WO2024200331A2 - Procédé de production du méthyl-4-isocyanatosulfonyl-5-méthyl-thiophène-3-carboxylate - Google Patents

Procédé de production du méthyl-4-isocyanatosulfonyl-5-méthyl-thiophène-3-carboxylate Download PDF

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WO2024200331A2
WO2024200331A2 PCT/EP2024/057902 EP2024057902W WO2024200331A2 WO 2024200331 A2 WO2024200331 A2 WO 2024200331A2 EP 2024057902 W EP2024057902 W EP 2024057902W WO 2024200331 A2 WO2024200331 A2 WO 2024200331A2
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methyl
carboxylate
xylene
formula
methylthiophene
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WO2024200331A3 (fr
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Alexander ARLT
Thomas Geller
Dirk Brohm
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Bayer AG
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Bayer AG
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Priority to JP2025555947A priority Critical patent/JP2026511628A/ja
Priority to EP24715486.7A priority patent/EP4688764A2/fr
Priority to KR1020257031996A priority patent/KR20250164206A/ko
Priority to CN202480012032.5A priority patent/CN120712257A/zh
Publication of WO2024200331A2 publication Critical patent/WO2024200331A2/fr
Publication of WO2024200331A3 publication Critical patent/WO2024200331A3/fr
Priority to MX2025011158A priority patent/MX2025011158A/es
Priority to IL323579A priority patent/IL323579A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the invention relates to a novel process for the preparation of methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate, which is known as an intermediate for the synthesis of the herbicide thiencarbazone-methyl (DE 19933260).
  • 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).
  • 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 process or in a two-step process.
  • Thiencarbazone-methyl was obtained in yields of 76% - 84%.
  • 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).
  • 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.
  • triphosgene has also been used in the literature for the synthesis of sulfonyl isocyanates.
  • the reported syntheses are disadvantageous due to various aspects. 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).
  • W02015/0615108 long reaction times
  • triphosgene Neongyao (2015), 54(2), 83-87.
  • several of the previously mentioned disadvantageous aspects apply (Journal of the American Chemical Society 2009, 131(25), 8754 - 8755).
  • Triphosgene is also toxic. However, unlike phosgene, it is a solid. Phosgene is usually only released from triphosgene in the reactor. Triphosgene can be added dropwise to a reaction solution as a solution. The phosgene is therefore released locally and in a controlled manner. The risk of gas release is therefore significantly reduced.
  • methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate obtainable by this process should preferably be obtained in high yield and in 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.
  • toxic hazardous substances e.g. phosgene
  • 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 since increasing the concentration without simultaneously reducing the amount of catalyst leads to a reduced yield and reduction in product purity.
  • the present invention therefore 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 the 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 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 molar ratio between the methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) and the catalyst can be selected depending on the concentration of the reactant of the formula (II) in the reaction solvent.
  • 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.
  • 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.
  • the preferred molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of formula (II) to Catalyst 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.
  • 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.
  • 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.
  • 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.
  • methyl 4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate of the formula (I) can be prepared with very good yields and in very good quality using the process according to the invention.
  • the process according to the invention overcomes further disadvantages resulting from the prior art.
  • the compounds of formula (II) can be obtained, for example, according to the process described in DE19933260.
  • alkyl stands for 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,
  • phosgene equivalent used in the present patent application is based on the following relationship: 1 equivalent of triphosgene corresponds to 3 phosgene equivalents; 1 equivalent of diphosgene corresponds to 2 phosgene equivalents.
  • the term technical xylene is understood to mean a mixture of o-xylene, m-xylene, p-xylene and ethylbenzene.
  • 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, dichlor
  • 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.
  • aromatic hydrocarbons such as difluorobenzene, benzotrifluoride, 4-chlorobenzotrifluoride, benzene, toluene, anisole, o-xylene, m-xylene, p-xylene, technical xylene, e
  • Particularly preferred solvents are chlorobenzene, toluene, o-xylene, m-xylene, p-xylene, technical xylene, ethylbenzene or mixtures thereof.
  • Particularly preferred solvents are o-xylene, m-xylene, p-xylene and technical xylene.
  • Triphosgene is preferably used.
  • the triphosgene is preferably used as a solution in a suitable solvent.
  • the solvents or solvent mixtures mentioned above are suitable solvents.
  • 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.
  • aromatic hydrocarbons and halogenated hydrocarbons such as difluorobenzene, benzotrifluoride, 4-chlorobenzotrifluoride, benzene, toluene, anisole, o-xylene, m-xylene,
  • Particularly preferred solvents for triphosgene are chlorobenzene, toluene, o-xylene, m-xylene, p-xylene, technical xylene, ethylbenzene or mixtures thereof.
  • Particularly preferred solvents for triphosgene are o-xylene, m-xylene, p-xylene and technical xylene.
  • triphosgene can also be used in solid form or as a melt.
  • the triphosgene concentration is in the range of 1 to 99%, preferably between 10 and 80%, particularly preferably between 20% and 60% and most particularly preferably between 30 and 50%.
  • the solvent can be heated.
  • the molar ratio of methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate to triphosgene is in the range of 1.0:0.333 to 1.0:1.5, preferably between 1.0:0.333 and 1.0:1.0, particularly preferably between 1.0:0.333 and 1.0:0.7, and most preferably between 1.0:0.4 and 1.0:0.7.
  • 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 preferably between 1.0:0.6 and 1.0:1.05.
  • 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.
  • 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.
  • 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).
  • R in formula (III) is alkyl.
  • R in formula (III) is propyl, butyl and pentyl, particularly preferably butyl.
  • 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 preparing 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.
  • the compounds of formula (I) obtained by the process according to the invention can be isolated before they are used to produce herbicidal end products. However, it is also possible and advantageous to further react the compounds of formula (I) obtained immediately without intermediate isolation. The concentration of the reaction solution can be increased further by separating off part of the solvent by distillation. The catalyst present can also be largely recovered in this way.
  • the process for preparing methyl 4-isocyanatosulfonyl-5-methyl-thiophene-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 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.
  • 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 and 1.0:0.7, preferably in the range from 1.0:0.4 and 1.0:0.7.
  • the molar ratio of the methyl 4-(aminosulfonyl)-5-methylthiophene-3-carboxylate of the formula (II) to the catalyst is in the range from 1.0:0.05 and 1.0:2.0, preferably in the range from 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 xylene, ethylbenzene or mixtures thereof, preferably 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, very particularly preferably between 110 °C and 140 °C.
  • the process for preparing methyl 4-isocyanatosulfonyl-5-methyl-thiophene-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.
  • the molar ratio of 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 and the molar ratio of 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, 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 may be chlorobenzene, toluene, o-xylene, m-xylene, p-xylene, technical xylene, ethylbenzene or mixtures thereof, preferably o-xylene, m-xylene, p-xylene, technical xylene or mixtures thereof.
  • the process may be carried out at a temperature between 20 °C and 200 °C, preferably between 80 °C and 160 °C, very particularly preferably between 110 °C and 140 °C.
  • the process for preparing methyl 4-isocyanatosulfonyl-5-methyl-thiophene-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, very particularly 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, very particularly preferably between 110 °C and 140 °C.
  • the process for preparing methyl 4-isocyanatosulfonyl-5-methyl-thiophene-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, very particularly 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, very particularly preferably between 110 °C and 140 °C.
  • a 250 mL glass reactor equipped with an overhead stirrer, a gas inlet, a dosing line, and a reflux condenser was used.
  • 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 placed in the reactor flushed with nitrogen. 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 were evenly metered into the clear reaction solution over the course of 135 min.
  • 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% by weight)
  • a 250 mL glass reactor equipped with an overhead stirrer, a gas inlet, a dosing line, and a reflux condenser was used.
  • 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 placed in the reactor flushed with nitrogen. 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 were evenly metered into the clear reaction solution over the course of 106 min.
  • 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 increased concentration of the reaction solution (concentration: 20 percent by weight)
  • a 250 mL glass reactor equipped with an overhead stirrer, a gas inlet, a dosing line, and a reflux condenser was used.
  • 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 placed in the reactor flushed with nitrogen. 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 were evenly metered into the clear reaction solution over the course of 116 min.
  • 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 percent by weight)
  • a 250 mL glass reactor equipped with an overhead stirrer, a gas inlet, a dosing line, and a reflux condenser was used.
  • 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 placed in the reactor flushed with nitrogen. 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. The clear reaction solution was added within 110.4 g of a solution of 27.6 g (98%, 91.1 mmol) of triphosgene in xylene were added evenly over a period of 118 minutes.
  • 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 percent by weight)
  • a 250 mL glass reactor equipped with an overhead stirrer, a gas inlet, a dosing line, and a reflux condenser was used.
  • 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 placed in the reactor flushed with nitrogen. 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 were added evenly to the clear reaction solution over the course of 183 min.
  • 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 percent by weight)
  • a 250 mL glass reactor equipped with an overhead stirrer, a gas inlet, a dosing line, and a reflux condenser was used.
  • 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 introduced. 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 were added evenly to the clear reaction solution over the course of 245 min.
  • the metering line was rinsed with 9.6 g of xylene and the mixture was stirred for 2 h 57 min at 124 - 130 °C.
  • the reaction mixture was then cooled to room temperature and the reflux condenser was heated to 20 °C. Residual phosgene was removed by introducing a stream of nitrogen. 158.9 g of a solution of methyl -4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate in xylene were obtained.
  • 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.
  • 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 percent by weight)
  • 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 percent by weight)
  • a 250 mL glass reactor equipped with an overhead stirrer, a gas inlet, a dosing line, and a reflux condenser was used.
  • 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 placed in the reactor flushed with nitrogen. 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 were added evenly to the clear reaction solution over the course of 238 min.
  • 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 weight percent)
  • a 500 mL glass reactor equipped with an overhead stirrer, a gas inlet and a reflux condenser was used.
  • 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 placed in the reactor flushed with nitrogen. 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 introduced into the clear reaction solution over the course of 3 h. After the addition had been completed, the mixture was stirred for 1 h 30 min. The reaction mixture was then cooled to room temperature.
  • Residual phosgene was removed by introducing 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.
  • the yield is 6 percentage points lower than in Example 2 where the same number of phosgene equivalents was used.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Catalysts (AREA)

Abstract

L'invention concerne un procédé de production du méthyl-4-isocyanatosulfonyl-5-méthyl-thiophène-3-carboxylate de formule (I) par réaction du méthyl-4-(aminosulfonyl)-5-méthylthiophène-3-carboxylate de formule (II) avec du diphosgène ou du triphosgène en présence d'un ou plusieurs solvants et d'un catalyseur, procédé selon lequel, pour ce qui est du disphogène, le rapport molaire du méthyl-4-(aminosulfonyl)-5-méthylthiophène-3-carboxylate de formule (II) au diphosgène est compris entre 1,0 : 0,5 et 1,0 : 2,25 ; ou, pour ce qui est du triphosgène, le rapport molaire du méthyl-4-(aminosulfonyl)-5-méthylthiophène-3-carboxylate de formule (II) au triphosgène est compris entre 1,0 : 0,333 et 1,0 : 1,5 ; et le rapport molaire du méthyl-4-(aminosulfonyl)-5-méthylthiophène-3-carboxylate de formule (II) au catalyseur est compris entre 1,0 : 0,01 et 1,0 : 2,0.
PCT/EP2024/057902 2023-03-29 2024-03-25 Procédé de production du méthyl-4-isocyanatosulfonyl-5-méthyl-thiophène-3-carboxylate Ceased WO2024200331A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP2025555947A JP2026511628A (ja) 2023-03-29 2024-03-25 メチル－４－イソシアナトスルホニル－５－メチル－チオフェン－３－カルボキシレートの製造方法
EP24715486.7A EP4688764A2 (fr) 2023-03-29 2024-03-25 Procédé de production du méthyl-4-isocyanatosulfonyl-5-méthyl-thiophène-3-carboxylate
KR1020257031996A KR20250164206A (ko) 2023-03-29 2024-03-25 메틸 4-이소시아네이토술포닐-5-메틸티오펜-3-카르복실레이트의 제조 방법
CN202480012032.5A CN120712257A (zh) 2023-03-29 2024-03-25 制备4-异氰酸基磺酰基-5-甲基噻吩-3-羧酸甲酯的方法
MX2025011158A MX2025011158A (es) 2023-03-29 2025-09-19 Procedimiento para la preparacion de metil-4-isocianatosulfonil-5-metil-tiofeno-3-carboxilato
IL323579A IL323579A (en) 2023-03-29 2025-09-25 Method for producing methyl-4-isocyanatosulfonyl-5-methyl-thiophene-3-carboxylate

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EP23165099 2023-03-29
EP23165099.5 2023-03-29

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19933260A1 (de) 1999-07-15 2001-01-18 Bayer Ag Substituierte Thien-3-yl-sulfonylamino(thio)carbonyl-triazolin(thi)one
WO2006072376A1 (fr) 2004-12-29 2006-07-13 Bayer Cropscience Ag Procede pour produire des thiophenesulfonylisocyanates substitues
WO2015061518A1 (fr) 2013-10-24 2015-04-30 Bristol-Myers Squibb Company Inhibiteurs de réplication du virus de l'immunodéficience humaine
WO2018153767A1 (fr) 2017-02-23 2018-08-30 Bayer Cropscience Aktiengesellschaft Procédé pour produire du 4-[(4,5-dihydro-3-méthoxy-4-méthyl-5-oxo-1h-1,2,4-triazole-1-yl)carbonyl)sulfamoyl]-5-méthylthiophène-3-carboxylate de méthyle

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Publication number Priority date Publication date Assignee Title
DE19937118A1 (de) * 1999-08-06 2001-02-08 Bayer Ag Substituierte Thienyl(amino)sulfonylharnstoffe
US10053419B2 (en) * 2014-12-17 2018-08-21 Sumitomo Chemical Company, Limited Isocyanate compound manufacturing method
CN114181120A (zh) * 2022-02-14 2022-03-15 寿光诺盟化工有限公司 一种对甲苯磺酰异氰酸酯的制备方法

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Publication number Priority date Publication date Assignee Title
DE19933260A1 (de) 1999-07-15 2001-01-18 Bayer Ag Substituierte Thien-3-yl-sulfonylamino(thio)carbonyl-triazolin(thi)one
WO2006072376A1 (fr) 2004-12-29 2006-07-13 Bayer Cropscience Ag Procede pour produire des thiophenesulfonylisocyanates substitues
WO2015061518A1 (fr) 2013-10-24 2015-04-30 Bristol-Myers Squibb Company Inhibiteurs de réplication du virus de l'immunodéficience humaine
WO2018153767A1 (fr) 2017-02-23 2018-08-30 Bayer Cropscience Aktiengesellschaft Procédé pour produire du 4-[(4,5-dihydro-3-méthoxy-4-méthyl-5-oxo-1h-1,2,4-triazole-1-yl)carbonyl)sulfamoyl]-5-méthylthiophène-3-carboxylate de méthyle

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CHEMCATCHEM, vol. 12, no. 17, 2020, pages 4352 - 4372
JOURNAL OFTHE AMERICAN CHEMICAL SOCIETY, vol. 131, no. 25, 2009, pages 8754 - 8755
NONGYAO, vol. 54, no. 2, 2015, pages 83 - 87

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WO2024200331A3 (fr) 2024-11-21
JP2026511628A (ja) 2026-04-14
IL323579A (en) 2025-11-01
TW202500015A (zh) 2025-01-01
CN120712257A (zh) 2025-09-26
KR20250164206A (ko) 2025-11-24
EP4688764A2 (fr) 2026-02-11

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