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WO2025074365A1 - Process for the preparation of substituted thiophene 3-sulphonyl chloride - Google Patents

Process for the preparation of substituted thiophene 3-sulphonyl chloride Download PDF

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Publication number
WO2025074365A1
WO2025074365A1 PCT/IL2024/050974 IL2024050974W WO2025074365A1 WO 2025074365 A1 WO2025074365 A1 WO 2025074365A1 IL 2024050974 W IL2024050974 W IL 2024050974W WO 2025074365 A1 WO2025074365 A1 WO 2025074365A1
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formula
compound
nitrite
chloride
salt
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French (fr)
Inventor
Michael Grabarnick
Wenjun Wang
Shaoxiang WU
Wei Liu
Rui Gao
Jinping Zhang
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Adama Agan Ltd
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Adama Agan Ltd
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to a process for preparing substituted 4-alkoxy carbonyl thiophene 3- sulphonyl chloride of formula (I), which are known as intermediates for active ingredients in agriculture, especially used for the preparation of herbicidal active compound of formula (X).
  • the present invention provides that the acidic medium comprises of aqueous solution of hydrochloric acid, wherein the strength of hydrochloric acid in the range from 10 to 35%.
  • the present invention provides that the diazotising agent is nitrite salt or organic nitrite.
  • the nitrite salt or organic nitrite is selected from the group comprising ammonium nitrite, butyl nitrite, amyl nitrite, dicyclohexyl ammonium nitrite, ethyl nitrite, isoamyl nitrite, lithium nitrite, sodium nitrite, potassium nitrite, zinc nitrite and mixtures thereof.
  • the molar ratio of diazotising agent and compound of formula (II) is 1 : 1 to 2: 1.
  • the present invention provides that the phase transfer catalyst is selected from the group comprising quaternary ammonium salt, quaternary phosphonium salt and mixtures thereof. Further, the phase transfer catalyst is selected from the group comprising tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), dodecyltrimethylammonium bromide (DOTAB), dodecyltrimethylammonium chloride (DTAC), dodecyldimethylammonium chloride (DDAC), benzyltriethylammonium chloride (TEBAC), tetraethylammonium bromide (TEAB), methyl tricapryl ammonium chloride, methyl tributyl ammonium chloride (MTBAC), methyl trioctyl ammonium chloride, hexadecyltributylphosphonium bromide and mixtures thereof.
  • the present invention provides that the molar ratio of chlorine gas and compound of formula (II) is 1 : 1.5 to 1 : 5.
  • the present invention provides that the compound of formula (I), formula (II) and formula (III), wherein Ri is selected from the group comprising methoxy, ethoxy, propoxy, butoxy and R2 is selected from the group comprising methyl, ethyl, n-propyl, isopropyl or butyl.
  • the compound of formula (I) is 4-methoxycarbonyl 2-methyl-thiophene-3- sulphonyl chloride.
  • phase-transfer catalyst refers to a catalyst that facilitates the transition of reactant from one phase to another phase where reaction occurs.
  • step (i) the diazotising agent is dropped into the reaction mixture of compound of formula (II) in an acidic medium at a temperature in the range of 0 to 10°C, preferably 0 to 5°C.
  • the reaction progress was monitored by HPLC to obtain compound of formula (III).
  • step (ii) and step (iii) carried out at a temperature in the range of 20 to 40°C.
  • the organic solvent may comprise one or more of a polar aprotic water immiscible solvent, in which solubility of sulphur dioxide is high enough to carry out the reaction, like the solvent of 1,2-di chloroethane, di chloromethane and mixture thereof.
  • the metal catalyst and the phase transfer catalyst were added to the solution of sulphur dioxide in the organic solvent.
  • the metal catalyst is selected from the group comprising salt of copper (I), salt of copper (II) and mixtures thereof.
  • copper (I) chloride or copper (II) chloride is used as metal catalyst, preferably copper (II) chloride is used as a metal catalyst.
  • the molar ratio of metal catalyst and compound of formula (II) is 1 : 10 to 1 : 100. In particular, the molar ratio of metal catalyst and compound of formula (II) is 1 : 10 to 1 : 50.
  • the chlorine gas is the cheapest reagent, easily available and producing minimum waste in chlorination processes.
  • the only by-product of the reaction of the present invention is hydrogen chloride.
  • the amount of the chlorine gas needed for production with maximum yield mainly is the function of three parameters:
  • the molar ratio of chlorine gas and compound of formula (II) is 1 : 1.5 to 1 : 5. In particular, the molar ratio of chlorine gas and compound of formula (II) is 1 : 1.5 to 1 : 2.5.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The present invention relates to a process for preparing substituted 4- alkoxy carbonyl thiophene 3-sulphonyl chloride of formula (I), which are known as intermediates for active ingredients in agriculture, especially used for the preparation of herbicidal active compound of formula (X).

Description

PROCESS FOR THE PREPARATION OF SUBSTITUTED THIOPHENE 3- SULPHONYL CHLORIDE
Field of the Invention:
The invention relates to a process for preparing substituted 4-alkoxy carbonyl thiophene 3- sulphonyl chloride of formula (I), which are known as intermediates for active ingredients in agriculture, especially used for the preparation of herbicidal active compound of formula (X).
Figure imgf000002_0001
Background of the Invention:
Substituted 4-alkoxy carbonyl thiophene 3 -sulphonyl chloride are useful as intermediates in the preparation of agrochemical compound.
WO 2001/005788 patent discloses a process for the synthesis of 4-methoxy carbonyl 2-methyl- thiophene-3 -sulphonyl chloride, the method involves a reaction mixture of methyl 3 -amino 2- methyl-thiophene-4-carboxylate with sodium nitrite and aqueous hydrochloric acid. The mixture is then added to solution of sulphur dioxide in methylene chloride. After addition of copper (I) chloride and dodecyl-trimethylammonium bromide the reaction mixture is stirred to obtain 4-methoxy carbonyl 2-methyl-thiophene-3 -sulphonyl chloride.
The conventional processes for the preparation of substituted thiophene 3 -sulphonyl chloride associated with poor yield and impurities. The impurities are present due to use of the sulphur dioxide in the reaction mixture and its ability to act as a reducing agent leads to the synthesis of number of side products, which results in the significant yield reduction.
Therefore, there is an unfelt need to overcome the limitation of the conventional processes and to increase yield by minimizing the formation of the impurities and conversion of them to the substituted thiophene 3-sulphonyl chloride compound.
Therefore, there is a need to develop an effective process for the preparation of substituted thiophene 3-sulphonyl chloride compound with higher yield and efficiency. Summary of the Invention:
The present invention provides a process for preparation of 4-alkoxy carbonyl thiophene 3- sulphonyl chloride of formula (I)
Figure imgf000003_0001
in which Ri is Ci-C4-alkoxy having from 1 to 4 carbon atoms, and R2 is C1-C4 alkyl; the process comprising the following steps:
(i) reacting the compound of formula (II) or its hydrochloride salt in an acidic medium
Figure imgf000003_0002
in which Ri is Ci-C4-alkoxy having from 1 to 4 carbon atoms, and R2 is C1-C4 alkyl; with a diazotising agent to obtain a solution of diazonium salt of formula (III);
Figure imgf000003_0003
in which Ri is Ci-C4-alkoxy having from 1 to 4 carbon atoms, and R2 is C1-C4 alkyl;
(ii) preparing a solution of sulphur dioxide in an organic solvent followed by mixing with a metal catalyst and a phase transfer catalyst;
(iii) adding the solution of diazonium salt of formula (III) of step (i) to the mixture of step (ii);
(iv) mixing the reaction mixture of step (iii) with chlorine gas to obtain the compound of formula (I).
In an aspect, the present invention provides that the process of step (i) carried out at a temperature in the range of 0 to 10°C. In another aspect, the present invention provides that the process of step (ii) and step (iii) carried out at a temperature in the range of 20 to 40°C.
In a further aspect, the present invention provides that the process of step (iv) carried out at a temperature in the range of 0 to 10°C.
In yet another aspect, the present invention provides that the acidic medium comprises of aqueous solution of hydrochloric acid, wherein the strength of hydrochloric acid in the range from 10 to 35%.
In an aspect, the present invention provides that the diazotising agent is nitrite salt or organic nitrite. The nitrite salt or organic nitrite is selected from the group comprising ammonium nitrite, butyl nitrite, amyl nitrite, dicyclohexyl ammonium nitrite, ethyl nitrite, isoamyl nitrite, lithium nitrite, sodium nitrite, potassium nitrite, zinc nitrite and mixtures thereof. The molar ratio of diazotising agent and compound of formula (II) is 1 : 1 to 2: 1.
In another aspect, the present invention provides that the organic solvent is selected from the group comprising a polar aprotic water immiscible solvent, in which solubility of sulphur dioxide is high enough to carry out the reaction, like the solvent of 1,2-di chloroethane, dichloromethane and mixtures thereof.
In a further aspect, the present invention provides that the metal catalyst is selected from the group comprising salt of copper (I), salt of copper (II) and mixtures thereof. The molar ratio of metal catalyst and compound of formula (II) is 1 : 10 to 1 : 100.
In yet another aspect, the present invention provides that the phase transfer catalyst is selected from the group comprising quaternary ammonium salt, quaternary phosphonium salt and mixtures thereof. Further, the phase transfer catalyst is selected from the group comprising tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), dodecyltrimethylammonium bromide (DOTAB), dodecyltrimethylammonium chloride (DTAC), dodecyldimethylammonium chloride (DDAC), benzyltriethylammonium chloride (TEBAC), tetraethylammonium bromide (TEAB), methyl tricapryl ammonium chloride, methyl tributyl ammonium chloride (MTBAC), methyl trioctyl ammonium chloride, hexadecyltributylphosphonium bromide and mixtures thereof. The molar ratio of phase transfer catalyst and compound of formula (II) is 1 : 10 to 1 : 100.
In an aspect, the present invention provides that the molar ratio of chlorine gas and compound of formula (II) is 1 : 1.5 to 1 : 5. In a further aspect, the present invention provides that the compound of formula (I), formula (II) and formula (III), wherein Ri is selected from the group comprising methoxy, ethoxy, propoxy, butoxy and R2 is selected from the group comprising methyl, ethyl, n-propyl, isopropyl or butyl. The compound of formula (I) is 4-methoxycarbonyl 2-methyl-thiophene-3- sulphonyl chloride.
In an aspect, the present invention is a multistep batch process for preparation of compound of formula (I) that is carried out by telescopic manner without isolation of intermediates produced during the synthesis.
In a preferred aspect, the present invention provides a process for preparation of compound of formula (X)
Figure imgf000005_0001
comprising preparation of compound of formula (I) and further converting to compound of formula (X).
In another preferred aspect, the present invention provides a process for preparation of 4- methoxycarbonyl 2-methyl-thiophene-3 -sulphonyl chloride comprises the reaction of methyl 4-amino-5-methylthiophene-3-carboxylate or its hydrochloride salt in an aqueous hydrochloric acid medium with sodium nitrite to form a diazonium salt. The solution of sulphur dioxide in 1,2-di chloroethane is mixed with copper (II) chloride and tetrabutylammonium bromide. The solution of diazonium salt is added dropwise to the sulphur dioxide reaction mixture followed by addition of chlorine gas to obtain 4-methoxycarbonyl 2-methyl-thiophene-3 -sulphonyl chloride.
Description of the Invention:
For the sake of clarity, specific terminology is resorted to in describing the embodiments of the invention. However, it is not intended that the invention be limited to the specific terms so selected, and it is to be understood that each specific term includes all technical equivalents that operate in a similar manner to accomplish a similar purpose. It will be understood that the terminology used herein is for the purpose of describing embodiments only and is not intended to be limiting. As used in this specification, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, the reference to “a compound” includes one or more of such compounds.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one ordinarily skilled in the art to which the invention pertains. Although other methods and materials similar to or equivalent to those described herein can be used in the practise of the present invention, the preferred materials and methods are described herein.
As used herein, the term “or” means “and/or”. It will be further understood that the terms “comprises”, “comprising”, “includes”, “including”, or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition or a method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such a composition or method.
Throughout the application, descriptions of various embodiments use the term “comprising”. However, it will be understood by one of skill in the art that in some specific instances, an embodiment can alternatively be described using the language “consisting essentially of’ or “consisting of.”
Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed considering the number of reported significant digits and by applying ordinary rounding techniques.
In addition, the endpoints of all ranges directed to the same component or property herein are inclusive of the endpoints, are independently combinable, and include all intermediate points and ranges.
As used herein, the term “alkyl” refers to straight or branched chain, saturated alkyl groups having from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, butyl and the like.
As used herein, the term “alkoxy” refers to saturated straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, and the like. As used herein, the term “diazotising agent” refers to any compound which will donate a nitrogen atom during the reaction with the diazotizable group to form the diazonium salt.
As used herein, the term “metal catalyst” refers to salts, complexes, compositions of the metal catalyst with any organic compound. “Metal catalyst” for example may be salt of copper.
As used herein, the term “phase-transfer catalyst” refers to a catalyst that facilitates the transition of reactant from one phase to another phase where reaction occurs.
As used herein, the term “batch process” refers to a chemical process that involves a series of operations on a separate, identifiable item or parcel of material, in which the product comes out in groups and not continuously.
All ranges are inclusive. As used throughout the specification, the following abbreviations are applied: °C = Centigrade or min.= minutes or h = hours.
Substituted 4-alkoxy carbonyl thiophene 3 -sulphonyl chloride are useful as intermediates in the preparation of agrochemical compound. For example, it is used as an intermediate in the preparation of herbicidal active compound of Formula (X). PCT Application No. WO 2001/005788 discloses the use of substituted 4-alkoxy carbonyl thiophene 3 -sulphonyl chloride for further conversion to compound of Formula (X).
Figure imgf000007_0001
The present invention provides a process for preparation of 4-alkoxy carbonyl thiophene 3- sulphonyl chloride of formula (I)
Figure imgf000007_0002
in which Ri is Ci-C4-alkoxy having from 1 to 4 carbon atoms, and R2 is C1-C4 alkyl; the process comprising the following steps: (i) reacting the compound of formula (II) or its hydrochloride salt in an acidic medium
Figure imgf000008_0001
in which Ri is Ci-C4-alkoxy having from 1 to 4 carbon atoms, and R2 is C1-C4 alkyl; with a diazotising agent to obtain a solution of diazonium salt of formula (III);
Figure imgf000008_0002
in which Ri is Ci-C4-alkoxy having from 1 to 4 carbon atoms, and R2 is C1-C4 alkyl;
(ii) preparing a solution of sulphur dioxide in an organic solvent followed by mixing with a metal catalyst and a phase transfer catalyst;
(iii) adding the solution of diazonium salt of formula (III) of step (i) to the mixture of step
(ii);
(iv) mixing the reaction mixture of step (iii) with chlorine gas to obtain the compound of formula (I).
In an embodiment, the present invention provides Ri and R2 in the compound of formula (I), formula (II) or formula (III), wherein Ri is C1-C4 alkoxy, and R2 is C1-C4 alkyl. Ri is selected from the group comprising methoxy, ethoxy, propoxy, butoxy and R2 is selected from the group comprising methyl, ethyl, n-propyl, iso-propyl and butyl and preferably Ri is methoxy, and R2 is methyl.
In a preferred embodiment, the compound of formula (I) is 4-methoxycarbonyl 2-methyl- thiophene-3 -sulphonyl chloride.
In another preferred embodiment, the compound of formula (II) is methyl 4-amino-5- m ethylthiophene-3 -carboxylate or its hydrochloride salt.
In an embodiment, the process of step (i) carried out at a temperature in the range of 0 to 10°C. The mixture of compound of formula (II) and an acidic medium was stirred at room temperature and it was cooled to 0 to 5°C. In another embodiment, the acidic medium comprises of an aqueous solution of hydrochloric acid, wherein the strength of hydrochloric acid in the range from 10 to 35%, preferably 10 to 30%.
In step (i), the diazotising agent is dropped into the reaction mixture of compound of formula (II) in an acidic medium at a temperature in the range of 0 to 10°C, preferably 0 to 5°C. The reaction progress was monitored by HPLC to obtain compound of formula (III). FL © Q
Diazotising Agent 11 N2CI
- - R, T Acidic medium
Figure imgf000009_0001
Step (i) (III)
All agents which cause nitrous acid to form in the reaction mixture may be used as diazotising agents, for example esters of nitrous acid or nitrosyl compounds such as nitrosylsulfuric acid or nitrosyl halides. It is preferred to use nitrites, in particular to use nitrite salt or organic nitrite optionally in conjunction with an acid, preferably a mineral acid. The nitrite salt or organic nitrite is selected from the group comprising ammonium nitrite, butyl nitrite, amyl nitrite, dicyclohexyl ammonium nitrite, ethyl nitrite, isoamyl nitrite, lithium nitrite, sodium nitrite, potassium nitrite, or zinc nitrite and mixtures thereof. The mineral acid used is selected from sulphuric acid or hydrochloric acid preferably hydrochloric acid.
In a further embodiment, the diazotising agent is nitrite salt, preferably the nitrite salt is sodium nitrite.
In an embodiment, the molar ratio of diazotising agent and compound of formula (II) is 1 : 1 to 2: 1.
In another embodiment, the process of step (ii) and step (iii) carried out at a temperature in the range of 20 to 40°C.
In step (ii), the sulphur dioxide was dissolved in the organic solvent at a temperature in the range from 20 to 30°C.
In general, the organic solvent may comprise one or more of a polar aprotic water immiscible solvent, in which solubility of sulphur dioxide is high enough to carry out the reaction, like the solvent of 1,2-di chloroethane, di chloromethane and mixture thereof. In step (ii) the metal catalyst and the phase transfer catalyst were added to the solution of sulphur dioxide in the organic solvent. The metal catalyst is selected from the group comprising salt of copper (I), salt of copper (II) and mixtures thereof. In particular, copper (I) chloride or copper (II) chloride is used as metal catalyst, preferably copper (II) chloride is used as a metal catalyst.
In another embodiment, the molar ratio of metal catalyst and compound of formula (II) is 1 : 10 to 1 : 100. In particular, the molar ratio of metal catalyst and compound of formula (II) is 1 : 10 to 1 : 50.
The phase transfer catalyst is a catalyst that helps the reactant move from one phase to another phase during the reaction. It allows the reactions to proceed quickly, at lower temperatures and with improved selectivity.
Suitable phase transfer catalyst includes quaternary ammonium salts, quaternary phosphonium salts and mixtures thereof. It is selected from the group comprising tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), dodecyltrimethylammonium bromide (DOTAB), dodecyltrimethylammonium chloride (DTAC), dodecyldimethylammonium chloride (DDAC), benzyltriethylammonium chloride (TEBAC), tetraethylammonium bromide (TEAB), methyl tricapryl ammonium chloride, methyl tributyl ammonium chloride (MTBAC), methyl trioctyl ammonium chloride, hexadecyltributylphosphonium bromide and mixtures thereof.
More preferably, the phase transfer catalyst is a quaternary ammonium salt selected from the group comprising tetrabutylammonium bromide (TBAB) and dodecyltrimethylammonium bromide (DOTAB).
In an embodiment, the molar ratio of phase transfer catalyst and compound of formula (II) is 1 : 10 to 1 : 100. In particular, the molar ratio of phase transfer catalyst and compound of formula (II) is 1 : 10 to 1 : 50.
In step (iii), the solution of diazonium salt of step (i) is added into the reaction mixture of step (ii) slowly with stirring at a temperature in the range of 25 to 35°C.
In a further embodiment, the process of step (iv) carried out at a temperature in the range of 0 to 10°C. Step (ii)Z Step (iii) Step (iv)
SO2 Cl2
Metal Catalyst/ Phase Transfer Catalyst
Figure imgf000011_0001
Figure imgf000011_0002
In step (iv), the reaction mixture of step (iii) was cooled to a temperature in the range from 0 to 10°C, preferably 0 to 5 °C and chlorine gas was mix with the reaction mixture of step (iii) at a temperature in the range from 0 to 10°C.
The chlorine gas is the cheapest reagent, easily available and producing minimum waste in chlorination processes. The only by-product of the reaction of the present invention is hydrogen chloride. The amount of the chlorine gas needed for production with maximum yield mainly is the function of three parameters:
1. The amount of the impurities presents in the reaction mixture.
2. Residue of sulphur dioxide in the reaction mass before feeding of chlorine.
3. The efficiency of the equipment used for chlorination as chlorination process takes time, solubility of the chlorine gas is restricted and, so, part of the chlorine may go to the scrubber.
In another embodiment, the molar ratio of chlorine gas and compound of formula (II) is 1 : 1.5 to 1 : 5. In particular, the molar ratio of chlorine gas and compound of formula (II) is 1 : 1.5 to 1 : 2.5.
The present invention provides an improved process in comparison to the process disclosed in PCT Application No. WO 2001/005788, wherein in the present invention the use of chlorine gas helps in the selective chlorination of the by-products only, without affecting the compound of formula (I).
The preparation of the compound of formula (I) leads to the formation of the different byproducts. Structures of part of them are presented as follows:
Figure imgf000011_0003
In a further embodiment, the chlorine gas in the presence of water used for the conversion of the by-products as mentioned above to the compound of formula (I).
In a preferred embodiment, the present invention provides process for preparation of 4- methoxy carbonyl 2-methyl-thiophene-3 -sulphonyl chloride
Figure imgf000012_0001
the process comprising the following steps:
(i) reacting the methyl 4-amino-5-methylthiophene-3-carboxylate or its hydrochloride salt in an acidic medium
Figure imgf000012_0002
with sodium nitrite to obtain a solution of diazonium salt of 4-amino-5- methylthiophene-3 -carboxylate;
Figure imgf000012_0003
(ii) preparing a solution of sulphur dioxide in 1,2-dichloroethane and mixing with copper (II) chloride and tetrabutylammonium bromide (TBAB);
(iii) adding the solution of diazonium salt of 4-amino-5-methylthiophene-3-carboxylate into the mixture solution of step (ii);
(iv) mixing of reaction mixture of step (iii) with chlorine gas to obtain methyl 4- (chlorosulfonyl)-5-methylthiophene-3-carboxylate.
In an embodiment, the present invention provides an integrated process, that is carried out by a telescopic manner without isolation of the intermediates produced during the synthesis for the preparation of the compound of formula (I)
Figure imgf000013_0001
in which Ri is Ci-C4-alkoxy having from 1 to 4 carbon atoms, and R2 is C1-C4 alkyl; the process comprising the following steps:
(i) reacting the compound of formula (II) or its hydrochloride salt in an acidic medium
Figure imgf000013_0002
in which Ri is Ci-C4-alkoxy having from 1 to 4 carbon atoms, and R2 is C1-C4 alkyl; with a diazotising agent to obtain a solution of diazonium salt of formula (III);
Figure imgf000013_0003
in which Ri is Ci-C4-alkoxy having from 1 to 4 carbon atoms, and R2 is C1-C4 alkyl;
(ii) preparing a solution of sulphur dioxide in an organic solvent followed by mixing with a metal catalyst and a phase transfer catalyst;
(iii) adding the solution of diazonium salt of formula (III) of step (i) to the mixture of step (ii);
(iv) mixing the reaction mixture of step (iii) with chlorine gas to obtain the compound of formula (I).
In another embodiment, the present invention provides a process for preparation of compound of formula (X) comprising preparation of aforementioned compound of formula (I) and further converting to compound of formula (X). The compound of formula (I) is converted to formula (X) as described in PCT Application No. WO 2001/005788.
Figure imgf000014_0001
The process of the present invention has many advantages as follows:
1. It minimizes the number of effluents.
2. It decreases the amount of waste generation.
3. It improves the yield of the final product.
The following examples illustrate the practice of the present invention in some of its embodiments but should not be construed as limiting the scope of the present invention. From consideration of the specification and examples, other embodiments will be apparent to one skilled in the art. It is intended that the specification, including the examples, be considered exemplary only without limiting the scope and spirit of the present invention.
An exemplary experimental procedure for producing 4-methoxycarbonyl 2-methyl-thiophene- 3-sulphonyl chloride is described as follows:
Examples:
Example 1:
Figure imgf000014_0002
30% aqueous hydrochloric acid (810 g, 6.66 mol) and methyl 4-amino-5-methylthiophene-3- carboxylate hydrochloride (466 g, 2.2 mol) were added to a 2 L flask. The mixture was stirred at room temperature for a 10 min. and after that was cooled to 0 °C to 5 °C. Solution of sodium nitrite (167 g, 2.4 mol) in 335 ml water was prepared in a separated vessel and dropped into the reaction mixture keeping the temperature 0 °C to 5 °C. The mixture was stirred at the same temperature for additional 0.5 h. HPLC analysis showed the concentration of 4-amino-5- methylthiophene-3 -carboxylate hydrochloride < 0.5 area %. 1,2-di chloroethane (2225 g) was added to a 5 L flask and sulphur dioxide (288 g, 4.5 mol) was dissolved in it at the temperature 20 °C to 25 °C. Copper (II) chloride (15.1 g, 0.11 mol) and tetrabutylammonium bromide (18.1 g, 0.06 mol) were added into the solution of sulphur dioxide in 1,2-di chloroethane. The aforementioned the mixture of diazonium salt solution was fed with peristaltic pump slowly into sulphur dioxide mixture, during 6 h, with good stirring keeping the temperature of the reaction mass 27 °C to 33 °C. The mixture was stirred for 3 additional hours at the same temperature. HPLC analysis showed the concentration of diazonium salt < 1 area %.
The reaction mixture was cooled to 0 °C to 5 °C and chlorine gas (80 g, 1.1 mol) was ventilated into the mixture at the same temperature for 1 hour. HPLC analysis showed the concentration of impurity of formula (V) < 0.5 area %.
Figure imgf000015_0001
HPLC analysis was done using Agilent 1260 HPLC system with diode array detector (DAD).
HPLC Method of Analysis:
HPLC column: Eclipse Plus-C18 (150x4.6mm, 5mm).
Mobile phase: A) Acetonitrile, B) Orthophosphoric acid in water (pH=3) with gradient:
Figure imgf000015_0002
Stop time: 16 min
Post time: 5 min
Column temperature: 30 °C Sample size injected: 2.0 pL Flow rate: 1.0 ml/min
Wavelength: 240 nm Cold water (475 g) was added to the mixture and the phases were separated at the temperature 5 °C to 10 °C. The aqueous phase was extracted with 1,2-di chloroethane (190 g) and combined organic phase was washed with 475 g of water.
The organic phase was the 4-m ethoxy carbonyl 2-methyl-thiophene-3 -sulphonyl chloride solution. Quantitative analysis shows presence of 476 g, 1.87 mol of the reaction product (Yield 85%).
Comparative Example:
Figure imgf000016_0001
30% strength aqueous hydrochloric acid (810 g, 6.66 mol) and methyl 4-amino-5- methylthiophene-3 -carboxylate hydrochloride (466 g, 2.2 mol) were added to a 2 L flask. The mixture was stirred at room temperature for a 10 min. and after that was cooled to 0 °C to 5 °C. Solution of sodium nitrite (167 g, 2.4 mol) in 335 ml water was prepared in a separated vessel and dropped into the reaction mixture keeping the temperature 0 °C to 5 °C. The mixture was stirred at the same temperature for additional 0.5 h. HPLC analysis showed the concentration of 4-amino-5-methylthiophene-3-carboxylate hydrochloride < 0.5 area %.
1,2-di chloroethane (2225 g) was added to a 5 L flask and sulphur dioxide (288 g, 4.5 mol) was dissolved in it at the temperature 20 °C to 25 °C. Copper (II) chloride (15.1 g, 0.11 mol) and tetrabutylammonium bromide (18.1 g, 0.06 mol) were added into the solution of sulphur dioxide in 1,2-di chloroethane. The aforementioned the mixture of diazonium salt solution was fed with peristaltic pump slowly into sulphur dioxide mixture, during 6 h, with good stirring keeping the temperature of the reaction mass 27 °C to 33 °C. The mixture was stirred for 3 additional hours at the same temperature. HPLC analysis showed the concentration of diazonium salt < 1 area %.
Cold water (475 g) was added to the mixture and the phases were separated at the temperature 5 °C to 10 °C. The aqueous phase was extracted with 1,2-di chloroethane (190 g) and combined organic phase was washed with 475 g of water. The organic phase was the methyl 4-m ethoxy carbonyl 2-methyl-thiophene-3 -sulphonyl chloride solution. Quantitative analysis shows presence of 443 g, 1.74 mol of the reaction product (Yield 79%).
The numerical values mentioned in the foregoing description and the appended claims though might form a critical part of the present invention of the present disclosure, any deviation from such numerical values shall still fall within the scope of the present disclosure if that deviation follows the same scientific principle as that of the present invention disclosed in the present disclosure.
Any processes and reagents similar or equivalent to those described herein can be employed in the practice of the present invention. Accordingly, the present invention is not to be limited by the foregoing description but is intended to be defined by the claims and their equivalents. Those equivalents fall within the scope of the present invention as defined by the appended claims.

Claims

We Claim:
1. A process for preparation of 4-alkoxy carbonyl thiophene 3-sulphonyl chloride of formula (I)
Figure imgf000018_0001
in which Ri is Ci-C4-alkoxy having from 1 to 4 carbon atoms, and R2 is C1-C4 alkyl; the process comprising:
(i) reacting the compound of formula (II) or its hydrochloride salt in an acidic medium
Figure imgf000018_0002
in which Ri is Ci-C4-alkoxy having from 1 to 4 carbon atoms, and R2 is C1-C4 alkyl; with a diazotising agent to obtain a solution of diazonium salt of formula (III);
Figure imgf000018_0003
in which Ri is Ci-C4-alkoxy having from 1 to 4 carbon atoms, and R2 is C1-C4 alkyl;
(ii) preparing a solution of sulphur dioxide in an organic solvent followed by mixing with a metal catalyst and a phase transfer catalyst;
(iii) adding the solution of diazonium salt of formula (III) of step (i) to the mixture of step (ii);
(iv) mixing the reaction mixture of step (iii) with chlorine gas to obtain the compound of formula (I).
2. The process as claimed in claim 1, wherein the process of step (i) carried out at a temperature in the range of 0 to 10°C.
3. The process as claimed in claim 1, wherein the process of step (ii) and step (iii) carried out at a temperature in the range of 20 to 40°C.
4. The process as claimed in claim 1, wherein the process of step (iv) carried out at a temperature in the range of 0 to 10°C.
5. The process as claimed in claim 1, wherein the acidic medium comprises of aqueous solution of hydrochloric acid.
6. The process as claimed in claim 1, wherein the diazotising agent is nitrite salt or organic nitrite.
7. The process as claimed in claim 6, wherein the nitrite salt or organic nitrite is selected from the group comprising ammonium nitrite, butyl nitrite, amyl nitrite, dicyclohexyl ammonium nitrite, ethyl nitrite, isoamyl nitrite, lithium nitrite, sodium nitrite, potassium nitrite, or zinc nitrite and mixtures thereof.
8. The process as claimed in claim 1, wherein the organic solvent is selected from the group comprising a polar aprotic water immiscible solvent, in which solubility of sulphur dioxide is high enough to carry out the reaction.
9. The process as claimed in claim 8, wherein the solvent is 1,2-di chloroethane, dichloromethane and mixtures thereof.
10. The process as claimed in claim 1, wherein the metal catalyst is selected from the group comprising salt of copper (I), salt of copper (II) and mixtures thereof.
11. The process as claimed in claim 10, wherein the salt of either copper (I) or copper (II) is chloride.
12. The process as claimed in claim 1, wherein the phase transfer catalyst is selected from the group comprising quaternary ammonium salt, quaternary phosphonium salt and mixtures thereof.
13. The process as claimed in claim 12, wherein the phase transfer catalyst is selected from the group comprising tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), dodecyltrimethylammonium bromide (DOTAB), dodecyltrimethylammonium chloride (DTAC), dodecyldimethylammonium chloride (DDAC), benzyltriethylammonium chloride (TEBAC), tetraethylammonium bromide (TEAB), methyl tricapryl ammonium chloride, methyl tributyl ammonium chloride (MTBAC), methyl trioctyl ammonium chloride, hexadecyltributylphosphonium bromide and mixtures thereof.
14. The process as claimed in claim 1, wherein the molar ratio of diazotising agent and compound of formula (II) is. 1: 1 to 2: 1.
15. The process as claimed in claim 1, wherein the molar ratio of metal catalyst and compound of formula (II) is 1: 10 to 1: 100.
16. The process as claimed in claim 1, wherein the molar ratio of phase transfer catalyst and compound of formula (II) is 1: 10 to 1: 100.
17. The process as claimed in claim 1, wherein the molar ratio of chlorine gas and compound of formula (II) is 1: 1.5 to 1: 5.
18. The process as claimed in claim 1, wherein the compound of formula (I), formula (II) and formula (III), wherein Ri is selected from the group comprising methoxy, ethoxy, propoxy, butoxy and R2 is selected from the group comprising methyl, ethyl, n-propyl, iso-propyl or butyl.
19. The process as claimed in claim 1, wherein the compound of formula (I) is 4- methoxy carbonyl 2-methyl-thiophene-3 -sulphonyl chloride.
20. The process as claimed in claim 1, wherein the compound of formula (I) is further converted to compound of formula (X).
Figure imgf000020_0001
21. A process for preparation of compound of formula (X)
Figure imgf000021_0001
comprising preparation of compound of formula (I) as claimed in claim 1 and further converting to the compound of formula (X).
PCT/IL2024/050974 2023-10-03 2024-10-01 Process for the preparation of substituted thiophene 3-sulphonyl chloride Pending WO2025074365A1 (en)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2001005788A1 (en) 1999-07-15 2001-01-25 Bayer Aktiengesellschaft Substituted thiene-3-yl-sulfonyl amino(thio)carbonyl-triazolin(thi)ones
CN109265436A (en) * 2018-11-29 2019-01-25 常州沃腾化工科技有限公司 A kind of synthetic method of 4- methoxycarbonyl group -2- methylthiophene -3- sulfonic acid chloride
CN111732568A (en) * 2020-06-23 2020-10-02 北京怡力生物科技有限公司 Synthesis method of 4-methoxycarbonyl-2-methylthiophene-3-sulfonyl chloride

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001005788A1 (en) 1999-07-15 2001-01-25 Bayer Aktiengesellschaft Substituted thiene-3-yl-sulfonyl amino(thio)carbonyl-triazolin(thi)ones
CN109265436A (en) * 2018-11-29 2019-01-25 常州沃腾化工科技有限公司 A kind of synthetic method of 4- methoxycarbonyl group -2- methylthiophene -3- sulfonic acid chloride
CN111732568A (en) * 2020-06-23 2020-10-02 北京怡力生物科技有限公司 Synthesis method of 4-methoxycarbonyl-2-methylthiophene-3-sulfonyl chloride

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Title
ROSSY, P.A. ET AL.: "Aromatization of dihydrothiophenes. Thiophenesaccharin: a sweet surprise", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 45, no. 4, 1980, pages 617 - 620, XP055817029, ISSN: 0022-3263, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/jo01292a012> DOI: 10.1021/jo01292a012 *

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