.0:1.5; and the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) to the catalyst is in the range from 1.0:0.01 to 1.0:2.0. Preferably, the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to triphosgene is in the range of 1.0 : 0.333 and 1.0 : 0.7, preferably in the range of 1.0 : 0.4 and 1.0 : 0.7.The molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is preferably in the range of 1.0:0.05 and 1.0:2.0, more preferably in the range of 1.0:0.05 and 1.0:1.8. An alkyl isocyanate can be used as the catalyst, preferably n-butyl isocyanate, propyl isocyanate, or pentyl isocyanate, most preferably n-butyl isocyanate. The solvent used can be chlorobenzene, toluene, o-xylene, m-xylene, p-xylene, technical-grade xylene, ethylbenzene, or mixtures thereof, preferably o-xylene, m-xylene, p-xylene, technical-grade xylene, or mixtures thereof. The process can be carried out at a temperature between 20 °C and 200 °C, preferably between 80 °C and 160 °C, most preferably between 110 °C and 140 °C.

[0053] In a further preferred embodiment, the process for preparing methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate of the formula (I) is carried out by reacting methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) with triphosgene in the presence of one or more solvents and a catalyst, wherein the molar ratio of the methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) to triphosgene is in the range from 1.0:0.333 to 1.0:1.5; and the molar ratio of the methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) to the catalyst is in the range from 1.0:0.01 to 1.0:2.0. Preferably, the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to triphosgene is in the range of 1.0 : 0.333 and 1.0 : 0.7, more preferably in the range of 1.0 : 0.4 and 1.0 : 0.7 and the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is in the range of 1.0:0.05 and 1.0:2.0, preferably in the range of 1.0:0.05 and 1.0:1.8. An alkyl isocyanate can be used as the catalyst, preferably n-butyl isocyanate, propyl isocyanate, or pentyl isocyanate, very particularly preferably n-butyl isocyanate. The solvent used can be chlorobenzene, toluene, o-xylene, m-xylene, p-xylene, technical-grade xylene, ethylbenzene, or mixtures thereof, preferably o-xylene, m-xylene, p-xylene, technical-grade xylene, or mixtures thereof. The process can be carried out at a temperature between 20 °C and 200 °C, preferably between 80 °C and 160 °C, most preferably between 110 °C and 140 °C.

[0054] In a particularly preferred embodiment, the process for preparing methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate of the formula (I) is carried out by reacting methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) with triphosgene in the presence of one or more solvents and a catalyst, wherein the molar ratio of the methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) to triphosgene is in the range of 1.0 : 0.333 and 1.0 : 0.7 and the molar ratio of the methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) to the catalyst is in the range of 1.0 : 0.05 and 1.0 : 2.0. An alkyl isocyanate can be used as the catalyst, preferably n-butyl isocyanate, propyl isocyanate, or pentyl isocyanate, most preferably n-butyl isocyanate. The solvent used can be o-xylene, m-xylene, p-xylene, technical xylene, or mixtures thereof.The process can be carried out at a temperature between 20 °C and 200 °C, preferably between 80 °C and 160 °C, most preferably between 110 °C and 140 °C.

[0055] In a very particularly preferred embodiment, the process for preparing methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate of the formula (I) is carried out by reacting methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) with triphosgene in the presence of one or more solvents and a catalyst, wherein the molar ratio of the methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) to triphosgene is in the range of 1.0:0.4 and 1.0:0.7 and the molar ratio of the methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) to the catalyst is in the range of 1.0:0.05 and 1.0:1.8. An alkyl isocyanate can be used as the catalyst, preferably n-butyl isocyanate, propyl isocyanate, or pentyl isocyanate, most preferably n-butyl isocyanate. The solvent used can be o-xylene, m-xylene, p-xylene, technical xylene, or mixtures thereof.The process can be carried out at a temperature between 20 °C and 200 °C, preferably between 80 °C and 160 °C, most preferably between 110 °C and 140 °C. The present invention is further illustrated by the following examples, which are not to be interpreted as limiting the invention.

[0056] Examples:

[0057] The reported yields were calculated by weighing the resulting organic phase and correcting this weight by the weight percent determined by HPLC. For HPLC determination, a sample of the product solution was reacted with anhydrous methanol, and the resulting methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate was derivatized to methyl 4-(methoxycarbonylsulfamoyl)-5-methyl-thiophene-3-carboxylate. The proportion of this compound in weight percent was determined using methyl 4-(methoxycarbonylsulfamoyl)-5-methyl-thiophene-3-carboxylate as an external standard, and the proportion of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate in the product phase was subsequently inferred. Example 1: Synthesis of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate using 1.0 equivalents of n-butyl isocyanate and 0.5 equivalents of triphosgene (concentration: 9.9 wt%)

[0058] A 250 ml glass reactor equipped with an overhead stirrer, a gas inlet, a dosing line, and a reflux condenser was used.

[0059] The reflux condenser was cooled to -15 °C. 19.1 g (98.6%, 80.0 mmol) of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate and 173 g of xylene were initially charged to the nitrogen-purged reactor. The mixture was heated to 136 °C with stirring. At an internal temperature of 100 °C, 8.12 g (98%, 80.3 mmol) of n-butyl isocyanate were added. 44.2 g of a solution of 12.2 g (98%, 40.2 mmol) of triphosgene in xylene was added evenly to the clear reaction solution over a period of 135 min. After the addition was complete, the metering line was flushed with 7.2 g of xylene, and the mixture was stirred at 135–136 °C for 4 h 31 min. The reaction mixture was then cooled to room temperature and warmed to 20 °C using a reflux condenser. Residual phosgene was removed by passing a stream of nitrogen. This yielded 220.2 g of a solution of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate in xylene.After derivatization, the proportion of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate was determined by quantitative HPLC (against external standard) to be 8.7%. This corresponds to a yield of 92% starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0060] Example 2: Synthesis of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate using 1.0 equivalents of n-butyl isocyanate and 0.7 equivalents of triphosgene (concentration: 9.9 wt%)

[0061] A 250 ml glass reactor equipped with an overhead stirrer, a gas inlet, a dosing line, and a reflux condenser was used.

[0062] The reflux condenser was cooled to -15 °C. 19.1 g (98.6%, 80.0 mmol) of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate and 173 g of xylene were initially charged to the nitrogen-purged reactor. The mixture was heated to 137 °C with stirring. At an internal temperature of 104 °C, 8.1 g (98%, 81 mmol) of n-butyl isocyanate were added. 68.1 g of a solution of 17.1 g (98%, 56.2 mmol) of triphosgene in xylene was metered evenly to the clear reaction solution over a period of 106 min. After the addition was complete, the metering line was flushed with 7.9 g of xylene, and the mixture was stirred for 4 h 30 min at 119 to 135 °C. The reaction mixture was then cooled to room temperature and warmed to 20 °C using a reflux condenser. Residual phosgene was removed by passing a stream of nitrogen. This yielded 233.8 g of a solution of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate in xylene.The proportion of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate was determined to be 8.6% after derivatization by quantitative HPLC (against external standard). This corresponds to a yield of 95% starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0063] Example 3: Synthesis of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate using 0.5 equivalents of n-butyl isocyanate and 0.5 equivalents of triphosgene at an increased concentration of the reaction solution (concentration: 20 wt%)

[0064] A 250 ml glass reactor equipped with an overhead stirrer, a gas inlet, a dosing line, and a reflux condenser was used.

[0065] The reflux condenser was cooled to -15 °C. 31.0 g (98.6%, 130.0 mmol) of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate and 124.1 g of xylene were initially charged to the nitrogen-purged reactor. The mixture was heated to 137 °C with stirring. At an internal temperature of 102 °C, 6.7 g (98%, 66 mmol) of n-butyl isocyanate were added. 78.7 g of a solution of 19.6 g (98%, 64.7 mmol) of triphosgene in xylene was metered evenly to the clear reaction solution over a period of 116 min. After the addition was complete, the metering line was flushed with 7.6 g of xylene, and the mixture was stirred at 135–136 °C for 2 h 32 min. The reaction mixture was then cooled to room temperature and warmed to 20 °C using a reflux condenser. Residual phosgene was removed by passing a stream of nitrogen. This yielded 225.3 g of a solution of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate in xylene.After derivatization, the proportion of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate was determined by quantitative HPLC (against external standard) to be 13.8%. This corresponds to a yield of 92% starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0066] Example 4: Synthesis of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate using 0.5 equivalents of n-butyl isocyanate and 0.7 equivalents of triphosgene at increased concentration of the reaction solution (concentration: 20 wt%)

[0067] A 250 ml glass reactor equipped with an overhead stirrer, a gas inlet, a dosing line, and a reflux condenser was used.

[0068] The reflux condenser was cooled to -15 °C. 31.0 g (98.6%, 130.0 mmol) of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate and 124.1 g of xylene were initially charged to the nitrogen-purged reactor. The mixture was heated to 137 °C with stirring. At an internal temperature of 102 °C, 6.6 g (98%, 65 mmol) of n-butyl isocyanate were added. 110.4 g of a solution of 27.6 g (98%, 91.1 mmol) of triphosgene in xylene was metered evenly to the clear reaction solution over a period of 118 min. After the addition was complete, the metering line was flushed with 9.6 g of xylene, and the mixture was stirred at 124–132 °C for 3 h 11 min. The reaction mixture was then cooled to room temperature and warmed to 20 °C using a reflux condenser. Residual phosgene was removed by passing a stream of nitrogen. This yielded 180.9 g of a solution of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate in xylene.After derivatization, the proportion of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate was determined by quantitative HPLC (against external standard) to be 17.7%. This corresponds to a yield of 94% starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0069] Example 5: Synthesis of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate using 0.3 equivalents of n-butyl isocyanate and 0.7 equivalents of triphosgene at increased concentration of the reaction solution (concentration: 25 wt%)

[0070] A 250 ml glass reactor equipped with an overhead stirrer, a gas inlet, a dosing line, and a reflux condenser was used.

[0071] The reflux condenser was cooled to -15 °C. 30.83 g (99.2%, 130.0 mmol) of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate, 91.33 g of xylene, and 3.95 g (98%, 39.0 mmol) of n-butyl isocyanate were initially charged into the nitrogen-purged reactor. The mixture was heated to 139 °C with stirring. 90.6 g of a solution of 27.6 g (98%, 91.1 mmol) of triphosgene in xylene was added evenly to the clear reaction solution over a period of 183 min. After the addition was complete, the metering line was flushed with 9.6 g of xylene, and the mixture was stirred at 125–139 °C for 3 h 4 min. The reaction mixture was then cooled to room temperature and warmed to 20 °C using a reflux condenser. Residual phosgene was removed by passing a stream of nitrogen. This yielded 182.8 g of a solution of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate in xylene.After derivatization, the proportion of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate was determined by quantitative HPLC (against external standard) to be 17.0%. This corresponds to a yield of 92% starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0072] Example 6: Synthesis of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate using 0.25 equivalents of n-butyl isocyanate and 0.7 equivalents of triphosgene at increased concentration of the reaction solution (concentration: 30 wt%)

[0073] A 250 ml glass reactor equipped with an overhead stirrer, a gas inlet, a dosing line, and a reflux condenser was used.

[0074] The reflux condenser was cooled to -15 °C. 30.83 g (99.2%, 130.0 mmol) of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate, 71.20 g of xylene, and 3.29 g (98%, 32.5 mmol) of n-butyl isocyanate were initially charged into the nitrogen-purged reactor. The mixture was heated to 139 °C with stirring. 90.6 g of a solution of 27.6 g (98%, 91.1 mmol) of triphosgene in xylene was added evenly to the clear reaction solution over a period of 245 min. After the addition was complete, the metering line was flushed with 9.6 g of xylene, and the mixture was stirred at 124–130 °C for 2 h 57 min. The reaction mixture was then cooled to room temperature and warmed to 20 °C using a reflux condenser. Residual phosgene was removed by passing a stream of nitrogen. This yielded 158.9 g of a solution of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate in xylene.The proportion of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate was determined to be 19.5% after derivatization by quantitative HPLC (against external standard). This corresponds to a yield of 91% starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0075] Example 7: Synthesis of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate using 0.25 equivalents of n-butyl isocyanate and 0.6 equivalents of triphosgene at increased concentration of the reaction solution (concentration: 30 wt%)

[0076] The experiment was carried out as described in Example 6, except that a solution of 23.6 g (98%, 77.9 mmol) of triphosgene in 42.5 g of xylene was used. This yielded 169.9 g of a solution of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate in xylene. The proportion of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate was determined by quantitative HPLC (against an external standard) after derivatization to be 18.6%. This corresponds to a yield of 93% starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0077] Example 8: Synthesis of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate using 0.25 equivalents of n-butyl isocyanate and 0.6 equivalents of triphosgene at increased concentration of the reaction solution (concentration: 35 wt%)

[0078] A 250 ml glass reactor equipped with an overhead stirrer, a gas inlet, a dosing line, and a reflux condenser was used.

[0079] The reflux condenser was cooled to -15 °C. 30.83 g (99.2%, 130.0 mmol) of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate, 57.20 g of xylene, and 3.29 g (98%, 32.5 mmol) of n-butyl isocyanate were initially charged into the nitrogen-purged reactor. The mixture was heated to 139 °C with stirring. 77.1 g of a solution of 23.6 g (98%, 77.9 mmol) of triphosgene in xylene was added evenly to the clear reaction solution over a period of 238 min. After the addition was complete, the metering line was flushed with 9.6 g of xylene, and the mixture was stirred at 138-130 °C for 3 h 2 min. The reaction mixture was then cooled to room temperature and warmed to 20 °C using a reflux condenser. Residual phosgene was removed by passing a stream of nitrogen. This yielded 124.3 g of a solution of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate in xylene.After derivatization, the proportion of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate was determined by quantitative HPLC (against external standard) to be 25.0%. This corresponds to a yield of 92% starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0080] Comparative Example 1: Synthesis of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate using 1.0 equivalents of n-butyl isocyanate and 2.1 equivalents of phosgene (concentration: 10 wt%)

[0081] A 500 ml glass reactor equipped with an overhead stirrer, a gas inlet, and a reflux condenser was used.

[0082] The reflux condenser was cooled to -12 °C. 30.0 g (127.5 mmol) of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate and 270 g of xylene were initially charged to the nitrogen-purged reactor. The mixture was heated to 140 °C with stirring. At an internal temperature of 100 °C, 12.6 g (127.5 mmol) of n-butyl isocyanate were added. 26.5 g (268 mmol) of phosgene were passed into the clear reaction solution over a period of 3 h. After the addition was complete, the mixture was stirred for 1 h 30 min. The reaction mixture was then cooled to room temperature. Residual phosgene was removed by passing a stream of argon. 304.1 g of a solution of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate in xylene was obtained. The proportion of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate was determined to be 9.7% after derivatization by quantitative HPLC (against external standard).This corresponds to a yield of 89% starting from methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate.

[0083] The yield is 6 percentage points lower than in Example 2 where the same number of phosgene equivalents was used.

[0084] The following compounds were identified as intermediates of the process:

[0085] Dimethyl-4,4'-(carbonyldisulfamoyl)bis(5-methylthiophene-3-carboxylate)

[0086] MS (ESI negative): m / z = 495.1 [MH]'

[0087] Methyl 4-[(butylcarbamoyl)sulfamoyl]-5-methylthiophene-3-carboxylate

[0088] MS (ESI negative): m / z = 333.2 [MH]'

Claims

1. Process for the preparation of methyl -4-isocyanatosulfonyl-5-methyl -thiophene-3-carboxylate of formula (I) by reacting methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) with diphosgene or triphosgene in the presence of one or more solvents and a catalyst, wherein, with respect to diphosgene, the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) to diphosgene is in the range from 1.0:0.5 to 1.0:2.25; or, with respect to triphosgene, the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) to triphosgene is in the range from 1.0:0.333 to 1.0:1.5; and the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) to the catalyst is in the range from 1.0:0.01 to 1.0:2.

0.

2. The process according to claim 1, wherein triphosgene is used and the molar ratio of the methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) to triphosgene is in the range of 1.0 : 0.333 and 1.0 : 0.7, preferably in the range of 1.0 : 0.4 and 1.0 : 0.

7.

3. Process according to claim 1 or 2, wherein the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to the catalyst is in the range of 1.0:0.05 and 1.0:2.0, preferably in the range of 1.0:0.05 and 1.0:1.

8.

4. Process according to one of claims 1 to 3, wherein an alkyl isocyanate is used as catalyst.

5. The process according to claim 4, wherein the alkyl isocyanate is n-butyl isocyanate, propyl isocyanate or pentyl isocyanate.

6. The process of claim 5, wherein the alkyl isocyanate is n-butyl isocyanate.

7. Process according to one of claims 1 to 6, wherein the solvent used is chlorobenzene, toluene, o-xylene, m-xylene, p-xylene, technical xylene, ethylbenzene or mixtures thereof.

8. The process according to claim 7, wherein the solvent used is o-xylene, m-xylene, p-xylene, technical xylene or mixtures thereof.

9. The process according to any one of claims 1 to 8, wherein the process is carried out at a temperature between 20 °C and 200 °C, preferably between 80 °C and 160 °C, most preferably between 110 °C and 140 °C.

10. Process according to one of claims 1 to 9, wherein as intermediates of the process dimethyl 4,4'-(carbonyldisulfamoyl)bis(5-methylthiophene-3-carboxylate) and, depending on the alkyl isocyanate used, a compound of formula (III): is formed, where in formula (III) R represents alkyl.

11. The process according to claim 10, wherein in formula (III) R is propyl, butyl or pentyl.

12. The process according to claim 11, wherein in formula (III) R is butyl.

13. Use of dimethyl 4,4'-(carbonyldisulfamoyl)bis(5-methylthiophene-3-carboxylate) and / or a compound of formula (III) for a process for the preparation of methyl 4-isocyanatosulfonyl-5-methylthiophene-3-carboxylate of formula (I) where in formula (III) R is alkyl, preferably propyl, butyl or pentyl, particularly preferably butyl.

Images